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Sample records for severe clinical phenotype

  1. Severe Enterovirus Infections in Hospitalized Children in the South of England: Clinical Phenotypes and Causative Genotypes.

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    de Graaf, Hans; Pelosi, Emanuela; Cooper, Andrea; Pappachan, John; Sykes, Kim; MacIntosh, Iain; Gbesemete, Diane; Clark, Tristan W; Patel, Sanjay V; Faust, Saul N; Tebruegge, Marc

    2016-07-01

    Most enterovirus surveillance studies lack detailed clinical data, which limits their clinical usefulness. This study aimed to describe the clinical spectrum and outcome of severe enterovirus infections in children, and to determine whether there are associations between causative enterovirus genotypes and clinical phenotypes. Retrospective analysis of microbiological and clinical data from a tertiary children's hospital in the South of England over a 17-month period (2012-2013). In total, 30 patients were identified, comprising sepsis (n = 9), myocarditis (n = 8), meningitis (n = 8) and encephalitis (n = 5). Cases with sepsis or myocarditis were significantly younger than those with central nervous system disease (median age 21 and 15 days vs. 79 days; P = 0.0244 and P = 0.0310, respectively). There was considerable diversity in the causative genotypes in each of the clinical phenotypes, with some predominance of echoviruses in the meningitis group, and coxsackie B viruses in the myocarditis group. Thirteen cases required mechanical ventilation, 11 cases inotropic support, 3 cases dialysis and 3 cases extracorporal membrane oxygenation. The overall mortality was 10% (sepsis group, n = 1; myocarditis group, n = 2). Of the survivors, 5 (19%) had long-term sequelae (myocardial dysfunction, n = 2; neurological sequelae, n = 3). Patients with encephalitis had the longest hospital stay (median: 16 days), compared with 9, 6 and 3 days in patients with myocarditis, sepsis and meningitis, respectively (P = 0.005). Enterovirus infections, particularly enteroviral myocarditis and encephalitis, can cause significant morbidity and mortality. The results show that there are currently no strong associations between clinical phenotypes and particular causative enterovirus genotypes in the South of England.

  2. Fenótipos clínicos de asma grave Clinical phenotypes of severe asthma

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    Roseliane de Souza Araújo Alves

    2008-09-01

    Full Text Available OBJETIVO: Estabelecer os fenótipos clínicos em portadores de asma grave. MÉTODOS: Foram estudados, retrospectivamente, 111 pacientes em um ambulatório especializado. Os pacientes foram avaliados e acompanhados de maneira sistemática, estabelecendo-se ao final do acompanhamento a adesão e o controle ou não da doença por dados clínicos e funcionais. A resistência ao tratamento foi definida como o não preenchimento, ao final do acompanhamento, por pelo menos seis meses, dos critérios de controle de asma, apesar do uso correto e adesão à medicação. Os fenótipos foram determinados por análise fatorial e comparados por testes diversos. RESULTADOS: Ao final, 88 pacientes foram considerados aderentes e 23 não aderentes. Por análise fatorial do grupo aderente, quatro fenótipos foram determinados: o fenótipo 1 (28 pacientes, formado pelos pacientes resistentes ao tratamento, com maior freqüência de sintomas noturnos, maior número de exacerbações e uso mais freqüente de broncodilatador de resgate; o fenótipo 2 (48 pacientes, formado pelos pacientes com obstrução persistente, com menores valores de relação volume expiratório forçado no primeiro segundo/capacidade vital forçada na avaliação inicial, idade mais avançada e maior tempo de doença; o fenótipo 3 (42 pacientes, representa os pacientes com rinossinusite alérgica, sendo constituído de não fumantes com obstrução predominantemente reversível; e o fenótipo 4 (15 pacientes, formado por casos com história de intolerância à aspirina associado à asma quase fatal. CONCLUSÕES: Um número significativo de portadores de ama grave não adere ao tratamento. Muitos pacientes com asma grave têm obstrução irreversível, mas o fenótipo clínico mais relevante é constituído pelos pacientes resistentes ao tratamento habitual.OBJECTIVE: To characterize clinical phenotypes of severe asthma. METHODS: A total of 111 patients were retrospectively evaluated at a

  3. 14q12 and severe Rett-like phenotypes: new clinical insights and physical mapping of FOXG1-regulatory elements

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    Allou, Lila; Lambert, Laetitia; Amsallem, Daniel; Bieth, Eric; Edery, Patrick; Destrée, Anne; Rivier, François; Amor, David; Thompson, Elizabeth; Nicholl, Julian; Harbord, Michael; Nemos, Christophe; Saunier, Aline; Moustaïne, Aissa; Vigouroux, Adeline; Jonveaux, Philippe; Philippe, Christophe

    2012-01-01

    The Forkhead box G1 (FOXG1) gene has been implicated in severe Rett-like phenotypes. It encodes the Forkhead box protein G1, a winged-helix transcriptional repressor critical for forebrain development. Recently, the core FOXG1 syndrome was defined as postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and dysgenesis of the corpus callosum. We present seven additional patients with a severe Rett-like neurodevelopment disorder associated with de novo FOXG1 point mutations (two cases) or 14q12 deletions (five cases). We expand the mutational spectrum in patients with FOXG1-related encephalopathies and precise the core FOXG1 syndrome phenotype. Dysgenesis of the corpus callosum and dyskinesia are not always present in FOXG1-mutated patients. We believe that the FOXG1 gene should be considered in severely mentally retarded patients (no speech-language) with severe acquired microcephaly (−4 to−6 SD) and few clinical features suggestive of Rett syndrome. Interestingly enough, three 14q12 deletions that do not include the FOXG1 gene are associated with phenotypes very reminiscent to that of FOXG1-mutation-positive patients. We physically mapped a putative long-range FOXG1-regulatory element in a 0.43 Mb DNA segment encompassing the PRKD1 locus. In fibroblast cells, a cis-acting regulatory sequence located more than 0.6 Mb away from FOXG1 acts as a silencer at the transcriptional level. These data are important for clinicians and for molecular biologists involved in the management of patients with severe encephalopathies compatible with a FOXG1-related phenotype. PMID:22739344

  4. Clinical phenotypes of asthma

    NARCIS (Netherlands)

    Bel, Elisabeth H.

    2004-01-01

    PURPOSE OF REVIEW: Asthma is a phenotypically heterogeneous disorder and, over the years, many different clinical subtypes of asthma have been described. A precise definition of asthma phenotypes is now becoming more and more important, not only for a better understanding of pathophysiologic

  5. Different Clinical Phenotypes in Familial Severe Congenital Neutropenia Cases with Same Mutation of the ELANE Gene

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    Cho, Hye-Kyung; Jeon, In Sang

    2014-01-01

    Severe congenital neutropenia (SCN) is a heterogeneous group of disorders with a defect in granulopoiesis causing marked neutropenia and severe bacterial infections. A 17-month-old girl (patient 1) was admitted due to cervical lymphadenitis caused by methicillin-resistant Staphylococcus aureus, with neutropenia. She had Pseudomonas aeruginosa sepsis and peritonitis with perforated appendicitis at 8-month of age. Her sister, a 37-month-old girl (patient 2), had recurrent stomatitis with profou...

  6. Different clinical phenotypes in familial severe congenital neutropenia cases with same mutation of the ELANE gene.

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    Cho, Hye-Kyung; Jeon, In Sang

    2014-03-01

    Severe congenital neutropenia (SCN) is a heterogeneous group of disorders with a defect in granulopoiesis causing marked neutropenia and severe bacterial infections. A 17-month-old girl (patient 1) was admitted due to cervical lymphadenitis caused by methicillin-resistant Staphylococcus aureus, with neutropenia. She had Pseudomonas aeruginosa sepsis and peritonitis with perforated appendicitis at 8-month of age. Her sister, a 37-month-old girl (patient 2), had recurrent stomatitis with profound neutropenia, and her mother, a 32-yr-old woman (patient 3), had had recurrent stomatitis until her early 20s with neutropenia. We found an ELANE gene mutation (c.597+1G > A) from them in direct DNA sequencing analysis. Patients 1 and 2 did not respond to granulocyte colony stimulating factor and patient 1 was treated with prolonged antibiotics and excision. We demonstrated inherited SCN cases showing different severity even with the same mutation of the ELANE gene in a family.

  7. Kenny Caffey syndrome with severe respiratory and gastrointestinal involvement: expanding the clinical phenotype.

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    Christodoulou, Loucas; Krishnaiah, Anil; Spyridou, Christina; Salpietro, Vincenzo; Hannan, Siobhan; Saggar, Anand; Mankad, Kshitij; Deep, Akash; Kinali, Maria

    2015-06-01

    Kenny Caffey syndrome (KCS) is a rare syndrome reported almost exclusively in Middle Eastern populations. It is characterized by severe growth retardation-short stature, dysmorphic features, episodic hypocalcaemia, hypoparathyroidism, seizures, and medullary stenosis of long bones with thickened cortices. We report a 10-year-old boy with KCS with an unusually severe respiratory and gastrointestinal system involvement-features not previously described in the literature. He had severe psychomotor retardation and regressed developmentally from walking unaided to sitting with support. MRI brain showed bilateral hippocampal sclerosis, marked supra-tentorial volume loss and numerous calcifications. A 12 bp deletion of exon 2 of tubulin-specific chaperone E (TBCE) gene was identified and the diagnosis of KCS was confirmed. Hypercarbia following a sleep study warranted nocturnal continuous positive airway pressure (CPAP) when aged 6. When boy aged 8, persistent hypercarbia with increasing oxygen requirement and increased frequency and severity of lower respiratory tract infections led to progressive respiratory failure. He became fully dependent on non-invasive ventilation and by 9 years he had a tracheotomy and was established on long-term ventilation. He developed retching, vomiting and diarrhea. Chest CT showed changes consistent with chronic aspiration, but no interstitial pulmonary fibrosis. He died aged 10 from respiratory complications.

  8. The dynamics of herpesvirus reactivations during and after severe drug eruptions: their relation to the clinical phenotype and therapeutic outcome.

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    Ishida, T; Kano, Y; Mizukawa, Y; Shiohara, T

    2014-06-01

    Drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms (DIHS/DRESS) and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) represent contrasting poles of severe drug eruptions, and sequential reactivations of several herpesviruses have exclusively been demonstrated in the former. No previous studies, however, were extended beyond the acute stage. We sought to investigate whether herpesvirus reactivations could also be observed in SJS/TEN and beyond the acute stage of both diseases. Patients with SJS (n = 16), SJS/TEN overlap (n = 2), TEN (n = 10), and DIHS/DRESS (n = 34) were enrolled. We performed a retrospective analysis of Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and cytomegalovirus (CMV) DNA loads sequentially determined by real-time polymerase chain reaction during a 2-year period after onset. Persistently increased EBV loads were detected in SJS during the acute stage and long after resolution, but not in others. In contrast, high HHV-6 loads were exclusively detected in DIHS/DRESS during the acute stage. The dynamics of herpesvirus reactivation varied in DIHS/DRESS according to the use of systemic corticosteroids: While EBV loads were higher in patients not receiving systemic corticosteroids, CMV and HHV-6 loads were higher in those receiving them. Distinct patterns of herpesvirus reactivation according to the pathological phenotype and to the use of systemic corticosteroids were observed during the acute stage and follow-up period, which may contribute, at least in part, to the difference in the clinical manifestations and long-term outcomes. Systemic corticosteroids during the acute stage may improve the outcomes in DIHS/DRESS. © 2014 The Authors. Allergy Published by John Wiley & Sons Ltd.

  9. Clinical Epidemiology of Buruli Ulcer from Benin (2005-2013: Effect of Time-Delay to Diagnosis on Clinical Forms and Severe Phenotypes.

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    Carlos Capela

    Full Text Available Buruli Ulcer (BU is a neglected infectious disease caused by Mycobacterium ulcerans that is responsible for severe necrotizing cutaneous lesions that may be associated with bone involvement. Clinical presentations of BU lesions are classically classified as papules, nodules, plaques and edematous infiltration, ulcer or osteomyelitis. Within these different clinical forms, lesions can be further classified as severe forms based on focality (multiple lesions, lesions' size (>15 cm diameter or WHO Category (WHO Category 3 lesions. There are studies reporting an association between delay in seeking medical care and the development of ulcerative forms of BU or osteomyelitis, but the effect of time-delay on the emergence of lesions classified as severe has not been addressed. To address both issues, and in a cohort of laboratory-confirmed BU cases, 476 patients from a medical center in Allada, Benin, were studied. In this laboratory-confirmed cohort, we validated previous observations, demonstrating that time-delay is statistically related to the clinical form of BU. Indeed, for non-ulcerated forms (nodule, edema, and plaque the median time-delay was 32.5 days (IQR 30.0-67.5, while for ulcerated forms it was 60 days (IQR 20.0-120.0 (p = 0.009, and for bone lesions, 365 days (IQR 228.0-548.0. On the other hand, we show here that time-delay is not associated with the more severe phenotypes of BU, such as multi-focal lesions (median 90 days; IQR 56-217.5; p = 0.09, larger lesions (diameter >15 cm (median 60 days; IQR 30-120; p = 0.92 or category 3 WHO classification (median 60 days; IQR 30-150; p = 0.20, when compared with unifocal (median 60 days; IQR 30-90, small lesions (diameter ≤15 cm (median 60 days; IQR 30-90, or WHO category 1+2 lesions (median 60 days; IQR 30-90, respectively. Our results demonstrate that after an initial period of progression towards ulceration or bone involvement, BU lesions become stable regarding size and focal

  10. Comprehensive clinical evaluation of a large Spanish family with Anderson-Fabry disease, novel GLA mutation and severe cardiac phenotype.

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    San Román-Monserrat, Irene; Moreno-Flores, Victoria; López-Cuenca, David; Rodríguez-González-Herrero, Elena; Guillén-Navarro, Encarna; Rodríguez-González-Herrero, Beatriz; Alegría-Fernández, Marisol; Poza-Cisneros, Gabriela; Piñero-Fernández, Juan A; Sornichero-Martínez, Javier; Gimeno-Blanes, Juan R

    2014-06-06

    Fabry disease is an X-linked multisystemic lysosomal-storage condition. We describe a large family with a novel GLA mutation: p.M187R/g7219 T>G. Anamnesis/physical-exam, blood/urine analysis, α-Gal-A activity and/or genetic study of at-risk individuals and multidisciplinary evaluation in confirmed cases. 4 males and 13 heterozygous-females displayed the mutation. Cardiac/renal/neurological disease was diagnosed at a mean age of 41/29/39 years in males and 51/56/46 years in females. Onset mean age was 20 years versus 42 years. 9/15 had cardiomyopathy. Delta wave suggestive of accessory pathway was identified in 1 male and 2 females. 1 female had cardiac arrest (ventricular fibrillation, 61 years). 2 females and 1 male died suddenly (63, 64 and 57 years). Cardiac-subscore of Mainz Severity-Score-Index was severe for males and females over 40 years. 4/15(26%) developed early renal disease. 2 males needed dialysis. 1 male died at 69 years in spite of kidney-heart transplant. We describe the largest genetically confirmed Spanish family using multidisciplinary evaluation and MSSI calculation. The novel mutation p.M187R/g7219 T>G is associated with a particularly malignant cardiac phenotype in males and females over 40 years. Severity was higher than that of the largest Spanish FOS-cohort. Short-PR with delta is being reported for the first time. Copyright © 2013 Elsevier España, S.L. All rights reserved.

  11. Serum interleukin 17, interleukin 23, and interleukin 10 values in children with atopic eczema/dermatitis syndrome (AEDS): association with clinical severity and phenotype.

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    Leonardi, Salvatore; Cuppari, Caterina; Manti, Sara; Filippelli, Martina; Parisi, Giuseppe Fabio; Borgia, Francesco; Briuglia, Silvana; Cannavò, Patrizia; Salpietro, Annamaria; Arrigo, Teresa; Salpietro, Carmelo

    2015-01-01

    To date cytokines profile in AEDS is poorly described in children. We evaluated the interleukin (IL)-17, IL-23, and IL-10 levels in atopic eczema/dermatitis syndrome (AEDS) children and healthy controls, in atopic AEDS (aAEDS) and nonatopic (naAEDS) subtypes and their relationship with disease severity. A total of 181 children with aAEDS and 93 healthy children were evaluated. According to the skin-prick test (SPT) for allergens and serum total IgE, all patients were subdivided in two groups: 104 aAEDS and 77 naAEDS. In all patients, serum IL-17, IL-23, and IL-10 levels were detected. Serum IL-17 and IL-23 levels were significantly higher, and serum IL-10 levels were significantly lower in AEDS children than healthy group (p children with only allergic sensitization. Our study confirms the role of IL-17, IL-23, and IL-10 and their relationship with the severity of AEDS. We firstly found a correlation between high IL-17/IL-23 axis levels and different phenotypes of AEDS in children, suggesting its role as marker of "atopic march" and disease severity.

  12. HIV coreceptor phenotyping in the clinical setting.

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    Low, Andrew J; Swenson, Luke C; Harrigan, P Richard

    2008-01-01

    The introduction of CCR5 antagonists increases the options available for constructing antiretroviral regimens. However, this option is coupled with the caveat that patients should be tested for HIV coreceptor tropism prior to initiating CCR5 antagonist-based therapy. Failure to screen for CXCR4 usage increases the risk of using an ineffective drug, thus reducing the likelihood of viral suppression and increasing their risk for developing antiretroviral resistance. This review discusses current and future methods of determining HIV tropism, with a focus on their utility in the clinical setting for screening purposes. Some of these methods include recombinant phenotypic tests, such as the Monogram Trofile assay, as well as genotype-based predictors, heteroduplex tracking assays, and flow cytometry based methods. Currently, the best evidence supports the use of phenotypic methods, although other methods of screening for HIV coreceptor usage prior to the administration of CCR5 antagonists may reduce costs and increase turnaround time over phenotypic methods. The presence of low levels of X4 virus is a challenge to all assay methods, resulting in reduced sensitivity in clinical, patient-derived samples when compared to clonally derived samples. Gaining a better understanding of the output of these assays and correlating them with clinical progression and therapy response will provide some indication on how both genotype-based, and phenotypic assays for determining HIV coreceptor usage can be improved. In addition, leveraging new technologies capable of detecting low-level minority species may provide the most significant advances in ensuring that individuals with low levels of dual/mixed tropic virus are not inadvertently prescribed CCR5 antagonists.

  13. Factor VII Deficiency: Clinical Phenotype, Genotype and Therapy.

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    Napolitano, Mariasanta; Siragusa, Sergio; Mariani, Guglielmo

    2017-03-28

    Factor VII deficiency is the most common among rare inherited autosomal recessive bleeding disorders, and is a chameleon disease due to the lack of a direct correlation between plasma levels of coagulation Factor VII and bleeding manifestations. Clinical phenotypes range from asymptomatic condition-even in homozygous subjects-to severe life-threatening bleedings (central nervous system, gastrointestinal bleeding). Prediction of bleeding risk is thus based on multiple parameters that challenge disease management. Spontaneous or surgical bleedings require accurate treatment schedules, and patients at high risk of severe hemorrhages may need prophylaxis from childhood onwards. The aim of the current review is to depict an updated summary of clinical phenotype, laboratory diagnosis, and treatment of inherited Factor VII deficiency.

  14. Dystrophic Cardiomyopathy: Complex Pathobiological Processes to Generate Clinical Phenotype

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    Takeshi Tsuda

    2017-09-01

    Full Text Available Duchenne muscular dystrophy (DMD, Becker muscular dystrophy (BMD, and X-linked dilated cardiomyopathy (XL-DCM consist of a unique clinical entity, the dystrophinopathies, which are due to variable mutations in the dystrophin gene. Dilated cardiomyopathy (DCM is a common complication of dystrophinopathies, but the onset, progression, and severity of heart disease differ among these subgroups. Extensive molecular genetic studies have been conducted to assess genotype-phenotype correlation in DMD, BMD, and XL-DCM to understand the underlying mechanisms of these diseases, but the results are not always conclusive, suggesting the involvement of complex multi-layers of pathological processes that generate the final clinical phenotype. Dystrophin protein is a part of dystrophin-glycoprotein complex (DGC that is localized in skeletal muscles, myocardium, smooth muscles, and neuronal tissues. Diversity of cardiac phenotype in dystrophinopathies suggests multiple layers of pathogenetic mechanisms in forming dystrophic cardiomyopathy. In this review article, we review the complex molecular interactions involving the pathogenesis of dystrophic cardiomyopathy, including primary gene mutations and loss of structural integrity, secondary cellular responses, and certain epigenetic and other factors that modulate gene expressions. Involvement of epigenetic gene regulation appears to lead to specific cardiac phenotypes in dystrophic hearts.

  15. Prevalence of comorbidities according to predominant phenotype and severity of chronic obstructive pulmonary disease

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    Camiciottoli G

    2016-09-01

    Full Text Available Gianna Camiciottoli,1,2 Francesca Bigazzi,1 Chiara Magni,1 Viola Bonti,1 Stefano Diciotti,3 Maurizio Bartolucci,4 Mario Mascalchi,5 Massimo Pistolesi1 1Section of Respiratory Medicine, Department of Clinical and Experimental Medicine, 2Department of Clinical and Experimental Biomedical Sciences, University of Florence, Florence, 3Department of Electrical, Electronic, and Information Engineering “Guglielmo Marconi,” University of Bologna, Cesena, 4Department of Diagnostic Imaging, Careggi University Hospital, 5Radiodiagnostic Section, Department of Clinical and Experimental Biomedical Sciences, University of Florence, Florence, Italy Background: In addition to lung involvement, several other diseases and syndromes coexist in patients with chronic obstructive pulmonary disease (COPD. Our purpose was to investigate the prevalence of idiopathic arterial hypertension (IAH, ischemic heart disease, heart failure, peripheral vascular disease (PVD, diabetes, osteoporosis, and anxious depressive syndrome in a clinical setting of COPD outpatients whose phenotypes (predominant airway disease and predominant emphysema and severity (mild and severe diseases were determined by clinical and functional parameters. Methods: A total of 412 outpatients with COPD were assigned either a predominant airway disease or a predominant emphysema phenotype of mild or severe degree according to predictive models based on pulmonary functions (forced expiratory volume in 1 second/vital capacity; total lung capacity %; functional residual capacity %; and diffusing capacity of lung for carbon monoxide % and sputum characteristics. Comorbidities were assessed by objective medical records. Results: Eighty-four percent of patients suffered from at least one comorbidity and 75% from at least one cardiovascular comorbidity, with IAH and PVD being the most prevalent ones (62% and 28%, respectively. IAH prevailed significantly in predominant airway disease, osteoporosis prevailed

  16. COACH CV: The Seven Clinical Phenotypes of Concussion

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    Neil Craton

    2017-09-01

    Full Text Available Our understanding of the diverse physiological manifestations of concussion is changing rapidly. This has an influence on the clinical assessment of patients who have sustained a concussion. The 2017 Consensus Statement on Concussion in Sport states that numerous post-injury clinical findings, such as cognitive deficits, post-traumatic headaches, dizziness, difficulties with oculomotor function, and depression have all been associated with a poorer prognosis in concussed patients. This demonstrates that there are several potential clinical manifestations after head injury warranting clinical evaluation. We have developed an acronym to guide the office-based assessment of concussed patients to consider each of the potential clinical phenotypes. “COACH CV” prompts the clinician to evaluate for cognitive problems, oculomotor dysfunction, affective disturbances, cervical spine disorders, headaches, and cardiovascular and vestibular anomalies.

  17. Noonan syndrome: Severe phenotype and PTPN11 mutations.

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    Carrasco Salas, Pilar; Gómez-Molina, Gertrudis; Carreto-Alba, Páxedes; Granell-Escobar, Reyes; Vázquez-Rico, Ignacio; León-Justel, Antonio

    2018-04-24

    Noonan syndrome (NS) is a genetic disorder characterized by a wide range of distinctive features and health problems. It caused in 50% of cases by missense mutations in PTPN11 gene. It has been postulated that it is possible to predict the disease course based into the impact of mutations on the protein. We report two cases of severe NS phenotype including hydrops fetalis. PTPN11 gene was studied in germinal cells of both patients by sequencing. Two different mutations (p.Gly503Arg and p.Met504Val) was detected in PTPN11 gene. These mutations have been reported previously, and when they were germinal variants, patients presented classic NS, NS with other malignancies and recently, p.Gly503Arg has been also observed in a patient with severe NS and hydrops fetalis, as our cases. Therefore, these observations shade light on that it is not always possibly to determine the genotype-phenotype relation based into the impact of mutations on the protein in NS patients with PTPN11 mutations. Copyright © 2018 Elsevier España, S.L.U. All rights reserved.

  18. Multidimensional clinical phenotyping of an adult cystic fibrosis patient population.

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    Douglas J Conrad

    Full Text Available Cystic Fibrosis (CF is a multi-systemic disease resulting from mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR gene and has major manifestations in the sino-pulmonary, and gastro-intestinal tracts. Clinical phenotypes were generated using 26 common clinical variables to generate classes that overlapped quantiles of lung function and were based on multiple aspects of CF systemic disease.The variables included age, gender, CFTR mutations, FEV1% predicted, FVC% predicted, height, weight, Brasfield chest xray score, pancreatic sufficiency status and clinical microbiology results. Complete datasets were compiled on 211 subjects. Phenotypes were identified using a proximity matrix generated by the unsupervised Random Forests algorithm and subsequent clustering by the Partitioning around Medoids (PAM algorithm. The final phenotypic classes were then characterized and compared to a similar dataset obtained three years earlier.Clinical phenotypes were identified using a clustering strategy that generated four and five phenotypes. Each strategy identified 1 a low lung health scores phenotype, 2 a younger, well-nourished, male-dominated class, 3 various high lung health score phenotypes that varied in terms of age, gender and nutritional status. This multidimensional clinical phenotyping strategy identified classes with expected microbiology results and low risk clinical phenotypes with pancreatic sufficiency.This study demonstrated regional adult CF clinical phenotypes using non-parametric, continuous, ordinal and categorical data with a minimal amount of subjective data to identify clinically relevant phenotypes. These studies identified the relative stability of the phenotypes, demonstrated specific phenotypes consistent with published findings and identified others needing further study.

  19. Application of the asthma phenotype algorithm from the Severe Asthma Research Program to an urban population.

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    Paru Patrawalla

    Full Text Available Identification and characterization of asthma phenotypes are challenging due to disease complexity and heterogeneity. The Severe Asthma Research Program (SARP used unsupervised cluster analysis to define 5 phenotypically distinct asthma clusters that they replicated using 3 variables in a simplified algorithm. We evaluated whether this simplified SARP algorithm could be used in a separate and diverse urban asthma population to recreate these 5 phenotypic clusters.The SARP simplified algorithm was applied to adults with asthma recruited to the New York University/Bellevue Asthma Registry (NYUBAR to classify patients into five groups. The clinical phenotypes were summarized and compared.Asthma subjects in NYUBAR (n = 471 were predominantly women (70% and Hispanic (57%, which were demographically different from the SARP population. The clinical phenotypes of the five groups generated by the simplified SARP algorithm were distinct across groups and distributed similarly to those described for the SARP population. Groups 1 and 2 (6 and 63%, respectively had predominantly childhood onset atopic asthma. Groups 4 and 5 (20% were older, with the longest duration of asthma, increased symptoms and exacerbations. Group 4 subjects were the most atopic and had the highest peripheral eosinophils. Group 3 (10% had the least atopy, but included older obese women with adult-onset asthma, and increased exacerbations.Application of the simplified SARP algorithm to the NYUBAR yielded groups that were phenotypically distinct and useful to characterize disease heterogeneity. Differences across NYUBAR groups support phenotypic variation and support the use of the simplified SARP algorithm for classification of asthma phenotypes in future prospective studies to investigate treatment and outcome differences between these distinct groups.Clinicaltrials.gov NCT00212537.

  20. A simple algorithm for the identification of clinical COPD phenotypes

    DEFF Research Database (Denmark)

    Burgel, Pierre-Régis; Paillasseur, Jean-Louis; Janssens, Wim

    2017-01-01

    This study aimed to identify simple rules for allocating chronic obstructive pulmonary disease (COPD) patients to clinical phenotypes identified by cluster analyses. Data from 2409 COPD patients of French/Belgian COPD cohorts were analysed using cluster analysis resulting in the identification...... of subgroups, for which clinical relevance was determined by comparing 3-year all-cause mortality. Classification and regression trees (CARTs) were used to develop an algorithm for allocating patients to these subgroups. This algorithm was tested in 3651 patients from the COPD Cohorts Collaborative...... International Assessment (3CIA) initiative. Cluster analysis identified five subgroups of COPD patients with different clinical characteristics (especially regarding severity of respiratory disease and the presence of cardiovascular comorbidities and diabetes). The CART-based algorithm indicated...

  1. Familial adenomatous polyposis patients without an identified APC germline mutation have a severe phenotype

    DEFF Research Database (Denmark)

    Bisgaard, M L; Ripa, R; Knudsen, Anne Louise

    2004-01-01

    BACKGROUND: Development of more than 100 colorectal adenomas is diagnostic of the dominantly inherited autosomal disease familial adenomatous polyposis (FAP). Germline mutations can be identified in the adenomatous polyposis coli (APC) gene in approximately 80% of patients. The APC protein...... comprises several regions and domains for interaction with other proteins, and specific clinical manifestations are associated with the mutation assignment to one of these regions or domains. AIMS: The phenotype in patients without an identified causative APC mutation was compared with the phenotype...... in patients with a known APC mutation and with the phenotypes characteristic of patients with mutations in specific APC regions and domains. PATIENTS: Data on 121 FAP probands and 149 call up patients from 70 different families were extracted from the Danish Polyposis register. METHODS: Differences in 16...

  2. Two Clinical Phenotypes in Polycythemia Vera

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    Spivak, Jerry L.; Considine, Michael; Williams, Donna M.; Talbot, Conover C.; Rogers, Ophelia; Moliterno, Alison R.; Jie, Chunfa; Ochs, Michael F.

    2014-01-01

    BACKGROUND Polycythemia vera is the ultimate phenotypic consequence of the V617F mutation in Janus kinase 2 (encoded by JAK2), but the extent to which this mutation influences the behavior of the involved CD34+ hematopoietic stem cells is unknown. METHODS We analyzed gene expression in CD34+ peripheral-blood cells from 19 patients with polycythemia vera, using oligonucleotide microarray technology after correcting for potential confounding by sex, since the phenotypic features of the disease differ between men and women. RESULTS Men with polycythemia vera had twice as many up-regulated or down-regulated genes as women with polycythemia vera, in a comparison of gene expression in the patients and in healthy persons of the same sex, but there were 102 genes with differential regulation that was concordant in men and women. When these genes were used for class discovery by means of unsupervised hierarchical clustering, the 19 patients could be divided into two groups that did not differ significantly with respect to age, neutrophil JAK2 V617F allele burden, white-cell count, platelet count, or clonal dominance. However, they did differ significantly with respect to disease duration; hemoglobin level; frequency of thromboembolic events, palpable splenomegaly, and splenectomy; chemotherapy exposure; leukemic transformation; and survival. The unsupervised clustering was confirmed by a supervised approach with the use of a top-scoring-pair classifier that segregated the 19 patients into the same two phenotypic groups with 100% accuracy. CONCLUSIONS Removing sex as a potential confounder, we identified an accurate molecular method for classifying patients with polycythemia vera according to disease behavior, independently of their JAK2 V617F allele burden, and identified previously unrecognized molecular pathways in polycythemia vera outside the canonical JAK2 pathway that may be amenable to targeted therapy. PMID:25162887

  3. CKD Self-management: Phenotypes and Associations With Clinical Outcomes.

    Science.gov (United States)

    Schrauben, Sarah J; Hsu, Jesse Y; Rosas, Sylvia E; Jaar, Bernard G; Zhang, Xiaoming; Deo, Rajat; Saab, Georges; Chen, Jing; Lederer, Swati; Kanthety, Radhika; Hamm, L Lee; Ricardo, Ana C; Lash, James P; Feldman, Harold I; Anderson, Amanda H

    2018-03-24

    To slow chronic kidney disease (CKD) progression and its complications, patients need to engage in self-management behaviors. The objective of this study was to classify CKD self-management behaviors into phenotypes and assess the association of these phenotypes with clinical outcomes. Prospective cohort study. Adults with mild to moderate CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. 3,939 participants in the CRIC Study recruited between 2003 and 2008 served as the derivation cohort and 1,560 participants recruited between 2013 and 2015 served as the validation cohort. CKD self-management behavior phenotypes. CKD progression, atherosclerotic events, heart failure events, death from any cause. Latent class analysis stratified by diabetes was used to identify CKD self-management phenotypes based on measures of body mass index, diet, physical activity, blood pressure, smoking status, and hemoglobin A 1c concentration (if diabetic); Cox proportional hazards models. 3 identified phenotypes varied according to the extent of implementation of recommended CKD self-management behaviors: phenotype I characterized study participants with the most recommended behaviors; phenotype II, participants with a mixture of recommended and not recommended behaviors; and phenotype III, participants with minimal recommended behaviors. In multivariable-adjusted models for those with and without diabetes, phenotype III was strongly associated with CKD progression (HRs of 1.82 and 1.49), death (HRs of 1.95 and 4.14), and atherosclerotic events (HRs of 2.54 and 1.90; each P diabetes. No consensus definition of CKD self-management; limited to baseline behavior data. There are potentially 3 CKD self-management behavior phenotypes that distinguish risk for clinical outcomes. These phenotypes may inform the development of studies and guidelines regarding optimal self-management. Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights

  4. Phenotypes Determined by Cluster Analysis in Moderate to Severe Bronchial Asthma.

    Science.gov (United States)

    Youroukova, Vania M; Dimitrova, Denitsa G; Valerieva, Anna D; Lesichkova, Spaska S; Velikova, Tsvetelina V; Ivanova-Todorova, Ekaterina I; Tumangelova-Yuzeir, Kalina D

    2017-06-01

    Bronchial asthma is a heterogeneous disease that includes various subtypes. They may share similar clinical characteristics, but probably have different pathological mechanisms. To identify phenotypes using cluster analysis in moderate to severe bronchial asthma and to compare differences in clinical, physiological, immunological and inflammatory data between the clusters. Forty adult patients with moderate to severe bronchial asthma out of exacerbation were included. All underwent clinical assessment, anthropometric measurements, skin prick testing, standard spirometry and measurement fraction of exhaled nitric oxide. Blood eosinophilic count, serum total IgE and periostin levels were determined. Two-step cluster approach, hierarchical clustering method and k-mean analysis were used for identification of the clusters. We have identified four clusters. Cluster 1 (n=14) - late-onset, non-atopic asthma with impaired lung function, Cluster 2 (n=13) - late-onset, atopic asthma, Cluster 3 (n=6) - late-onset, aspirin sensitivity, eosinophilic asthma, and Cluster 4 (n=7) - early-onset, atopic asthma. Our study is the first in Bulgaria in which cluster analysis is applied to asthmatic patients. We identified four clusters. The variables with greatest force for differentiation in our study were: age of asthma onset, duration of diseases, atopy, smoking, blood eosinophils, nonsteroidal anti-inflammatory drugs hypersensitivity, baseline FEV1/FVC and symptoms severity. Our results support the concept of heterogeneity of bronchial asthma and demonstrate that cluster analysis can be an useful tool for phenotyping of disease and personalized approach to the treatment of patients.

  5. Clinical phenotype analysis of paroxysmal kinesigenic dyskinesia

    Directory of Open Access Journals (Sweden)

    Wo-tu TIAN

    2017-07-01

    Full Text Available Background Paroxysmal kinesigenic dyskinesia (PKD is a disorder characterized by recurrent and brief dystonic or choreoathetoid attacks that are induced by sudden voluntary movement with highly clinical and genetic heterogeneity. We aimed to investigate the clinical features of PKD in a large Chinese population. Methods One hundred and ninety five patients diagnosed as primary PKD were recruited. For all of the participants, neurological examinations were conducted and clinical manifestations were recorded and summarized in self - made uniform registration form for PKD patients. Clinical characteristics were statistically analyzed and compared between familial and sporadic PKD patients.  Results Among all of the 195 PKD patients in the present study, the gender ratio was 4.42∶1 (male∶ female. The average age of onset was (12.32 ± 3.49 years. There were 162 patients (83.08% manifestated with pure form and 33 (16.92% with complicated form of PKD. Among them 16 patients (8.21% had essential tremor (ET, and 144 patients (73.85% had premonitory symptom. The percentage of patients manifested as dystonia, chorea and mixed form during episodic attacks were 68.72% (134/195, 4.10% (8/195 and 27.18% (53/195 repectively. There were 134 cases (68.72% had facial involvement. It was recorded that 115 (58.97%, 54 (27.69% and 26 (13.33% patients had frequency of attack < 10 times/d, 10-20 times/d and > 20-30 times/d respectively. The percentages of patients whose duration of attack <10 s, 10-30 s and > 30-60 s were 60% (117/195, 29.74% (58/195 and 10.26% (20/195 respectively. There were 64 patietns (32.82% with family history of PKD and 131 (67.18% were sporadic PKD patients. Up to 40% (78/195 of patients did not require/take medications, as they had minor clinical manifestations or concerns about the side effects of anticonvulsants. Among 117 patients (60% prescribed with anticonvulsants, 114 patients showed a good response, including complete control (N

  6. The phenotypic spectrum of organic acidurias and urea cycle disorders Part 2: the evolving clinical phenotype

    NARCIS (Netherlands)

    Kölker, Stefan; Valayannopoulos, Vassili; Burlina, Alberto B.; Sykut-Cegielska, Jolanta; Wijburg, Frits A.; Teles, Elisa Leão; Zeman, Jiri; Dionisi-Vici, Carlo; Barić, Ivo; Karall, Daniela; Arnoux, Jean-Baptiste; Avram, Paula; Baumgartner, Matthias R.; Blasco-Alonso, Javier; Boy, S. P. Nikolas; Rasmussen, Marlene Bøgehus; Burgard, Peter; Chabrol, Brigitte; Chakrapani, Anupam; Chapman, Kimberly; Cortès I Saladelafont, Elisenda; Couce, Maria L.; de Meirleir, Linda; Dobbelaere, Dries; Furlan, Francesca; Gleich, Florian; González, Maria Julieta; Gradowska, Wanda; Grünewald, Stephanie; Honzik, Tomas; Hörster, Friederike; Ioannou, Hariklea; Jalan, Anil; Häberle, Johannes; Haege, Gisela; Langereis, Eveline; de Lonlay, Pascale; Martinelli, Diego; Matsumoto, Shirou; Mühlhausen, Chris; Murphy, Elaine; de Baulny, Hélène Ogier; Ortez, Carlos; Pedrón, Consuelo C.; Pintos-Morell, Guillem; Pena-Quintana, Luis; Ramadža, Danijela Petković; Rodrigues, Esmeralda; Scholl-Bürgi, Sabine; Sokal, Etienne; Summar, Marshall L.; Thompson, Nicholas; Vara, Roshni; Pinera, Inmaculada Vives; Walter, John H.; Williams, Monique; Lund, Allan M.; Garcia-Cazorla, Angeles; Garcia Cazorla, Angeles

    2015-01-01

    Background The disease course and long-term outcome of patients with organic acidurias (OAD) and urea cycle disorders (UCD) are incompletely understood. Aims To evaluate the complex clinical phenotype of OAD and UCD patients at different ages. Results Acquired microcephaly and movement disorders

  7. Clinical and molecular phenotype of Aicardi-Goutieres syndrome.

    Science.gov (United States)

    Rice, Gillian; Patrick, Teresa; Parmar, Rekha; Taylor, Claire F; Aeby, Alec; Aicardi, Jean; Artuch, Rafael; Montalto, Simon Attard; Bacino, Carlos A; Barroso, Bruno; Baxter, Peter; Benko, Willam S; Bergmann, Carsten; Bertini, Enrico; Biancheri, Roberta; Blair, Edward M; Blau, Nenad; Bonthron, David T; Briggs, Tracy; Brueton, Louise A; Brunner, Han G; Burke, Christopher J; Carr, Ian M; Carvalho, Daniel R; Chandler, Kate E; Christen, Hans-Jurgen; Corry, Peter C; Cowan, Frances M; Cox, Helen; D'Arrigo, Stefano; Dean, John; De Laet, Corinne; De Praeter, Claudine; Dery, Catherine; Ferrie, Colin D; Flintoff, Kim; Frints, Suzanna G M; Garcia-Cazorla, Angels; Gener, Blanca; Goizet, Cyril; Goutieres, Francoise; Green, Andrew J; Guet, Agnes; Hamel, Ben C J; Hayward, Bruce E; Heiberg, Arvid; Hennekam, Raoul C; Husson, Marie; Jackson, Andrew P; Jayatunga, Rasieka; Jiang, Yong-Hui; Kant, Sarina G; Kao, Amy; King, Mary D; Kingston, Helen M; Klepper, Joerg; van der Knaap, Marjo S; Kornberg, Andrew J; Kotzot, Dieter; Kratzer, Wilfried; Lacombe, Didier; Lagae, Lieven; Landrieu, Pierre Georges; Lanzi, Giovanni; Leitch, Andrea; Lim, Ming J; Livingston, John H; Lourenco, Charles M; Lyall, E G Hermione; Lynch, Sally A; Lyons, Michael J; Marom, Daphna; McClure, John P; McWilliam, Robert; Melancon, Serge B; Mewasingh, Leena D; Moutard, Marie-Laure; Nischal, Ken K; Ostergaard, John R; Prendiville, Julie; Rasmussen, Magnhild; Rogers, R Curtis; Roland, Dominique; Rosser, Elisabeth M; Rostasy, Kevin; Roubertie, Agathe; Sanchis, Amparo; Schiffmann, Raphael; Scholl-Burgi, Sabine; Seal, Sunita; Shalev, Stavit A; Corcoles, C Sierra; Sinha, Gyan P; Soler, Doriette; Spiegel, Ronen; Stephenson, John B P; Tacke, Uta; Tan, Tiong Yang; Till, Marianne; Tolmie, John L; Tomlin, Pam; Vagnarelli, Federica; Valente, Enza Maria; Van Coster, Rudy N A; Van der Aa, Nathalie; Vanderver, Adeline; Vles, Johannes S H; Voit, Thomas; Wassmer, Evangeline; Weschke, Bernhard; Whiteford, Margo L; Willemsen, Michel A A; Zankl, Andreas; Zuberi, Sameer M; Orcesi, Simona; Fazzi, Elisa; Lebon, Pierre; Crow, Yanick J

    2007-10-01

    Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.

  8. A simple algorithm for the identification of clinical COPD phenotypes

    NARCIS (Netherlands)

    Burgel, Pierre-Régis; Paillasseur, Jean-Louis; Janssens, Wim; Piquet, Jacques; ter Riet, Gerben; Garcia-Aymerich, Judith; Cosio, Borja; Bakke, Per; Puhan, Milo A.; Langhammer, Arnulf; Alfageme, Inmaculada; Almagro, Pere; Ancochea, Julio; Celli, Bartolome R.; Casanova, Ciro; de-Torres, Juan P.; Decramer, Marc; Echazarreta, Andrés; Esteban, Cristobal; Gomez Punter, Rosa Mar; Han, MeiLan K.; Johannessen, Ane; Kaiser, Bernhard; Lamprecht, Bernd; Lange, Peter; Leivseth, Linda; Marin, Jose M.; Martin, Francis; Martinez-Camblor, Pablo; Miravitlles, Marc; Oga, Toru; Sofia Ramírez, Ana; Sin, Don D.; Sobradillo, Patricia; Soler-Cataluña, Juan J.; Turner, Alice M.; Verdu Rivera, Francisco Javier; Soriano, Joan B.; Roche, Nicolas

    2017-01-01

    This study aimed to identify simple rules for allocating chronic obstructive pulmonary disease (COPD) patients to clinical phenotypes identified by cluster analyses. Data from 2409 COPD patients of French/Belgian COPD cohorts were analysed using cluster analysis resulting in the identification of

  9. Clinical and inflammatory markers in asthma and COPD phenotyping

    NARCIS (Netherlands)

    de Nijs, S.B.

    2013-01-01

    Based on the studies described in this thesis, we conclude that adult-onset respiratory diseases (asthma and COPD) are heterogeneous conditions characterized by different clinical features and inflammatory characteristics. The first part of the thesis focused on phenotypes of adult-onset asthma. We

  10. Sickle cell disease clinical phenotypes in children from South ...

    African Journals Online (AJOL)

    2014-07-20

    Jul 20, 2014 ... Background:The clinical phenotypes of children with sickle cell disease (SCD) are poorly described in many sub-Saharan countries ..... World Health Organization. ... apps.who.int/gb/ebwha/pdf_files/WHA59/A59_9‑en.pdf.

  11. COPD phenotypes on computed tomography and its correlation with selected lung function variables in severe patients

    Directory of Open Access Journals (Sweden)

    da Silva SMD

    2016-03-01

    Full Text Available Silvia Maria Doria da Silva, Ilma Aparecida Paschoal, Eduardo Mello De Capitani, Marcos Mello Moreira, Luciana Campanatti Palhares, Mônica Corso PereiraPneumology Service, Department of Internal Medicine, School of Medical Sciences, State University of Campinas (UNICAMP, Campinas, São Paulo, BrazilBackground: Computed tomography (CT phenotypic characterization helps in understanding the clinical diversity of chronic obstructive pulmonary disease (COPD patients, but its clinical relevance and its relationship with functional features are not clarified. Volumetric capnography (VC uses the principle of gas washout and analyzes the pattern of CO2 elimination as a function of expired volume. The main variables analyzed were end-tidal concentration of carbon dioxide (ETCO2, Slope of phase 2 (Slp2, and Slope of phase 3 (Slp3 of capnogram, the curve which represents the total amount of CO2 eliminated by the lungs during each breath.Objective: To investigate, in a group of patients with severe COPD, if the phenotypic analysis by CT could identify different subsets of patients, and if there was an association of CT findings and functional variables.Subjects and methods: Sixty-five patients with COPD Gold III–IV were admitted for clinical evaluation, high-resolution CT, and functional evaluation (spirometry, 6-minute walk test [6MWT], and VC. The presence and profusion of tomography findings were evaluated, and later, the patients were identified as having emphysema (EMP or airway disease (AWD phenotype. EMP and AWD groups were compared; tomography findings scores were evaluated versus spirometric, 6MWT, and VC variables.Results: Bronchiectasis was found in 33.8% and peribronchial thickening in 69.2% of the 65 patients. Structural findings of airways had no significant correlation with spirometric variables. Air trapping and EMP were strongly correlated with VC variables, but in opposite directions. There was some overlap between the EMP and AWD

  12. Parthenium dermatitis severity score to assess clinical severity of disease

    Directory of Open Access Journals (Sweden)

    Kaushal K Verma

    2017-01-01

    Full Text Available Background: Parthenium dermatitis is the most common type of airborne contact dermatitis in India. It is a chronic disease of a remitting and relapsing course with significant morbidity and distress, but there is no scoring system to assess its severity. Aim: To design a scoring system for the assessment of clinical severity of disease in Parthenium dermatitis and to use this scoring system in various studies to determine its sensitivity, specificity, and reproducibility. Methods and Results: In our first few studies on Parthenium dermatitis, we designed and used a basic clinical severity scoring system based on itching, morphology of the lesions, and areas involved. However, in subsequent studies, we modified it to the present scoring system as Parthenium dermatitis severity score (PDSS. Our studies showed the high sensitivity of PDSS in characterization of the disease severity at the given point of time, as well as to determine the efficacy of a prescribed treatment modality which was reliable and reproducible. Conclusion: Thus, PDSS may be used by clinicians for appropriate scoring of the clinical severity of Parthenium dermatitis and in monitoring the disease response to therapy.

  13. Concepts of pathogenesis in psoriatic arthritis: genotype determines clinical phenotype.

    LENUS (Irish Health Repository)

    FitzGerald, Oliver

    2015-05-07

    This review focuses on the genetic features of psoriatic arthritis (PsA) and their relationship to phenotypic heterogeneity in the disease, and addresses three questions: what do the recent studies on human leukocyte antigen (HLA) tell us about the genetic relationship between cutaneous psoriasis (PsO) and PsA - that is, is PsO a unitary phenotype; is PsA a genetically heterogeneous or homogeneous entity; and do the genetic factors implicated in determining susceptibility to PsA predict clinical phenotype? We first discuss the results from comparing the HLA typing of two PsO cohorts: one cohort providing the dermatologic perspective, consisting of patients with PsO without evidence of arthritic disease; and the second cohort providing the rheumatologic perspective, consisting of patients with PsA. We show that these two cohorts differ considerably in their predominant HLA alleles, indicating the heterogeneity of the overall PsO phenotype. Moreover, the genotype of patients in the PsA cohort was shown to be heterogeneous with significant elevations in the frequency of haplotypes containing HLA-B*08, HLA-C*06:02, HLA-B*27, HLA-B*38 and HLA-B*39. Because different genetic susceptibility genes imply different disease mechanisms, and possibly different clinical courses and therapeutic responses, we then review the evidence for a phenotypic difference among patients with PsA who have inherited different HLA alleles. We provide evidence that different alleles and, more importantly, different haplotypes implicated in determining PsA susceptibility are associated with different phenotypic characteristics that appear to be subphenotypes. The implication of these findings for the overall pathophysiologic mechanisms involved in PsA is discussed with specific reference to their bearing on the discussion of whether PsA is conceptualised as an autoimmune process or one that is based on entheseal responses.

  14. Persistence of the extended psychosis phenotype in young people: Link between vulnerability and clinical need

    NARCIS (Netherlands)

    Wigman, J.T.W.

    2011-01-01

    Psychosis is one of the most severe psychiatric conditions, in terms of both individual and societal burden. The pathway from the earliest and mildest expressions of psychosis to clinical disorder is highly variable and heterogeneous. A better understanding of the psychosis phenotype and its

  15. Clinical features of Friedreich's ataxia: classical and atypical phenotypes.

    Science.gov (United States)

    Parkinson, Michael H; Boesch, Sylvia; Nachbauer, Wolfgang; Mariotti, Caterina; Giunti, Paola

    2013-08-01

    One hundred and fifty years since Nikolaus Friedreich's first description of the degenerative ataxic syndrome which bears his name, his description remains at the core of the classical clinical phenotype of gait and limb ataxia, poor balance and coordination, leg weakness, sensory loss, areflexia, impaired walking, dysarthria, dysphagia, eye movement abnormalities, scoliosis, foot deformities, cardiomyopathy and diabetes. Onset is typically around puberty with slow progression and shortened life-span often related to cardiac complications. Inheritance is autosomal recessive with the vast majority of cases showing an unstable intronic GAA expansion in both alleles of the frataxin gene on chromosome 9q13. A small number of cases are caused by a compound heterozygous expansion with a point mutation or deletion. Understanding of the underlying molecular biology has enabled identification of atypical phenotypes with late onset, or atypical features such as retained reflexes. Late-onset cases tend to have slower progression and are associated with smaller GAA expansions. Early-onset cases tend to have more rapid progression and a higher frequency of non-neurological features such as diabetes, cardiomyopathy, scoliosis and pes cavus. Compound heterozygotes, including those with large deletions, often have atypical features. In this paper, we review the classical and atypical clinical phenotypes of Friedreich's ataxia. © 2013 International Society for Neurochemistry.

  16. Clinical phenotype-based gene prioritization: an initial study using semantic similarity and the human phenotype ontology.

    Science.gov (United States)

    Masino, Aaron J; Dechene, Elizabeth T; Dulik, Matthew C; Wilkens, Alisha; Spinner, Nancy B; Krantz, Ian D; Pennington, Jeffrey W; Robinson, Peter N; White, Peter S

    2014-07-21

    Exome sequencing is a promising method for diagnosing patients with a complex phenotype. However, variant interpretation relative to patient phenotype can be challenging in some scenarios, particularly clinical assessment of rare complex phenotypes. Each patient's sequence reveals many possibly damaging variants that must be individually assessed to establish clear association with patient phenotype. To assist interpretation, we implemented an algorithm that ranks a given set of genes relative to patient phenotype. The algorithm orders genes by the semantic similarity computed between phenotypic descriptors associated with each gene and those describing the patient. Phenotypic descriptor terms are taken from the Human Phenotype Ontology (HPO) and semantic similarity is derived from each term's information content. Model validation was performed via simulation and with clinical data. We simulated 33 Mendelian diseases with 100 patients per disease. We modeled clinical conditions by adding noise and imprecision, i.e. phenotypic terms unrelated to the disease and terms less specific than the actual disease terms. We ranked the causative gene against all 2488 HPO annotated genes. The median causative gene rank was 1 for the optimal and noise cases, 12 for the imprecision case, and 60 for the imprecision with noise case. Additionally, we examined a clinical cohort of subjects with hearing impairment. The disease gene median rank was 22. However, when also considering the patient's exome data and filtering non-exomic and common variants, the median rank improved to 3. Semantic similarity can rank a causative gene highly within a gene list relative to patient phenotype characteristics, provided that imprecision is mitigated. The clinical case results suggest that phenotype rank combined with variant analysis provides significant improvement over the individual approaches. We expect that this combined prioritization approach may increase accuracy and decrease effort for

  17. Successful Phenotype Improvement following Gene Therapy for Severe Hemophilia A in Privately Owned Dogs.

    Directory of Open Access Journals (Sweden)

    Mary Beth Callan

    Full Text Available Severe hemophilia A (HA is an inherited bleeding disorder characterized by <1% of residual factor VIII (FVIII clotting activity. The disease affects several mammals including dogs, and, like humans, is associated with high morbidity and mortality. In gene therapy using adeno-associated viral (AAV vectors, the canine model has been one of the best predictors of the therapeutic dose tested in clinical trials for hemophilia B (factor IX deficiency and other genetic diseases, such as congenital blindness. Here we report our experience with liver gene therapy with AAV-FVIII in two outbred, privately owned dogs with severe HA that resulted in sustained expression of 1-2% of normal FVIII levels and prevented 90% of expected bleeding episodes. A Thr62Met mutation in the F8 gene was identified in one dog. These data recapitulate the improvement of the disease phenotype in research animals, and in humans, with AAV liver gene therapy for hemophilia B. Our experience is a novel example of the benefits of a relevant preclinical canine model to facilitate both translational studies in humans and improved welfare of privately owned dogs.

  18. Cluster analysis in severe emphysema subjects using phenotype and genotype data: an exploratory investigation

    Directory of Open Access Journals (Sweden)

    Martinez Fernando J

    2010-03-01

    Full Text Available Abstract Background Numerous studies have demonstrated associations between genetic markers and COPD, but results have been inconsistent. One reason may be heterogeneity in disease definition. Unsupervised learning approaches may assist in understanding disease heterogeneity. Methods We selected 31 phenotypic variables and 12 SNPs from five candidate genes in 308 subjects in the National Emphysema Treatment Trial (NETT Genetics Ancillary Study cohort. We used factor analysis to select a subset of phenotypic variables, and then used cluster analysis to identify subtypes of severe emphysema. We examined the phenotypic and genotypic characteristics of each cluster. Results We identified six factors accounting for 75% of the shared variability among our initial phenotypic variables. We selected four phenotypic variables from these factors for cluster analysis: 1 post-bronchodilator FEV1 percent predicted, 2 percent bronchodilator responsiveness, and quantitative CT measurements of 3 apical emphysema and 4 airway wall thickness. K-means cluster analysis revealed four clusters, though separation between clusters was modest: 1 emphysema predominant, 2 bronchodilator responsive, with higher FEV1; 3 discordant, with a lower FEV1 despite less severe emphysema and lower airway wall thickness, and 4 airway predominant. Of the genotypes examined, membership in cluster 1 (emphysema-predominant was associated with TGFB1 SNP rs1800470. Conclusions Cluster analysis may identify meaningful disease subtypes and/or groups of related phenotypic variables even in a highly selected group of severe emphysema subjects, and may be useful for genetic association studies.

  19. Clinical phenotype of 5 females with a CDKL5 mutation.

    Science.gov (United States)

    Stalpers, Xenia L; Spruijt, Liesbeth; Yntema, Helger G; Verrips, Aad

    2012-01-01

    Mutations in the X-linked cyclin dependent kinase like 5 (CDKL5) gene have been reported in approximately 80 patients since the first description in 2003. The clinical presentation partly corresponds with Rett syndrome, considering clinical features as intellectual disability, hypotonia, and poor visual, language, and motor development. However, these patients do not meet the consensus criteria for Rett syndrome since they lack the clear period of regression. Furthermore, in contrast to Rett syndrome, patients with CDKL5 mutations, have seizures or infantile spasms starting in the first weeks of life. We present clinical phenotype of 5 girls having a mutation in the CDKL5 gene. All mutations are novel and are pathogenic since they either lead to a frameshift in the reading frame or affect a consensus splice site. Four of the mutations are detected de novo in the affected girl.

  20. Successful Phenotype Improvement following Gene Therapy for Severe Hemophilia A in Privately Owned Dogs.

    Science.gov (United States)

    Callan, Mary Beth; Haskins, Mark E; Wang, Ping; Zhou, Shangzhen; High, Katherine A; Arruda, Valder R

    2016-01-01

    Severe hemophilia A (HA) is an inherited bleeding disorder characterized by dogs, and, like humans, is associated with high morbidity and mortality. In gene therapy using adeno-associated viral (AAV) vectors, the canine model has been one of the best predictors of the therapeutic dose tested in clinical trials for hemophilia B (factor IX deficiency) and other genetic diseases, such as congenital blindness. Here we report our experience with liver gene therapy with AAV-FVIII in two outbred, privately owned dogs with severe HA that resulted in sustained expression of 1-2% of normal FVIII levels and prevented 90% of expected bleeding episodes. A Thr62Met mutation in the F8 gene was identified in one dog. These data recapitulate the improvement of the disease phenotype in research animals, and in humans, with AAV liver gene therapy for hemophilia B. Our experience is a novel example of the benefits of a relevant preclinical canine model to facilitate both translational studies in humans and improved welfare of privately owned dogs.

  1. Metabolic profile of clinically severe obese patients.

    Science.gov (United States)

    Faria, Silvia Leite; Faria, Orlando Pereira; Menezes, Caroline Soares; de Gouvêa, Heloisa Rodrigues; de Almeida Cardeal, Mariane

    2012-08-01

    Since low basal metabolic rate (BMR) is a risk factor for weight regain, it is important to measure BMR before bariatric surgery. We aimed to evaluate the BMR among clinically severe obese patients preoperatively. We compared it with that of the control group, with predictive formulas and correlated it with body composition. We used indirect calorimetry (IC) to collect BMR data and multifrequency bioelectrical impedance to collect body composition data. Our sample population consisted of 193 patients of whom 130 were clinically severe obese and 63 were normal/overweight individuals. BMR results were compared with the following predictive formulas: Harris-Benedict (HBE), Bobbioni-Harsch (BH), Cunningham (CUN), Mifflin-St. Jeor (MSJE), and Horie-Waitzberg & Gonzalez (HW & G). This study was approved by the Ethics Committee for Research of the University of Brasilia. Statistical analysis was used to compare and correlate variables. Clinically severe obese patients had higher absolute BMR values and lower adjusted BMR values (p BMR were found in both groups. Among the clinically severe obese patients, the formulas of HW & G and HBE overestimated BMR values (p = 0.0002 and p = 0.0193, respectively), while the BH and CUN underestimated this value; only the MSJE formulas showed similar results to those of IC. The clinically severe obese patients showed low BMR levels when adjusted per kilogram per body weight. Body composition may influence BMR. The use of the MSJE formula may be helpful in those cases where it is impossible to use IC.

  2. Homozygous PMS2 deletion causes a severe colorectal cancer and multiple adenoma phenotype without extraintestinal cancer.

    Science.gov (United States)

    Will, Olivia; Carvajal-Carmona, Luis G; Gorman, Patricia; Howarth, Kimberley M; Jones, Angela M; Polanco-Echeverry, Guadalupe M; Chinaleong, Jo-Anne; Günther, Thomas; Silver, Andrew; Clark, Susan K; Tomlinson, Ian

    2007-02-01

    We report a patient of Indian descent with parental consanguinity, who developed 10 carcinomas and 35 adenomatous polyps at age 23 and duodenal adenocarcinoma at age 25. He also had dysmorphic features, mental retardation, and café-au-lait spots but no brain tumor. We aimed to establish his molecular diagnosis. Germ-line screening for APC and MYH/MUTYH mutations was normal as was immunohistochemistry for MLH1 and MSH2 proteins. Investigation by array-comparative genomic hybridization revealed deletion of a small region on chromosome 7. Using polymerase chain reaction, this region was refined to a 400-kilobase deletion, which included exons 9-15 of the PMS2 gene, and all coding regions of oncomodulin, TRIAD3, and FSCN1. The deletion was confirmed as homozygous, and both parents were carriers. Immunohistochemistry showed absent PMS2 expression in all tumors and normal tissue. Most tumors showed microsatellite instability, more marked at dinucleotide than mononucleotide repeats. The tumors harbored no somatic mutations in APC, BRAF, AXIN2, or beta-catenin, but KRAS2 and TGFBR2 mutations were found. Our patient represents a novel phenotype for homozygous PMS2 mutation and perhaps the most severe colorectal cancer phenotype-in terms of numbers of malignancies at an early age-described to date. PMS2 mutations-and perhaps other homozygous mismatch repair mutations-should be considered in any patient presenting with multiple gastrointestinal tumors, since our patient could not be distinguished clinically from cases with attenuated familial adenomatous polyposis or MUTYH-associated polyposis.

  3. Gain-of-function KCNJ6 Mutation in a Severe Hyperkinetic Movement Disorder Phenotype.

    Science.gov (United States)

    Horvath, Gabriella A; Zhao, Yulin; Tarailo-Graovac, Maja; Boelman, Cyrus; Gill, Harinder; Shyr, Casper; Lee, James; Blydt-Hansen, Ingrid; Drögemöller, Britt I; Moreland, Jacqueline; Ross, Colin J; Wasserman, Wyeth W; Masotti, Andrea; Slesinger, Paul A; van Karnebeek, Clara D M

    2018-05-29

    Here, we describe a fourth case of a human with a de novo KCNJ6 (GIRK2) mutation, who presented with clinical findings of severe hyperkinetic movement disorder and developmental delay, similar to the Keppen-Lubinsky syndrome but without lipodystrophy. Whole-exome sequencing of the patient's DNA revealed a heterozygous de novo variant in the KCNJ6 (c.512T>G, p.Leu171Arg). We conducted in vitro functional studies to determine if this Leu-to-Arg mutation alters the function of GIRK2 channels. Heterologous expression of the mutant GIRK2 channel alone produced an aberrant basal inward current that lacked G protein activation, lost K + selectivity and gained Ca 2+ permeability. Notably, the inward current was inhibited by the Na + channel blocker QX-314, similar to the previously reported weaver mutation in murine GIRK2. Expression of a tandem dimer containing GIRK1 and GIRK2(p.Leu171Arg) did not lead to any currents, suggesting heterotetramers are not functional. In neurons expressing p.Leu171Arg GIRK2 channels, these changes in channel properties would be expected to generate a sustained depolarization, instead of the normal G protein-gated inhibitory response, which could be mitigated by expression of other GIRK subunits. The identification of the p.Leu171Arg GIRK2 mutation potentially expands the Keppen-Lubinsky syndrome phenotype to include severe dystonia and ballismus. Our study suggests screening for dominant KCNJ6 mutations in the evaluation of patients with severe movement disorders, which could provide evidence to support a causal role of KCNJ6 in neurological channelopathies. Copyright © 2018. Published by Elsevier Ltd.

  4. HUWE1 mutation explains phenotypic severity in a case of familial idiopathic intellectual disability

    OpenAIRE

    Isrie, M.; Kalscheuer, V.; Holvoet, M.; Fieremans, N.; Van Esch, H.; Devriendt, K.

    2013-01-01

    The advent of next-generation sequencing has proven to be a key force in the identification of new genes associated with intellectual disability. In this study, high-throughput sequencing of the coding regions of the X-chromosome led to the identification of a missense variant in the HUWE1 gene. The same variant has been reported before by Froyen et al. (2008). We compare the phenotypes and demonstrate that, in the present family, the HUWE1 mutation segregates with the more severe ID phenotyp...

  5. Acute Kidney Injury: Definition, Pathophysiology and Clinical Phenotypes.

    Science.gov (United States)

    Makris, Konstantinos; Spanou, Loukia

    2016-05-01

    Acute kidney injury (AKI) is a clinical syndrome that complicates the course and worsens the outcome in a significant number of hospitalised patients. Recent advances in clinical and basic research will help with a more accurate definition of this syndrome and in the elucidation of its pathogenesis. With this knowledge we will be able to conduct more accurate epidemiologic studies in an effort to gain a better understanding of the impact of this syndrome. AKI is a syndrome that rarely has a sole and distinct pathophysiology. Recent evidence, in both basic science and clinical research, is beginning to change our view for AKI from a single organ failure syndrome to a syndrome where the kidney plays an active role in the progress of multi-organ dysfunction. Accurate and prompt recognition of AKI and better understanding of the pathophysiologic mechanisms underlying the various clinical phenotypes are of great importance to research for effective therapeutic interventions. In this review we provide the most recent updates in the definition, epidemiology and pathophysiology of AKI.

  6. Severe hypertriglyceridemia. Clinical characteristics and therapeutic management.

    Science.gov (United States)

    Masson, Walter; Rossi, Emiliano; Siniawski, Daniel; Damonte, Juan; Halsband, Ana; Barolo, Ramiro; Scaramal, Miguel

    2018-05-19

    The therapeutic management of severe hypertriglyceridaemia represents a clinical challenge. The objectives of this study were 1) to identify the clinical characteristics of patients with severe hypertriglyceridaemia, and 2) to analyse the treatment established by the physicians in each case. A cross-sectional study was carried out using the computerised medical records of all patients>18 years of age with a blood triglyceride level≥1,000mg/dL between 1 January 2011 and 31 December 2016. Clinical and laboratory variables were collected. The behaviour of the physicians in the 6 months after the lipid finding was analysed. A total of 420 patients were included (mean age 49.1±11.4 years, males 78.8%). The median of triglycerides was 1,329mg/dL (interquartile range 1,174-1,658). No secondary causes were found in 34.1% of the patients. The most frequent secondary causes were obesity (38.6%) and diabetes (28.1%). Physical activity was recommended and a nutritionist was referred to in 49.1% and 44.2% of the patients, respectively. Secondary causes were identified and attempts were made to correct them in 40.7% of cases. The most indicated pharmacological treatments were fenofibrate 200mg/day (26.5%) and gemfibrozil 900mg/day (19.3%). Few patients received the indication of omega 3 fatty acids or niacin. This study showed, for the first time in our country, the characteristics of a population with severe hypertriglyceridaemia. The therapeutic measures instituted by the physicians were insufficient. Knowing the characteristics in this particular clinical scenario could improve the current approach of these patients. Copyright © 2018 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.

  7. Deletion of Dystrophin In-Frame Exon 5 Leads to a Severe Phenotype: Guidance for Exon Skipping Strategies.

    Directory of Open Access Journals (Sweden)

    Zhi Yon Charles Toh

    Full Text Available Duchenne and Becker muscular dystrophy severity depends upon the nature and location of the DMD gene lesion and generally correlates with the dystrophin open reading frame. However, there are striking exceptions where an in-frame genomic deletion leads to severe pathology or protein-truncating mutations (nonsense or frame-shifting indels manifest as mild disease. Exceptions to the dystrophin reading frame rule are usually resolved after molecular diagnosis on muscle RNA. We report a moderate/severe Becker muscular dystrophy patient with an in-frame genomic deletion of DMD exon 5. This mutation has been reported by others as resulting in Duchenne or Intermediate muscular dystrophy, and the loss of this in-frame exon in one patient led to multiple splicing events, including omission of exon 6, that disrupts the open reading frame and is consistent with a severe phenotype. The patient described has a deletion of dystrophin exon 5 that does not compromise recognition of exon 6, and although the deletion does not disrupt the reading frame, his clinical presentation is more severe than would be expected for classical Becker muscular dystrophy. We suggest that the dystrophin isoform lacking the actin-binding sequence encoded by exon 5 is compromised, reflected by the phenotype resulting from induction of this dystrophin isoform in mouse muscle in vivo. Hence, exon skipping to address DMD-causing mutations within DMD exon 5 may not yield an isoform that confers marked clinical benefit. Additional studies will be required to determine whether multi-exon skipping strategies could yield more functional dystrophin isoforms, since some BMD patients with larger in-frame deletions in this region have been reported with mild phenotypes.

  8. Mutations in RIT1 cause Noonan syndrome - additional functional evidence and expanding the clinical phenotype.

    Science.gov (United States)

    Koenighofer, M; Hung, C Y; McCauley, J L; Dallman, J; Back, E J; Mihalek, I; Gripp, K W; Sol-Church, K; Rusconi, P; Zhang, Z; Shi, G-X; Andres, D A; Bodamer, O A

    2016-03-01

    RASopathies are a clinically heterogeneous group of conditions caused by mutations in 1 of 16 proteins in the RAS-mitogen activated protein kinase (RAS-MAPK) pathway. Recently, mutations in RIT1 were identified as a novel cause for Noonan syndrome. Here we provide additional functional evidence for a causal role of RIT1 mutations and expand the associated phenotypic spectrum. We identified two de novo missense variants p.Met90Ile and p.Ala57Gly. Both variants resulted in increased MEK-ERK signaling compared to wild-type, underscoring gain-of-function as the primary functional mechanism. Introduction of p.Met90Ile and p.Ala57Gly into zebrafish embryos reproduced not only aspects of the human phenotype but also revealed abnormalities of eye development, emphasizing the importance of RIT1 for spatial and temporal organization of the growing organism. In addition, we observed severe lymphedema of the lower extremity and genitalia in one patient. We provide additional evidence for a causal relationship between pathogenic mutations in RIT1, increased RAS-MAPK/MEK-ERK signaling and the clinical phenotype. The mutant RIT1 protein may possess reduced GTPase activity or a diminished ability to interact with cellular GTPase activating proteins; however the precise mechanism remains unknown. The phenotypic spectrum is likely to expand and includes lymphedema of the lower extremities in addition to nuchal hygroma. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype.

    Science.gov (United States)

    Kölker, Stefan; Valayannopoulos, Vassili; Burlina, Alberto B; Sykut-Cegielska, Jolanta; Wijburg, Frits A; Teles, Elisa Leão; Zeman, Jiri; Dionisi-Vici, Carlo; Barić, Ivo; Karall, Daniela; Arnoux, Jean-Baptiste; Avram, Paula; Baumgartner, Matthias R; Blasco-Alonso, Javier; Boy, S P Nikolas; Rasmussen, Marlene Bøgehus; Burgard, Peter; Chabrol, Brigitte; Chakrapani, Anupam; Chapman, Kimberly; Cortès I Saladelafont, Elisenda; Couce, Maria L; de Meirleir, Linda; Dobbelaere, Dries; Furlan, Francesca; Gleich, Florian; González, Maria Julieta; Gradowska, Wanda; Grünewald, Stephanie; Honzik, Tomas; Hörster, Friederike; Ioannou, Hariklea; Jalan, Anil; Häberle, Johannes; Haege, Gisela; Langereis, Eveline; de Lonlay, Pascale; Martinelli, Diego; Matsumoto, Shirou; Mühlhausen, Chris; Murphy, Elaine; de Baulny, Hélène Ogier; Ortez, Carlos; Pedrón, Consuelo C; Pintos-Morell, Guillem; Pena-Quintana, Luis; Ramadža, Danijela Petković; Rodrigues, Esmeralda; Scholl-Bürgi, Sabine; Sokal, Etienne; Summar, Marshall L; Thompson, Nicholas; Vara, Roshni; Pinera, Inmaculada Vives; Walter, John H; Williams, Monique; Lund, Allan M; Garcia-Cazorla, Angeles; Garcia Cazorla, Angeles

    2015-11-01

    The disease course and long-term outcome of patients with organic acidurias (OAD) and urea cycle disorders (UCD) are incompletely understood. To evaluate the complex clinical phenotype of OAD and UCD patients at different ages. Acquired microcephaly and movement disorders were common in OAD and UCD highlighting that the brain is the major organ involved in these diseases. Cardiomyopathy [methylmalonic (MMA) and propionic aciduria (PA)], prolonged QTc interval (PA), optic nerve atrophy [MMA, isovaleric aciduria (IVA)], pancytopenia (PA), and macrocephaly [glutaric aciduria type 1 (GA1)] were exclusively found in OAD patients, whereas hepatic involvement was more frequent in UCD patients, in particular in argininosuccinate lyase (ASL) deficiency. Chronic renal failure was often found in MMA, with highest frequency in mut(0) patients. Unexpectedly, chronic renal failure was also observed in adolescent and adult patients with GA1 and ASL deficiency. It had a similar frequency in patients with or without a movement disorder suggesting different pathophysiology. Thirteen patients (classic OAD: 3, UCD: 10) died during the study interval, ten of them during the initial metabolic crisis in the newborn period. Male patients with late-onset ornithine transcarbamylase deficiency were presumably overrepresented in the study population. Neurologic impairment is common in OAD and UCD, whereas the involvement of other organs (heart, liver, kidneys, eyes) follows a disease-specific pattern. The identification of unexpected chronic renal failure in GA1 and ASL deficiency emphasizes the importance of a systematic follow-up in patients with rare diseases.

  10. Pseudoexon activation increases phenotype severity in a Becker muscular dystrophy patient.

    Science.gov (United States)

    Greer, Kane; Mizzi, Kayla; Rice, Emily; Kuster, Lukas; Barrero, Roberto A; Bellgard, Matthew I; Lynch, Bryan J; Foley, Aileen Reghan; O Rathallaigh, Eoin; Wilton, Steve D; Fletcher, Sue

    2015-07-01

    We report a dystrophinopathy patient with an in-frame deletion of DMD exons 45-47, and therefore a genetic diagnosis of Becker muscular dystrophy, who presented with a more severe than expected phenotype. Analysis of the patient DMD mRNA revealed an 82 bp pseudoexon, derived from intron 44, that disrupts the reading frame and is expected to yield a nonfunctional dystrophin. Since the sequence of the pseudoexon and canonical splice sites does not differ from the reference sequence, we concluded that the genomic rearrangement promoted recognition of the pseudoexon, causing a severe dystrophic phenotype. We characterized the deletion breakpoints and identified motifs that might influence selection of the pseudoexon. We concluded that the donor splice site was strengthened by juxtaposition of intron 47, and loss of intron 44 silencer elements, normally located downstream of the pseudoexon donor splice site, further enhanced pseudoexon selection and inclusion in the DMD transcript in this patient.

  11. Phenotype of CNTNAP1: a study of patients demonstrating a specific severe congenital hypomyelinating neuropathy with survival beyond infancy.

    Science.gov (United States)

    Low, K J; Stals, K; Caswell, R; Wakeling, M; Clayton-Smith, J; Donaldson, A; Foulds, N; Norman, A; Splitt, M; Urankar, K; Vijayakumar, K; Majumdar, A; Study, Ddd; Ellard, S; Smithson, S F

    2018-06-01

    CHN is genetically heterogeneous and its genetic basis is difficult to determine on features alone. CNTNAP1 encodes CASPR, integral in the paranodal junction high molecular mass complex. Nineteen individuals with biallelic variants have been described in association with severe congenital hypomyelinating neuropathy, respiratory compromise, profound intellectual disability and death within the first year. We report 7 additional patients ascertained through exome sequencing. We identified 9 novel CNTNAP1 variants in 6 families: three missense variants, four nonsense variants, one frameshift variant and one splice site variant. Significant polyhydramnios occurred in 6/7 pregnancies. Severe respiratory compromise was seen in 6/7 (tracheostomy in 5). A complex neurological phenotype was seen in all patients who had marked brain hypomyelination/demyelination and profound developmental delay. Additional neurological findings included cranial nerve compromise: orobulbar dysfunction in 5/7, facial nerve weakness in 4/7 and vocal cord paresis in 5/7. Dystonia occurred in 2/7 patients and limb contractures in 5/7. All had severe gastroesophageal reflux, and a gastrostomy was required in 5/7. In contrast to most previous reports, only one patient died in the first year of life. Protein modelling was performed for all detected CNTNAP1 variants. We propose a genotype-phenotype correlation, whereby hypomorphic missense variants partially ameliorate the phenotype, prolonging survival. This study suggests that biallelic variants in CNTNAP1 cause a distinct recognisable syndrome, which is not caused by other genes associated with CHN. Neonates presenting with this phenotype will benefit from early genetic definition to inform clinical management and enable essential genetic counselling for their families.

  12. Xq28 duplications including MECP2 in five females: Expanding the phenotype to severe mental retardation.

    Science.gov (United States)

    Bijlsma, E K; Collins, A; Papa, F T; Tejada, M I; Wheeler, P; Peeters, E A J; Gijsbers, A C J; van de Kamp, J M; Kriek, M; Losekoot, M; Broekma, A J; Crolla, J A; Pollazzon, M; Mucciolo, M; Katzaki, E; Disciglio, V; Ferreri, M I; Marozza, A; Mencarelli, M A; Castagnini, C; Dosa, L; Ariani, F; Mari, F; Canitano, R; Hayek, G; Botella, M P; Gener, B; Mínguez, M; Renieri, A; Ruivenkamp, C A L

    2012-06-01

    Duplications leading to functional disomy of chromosome Xq28, including MECP2 as the critical dosage-sensitive gene, are associated with a distinct clinical phenotype in males, characterized by severe mental retardation, infantile hypotonia, progressive neurologic impairment, recurrent infections, bladder dysfunction, and absent speech. Female patients with Xq duplications including MECP2 are rare. Only recently submicroscopic duplications of this region on Xq28 have been recognized in four females, and a triplication in a fifth, all in combination with random X-chromosome inactivation (XCI). Based on this small series, it was concluded that in females with MECP2 duplication and random XCI, the typical symptoms of affected boys are not present. We present clinical and molecular data on a series of five females with an Xq28 duplication including the MECP2 gene, both isolated and as the result of a translocation, and compare them with the previously reported cases of small duplications in females. The collected data indicate that the associated phenotype in females is distinct from males with similar duplications, but the clinical effects may be as severe as seen in males. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  13. Determinants of gingival overgrowth severity in organ transplant patients. An examination of the rôle of HLA phenotype.

    Science.gov (United States)

    Thomason, J M; Seymour, R A; Ellis, J S; Kelly, P J; Parry, G; Dark, J; Wilkinson, R; Ilde, J R

    1996-07-01

    The role of HLA phenotype as a risk factor for drug-induced gingival overgrowth was investigated in a cohort of 172 transplant recipients. Clinically significant overgrowth warranting surgical correction was observed in 72 patients (42%). Using stepwise regression modelling, 6 clinical parameters were identified as significant risk factors for the severity of gingival overgrowth. These were; age, sex, creatinine plasma level, duration of therapy, papilla bleeding index and concomitant medication with a calcium channel blocking drug. 3 HLA alleles were also identified as risk factors when adjusted for other clinically significant risk factors (HLA -DR2, A24, B37). However, when the p-values for the HLA variables were corrected to compensate for the use of multiple significance testing, only HLA-B37 remained statistically significant at the 5% level. Organ transplant patients are at risk of developing gingival overgrowth, with approximately 25% medicated with cyclosporin alone requiring corrective gingival surgery. This figure more than doubles in patients concomitantly medicated with a calcium blocking drug. The data at present available would suggest that the severity of gingival overgrowth is also significantly associated with the HLA-B37 phenotype.

  14. Phenotypic Characteristics Associated with Virulence of Clinical Isolates from the Sporothrix Complex

    Science.gov (United States)

    Almeida-Paes, Rodrigo; de Oliveira, Luã Cardoso; Oliveira, Manoel Marques Evangelista; Gutierrez-Galhardo, Maria Clara; Nosanchuk, Joshua Daniel; Zancopé-Oliveira, Rosely Maria

    2015-01-01

    The Sporothrix complex members cause sporotrichosis, a subcutaneous mycosis with a wide spectrum of clinical manifestations. Several specific phenotypic characteristics are associated with virulence in many fungi, but studies in this field involving the Sporothrix complex species are scarce. Melanization, thermotolerance, and production of proteases, catalase, and urease were investigated in 61 S. brasiliensis, one S. globosa, and 10 S. schenckii strains. The S. brasiliensis strains showed a higher expression of melanin and urease compared with S. schenckii. These two species, however, presented similar thermotolerances. Our S. globosa strain had low expression of all studied virulence factors. The relationship between these phenotypes and clinical aspects of sporotrichosis was also evaluated. Strains isolated from patients with spontaneous regression of infection were heavily melanized and produced high urease levels. Melanin was also related to dissemination of internal organs and protease production was associated with HIV-coinfection. A murine sporotrichosis model showed that a S. brasiliensis strain with high expression of virulence factors was able to disseminate and yield a high fungal burden in comparison with a control S. schenckii strain. Our results show that virulence-related phenotypes are variably expressed within the Sporothrix complex species and might be involved in clinical aspects of sporotrichosis. PMID:25961005

  15. Broad phenotypic spectrum in familial adenomatous polyposis; from early onset and severe phenotypes to late onset of attenuated polyposis with the first manifestation at age 72

    Directory of Open Access Journals (Sweden)

    Johannsson Oskar

    2008-11-01

    Full Text Available Abstract Background Familial adenomatous polyposis (FAP is typically characterized by multiple colonic polyps and frequent extracolonic features. Whereas the number of colonic polyps has been linked to the APC gene mutation, possible genotype-phenotype correlations largely remain to be defined for the extracolonic manifestations. Methods Full genomic sequencing combined with multiplex ligation-dependent probe amplification was used to identify APC gene mutations, which were correlated to the clinical presentations. Results 10 novel APC gene mutations were identified in 11 families. A broad spectrum of extracolonic manifestations was identified in most of these individuals. Two sisters with an insertion in codon 528 (c.1582_1583insGC both showed severe phenotypes with classical polyposis, upper gastrointestinal polyps and thyroid cancer. A woman with a 3'APC mutation (c.5030_5031insAA developed colon cancer at age 72 as the first manifestation of attenuated FAP. Conclusion With an increasing number of FAP families diagnosed, a broad and variable tumor spectrum and a high frequency of extracolonic manifestations are gradually recognized. We report novel APC mutations and present two FAP cases that suggest familial aggregation of thyroid cancer and demonstrate the need to consider attenuated FAP also among elderly patients with colon cancer.

  16. X-Linked Dystonia Parkinsonism: Clinical Phenotype, Genetics and Therapeutics

    Directory of Open Access Journals (Sweden)

    Raymond L. Rosales

    2010-10-01

    Full Text Available The clinical phenotype of X-Linked Dystonia Parkinsonism (XDP is typically one that involves a Filipino adult male whose ancestry is mostly traced in the Philippine island of Panay. Dystonia usually starts focally in the lower limbs or oromandibular regions, then spreads to become generalized eventually. Parkinsonism sets in later into the disease and usually in combination with dystonia. /DYT3/ and /TAF1/ are the two genes associated with XDP. An SVA retrotransposon insertion in an intron of /TAF1/ may reduce neuron-specific expression of the /TAF1/ isoform in the caudate nucleus, and subsequently interfere with the transcription of many neuronal genes. Polypharmacy with oral benzodiazepines, anticholinergic agents and muscle relaxants leaves much to be desired in terms of efficacy. The medications to date that may appear beneficial, especially in disabling dystonias, are zolpidem, muscle afferent block with lidocaine-ethanol and botulinum toxin type A. Despite the few cases undergoing deep brain stimulation, this functional surgery has shown the greatest promise in XDP. An illustrative case of XDP in a family depicts the variable course of illness, including a bout of “status dystonicus,” challenges in therapy, reckoning with the social impact of the disease, and eventual patient demise. Indeed, there remains some gaps in understanding some phenomenological, genetic and treatment aspects of XDP, the areas upon which future research directions may be worthwhile.

  17. Effect of the callipyge phenotype and cooking method on tenderness of several major lamb muscles.

    Science.gov (United States)

    Shackelford, S D; Wheeler, T L; Koohmaraie, M

    1997-08-01

    We conducted three experiments to determine the effects of the callipyge phenotype on the tenderness of several major lamb muscles and to determine the effect of method of cookery on the tenderness of callipyge lamb at 7 d postmortem. In Exp. 1, chops from normal (n = 23) and callipyge (n = 16) carcasses were open-hearth-broiled. Warner-Bratzler shear force values of longissimus, gluteus medius, semimembranosus, biceps femoris, semitendinosus, adductor, and quadriceps femoris were 123, 44, 28, 26, 19, 16, and 13% greater, respectively, for callipyge (P lamb carcasses (n = 60). Callipyge chops were less tender than normal chops (P cooking method, callipyge samples were less juicy than normal samples (P < .05). These data demonstrate that the callipyge phenotype will likely reduce consumer satisfaction due to reduced tenderness and juiciness; however, reduced tenderness in callipyge leg muscles could be prevented by ovenroasting.

  18. Expanded clinical phenotype of women with the FMR1 premutation.

    Science.gov (United States)

    Coffey, Sarah M; Cook, Kylee; Tartaglia, Nicole; Tassone, Flora; Nguyen, Danh V; Pan, Ruiqin; Bronsky, Hannah E; Yuhas, Jennifer; Borodyanskaya, Mariya; Grigsby, Jim; Doerflinger, Melanie; Hagerman, Paul J; Hagerman, Randi J

    2008-04-15

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is generally considered to be uncommon in older female carriers of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene; however, neither prevalence, nor the nature of the clinical phenotype, has been well characterized in female carriers. In this study, we evaluated 146 female carriers (mean, 42.3 years; range, 20-75 years) with and without core features of FXTAS (tremor; gait ataxia), and 69 age-matched controls (mean, 45.8 years; range, 21-78 years). Compared with controls, carriers with definite or probable FXTAS had greater medical co-morbidity, with increased prevalence of thyroid disease (P = 0.0096), hypertension (P = 0.0020), seizures (P = 0.0077), peripheral neuropathy (P = 0.0040), and fibromyalgia (P = 0.0097), in addition to the typical symptoms of FXTAS-tremor (P < 0.0001) and ataxia (P < 0.0001). The non-FXTAS premutation group had more complaints of chronic muscle pain (P = 0.0097), persistent paraesthesias in extremities (P < 0.0001), and history of tremor (P < 0.0123) than controls. The spectrum of clinical involvement in female carriers with FXTAS is quite broad, encompassing a number of medical co-morbidities as well as the core movement disorder. The remarkable degree of thyroid dysfunction (17% in the non-FXTAS group and 50% in the FXTAS group) warrants consideration of thyroid function studies in all female premutation carriers, particularly those with core features of FXTAS. Copyright 2008 Wiley-Liss, Inc.

  19. Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype.

    Science.gov (United States)

    Hsieh, Matthew M; Fitzhugh, Courtney D; Weitzel, R Patrick; Link, Mary E; Coles, Wynona A; Zhao, Xiongce; Rodgers, Griffin P; Powell, Jonathan D; Tisdale, John F

    2014-07-02

    Myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) is curative for children with severe sickle cell disease, but toxicity may be prohibitive for adults. Nonmyeloablative transplantation has been attempted with degrees of preparative regimen intensity, but graft rejection and graft-vs-host disease remain significant. To determine the efficacy, safety, and outcome on end-organ function with this low-intensity regimen for sickle cell phenotype with or without thalassemia. From July 16, 2004, to October 25, 2013, 30 patients aged 16-65 years with severe disease enrolled in this nonmyeloablative transplant study, consisting of alemtuzumab (1 mg/kg in divided doses), total-body irradiation (300 cGy), sirolimus, and infusion of unmanipulated filgrastim mobilized peripheral blood stem cells (5.5-31.7 × 10(6) cells/kg) from human leukocyte antigen-matched siblings. The primary end point was treatment success at 1 year after the transplant, defined as a full donor-type hemoglobin for patients with sickle cell disease and transfusion independence for patients with thalassemia. The secondary end points were the level of donor leukocyte chimerism; incidence of acute and chronic graft-vs-host disease; and sickle cell-thalassemia disease-free survival, immunologic recovery, and changes in organ function, assessed by annual brain imaging, pulmonary function, echocardiographic image, and laboratory testing. Twenty-nine patients survived a median 3.4 years (range, 1-8.6), with no nonrelapse mortality. One patient died from intracranial bleeding after relapse. As of October 25, 2013, 26 patients (87%) had long-term stable donor engraftment without acute or chronic graft-vs-host disease. The mean donor T-cell level was 48% (95% CI, 34%-62%); the myeloid chimerism levels, 86% (95% CI, 70%-100%). Fifteen engrafted patients discontinued immunosuppression medication with continued stable donor chimerism and no graft-vs-host disease. The normalized hemoglobin and

  20. Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848

    NARCIS (Netherlands)

    Koczkowska, M. (Magdalena); Chen, Y. (Yunjia); Callens, T. (Tom); Gomes, A. (Alicia); Sharp, A. (Angela); Johnson, S. (Sherrell); Hsiao, M.-C. (Meng-Chang); Chen, Z. (Zhenbin); Balasubramanian, M. (Meena); Barnett, C.P. (Christopher P.); Becker, T.A. (Troy A.); Ben-Shachar, S. (Shay); D.R. Bertola (Débora Romeo); J.O. Blakeley (Jaishri O.); Burkitt-Wright, E.M.M. (Emma M.M.); Callaway, A. (Alison); Crenshaw, M. (Melissa); Cunha, K.S. (Karin S.); Cunningham, M. (Mitch); M.D. D'Agostino (Maria Daniela); K. Dahan (Karin); De Luca, A. (Alessandro); A. Destrée (Anne); Dhamija, R. (Radhika); Eoli, M. (Marica); Evans, D.G.R. (D. Gareth R.); Galvin-Parton, P. (Patricia); George-Abraham, J.K. (Jaya K.); K.W. Gripp (Karen); Guevara-Campos, J. (Jose); Hanchard, N.A. (Neil A.); Hernández-Chico, C. (Concepcion); Immken, L. (LaDonna); S. Janssens (Sandra); K.J. Jones (Kristi); Keena, B.A. (Beth A.); Kochhar, A. (Aaina); Liebelt, J. (Jan); Martir-Negron, A. (Arelis); Mahoney, M.J. (Maurice J.); I. Maystadt (Isabelle); McDougall, C. (Carey); M. McEntagart (Meriel); N.J. Mendelsohn; Miller, D.T. (David T.); G. Mortier (Geert); J. Morton (Jenny); Pappas, J. (John); S.R. Plotkin (Scott R.); Pond, D. (Dinel); Rosenbaum, K. (Kenneth); Rubin, K. (Karol); Russell, L. (Laura); Rutledge, L.S. (Lane S.); Saletti, V. (Veronica); Schonberg, R. (Rhonda); Schreiber, A. (Allison); Seidel, M. (Meredith); Siqveland, E. (Elizabeth); D.W. Stockton (David); Trevisson, E. (Eva); N.J. Ullrich (Nicole J.); M. Upadhyaya (Meena); A.S. Thornton (Andrew); H. Verhelst (H.); M.R. Wallace (Margaret); Yap, Y.-S. (Yoon-Sim); Zackai, E. (Elaine); Zonana, J. (Jonathan); Zurcher, V. (Vickie); K. Claes (Kathleen); Martin, Y. (Yolanda); B. Korf (Bruce); E. Legius (Eric); L.M. Messiaen (Ludwine)

    2018-01-01

    textabstractNeurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000–3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations

  1. Clinical phenotypes and the biological parameters of Congolese patients suffering from sickle cell anemia: A first report from Central Africa.

    Science.gov (United States)

    Mikobi, Tite M; Lukusa Tshilobo, Prosper; Aloni, Michel N; Akilimali, Pierre Z; Mvumbi-Lelo, Georges; Mbuyi-Muamba, Jean Marie

    2017-11-01

    The influence of phenotype on the clinical course and laboratory features of sickle cell anemia (SCA) is rarely described in sub-Saharan Africa. A cross-sectional study was conducted in Kinshasa. A clinical phenotype score was built up. The following definitions were applied: asymptomatic clinical phenotype (ACP; score≤5), moderate clinical phenotype (MCP; score between 6 and 15), and severe clinical phenotype (SCP; score≥16). ANOVA test were used to compare differences among categorical variables. We have studied 140 patients. The mean body mass index (BMI) value of three groups was lower (Sickle cell patients with ACP have a high mean steady-state hemoglobin concentration compared to those with MCP and SCP (Psickle cell anemia clinical and biological variability in our midst. © 2017 Wiley Periodicals, Inc.

  2. HNF1B-associated clinical phenotypes: the kidney and beyond.

    Science.gov (United States)

    Bockenhauer, Detlef; Jaureguiberry, Graciana

    2016-05-01

    Mutations in HNF1B, the gene encoding hepatocyte nuclear factor 1β are the most commonly identified genetic cause of renal malformations. HNF1B was first identified as a disease gene for diabetes (MODY5) in 1997, and its involvement in renal disease was subsequently noted through clinical observations in pedigrees affected by MODY5. Since then, a whole spectrum of associated phenotypes have been reported, including genital malformations, autism, epilepsy, gout, hypomagnesaemia, primary hyperparathyroidism, liver and intestinal abnormalities and a rare form of kidney cancer. The most commonly identified mutation, in approximately 50 % of patients, is an entire gene deletion occurring in the context of a 17q12 chromosomal microdeletion that also includes several other genes. Some of the associated phenotypes, especially the neurologic ones, appear to occur only in the context of this microdeletion and thus may not be directly linked to HNF1B. Here we review the spectrum of associated phenotypes and discuss potential implications for clinical management.

  3. Tetralogy of Fallot and Hypoplastic Left Heart Syndrome – Complex Clinical Phenotypes Meet Complex Genetic Networks

    Science.gov (United States)

    Lahm, Harald; Schön, Patric; Doppler, Stefanie; Dreßen, Martina; Cleuziou, Julie; Deutsch, Marcus-André; Ewert, Peter; Lange, Rüdiger; Krane, Markus

    2015-01-01

    In many cases congenital heart disease (CHD) is represented by a complex phenotype and an array of several functional and morphological cardiac disorders. These malformations will be briefly summarized in the first part focusing on two severe CHD phenotypes, hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot (TOF). In most cases of CHD the genetic origin remains largely unknown, though the complexity of the clinical picture strongly argues against a dysregulation which can be attributed to a single candidate gene but rather suggests a multifaceted polygenetic origin with elaborate interactions. Consistent with this idea, genome-wide approaches using whole exome sequencing, comparative sequence analysis of multiplex families to identify de novo mutations and global technologies to identify single nucleotide polymorphisms, copy number variants, dysregulation of the transcriptome and epigenetic variations have been conducted to obtain information about genetic alterations and potential predispositions possibly linked to the occurrence of a CHD phenotype. In the second part of this review we will summarize and discuss the available literature on identified genetic alterations linked to TOF and HLHS. PMID:26069455

  4. The distribution of clinical phenotypes of preterm birth syndrome: implications for prevention.

    Science.gov (United States)

    Barros, Fernando C; Papageorghiou, Aris T; Victora, Cesar G; Noble, Julia A; Pang, Ruyan; Iams, Jay; Cheikh Ismail, Leila; Goldenberg, Robert L; Lambert, Ann; Kramer, Michael S; Carvalho, Maria; Conde-Agudelo, Agustin; Jaffer, Yasmin A; Bertino, Enrico; Gravett, Michael G; Altman, Doug G; Ohuma, Eric O; Purwar, Manorama; Frederick, Ihunnaya O; Bhutta, Zulfiqar A; Kennedy, Stephen H; Villar, José

    2015-03-01

    Preterm birth has been difficult to study and prevent because of its complex syndromic nature. To identify phenotypes of preterm delivery syndrome in the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project. A population-based, multiethnic, cross-sectional study conducted at 8 geographically demarcated sites in Brazil, China, India, Italy, Kenya, Oman, the United Kingdom, and the United States. A total of 60,058 births over a 12-month fixed period between April 27, 2009, and March 2, 2014. Of these, 53,871 had an ultrasonography estimate of gestational age, among which 5828 were preterm births (10.8%). Pregnancies were prospectively studied using a standardized data collection and online data management system. Newborns had anthropometric and clinical examinations using standardized methods and identical equipment and were followed up until hospital discharge. The main study outcomes were clusters of preterm phenotypes and for each cluster, we analyzed signs of presentation at hospital admission, admission rates for neonatal intensive care for 7 days or more, and neonatal mortality rates. Twelve preterm birth clusters were identified using our conceptual framework. Eleven consisted of combinations of conditions known to be associated with preterm birth, 10 of which were dominated by a single condition. However, the most common single cluster (30.0% of the total preterm cases; n = 1747) was not associated with any severe maternal, fetal, or placental condition that was clinically detectable based on the information available; within this cluster, many cases were caregiver initiated. Only 22% (n = 1284) of all the preterm births occurred spontaneously without any of these severe conditions. Maternal presentation on hospital admission, newborn anthropometry, and risk for death before hospital discharge or admission for 7 or more days to a neonatal intensive care unit, none of which were used to construct the clusters, also differed according to the identified

  5. Phenotype/genotype correlations in Gaucher disease type 1: Clinical and therapeutic implications

    Energy Technology Data Exchange (ETDEWEB)

    Sibille, A.; Eng, C.M.; Kim, S.J.; Pastores, G. (Mount Sinai School of Medicine, New York, NY (United States)); Grabowski, G.A. (Mount Sinai School of Medicine, New York, NY (United States) Univ. of Cincinnati, OH (United States))

    1993-06-01

    Gaucher disease is the most frequent lysosomal storage disease and the most prevalent genetic disease among Ashkenazi Jews. Gaucher disease type 1 is characterized by marked variability of the phenotype and by the absence of neuronopathic involvement. To test the hypothesis that this phenotypic variability was due to genetic compounds of several different mutant alleles, 161 symptomatic patients with Gaucher disease type 1 (> 90% Ashkenazi Jewish) were analyzed for clinical involvement, and their genotypes were determined. Qualitative and quantitative measures of disease involvement included age at onset of the disease manifestations, hepatic and splenic volumes, age at splenectomy, and severity of bony disease. High statistically significant differences (P < .005) were found in each clinical parameter in patients with the N370S/N370S genotype compared with those patients with the N370S/84GG, N370S/L444P, and N370/ genotypes. The symptomatic N370S homozygotes had onset of their disease two to three decades later than patients with the other genotypes. In addition, patients with the latter genotypes have much more severely involved livers, spleens, and bones and had a higher incidence of splenectomy at an earlier age. These predictive genotype analyses provide the basis for genetic care delivery and therapeutic recommendations in patients affected with Gaucher disease type 1. 38 refs., 1 fig., 4 tabs.

  6. Insomnia with Objective Short Sleep Duration: the Most Biologically Severe Phenotype of the Disorder

    Science.gov (United States)

    Vgontzas, Alexandros N.; Fernandez-Mendoza, Julio; Liao, Duanping; Bixler, Edward O.

    2013-01-01

    Summary Until recently, the association of chronic insomnia with significant medical morbidity was not established and its diagnosis was based solely on subjective complaints. We present evidence that insomnia with objective short sleep duration is the most biologically severe phenotype of the disorder, as it is associated with cognitive-emotional and cortical arousal, activation of both limbs of the stress system, and a higher risk for hypertension, impaired heart rate variability, diabetes, neurocognitive impairment, and mortality. Also, it appears that objective short sleep duration is a biological marker of genetic predisposition to chronic insomnia. In contrast, insomnia with objective normal sleep duration is associated with cognitive-emotional and cortical arousal and sleep misperception but not with signs of activation of both limbs of the stress system or medical complications. Furthermore, the first phenotype is associated with unremitting course, whereas the latter is more likely to remit. We propose that short sleep duration in insomnia is a reliable marker of the biological severity and medical impact of the disorder. Objective measures of sleep obtained in the home environment of the patient would become part of the routine assessment of insomnia patients in a clinician’s office setting. We speculate that insomnia with objective short sleep duration has primarily biological roots and may respond better to biological treatments, whereas insomnia with objective normal sleep duration has primarily psychological roots and may respond better to psychological interventions alone. PMID:23419741

  7. Insomnia with objective short sleep duration: the most biologically severe phenotype of the disorder.

    Science.gov (United States)

    Vgontzas, Alexandros N; Fernandez-Mendoza, Julio; Liao, Duanping; Bixler, Edward O

    2013-08-01

    Until recently, the association of chronic insomnia with significant medical morbidity was not established and its diagnosis was based solely on subjective complaints. We present evidence that insomnia with objective short sleep duration is the most biologically severe phenotype of the disorder, as it is associated with cognitive-emotional and cortical arousal, activation of both limbs of the stress system, and a higher risk for hypertension, impaired heart rate variability, diabetes, neurocognitive impairment, and mortality. Also, it appears that objective short sleep duration is a biological marker of genetic predisposition to chronic insomnia. In contrast, insomnia with objective normal sleep duration is associated with cognitive-emotional and cortical arousal and sleep misperception but not with signs of activation of both limbs of the stress system or medical complications. Furthermore, the first phenotype is associated with unremitting course, whereas the latter is more likely to remit. We propose that short sleep duration in insomnia is a reliable marker of the biological severity and medical impact of the disorder. Objective measures of sleep obtained in the home environment of the patient would become part of the routine assessment of insomnia patients in a clinician's office setting. We speculate that insomnia with objective short sleep duration has primarily biological roots and may respond better to biological treatments, whereas insomnia with objective normal sleep duration has primarily psychological roots and may respond better to psychological interventions alone. Copyright © 2012 Elsevier Ltd. All rights reserved.

  8. Mutations at the flavin binding site of ETF:QO yield a MADD-like severe phenotype in Drosophila.

    Science.gov (United States)

    Alves, Ema; Henriques, Bárbara J; Rodrigues, João V; Prudêncio, Pedro; Rocha, Hugo; Vilarinho, Laura; Martinho, Rui G; Gomes, Cláudio M

    2012-08-01

    Following a screening on EMS-induced Drosophila mutants defective for formation and morphogenesis of epithelial cells, we have identified three lethal mutants defective for the production of embryonic cuticle. The mutants are allelic to the CG12140 gene, the fly homologue of electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO). In humans, inherited defects in this inner membrane protein account for multiple acyl-CoA dehydrogenase deficiency (MADD), a metabolic disease of β-oxidation, with a broad range of clinical phenotypes, varying from embryonic lethal to mild forms. The three mutant alleles carried distinct missense mutations in ETF:QO (G65E, A68V and S104F) and maternal mutant embryos for ETF:QO showed lethal morphogenetic defects and a significant induction of apoptosis following germ-band elongation. This phenotype is accompanied by an embryonic accumulation of short- and medium-chain acylcarnitines (C4, C8 and C12) as well as long-chain acylcarnitines (C14 and C16:1), whose elevation is also found in severe MADD forms in humans under intense metabolic decompensation. In agreement the ETF:QO activity in the mutant embryos is markedly decreased in relation to wild type activity. Amino acid sequence analysis and structural mapping into a molecular model of ETF:QO show that all mutations map at FAD interacting residues, two of which at the nucleotide-binding Rossmann fold. This structural domain is composed by a β-strand connected by a short loop to an α-helix, and its perturbation results in impaired cofactor association via structural destabilisation and consequently enzymatic inactivation. This work thus pinpoints the molecular origins of a severe MADD-like phenotype in the fruit fly and establishes the proof of concept concerning the suitability of this organism as a potential model organism for MADD. © 2012 Elsevier B.V. All rights reserved.

  9. A novel missense Norrie disease mutation associated with a severe ocular phenotype.

    Science.gov (United States)

    Khan, Arif O; Shamsi, Farrukh A; Al-Saif, Amr; Kambouris, Marios

    2004-01-01

    Clinical findings and pedigree analysis led to the diagnosis of severe Norrie disease in two brothers. DNA sequencing demonstrated a novel missense mutation (703G>T) that significantly alters predicted protein structure. Less severe retinal developmental disease may be associated with milder mutations in the Norrie disease gene.

  10. Network science meets respiratory medicine for OSAS phenotyping and severity prediction

    Directory of Open Access Journals (Sweden)

    Stefan Mihaicuta

    2017-05-01

    Full Text Available Obstructive sleep apnea syndrome (OSAS is a common clinical condition. The way that OSAS risk factors associate and converge is not a random process. As such, defining OSAS phenotypes fosters personalized patient management and population screening. In this paper, we present a network-based observational, retrospective study on a cohort of 1,371 consecutive OSAS patients and 611 non-OSAS control patients in order to explore the risk factor associations and their correlation with OSAS comorbidities. To this end, we construct the Apnea Patients Network (APN using patient compatibility relationships according to six objective parameters: age, gender, body mass index (BMI, blood pressure (BP, neck circumference (NC and the Epworth sleepiness score (ESS. By running targeted network clustering algorithms, we identify eight patient phenotypes and corroborate them with the co-morbidity types. Also, by employing machine learning on the uncovered phenotypes, we derive a classification tree and introduce a computational framework which render the Sleep Apnea Syndrome Score (SASScore; our OSAS score is implemented as an easy-to-use, web-based computer program which requires less than one minute for processing one individual. Our evaluation, performed on a distinct validation database with 231 consecutive patients, reveals that OSAS prediction with SASScore has a significant specificity improvement (an increase of 234% for only 8.2% sensitivity decrease in comparison with the state-of-the-art score STOP-BANG. The fact that SASScore has bigger specificity makes it appropriate for OSAS screening and risk prediction in big, general populations.

  11. Associations between speech features and phenotypic severity in Treacher Collins syndrome.

    Science.gov (United States)

    Asten, Pamela; Akre, Harriet; Persson, Christina

    2014-04-28

    Treacher Collins syndrome (TCS, OMIM 154500) is a rare congenital disorder of craniofacial development. Characteristic hypoplastic malformations of the ears, zygomatic arch, mandible and pharynx have been described in detail. However, reports on the impact of these malformations on speech are few. Exploring speech features and investigating if speech function is related to phenotypic severity are essential for optimizing follow-up and treatment. Articulation, nasal resonance, voice and intelligibility were examined in 19 individuals (5-74 years, median 34 years) divided into three groups comprising children 5-10 years (n = 4), adolescents 11-18 years (n = 4) and adults 29 years and older (n = 11). A speech composite score (0-6) was calculated to reflect the variability of speech deviations. TCS severity scores of phenotypic expression and total scores of Nordic Orofacial Test-Screening (NOT-S) measuring orofacial dysfunction were used in analyses of correlation with speech characteristics (speech composite scores). Children and adolescents presented with significantly higher speech composite scores (median 4, range 1-6) than adults (median 1, range 0-5). Nearly all children and adolescents (6/8) displayed speech deviations of articulation, nasal resonance and voice, while only three adults were identified with multiple speech aberrations. The variability of speech dysfunction in TCS was exhibited by individual combinations of speech deviations in 13/19 participants. The speech composite scores correlated with TCS severity scores and NOT-S total scores. Speech composite scores higher than 4 were associated with cleft palate. The percent of intelligible words in connected speech was significantly lower in children and adolescents (median 77%, range 31-99) than in adults (98%, range 93-100). Intelligibility of speech among the children was markedly inconsistent and clearly affecting the understandability. Multiple speech deviations were identified in

  12. [Clinical characteristics of human recombination activating gene 1 mutations in 8 immunodeficiency patients with diverse phenotypes].

    Science.gov (United States)

    Yu, G; Wang, W J; Liu, D R; Tao, Z F; Hui, X Y; Hou, J; Sun, J Q; Wang, X C

    2018-03-02

    Objective: To investigate the clinical characteristics of 8 immunodeficiency cases caused by human recombination activating gene 1 (RAG1) mutations, and to explore the relationship among genotypes, clinical manifestations and immunophenotypes. Methods: Clinical data were collected and analyzed from patients with RAG1 mutations who visited the Department of Clinical Immunology, Children's Hospital of Fudan University between October 2013 and June 2017. The data included clinical manifestations, immunophenotypes and genotypes. Results: A total of 8 patients were diagnosed with RAG1 deficiency (6 boys and 2 girls). The minimum age of onset was 2 months, and the maximum age was 4 months. The minimum age of diagnosis was 2 months, and the maximum age was 13 years. Four patients had a family history of infant death due to severe infections. Two cases were born to the same consanguineous parents. All cases had recurrent infections, including involvement of respiratory tract (8 cases), digestive tract (6 cases), urinary tract (1 case), and central nervous system (1 case). The pathogens of infection included bacteria, viruses and fungi. Rotavirus was found in 3 cases, cytomegalovirus (CMV) in 5 cases, bacillus Calmette-Guérin adverse reaction in 2 cases (1 of whom had a positive acid-fast smear from lymph node puncture fluid), fungal infection in 3 cases. One case had multiple nodular space-occupying lesions in lungs and abdominal cavity complicated with multiple bone destruction. The peripheral blood lymphocyte counts of all patients ranged between 0.1 ×10(9)/L and 3.3×10(9)/L (median, 0.65×10(9)/L). Eosinophilia was found in 3 cases (range, (0.48-1.69) ×10(9)/L). The patients were classified according to immunophenotype as severe combined immunodeficiency phenotype (4 cases), leaky severe combined immunodeficiency (2 cases), Omenn syndrome (1 case) and combined immunodeficiency (1 case) . Decreased serum IgG levels were found in 3 cases, increased serum IgM levels in

  13. Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment.

    Science.gov (United States)

    Van Dijk, F S; Sillence, D O

    2014-06-01

    Recently, the genetic heterogeneity in osteogenesis imperfecta (OI), proposed in 1979 by Sillence et al., has been confirmed with molecular genetic studies. At present, 17 genetic causes of OI and closely related disorders have been identified and it is expected that more will follow. Unlike most reviews that have been published in the last decade on the genetic causes and biochemical processes leading to OI, this review focuses on the clinical classification of OI and elaborates on the newly proposed OI classification from 2010, which returned to a descriptive and numerical grouping of five OI syndromic groups. The new OI nomenclature and the pre-and postnatal severity assessment introduced in this review, emphasize the importance of phenotyping in order to diagnose, classify, and assess severity of OI. This will provide patients and their families with insight into the probable course of the disorder and it will allow physicians to evaluate the effect of therapy. A careful clinical description in combination with knowledge of the specific molecular genetic cause is the starting point for development and assessment of therapy in patients with heritable disorders including OI. © 2014 The Authors. American Journal of Medical Genetics Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2014 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

  14. Severe bronchial asthma in children: the role of clinical and anamnestic indices in diagnosis verification

    Directory of Open Access Journals (Sweden)

    Kolyubakina L.V.

    2016-03-01

    Full Text Available The paper presents comparative analysis of results of clinical and anamnestic examination of children depending on the asthma severity. Severe asthma in schoolchildren relative to moderate phenotype characterized by birth overweight, more burdened individual allergic history, highly infectious index, drug or combined (medication, food and household allergies, seasonal exacerbations (mainly from November to March, what associated with the trigger role of ARVI and meteorological factors, inadequate asthma control during standard basic therapy.

  15. Clinical severity and prognosis of hand eczema

    DEFF Research Database (Denmark)

    Hald, M; Agner, T; Blands, J

    2009-01-01

    ) and by patients using a self-administered photographic guide. Additional information was obtained from a baseline questionnaire. RESULTS: At baseline, 60.3% assessed their HE as moderate to very severe using the self-administered photographic guide compared with 36.1% at follow-up. The mean HECSI value decreased...

  16. Broad phenotypic spectrum in familial adenomatous polyposis; from early onset and severe phenotypes to late onset of attenuated polyposis with the first manifestation at age 72

    DEFF Research Database (Denmark)

    Nilbert, Mef; Kristoffersson, Ulf; Ericsson, Mats

    2008-01-01

    ABSTRACT: Background Familial adenomatous polyposis (FAP) is typically characterized by multiple colonic polyps and frequent extracolonic features. Whereas the number of colonic polyps has been linked to the APC gene mutation, possible genotype-phenotype correlations largely remain to be defined...... of extracolonic manifestations was identified in most of these individuals. Two sisters with an insertion in codon 528 (c.1582_1583insGC) both showed severe phenotypes with classical polyposis, upper gastrointestinal polyps and thyroid cancer. A woman with a 3'APC mutation (c.5030_5031insAA) developed colon...

  17. Expression of Caytaxin protein in Cayman Ataxia mouse models correlates with phenotype severity.

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    Kristine M Sikora

    Full Text Available Caytaxin is a highly-conserved protein, which is encoded by the Atcay/ATCAY gene. Mutations in Atcay/ATCAY have been identified as causative of cerebellar disorders such as the rare hereditary disease Cayman ataxia in humans, generalized dystonia in the dystonic (dt rat, and marked motor defects in three ataxic mouse lines. While several lines of evidence suggest that Caytaxin plays a critical role in maintaining nervous system processes, the physiological function of Caytaxin has not been fully characterized. In the study presented here, we generated novel specific monoclonal antibodies against full-length Caytaxin to examine endogenous Caytaxin expression in wild type and Atcay mutant mouse lines. Caytaxin protein is absent from brain tissues in the two severely ataxic Atcay(jit (jittery and Atcay(swd (sidewinder mutant lines, and markedly decreased in the mildly ataxic/dystonic Atcay(ji-hes (hesitant line, indicating a correlation between Caytaxin expression and disease severity. As the expression of wild type human Caytaxin in mutant sidewinder and jittery mice rescues the ataxic phenotype, Caytaxin's physiological function appears to be conserved between the human and mouse orthologs. Across multiple species and in several neuronal cell lines Caytaxin is expressed as several protein isoforms, the two largest of which are caused by the usage of conserved methionine translation start sites. The work described in this manuscript presents an initial characterization of the Caytaxin protein and its expression in wild type and several mutant mouse models. Utilizing these animal models of human Cayman Ataxia will now allow an in-depth analysis to elucidate Caytaxin's role in maintaining normal neuronal function.

  18. Clinical spectrum and genotype-phenotype associations of KCNA2-related encephalopathies.

    Science.gov (United States)

    Masnada, Silvia; Hedrich, Ulrike B S; Gardella, Elena; Schubert, Julian; Kaiwar, Charu; Klee, Eric W; Lanpher, Brendan C; Gavrilova, Ralitza H; Synofzik, Matthis; Bast, Thomas; Gorman, Kathleen; King, Mary D; Allen, Nicholas M; Conroy, Judith; Ben Zeev, Bruria; Tzadok, Michal; Korff, Christian; Dubois, Fanny; Ramsey, Keri; Narayanan, Vinodh; Serratosa, Jose M; Giraldez, Beatriz G; Helbig, Ingo; Marsh, Eric; O'Brien, Margaret; Bergqvist, Christina A; Binelli, Adrian; Porter, Brenda; Zaeyen, Eduardo; Horovitz, Dafne D; Wolff, Markus; Marjanovic, Dragan; Caglayan, Hande S; Arslan, Mutluay; Pena, Sergio D J; Sisodiya, Sanjay M; Balestrini, Simona; Syrbe, Steffen; Veggiotti, Pierangelo; Lemke, Johannes R; Møller, Rikke S; Lerche, Holger; Rubboli, Guido

    2017-09-01

    Recently, de novo mutations in the gene KCNA2, causing either a dominant-negative loss-of-function or a gain-of-function of the voltage-gated K+ channel Kv1.2, were described to cause a new molecular entity within the epileptic encephalopathies. Here, we report a cohort of 23 patients (eight previously described) with epileptic encephalopathy carrying either novel or known KCNA2 mutations, with the aim to detail the clinical phenotype associated with each of them, to characterize the functional effects of the newly identified mutations, and to assess genotype-phenotype associations. We identified five novel and confirmed six known mutations, three of which recurred in three, five and seven patients, respectively. Ten mutations were missense and one was a truncation mutation; de novo occurrence could be shown in 20 patients. Functional studies using a Xenopus oocyte two-microelectrode voltage clamp system revealed mutations with only loss-of-function effects (mostly dominant-negative current amplitude reduction) in eight patients or only gain-of-function effects (hyperpolarizing shift of voltage-dependent activation, increased amplitude) in nine patients. In six patients, the gain-of-function was diminished by an additional loss-of-function (gain-and loss-of-function) due to a hyperpolarizing shift of voltage-dependent activation combined with either decreased amplitudes or an additional hyperpolarizing shift of the inactivation curve. These electrophysiological findings correlated with distinct phenotypic features. The main differences were (i) predominant focal (loss-of-function) versus generalized (gain-of-function) seizures and corresponding epileptic discharges with prominent sleep activation in most cases with loss-of-function mutations; (ii) more severe epilepsy, developmental problems and ataxia, and atrophy of the cerebellum or even the whole brain in about half of the patients with gain-of-function mutations; and (iii) most severe early-onset phenotypes

  19. Clinical and Phenotypic Differences in Inflammatory Bowel Disease Among Arab and Jewish Children in Israel.

    Science.gov (United States)

    Rinawi, Firas; Assa, Amit; Bashir, Husam; Peleg, Sarit; Shamir, Raanan

    2017-08-01

    Data on inflammatory bowel disease (IBD) phenotypes among the Arab population in Israel or in the neighboring Arab countries is scarce. We aimed to assess differences in disease phenotype among Arab and Jewish children living in Israel. We performed a retrospective chart review of pediatric IBD cases, which were diagnosed at the Schneider Children's Medical Center and Ha'Emek Medical Center in Israel between 2000 and 2014. Demographic, clinical, and phenotypic variables were compared between Arabs and Jews from Eastern (Sephardic) and Western (Ashkenazi) origin. Seventy-one Arab children with IBD were compared with 165 Ashkenazi and 158 Sephardic Jewish children. Age and gender did not differ between groups. Sephardic and Ashkenazi Jewish Crohn's disease (CD) patients had significantly more stenotic behavior (24 and 26 vs. 5%, p = 0.03) and less fistulzing perianal disease (15 and 11 vs. 31%, p = 0.014) compared with Arab patients. Arab children with ulcerative colitis (UC) had more severe disease at diagnosis compared to Sephardic and Ashkenazi Jews reflected by higher Pediatric UC Activity Index (45 vs. 35 and 35, respectively, p = 0.03). Arab patients had significantly lower proportion of anti-Saccharomyces cerevisiae antibodies positivity (in CD) and perinuclear anti-neutrophil cytoplasmic antibodies positivity (in UC) than both Sephardic and Ashkenazi Jewish children (23 vs. 53 and 65%, p = 0.002 and 35 vs. 60 and 75%, respectively, p = 0.002). Arab and Jewish children with IBD differ in disease characteristics and severity. Whether genetic or environmental factors are the cause for these differences is yet to be determined.

  20. Predictive genomics: A cancer hallmark network framework for predicting tumor clinical phenotypes using genome sequencing data

    OpenAIRE

    Wang, Edwin; Zaman, Naif; Mcgee, Shauna; Milanese, Jean-Sébastien; Masoudi-Nejad, Ali; O'Connor, Maureen

    2014-01-01

    We discuss a cancer hallmark network framework for modelling genome-sequencing data to predict cancer clonal evolution and associated clinical phenotypes. Strategies of using this framework in conjunction with genome sequencing data in an attempt to predict personalized drug targets, drug resistance, and metastasis for a cancer patient, as well as cancer risks for a healthy individual are discussed. Accurate prediction of cancer clonal evolution and clinical phenotypes will have substantial i...

  1. NCI Workshop Report: Clinical and Computational Requirements for Correlating Imaging Phenotypes with Genomics Signatures

    Directory of Open Access Journals (Sweden)

    Rivka Colen

    2014-10-01

    Full Text Available The National Cancer Institute (NCI Cancer Imaging Program organized two related workshops on June 26–27, 2013, entitled “Correlating Imaging Phenotypes with Genomics Signatures Research” and “Scalable Computational Resources as Required for Imaging-Genomics Decision Support Systems.” The first workshop focused on clinical and scientific requirements, exploring our knowledge of phenotypic characteristics of cancer biological properties to determine whether the field is sufficiently advanced to correlate with imaging phenotypes that underpin genomics and clinical outcomes, and exploring new scientific methods to extract phenotypic features from medical images and relate them to genomics analyses. The second workshop focused on computational methods that explore informatics and computational requirements to extract phenotypic features from medical images and relate them to genomics analyses and improve the accessibility and speed of dissemination of existing NIH resources. These workshops linked clinical and scientific requirements of currently known phenotypic and genotypic cancer biology characteristics with imaging phenotypes that underpin genomics and clinical outcomes. The group generated a set of recommendations to NCI leadership and the research community that encourage and support development of the emerging radiogenomics research field to address short-and longer-term goals in cancer research.

  2. DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency.

    Science.gov (United States)

    Volk, Timo; Pannicke, Ulrich; Reisli, Ismail; Bulashevska, Alla; Ritter, Julia; Björkman, Andrea; Schäffer, Alejandro A; Fliegauf, Manfred; Sayar, Esra H; Salzer, Ulrich; Fisch, Paul; Pfeifer, Dietmar; Di Virgilio, Michela; Cao, Hongzhi; Yang, Fang; Zimmermann, Karin; Keles, Sevgi; Caliskaner, Zafer; Güner, S Ükrü; Schindler, Detlev; Hammarström, Lennart; Rizzi, Marta; Hummel, Michael; Pan-Hammarström, Qiang; Schwarz, Klaus; Grimbacher, Bodo

    2015-12-20

    Null mutations in genes involved in V(D)J recombination cause a block in B- and T-cell development, clinically presenting as severe combined immunodeficiency (SCID). Hypomorphic mutations in the non-homologous end-joining gene DCLRE1C (encoding ARTEMIS) have been described to cause atypical SCID, Omenn syndrome, Hyper IgM syndrome and inflammatory bowel disease-all with severely impaired T-cell immunity. By whole-exome sequencing, we investigated the molecular defect in a consanguineous family with three children clinically diagnosed with antibody deficiency. We identified perfectly segregating homozygous variants in DCLRE1C in three index patients with recurrent respiratory tract infections, very low B-cell numbers and serum IgA levels. In patients, decreased colony survival after irradiation, impaired proliferative response and reduced counts of naïve T cells were observed in addition to a restricted T-cell receptor repertoire, increased palindromic nucleotides in the complementarity determining regions 3 and long stretches of microhomology at switch junctions. Defective V(D)J recombination was complemented by wild-type ARTEMIS protein in vitro. Subsequently, homozygous or compound heterozygous DCLRE1C mutations were identified in nine patients from the same geographic region. We demonstrate that DCLRE1C mutations can cause a phenotype presenting as only antibody deficiency. This novel association broadens the clinical spectrum associated with ARTEMIS mutations. Clinicians should consider the possibility that an immunodeficiency with a clinically mild initial presentation could be a combined immunodeficiency, so as to provide appropriate care for affected patients. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  3. Omalizumab for severe asthma: toward personalized treatment based on biomarker profile and clinical history

    Directory of Open Access Journals (Sweden)

    Tabatabaian F

    2018-04-01

    Full Text Available Farnaz Tabatabaian, Dennis K Ledford Division of Allergy and Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA Abstract: Asthma is a heterogeneous syndrome with numerous underlining molecular and inflammatory mechanisms contributing to the wide spectrum of clinical phenotypes. Multiple therapies targeting severe asthma with type 2 (T2 high inflammation are or soon will be available. T2 high inflammation is defined as inflammation associated with atopy or eosinophilia or an increase in cytokines associated with T-helper 2 lymphocytes. Omalizumab is a humanized anti-IgE monoclonal antibody and the first biologic therapy approved for moderate–severe allergic asthma. Despite the specificity of biologic therapies like omalizumab, clinical response is variable, with approximately 50% of treated patients achieving the primary outcome. A prior identification of the ideal candidate for therapy would improve patient outcomes and optimize the use of health care resources. As the number of biologic therapies for asthma increases, the goal is identification of biomarkers or clinical phenotypes likely to respond to a specific therapy. This review focuses on potential biomarkers and clinical history that may identify responders to omalizumab therapy for asthma. Keywords: severe persistent asthma, asthma phenotype and endotype, T2 high inflammation, omalizumab, asthma biomarkers, eosinophils, fractional exhaled nitric oxide, IgE

  4. PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature

    Science.gov (United States)

    Reijnders, Margot R F; Janowski, Robert; Alvi, Mohsan; Self, Jay E; van Essen, Ton J; Vreeburg, Maaike; Rouhl, Rob P W; Stevens, Servi J C; Stegmann, Alexander P A; Schieving, Jolanda; Pfundt, Rolph; van Dijk, Katinke; Smeets, Eric; Stumpel, Connie T R M; Bok, Levinus A; Cobben, Jan Maarten; Engelen, Marc; Mansour, Sahar; Whiteford, Margo; Chandler, Kate E; Douzgou, Sofia; Cooper, Nicola S; Tan, Ene-Choo; Foo, Roger; Lai, Angeline H M; Rankin, Julia; Green, Andrew; Lönnqvist, Tuula; Isohanni, Pirjo; Williams, Shelley; Ruhoy, Ilene; Carvalho, Karen S; Dowling, James J; Lev, Dorit L; Sterbova, Katalin; Lassuthova, Petra; Neupauerová, Jana; Waugh, Jeff L; Keros, Sotirios; Clayton-Smith, Jill; Smithson, Sarah F; Brunner, Han G; van Hoeckel, Ceciel; Anderson, Mel; Clowes, Virginia E; Siu, Victoria Mok; DDD study, The; Selber, Paulo; Leventer, Richard J; Nellaker, Christoffer; Niessing, Dierk; Hunt, David; Baralle, Diana

    2018-01-01

    Background De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. Objectives To delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. Methods Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes. Results We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. Conclusion We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and

  5. Clinical phenotype of 5 females with a CDKL5 mutation

    NARCIS (Netherlands)

    Stalpers, X.L.; Spruijt, L.; Yntema, H.G.; Verrips, A.

    2012-01-01

    Mutations in the X-linked cyclin dependent kinase like 5 (CDKL5) gene have been reported in approximately 80 patients since the first description in 2003. The clinical presentation partly corresponds with Rett syndrome, considering clinical features as intellectual disability, hypotonia, and poor

  6. Use of global assays to understand clinical phenotype in congenital factor VII deficiency.

    Science.gov (United States)

    Greene, L A; Goldenberg, N A; Simpson, M L; Villalobos-Menuey, E; Bombardier, C; Acharya, S S; Santiago-Borrero, P J; Cambara, A; DiMichele, D M

    2013-09-01

    Congenital factor VII (FVII) deficiency is characterized by genotypic variability and phenotypic heterogeneity. Traditional screening and factor assays are unable to reliably predict clinical bleeding phenotype and guide haemorrhage prevention strategy. Global assays of coagulation and fibrinolysis may better characterize overall haemostatic balance and aid in haemorrhagic risk assessment. We evaluated the ability of novel global assays to better understand clinical bleeding severity in congenital FVII deficiency. Subjects underwent central determination of factor VII activity (FVII:C) as well as clot formation and lysis (CloFAL) and simultaneous thrombin and plasmin generation (STP) global assay analysis. A bleeding score was assigned to each subject through medical chart review. Global assay parameters were analysed with respect to bleeding score and FVII:C. Subgroup analyses were performed on paediatric subjects and subjects with FVII ≥ 1 IU dL(-1). CloFAL fibrinolytic index (FI2 ) inversely correlated with FVII:C while CloFAL maximum amplitude (MA) and STP maximum velocity of thrombin generation (VT max) varied directly with FVII:C. CloFAL FI2 directly correlated with bleeding score among subjects in both the total cohort and paediatric subcohort, but not among subjects with FVII ≥ 1 IU dL(-1) . Among subjects with FVII ≥ 1 IU dL(-1), STP time to maximum velocity of thrombin generation and time to maximum velocity of plasmin generation inversely correlated with bleeding score. These preliminary findings suggest a novel potential link between a hyperfibrinolytic state in bleeding severity and congenital FVII deficiency, an observation that should be further explored. © 2013 John Wiley & Sons Ltd.

  7. In vivo urea cycle flux distinguishes and correlates with phenotypic severity in disorders of the urea cycle

    Science.gov (United States)

    Lee, Brendan; Yu, Hong; Jahoor, Farook; O'Brien, William; Beaudet, Arthur L.; Reeds, Peter

    2000-01-01

    Urea cycle disorders are a group of inborn errors of hepatic metabolism that result in often life-threatening hyperammonemia and hyperglutaminemia. Clinical and laboratory diagnosis of partial deficiencies during asymptomatic periods is difficult, and correlation of phenotypic severity with either genotype and/or in vitro enzyme activity is often imprecise. We hypothesized that stable isotopically determined in vivo rates of total body urea synthesis and urea cycle-specific nitrogen flux would correlate with both phenotypic severity and carrier status in patients with a variety of different enzymatic deficiencies of the urea cycle. We studied control subjects, patients, and their relatives with different enzymatic deficiencies affecting the urea cycle while consuming a low protein diet. On a separate occasion the subjects either received a higher protein intake or were treated with an alternative route medication sodium phenylacetate/benzoate (Ucephan), or oral arginine supplementation. Total urea synthesis from all nitrogen sources was determined from [18O]urea labeling, and the utilization of peripheral nitrogen was estimated from the relative isotopic enrichments of [15N]urea and [15N]glutamine during i.v. co-infusions of [5-(amide)15N]glutamine and [18O]urea. The ratio of the isotopic enrichments of 15N-urea/15N-glutamine distinguished normal control subjects (ratio = 0.42 ± 0.06) from urea cycle patients with late (0.17 ± 0.03) and neonatal (0.003 ± 0.007) presentations irrespective of enzymatic deficiency. This index of urea cycle activity also distinguished asymptomatic heterozygous carriers of argininosuccinate synthetase deficiency (0.22 ± 0.03), argininosuccinate lyase deficiency (0.35 ± 0.11), and partial ornithine transcarbamylase deficiency (0.26 ± 0.06) from normal controls. Administration of Ucephan lowered, and arginine increased, urea synthesis to the degree predicted from their respective rates of metabolism. The 15N-urea/15N-glutamine ratio

  8. Heterozygous truncation mutations of the SMC1A gene cause a severe early onset epilepsy with cluster seizures in females: Detailed phenotyping of 10 new cases.

    Science.gov (United States)

    Symonds, Joseph D; Joss, Shelagh; Metcalfe, Kay A; Somarathi, Suresh; Cruden, Jamie; Devlin, Anita M; Donaldson, Alan; DiDonato, Nataliya; Fitzpatrick, David; Kaiser, Frank J; Lampe, Anne K; Lees, Melissa M; McLellan, Ailsa; Montgomery, Tara; Mundada, Vivek; Nairn, Lesley; Sarkar, Ajoy; Schallner, Jens; Pozojevic, Jelena; Parenti, Ilaria; Tan, Jeen; Turnpenny, Peter; Whitehouse, William P; Zuberi, Sameer M

    2017-04-01

    The phenotype of seizure clustering with febrile illnesses in infancy/early childhood is well recognized. To date the only genetic epilepsy consistently associated with this phenotype is PCDH19, an X-linked disorder restricted to females, and males with mosaicism. The SMC1A gene, which encodes a structural component of the cohesin complex is also located on the X chromosome. Missense variants and small in-frame deletions of SMC1A cause approximately 5% of Cornelia de Lange Syndrome (CdLS). Recently, protein truncating mutations in SMC1A have been reported in five females, all of whom have been affected by a drug-resistant epilepsy, and severe developmental impairment. Our objective was to further delineate the phenotype of SMC1A truncation. Female cases with de novo truncation mutations in SMC1A were identified from the Deciphering Developmental Disorders (DDD) study (n = 8), from postmortem testing of an affected twin (n = 1), and from clinical testing with an epilepsy gene panel (n = 1). Detailed information on the phenotype in each case was obtained. Ten cases with heterozygous de novo mutations in the SMC1A gene are presented. All 10 mutations identified are predicted to result in premature truncation of the SMC1A protein. All cases are female, and none had a clinical diagnosis of CdLS. They presented with onset of epileptic seizures between <4 weeks and 28 months of age. In the majority of cases, a marked preponderance for seizures to occur in clusters was noted. Seizure clusters were associated with developmental regression. Moderate or severe developmental impairment was apparent in all cases. Truncation mutations in SMC1A cause a severe epilepsy phenotype with cluster seizures in females. These mutations are likely to be nonviable in males. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

  9. PhenoTips: patient phenotyping software for clinical and research use.

    Science.gov (United States)

    Girdea, Marta; Dumitriu, Sergiu; Fiume, Marc; Bowdin, Sarah; Boycott, Kym M; Chénier, Sébastien; Chitayat, David; Faghfoury, Hanna; Meyn, M Stephen; Ray, Peter N; So, Joyce; Stavropoulos, Dimitri J; Brudno, Michael

    2013-08-01

    We have developed PhenoTips: open source software for collecting and analyzing phenotypic information for patients with genetic disorders. Our software combines an easy-to-use interface, compatible with any device that runs a Web browser, with a standardized database back end. The PhenoTips' user interface closely mirrors clinician workflows so as to facilitate the recording of observations made during the patient encounter. Collected data include demographics, medical history, family history, physical and laboratory measurements, physical findings, and additional notes. Phenotypic information is represented using the Human Phenotype Ontology; however, the complexity of the ontology is hidden behind a user interface, which combines simple selection of common phenotypes with error-tolerant, predictive search of the entire ontology. PhenoTips supports accurate diagnosis by analyzing the entered data, then suggesting additional clinical investigations and providing Online Mendelian Inheritance in Man (OMIM) links to likely disorders. By collecting, classifying, and analyzing phenotypic information during the patient encounter, PhenoTips allows for streamlining of clinic workflow, efficient data entry, improved diagnosis, standardization of collected patient phenotypes, and sharing of anonymized patient phenotype data for the study of rare disorders. Our source code and a demo version of PhenoTips are available at http://phenotips.org. © 2013 WILEY PERIODICALS, INC.

  10. Parkinsonian syndroms: Clinical phenotype, differential diagnosis and disease progression

    International Nuclear Information System (INIS)

    Storch, A.

    2002-01-01

    Parkinsonian syndromes include idiopathic Parkinson's disease (IPD), other neurodegenerative diseases with parkinsonism, the so-called atypical parkinsonian syndromes, and symptomatic parkinsonian syndromes, such as Wilson's disease. IPD is the most frequent disease with parkinsonism as the main clinical feature and is responsible for approx. 80% of all parkinsonian syndromes. Atypical parkinsonian syndromes are the most important differential diagnoses of IPD. The two most frequent types are multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). For clinical diagnosis it is essential to take a careful medical history and to examine the patients physically in regular intervals. However, various clinico-pathological studies have shown that approx. 25% of patients with clinical diagnosis of IPD may have other causes of parkinsonism. Selected technical investigations, in particular functional imaging of the central dopaminergic system using PET or SPECT, may help to make clinical diagnosis more secure. This paper reviews the clinical features and diagnostic findings in diseases with parkinsonism and summarises the difficulties in establishing early and differential diagnoses. (orig.) [de

  11. Clinical phenotype and outcome of hepatitis E virus-associated neuralgic amyotrophy

    NARCIS (Netherlands)

    Eijk, J.J.J. van; Dalton, H.R.; Ripellino, P.; Madden, R.G.; Jones, C.; Fritz, M.; Gobbi, C.; Melli, G.; Pasi, E.; Herrod, J.; Lissmann, R.F.; Ashraf, H.H.; Abdelrahim, M.; Masri, O.; Fraga, M.; Benninger, D.; Kuntzer, T.; Aubert, V.; Sahli, R.; Moradpour, D.; Blasco-Perrin, H.; Attarian, S.; Gerolami, R.; Colson, P.; Giordani, M.T.; Hartl, J.; Pischke, S.; Lin, N.X.; McLean, B.N.; Bendall, R.P.; Panning, M.; Peron, J.M.; Kamar, N.; Izopet, J.; Jacobs, B.C.; Alfen, N. van; Engelen, B.G.M. van

    2017-01-01

    OBJECTIVE: To determine the clinical phenotype and outcome in hepatitis E virus-associated neuralgic amyotrophy (HEV-NA). METHODS: Cases of NA were identified in 11 centers from 7 European countries, with retrospective analysis of demographics, clinical/laboratory findings, and treatment and

  12. From genotype to phenotype; clinical variability in Lesch-Nyhan disease. The role of epigenetics.

    Science.gov (United States)

    Trigueros Genao, M; Torres, R J

    2014-11-01

    Lesch-Nyhan disease is a rare genetic disease characterized by a deficiency in the function of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Patients affected by this disease experience hyperuricemia, motor disorders, mental retardation and, in the most severe cases, self-mutilation. Its clinical manifestations depend on the enzymatic activity of HGPRT, which is classically linked to the type of alteration in the HGPRT gene. More than 400 mutations of this gene have been found. At present, one of the controversial aspects of the disease is the relationship between the genotype and phenotype; cases have been described lacking a mutation, such as the patient presented in this article, as well as families who despite sharing the same genetic defect show disorders with differing severity. Epigenetic processes, which modify the genetic expression without changing the sequence of the deoxyribonucleic acid (DNA), could explain the clinical variability observed in this disease. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  13. A novel mutation in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene associated with a severe Rett phenotype.

    Science.gov (United States)

    Sprovieri, T; Conforti, F L; Fiumara, A; Mazzei, R; Ungaro, C; Citrigno, L; Muglia, M; Arena, A; Quattrone, A

    2009-02-15

    Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have recently been reported in patients with severe neurodevelopmental disorder characterized by early-onset seizures, infantile spasms, severe psychomotor impairment and very recently, in patients with Rett syndrome (RTT)-like phenotype. Although the involvement of CDKL5 in specific biological pathways and its neurodevelopmental role have not been completely elucidated, the CDKL5 appears to be physiologically related to the MECP2 gene. Here we report on the clinical and CDKL5 molecular investigation in a very unusual RTT case, with severe, early-neurological involvement in which we have shown in a previous report, a novel P388S MECP2 mutation [Conforti et al. (2003); Am J Med Genet A 117A: 184-187]. The patient has had severe psychomotor delay since the first month of life and infantile spasms since age 5 months. Moreover, at age 5 years the patient suddenly presented with renal failure. The severe pattern of symptoms in our patient, similar to a CDKL5 phenotype, prompted us to perform an analysis of the CDKL5, which revealed a novel missense mutation never previously described. The X-inactivation assay was non-informative. In conclusion, this report reinforces the observation that the CDKL5 phenotype overlaps with RTT and that CDKL5 analysis is recommended in patients with a seizure disorder commencing during the first months of life.

  14. Deconstructing oppositional defiant disorder: clinic-based evidence for an anger/irritability phenotype.

    Science.gov (United States)

    Drabick, Deborah A G; Gadow, Kenneth D

    2012-04-01

    To examine risk factors and co-occurring symptoms associated with mother-reported versus teacher-reported anger/irritability symptoms (AIS) of oppositional defiant disorder (ODD) in a clinic-based sample of 1,160 youth aged 6 through 18 years. Participants completed a background history questionnaire (mothers), school functioning questionnaire (mothers, teachers), and DSM-IV-referenced symptom checklists (mothers, teachers). Youth meeting AIS criteria for ODD were compared to youth with ODD who met criteria for noncompliant symptoms (NS) but not AIS and to clinic controls. Compared with NS youth, youth with AIS were rated as exhibiting higher levels of anxiety and mood symptoms for both mother- and teacher-defined groups, and higher levels of conduct disorder symptoms for mother-defined younger and older youth. The remaining group differences for developmental, psychosocial, and psychiatric correlates varied as a function of informant and youth's age. Evidence suggests that AIS may constitute a more severe and qualitatively different ODD clinical phenotype, but informant and age of youth appear to be important considerations. Copyright © 2012 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

  15. Clinical and molecular phenotype of Aicardi-Goutieres syndrome

    NARCIS (Netherlands)

    Rice, Gillian; Patrick, Teresa; Parmar, Rekha; Taylor, Claire F.; Aeby, Alec; Aicardi, Jean; Artuch, Rafael; Montalto, Simon Attard; Bacino, Carlos A.; Barroso, Bruno; Baxter, Peter; Benko, Willam S.; Bergmann, Carsten; Bertini, Enrico; Biancheri, Roberta; Blair, Edward M.; Blau, Nenad; Bonthron, David T.; Briggs, Tracy; Brueton, Louise A.; Brunner, Han G.; Burke, Christopher J.; Carr, Ian M.; Carvalho, Daniel R.; Chandler, Kate E.; Christen, Hans-Jurgen; Corry, Peter C.; Cowan, Frances M.; Cox, Helen; D'Arrigo, Stefano; Dean, John; de Laet, Corinne; de Praeter, Claudine; Dery, Catherine; Ferrie, Colin D.; Flintoff, Kim; Frints, Suzanna G. M.; Garcia-Cazorla, Angels; Gener, Blanca; Goizet, Cyril; Goutieres, Francoise; Green, Andrew J.; Guet, Agnes; Hamel, Ben C. J.; Hayward, Bruce E.; Heiberg, Arvid; Hennekam, Raoul C.; Husson, Marie; Jackson, Andrew P.; Jayatunga, Rasieka; Jiang, Yong-Hui; Kant, Sarina G.; Kao, Amy; King, Mary D.; Kingston, Helen M.; Klepper, Joerg; van der Knaap, Marjo S.; Kornberg, Andrew J.; Kotzot, Dieter; Kratzer, Wilfried; Lacombe, Didier; Lagae, Lieven; Landrieu, Pierre Georges; Lanzi, Giovanni; Leitch, Andrea; Lim, Ming J.; Livingston, John H.; Lourenco, Charles M.; Lyall, E. G. Hermione; Lynch, Sally A.; Lyons, Michael J.; Marom, Daphna; McClure, John P.; McWilliam, Robert; Melancon, Serge B.; Mewasingh, Leena D.; Moutard, Marie-Laure; Nischal, Ken K.; Ostergaard, John R.; Prendiville, Julie; Rasmussen, Magnhild; Rogers, R. Curtis; Roland, Dominique; Rosser, Elisabeth M.; Rostasy, Kevin; Roubertie, Agathe; Sanchis, Amparo; Schiffmann, Raphael; Scholl-Burgi, Sabine; Seal, Sunita; Shalev, Stavit A.; Corcoles, C. Sierra; Sinha, Gyan P.; Soler, Doriette; Spiegel, Ronen; Stephenson, John B. P.; Tacke, Uta; Tan, Tiong Yang; Till, Marianne; Tolmie, John L.; Tomlin, Pam; Vagnarelli, Federica; Valente, Enza Maria; van Coster, Rudy N. A.; van der Aa, Nathalie; Vanderver, Adeline; Vles, Johannes S. H.; Voit, Thomas; Wassmer, Evangeline; Weschke, Bernhard; Whiteford, Margo L.; Willemsen, Michel A. A.; Zankl, Andreas; Zuberi, Sameer M.; Orcesi, Simona; Fazzi, Elisa; Lebon, Pierre; Crow, Yanick J.

    2007-01-01

    Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease

  16. Clinical and molecular phenotype of Aicardi-Goutieres syndrome

    DEFF Research Database (Denmark)

    Rice, Gillian; Patrick, Teresa; Parmar, Rekha

    2007-01-01

    complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we...

  17. Polycystic ovary syndrome in type 2 diabetes: does it predict a more severe phenotype?

    Science.gov (United States)

    Sim, Stephanie Y T; Chin, Sian L; Tan, Jocelyn L K; Brown, Suzanne J; Cussons, Andrea J; Stuckey, Bronwyn G A

    2016-10-01

    To examine the prevalence of a history of polycystic ovary syndrome (PCOS) in women with type 2 diabetes (DM2) and to compare metabolic and reproductive outcomes between women with and without PCOS. Cross-sectional study. Tertiary hospital. Female inpatients age 18-75 years with DM2. A face-to-face questionnaire was administered. Age at diagnosis of diabetes, history of gestational diabetes, family history of diabetes, and reproductive history, fertility history, number of miscarriages, and morbidity in pregnancy. One hundred seventy-one inpatients with DM2 participated. The prevalence of a history of PCOS was 37%. Women with PCOS had an earlier mean age of diagnosis of DM2 (44.2 vs. 48.8 years), higher recalled peak body mass index (BMI; 43.1 kg/m 2 vs. 36.8 kg/m 2 ), higher rate of gestational diabetes (28% vs. 18%), and higher rate of hypertension in pregnancy (40% vs. 22%). Women with PCOS were less likely to have a family history of DM2 than those without PCOS (45% vs. 67%). A history of PCOS in women with DM2 is associated with earlier onset of DM2, higher BMI, and a more severe phenotype. Since PCOS subjects were less likely to have a family history of DM2, lack of a family history of DM2 in women with PCOS is not reassuring for DM2 risk. We recommend identifying PCOS in early life and intervening to reduce the risk of diabetes and its comorbidities and suboptimal reproductive outcomes. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

  18. Clinical Phenotype of Depression Affects Interleukin-6 Synthesis.

    Science.gov (United States)

    Zadka, Łukasz; Dzięgiel, Piotr; Kulus, Michał; Olajossy, Marcin

    2017-06-01

    Major depressive disorder (MDD) is not a single disease, but a number of various ailments that form one entity. Psychomotor retardation, anhedonia, sleep disorders, an increased suicide risk, and anxiety are the main symptoms that often define the clinical diagnosis of depression. Interleukin-6 (IL-6), as one of the proinflammatory cytokines, seems to be overexpressed during certain mental disorders, including MDD. Overexpression of IL-6 in depression is thought to be a factor associated with bad prognosis and worse disease course. IL-6 may directly affect brain functioning and production of neurotransmitters; moreover, its concentration is correlated with certain clinical symptoms within the wide range of depressive symptomatology. Furthermore, there is a strong correlation between IL-6 synthesis and psychosomatic functioning of the patient. This article discusses potential sources and significance of IL-6 in the pathogenesis of depression.

  19. Refining the clinical phenotype of Okur–Chung neurodevelopmental syndrome

    Science.gov (United States)

    Akahira-Azuma, Moe; Tsurusaki, Yoshinori; Enomoto, Yumi; Mitsui, Jun; Kurosawa, Kenji

    2018-01-01

    We describe an 8-year-old Japanese boy with a de novo recurrent missense mutation in CSNK2A1, c.593A>G, that is causative of Okur–Chung neurodevelopmental syndrome. He exhibited distinctive facial features, severe growth retardation with relative macrocephaly, and friendly, hyperactive behavior. His dysmorphic features might suggest a congenital histone modification defect syndrome, such as Kleefstra, Coffin–Siris, or Rubinstein–Taybi syndromes, which are indicative of functional interactions between the casein kinase II, alpha 1 gene and histone modification factors. PMID:29619237

  20. Determining triglyceride reductions needed for clinical impact in severe hypertriglyceridemia.

    Science.gov (United States)

    Christian, Jennifer B; Arondekar, Bhakti; Buysman, Erin K; Jacobson, Terry A; Snipes, Rose G; Horwitz, Ralph I

    2014-01-01

    Patients with severe hypertriglyceridemia have an increased risk of cardiovascular disease and pancreatitis. Target triglyceride levels associated with clinical benefit for patients with severe hypertriglyceridemia are not currently known. This study evaluates the association between lower follow-up triglyceride levels and incidence of clinical events for patients with severe hypertriglyceridemia. By using claims data from 2 large US healthcare databases, we conducted a retrospective cohort study and identified 41,210 adults with severe hypertriglyceridemia (triglycerides ≥ 500 mg/dL) between June 2001 and September 2010. The date of the first severe hypertriglyceridemia laboratory result was the index date. Patients were categorized into 1 of 5 triglyceride ranges (severe hypertriglyceridemia with follow-up triglyceride levels severe hypertriglyceridemia with follow-up triglyceride levels 200 to 299 mg/dL and 300 to 399 mg/dL (P severe hypertriglyceridemia with the lowest follow-up triglyceride levels. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Sequence homology at the breakpoint and clinical phenotype of mitochondrial DNA deletion syndromes.

    Science.gov (United States)

    Sadikovic, Bekim; Wang, Jing; El-Hattab, Ayman W; Landsverk, Megan; Douglas, Ganka; Brundage, Ellen K; Craigen, William J; Schmitt, Eric S; Wong, Lee-Jun C

    2010-12-20

    Mitochondrial DNA (mtDNA) deletions are a common cause of mitochondrial disorders. Large mtDNA deletions can lead to a broad spectrum of clinical features with different age of onset, ranging from mild mitochondrial myopathies (MM), progressive external ophthalmoplegia (PEO), and Kearns-Sayre syndrome (KSS), to severe Pearson syndrome. The aim of this study is to investigate the molecular signatures surrounding the deletion breakpoints and their association with the clinical phenotype and age at onset. MtDNA deletions in 67 patients were characterized using array comparative genomic hybridization (aCGH) followed by PCR-sequencing of the deletion junctions. Sequence homology including both perfect and imperfect short repeats flanking the deletion regions were analyzed and correlated with clinical features and patients' age group. In all age groups, there was a significant increase in sequence homology flanking the deletion compared to mtDNA background. The youngest patient group (deletion distribution in size and locations, with a significantly lower sequence homology flanking the deletion, and the highest percentage of deletion mutant heteroplasmy. The older age groups showed rather discrete pattern of deletions with 44% of all patients over 6 years old carrying the most common 5 kb mtDNA deletion, which was found mostly in muscle specimens (22/41). Only 15% (3/20) of the young patients (deletion, which is usually present in blood rather than muscle. This group of patients predominantly (16 out of 17) exhibit multisystem disorder and/or Pearson syndrome, while older patients had predominantly neuromuscular manifestations including KSS, PEO, and MM. In conclusion, sequence homology at the deletion flanking regions is a consistent feature of mtDNA deletions. Decreased levels of sequence homology and increased levels of deletion mutant heteroplasmy appear to correlate with earlier onset and more severe disease with multisystem involvement.

  2. 'Impulsive compulsivity' in obsessive-compulsive disorder: a phenotypic marker of patients with poor clinical outcome.

    Science.gov (United States)

    Kashyap, Himani; Fontenelle, Leonardo F; Miguel, Euripedes C; Ferrão, Ygor A; Torres, Albina R; Shavitt, Roseli G; Ferreira-Garcia, Rafael; do Rosário, Maria C; Yücel, Murat

    2012-09-01

    Although traditionally obsessive-compulsive disorder (OCD) and impulse control disorders (ICD) have represented opposing ends of a continuum, recent research has demonstrated a frequent co-occurrence of impulsive and compulsive behaviours, which may contribute to a worse clinical picture of some psychiatric disorders. We hypothesize that individuals with 'impulsive' OCD as characterized by poor insight, low resistance, and reduced control towards their compulsions will have a deteriorative course, greater severity of hoarding and/or symmetry/ordering symptoms, and comorbid ICD and/or substance use disorders (SUD). The sample consisted of 869 individuals with a minimum score of 16 on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Of these, 65 had poor insight, low resistance, and reduced control towards compulsions ('poor IRC') and 444 had preserved insight, greater resistance and better control over compulsions ('good IRC'). These two groups were compared on a number of clinical and demographic variables. Individuals with poor IRC were significantly more likely to have a deteriorative course (p disorder (p = 0.026), trichotillomania (p = 0.014) and compulsive buying (p = 0.040). Regression analysis revealed that duration of obsessions (p = 0.037) and hoarding severity (p = 0.005) were significant predictors of poor IRC. In the absence of specific measures for impulsivity in OCD, the study highlights the utility of simple measures such as insight, resistance and control over compulsions as a phenotypic marker of a subgroup of OCD with impulsive features demonstrating poor clinical outcome. Copyright © 2012 Elsevier Ltd. All rights reserved.

  3. [Tuberous sclerosis: clinical characteristics and their relationship to genotype/phenotype].

    Science.gov (United States)

    Monteiro, T; Garrido, C; Pina, S; Chorão, R; Carrilho, I; Figueiroa, S; Santos, M; Temudo, T

    2014-11-01

    Tuberous sclerosis (TS) is an inherited disorder with multisystemic involvement and a high phenotypic variability. There are two genes that cause this condition: TSC1 and TSC2. Our goal was to clinically characterize patients with TS followed up in the Pediatric Neurology Clinic of a tertiary hospital during the last 10 years, and correlate the genotype with the severity of neurological manifestations and imaging studies. Retrospective analysis of patients with TS, including review of medical records and available MRI imaging. We studied 35 cases with a median age at diagnosis of ten months. Seizures were the first manifestation in 91.4% of cases, with a predominance of epileptic spasms. Over 50% had cognitive impairment and 49% behavioral disorders. A genetic study was performed on 24 children, and TSC2 mutations identified in 58.3% of them. Of the 11 cases of refractory epilepsy, six had the TSC2 gene mutation. In the group of eight patients with moderate/severe cognitive deficits, five had TSC2 mutations. We reviewed 26 MRI scans, in which it was observed that 76.9% had diffuse involvement of cerebral lobes, which reflects a greater burden of injury. Of the patients who had an MRI scan performed and had TSC2 mutations, all had a high tuber load, and5 of them had refractory epilepsy. In our sample we observe a high percentage of mutations in the TSC2 gene. This mutation carries a worse neurological prognosis, with drug-resistant epilepsy and a more severe cognitive impairment. Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

  4. Clinical and Molecular Phenotype of Aicardi-Goutières Syndrome

    Science.gov (United States)

    Rice, Gillian ; Patrick, Teresa ; Parmar, Rekha ; Taylor, Claire F. ; Aeby, Alec ; Aicardi, Jean ; Artuch, Rafael ; Montalto, Simon Attard ; Bacino, Carlos A. ; Barroso, Bruno ; Baxter, Peter ; Benko, Willam S. ; Bergmann, Carsten ; Bertini, Enrico ; Biancheri, Roberta ; Blair, Edward M. ; Blau, Nenad ; Bonthron, David T. ; Briggs, Tracy ; Brueton, Louise A. ; Brunner, Han G. ; Burke, Christopher J. ; Carr, Ian M. ; Carvalho, Daniel R. ; Chandler, Kate E. ; Christen, Hans-Jürgen ; Corry, Peter C. ; Cowan, Frances M. ; Cox, Helen ; D’Arrigo, Stefano ; Dean, John ; De Laet, Corinne ; De Praeter, Claudine ; Déry, Catherine ; Ferrie, Colin D. ; Flintoff, Kim ; Frints, Suzanna G. M. ; Garcia-Cazorla, Angels ; Gener, Blanca ; Goizet, Cyril ; Goutières, Françoise ; Green, Andrew J. ; Guët, Agnès ; Hamel, Ben C. J. ; Hayward, Bruce E. ; Heiberg, Arvid ; Hennekam, Raoul C. ; Husson, Marie ; Jackson, Andrew P. ; Jayatunga, Rasieka ; Jiang, Yong-Hui ; Kant, Sarina G. ; Kao, Amy ; King, Mary D. ; Kingston, Helen M. ; Klepper, Joerg ; van der Knaap, Marjo S. ; Kornberg, Andrew J. ; Kotzot, Dieter ; Kratzer, Wilfried ; Lacombe, Didier ; Lagae, Lieven ; Landrieu, Pierre Georges ; Lanzi, Giovanni ; Leitch, Andrea ; Lim, Ming J. ; Livingston, John H. ; Lourenco, Charles M. ; Lyall, E. G. Hermione ; Lynch, Sally A. ; Lyons, Michael J. ; Marom, Daphna ; McClure, John P. ; McWilliam, Robert ; Melancon, Serge B. ; Mewasingh, Leena D. ; Moutard, Marie-Laure ; Nischal, Ken K. ; Østergaard, John R. ; Prendiville, Julie ; Rasmussen, Magnhild ; Rogers, R. Curtis ; Roland, Dominique ; Rosser, Elisabeth M. ; Rostasy, Kevin ; Roubertie, Agathe ; Sanchis, Amparo ; Schiffmann, Raphael ; Scholl-Bürgi, Sabine ; Seal, Sunita ; Shalev, Stavit A. ; Corcoles, C. Sierra ; Sinha, Gyan P. ; Soler, Doriette ; Spiegel, Ronen ; Stephenson, John B. P. ; Tacke, Uta ; Tan, Tiong Yang ; Till, Marianne ; Tolmie, John L. ; Tomlin, Pam ; Vagnarelli, Federica ; Valente, Enza Maria ; Van Coster, Rudy N. A. ; Van der Aa, Nathalie ; Vanderver, Adeline ; Vles, Johannes S. H. ; Voit, Thomas ; Wassmer, Evangeline ; Weschke, Bernhard ; Whiteford, Margo L. ; Willemsen, Michel A. A. ; Zankl, Andreas ; Zuberi, Sameer M. ; Orcesi, Simona ; Fazzi, Elisa ; Lebon, Pierre ; Crow, Yanick J. 

    2007-01-01

    Aicardi-Goutières syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3′→5′ exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation–positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified. PMID:17846997

  5. Variability in clinical phenotypes of PRPF8-linked autosomal dominant retinitis pigmentosa correlates with differential PRPF8/SNRNP200 interactions.

    Science.gov (United States)

    Escher, Pascal; Passarin, Olga; Munier, Francis L; Tran, Viet H; Vaclavik, Veronika

    2018-01-01

    To expand the genotype/phenotype correlations in patients with autosomal dominant retinitis pigmentosa (adRP) harboring PRPF8 variants. Two patients, a father and his daughter, harboring a novel p.PRPF8-Glu2331* variant, underwent ophthalmic examination at 3-year-interval, including fundus photography, fundus autofluorescence, optical coherence tomography, and ISCEV standard full field ERGs. All reported disease-causing PRPF8 variants were collected and localized in the PRPF8 and PRPF8/SNRNP200 protein structures. The p.PRPF8-Glu2331* variant results in a truncated PRPF8 protein lacking the last five C-terminal amino acids and caused in the two patients a severe clinical phenotype, with the macula being affected from the second decade on. All but two adRP-linked variants are located in the last exon 43 encoding the C-terminal tail of the C-terminal PRPF8 Jab1 domain. The p.PRPF8-Ser2118Phe and -Asn2280Lys variants encoded by exons 39 and 42, respectively, are located at the basis of the C-terminal tail. Frame-shift mutations and nonconservative amino acid changes in PRPF8 typically cause severe clinical phenotypes. The conservative missense variant p.PRPF8-Arg2310Lys that is not altering the global charge of the C-terminal tail, and variants located at the basis of the C-terminal tail show milder clinical phenotypes, in accordance with functional data on PRPF8/SNRNP200 interactions in yeast.

  6. Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of tuberous sclerosis complex.

    Science.gov (United States)

    Zeng, Ling-Hui; Rensing, Nicholas R; Zhang, Bo; Gutmann, David H; Gambello, Michael J; Wong, Michael

    2011-02-01

    Tuberous Sclerosis Complex (TSC) is an autosomal dominant, multi-system disorder, typically involving severe neurological symptoms, such as epilepsy, cognitive deficits and autism. Two genes, TSC1 and TSC2, encoding the proteins hamartin and tuberin, respectively, have been identified as causing TSC. Although there is a substantial overlap in the clinical phenotype produced by TSC1 and TSC2 mutations, accumulating evidence indicates that TSC2 mutations cause more severe neurological manifestations than TSC1 mutations. In this study, the neurological phenotype of a novel mouse model involving conditional inactivation of the Tsc2 gene in glial-fibrillary acidic protein (GFAP)-positive cells (Tsc2(GFAP1)CKO mice) was characterized and compared with previously generated Tsc1(GFAP1)CKO mice. Similar to Tsc1(GFAP1)CKO mice, Tsc2(GFAP1)CKO mice exhibited epilepsy, premature death, progressive megencephaly, diffuse glial proliferation, dispersion of hippocampal pyramidal cells and decreased astrocyte glutamate transporter expression. However, Tsc2(GFAP1)CKO mice had an earlier onset and higher frequency of seizures, as well as significantly more severe histological abnormalities, compared with Tsc1(GFAP1)CKO mice. The differences between Tsc1(GFAP1)CKO and Tsc2(GFAP1)CKO mice were correlated with higher levels of mammalian target of rapamycin (mTOR) activation in Tsc2(GFAP1)CKO mice and were reversed by the mTOR inhibitor, rapamycin. These findings provide novel evidence in mouse models that Tsc2 mutations intrinsically cause a more severe neurological phenotype than Tsc1 mutations and suggest that the difference in phenotype may be related to the degree to which Tsc1 and Tsc2 inactivation causes abnormal mTOR activation.

  7. [Phenotypic variability in 47, XXX patients: Clinical report of four new cases].

    Science.gov (United States)

    Goldschmidt, Ernesto; Márquez, Marisa; Solari, Andrea; Ziembar, María I; Laudicina, Alejandro

    2010-08-01

    The 47, XXX karyotype has a frequency of 1 in 1000 female newborns. However, this karyotype is not usually suspected at birth or childhood. These patients are usually diagnosed during adulthood when they develop premature ovarian failure or infertility, because the early phenotype doesn t have any specific features. The study describes four cases and the clinical variability of the 47, XXX karyotype.

  8. The Broader Autism Phenotype and Friendships in Non-Clinical Dyads

    Science.gov (United States)

    Wainer, Allison L.; Block, Nicole; Donnellan, M. Brent; Ingersoll, Brooke

    2013-01-01

    The broader autism phenotype (BAP) is a set of subclinical traits qualitatively similar to those observed in autism spectrum disorders. The current study sought to elucidate the association between self- and informant-reports of the BAP and friendships, in a non-clinical sample of college student dyads. Self-informant agreement of the BAP and…

  9. The clinical phenotype of hereditary versus sporadic prostate cancer: HPC definition revisited

    NARCIS (Netherlands)

    Cremers, R.G.H.M.; Aben, K.K.H.; Oort, I.M. van; Sedelaar, J.P.M.; Vasen, H.F.A.; Vermeulen, S.H.; Kiemeney, L.A.L.M.

    2016-01-01

    BACKGROUND: The definition of hereditary prostate cancer (HPC) is based on family history and age at onset. Intuitively, HPC is a serious subtype of prostate cancer but there are only limited data on the clinical phenotype of HPC. Here, we aimed to compare the prognosis of HPC to the sporadic form

  10. Viral phenotype, antiretroviral resistance and clinical evolution in human immunodeficiency virus-infected children.

    Science.gov (United States)

    Mellado, M J; Cilleruelo, M J; Ortiz, M; Villota, J; García, M; Perez-Jurado, M L; Barreiro, G; Martín-Fontelos, P; Bernal, A

    1997-11-01

    The syncytium-inducing (SI) viral phenotype and the emergence of viral strains resistant to zidovudine have been described in persons infected with HIV, and in some cases they have been associated with poor prognosis. HIV isolates obtained from 37 HIV-infected children were analyzed to determine whether the SI viral phenotype and the mutation on the 215 position of the reverse transcriptase (M215) could be used as markers of disease progression. We performed peripheral blood coculture mononuclear cells, and we analyzed the induction of syncytia using the MT-2 cell line. The emergence of mutations on the 215 position was determined by PCR. We found a statistically significant association (P < 0.05) between SI viral phenotype and (1) recurrent serious bacterial infections, (2) absolute CD4+ cell counts <2 SD, (3) progression to AIDS and (4) death. Sixty percent of the children treated with zidovudine developed 215 mutant viral strains without statistically significant association with clinical or immunologic findings. The SI viral phenotype was statistically associated with the presence of the 215 mutation (P < 0.05). SI viral phenotype is a marker associated with a poor clinical and immunologic progression of the disease and it may facilitate the emergence of mutant strains in children treated with zidovudine.

  11. Predictive genomics: a cancer hallmark network framework for predicting tumor clinical phenotypes using genome sequencing data.

    Science.gov (United States)

    Wang, Edwin; Zaman, Naif; Mcgee, Shauna; Milanese, Jean-Sébastien; Masoudi-Nejad, Ali; O'Connor-McCourt, Maureen

    2015-02-01

    Tumor genome sequencing leads to documenting thousands of DNA mutations and other genomic alterations. At present, these data cannot be analyzed adequately to aid in the understanding of tumorigenesis and its evolution. Moreover, we have little insight into how to use these data to predict clinical phenotypes and tumor progression to better design patient treatment. To meet these challenges, we discuss a cancer hallmark network framework for modeling genome sequencing data to predict cancer clonal evolution and associated clinical phenotypes. The framework includes: (1) cancer hallmarks that can be represented by a few molecular/signaling networks. 'Network operational signatures' which represent gene regulatory logics/strengths enable to quantify state transitions and measures of hallmark traits. Thus, sets of genomic alterations which are associated with network operational signatures could be linked to the state/measure of hallmark traits. The network operational signature transforms genotypic data (i.e., genomic alterations) to regulatory phenotypic profiles (i.e., regulatory logics/strengths), to cellular phenotypic profiles (i.e., hallmark traits) which lead to clinical phenotypic profiles (i.e., a collection of hallmark traits). Furthermore, the framework considers regulatory logics of the hallmark networks under tumor evolutionary dynamics and therefore also includes: (2) a self-promoting positive feedback loop that is dominated by a genomic instability network and a cell survival/proliferation network is the main driver of tumor clonal evolution. Surrounding tumor stroma and its host immune systems shape the evolutionary paths; (3) cell motility initiating metastasis is a byproduct of the above self-promoting loop activity during tumorigenesis; (4) an emerging hallmark network which triggers genome duplication dominates a feed-forward loop which in turn could act as a rate-limiting step for tumor formation; (5) mutations and other genomic alterations have

  12. Exploring the Genome and Phenotype of Multi-Drug Resistant Klebsiella pneumoniae of Clinical Origin

    OpenAIRE

    João Anes; Daniel Hurley; Marta Martins; Séamus Fanning; Séamus Fanning

    2017-01-01

    Klebsiella pneumoniae is an important nosocomial pathogen with an extraordinary resistant phenotype due to a combination of acquired resistant-elements and efflux mechanisms. In this study a detailed molecular characterization of 11 K. pneumoniae isolates of clinical origin was carried out. Eleven clinical isolates were tested for their susceptibilities, by disk diffusion and broth microdilution and interpreted according to CLSI guidelines. Efflux activity was determined by measuring the extr...

  13. Cognitive impairment, clinical severity and MRI changes in MELAS syndrome.

    Science.gov (United States)

    Kraya, Torsten; Neumann, Lena; Paelecke-Habermann, Yvonne; Deschauer, Marcus; Stoevesandt, Dietrich; Zierz, Stephan; Watzke, Stefan

    2017-12-29

    To examine clinical severity, cognitive impairment, and MRI changes in patients with MELAS syndrome. Cognitive-mnestic functions, brain MRI (lesion load, cella media index) and clinical severity of ten patients with MELAS syndrome were examined. All patients carried the m.3243A>G mutation. The detailed neuropsychological assessment revealed cognitive deficits in attention, executive function, visuoperception, and -construction. There were significant correlations between these cognitive changes, lesion load in MRI, disturbances in everyday life (clinical scale), and high scores in NMDAS. Patients with MELAS syndrome showed no global neuropsychological deficit, but rather distinct cognitive deficits. Copyright © 2018 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

  14. Macrophage phenotype is associated with disease severity in preterm infants with chronic lung disease.

    Science.gov (United States)

    Prince, Lynne R; Maxwell, Nicola C; Gill, Sharonjit K; Dockrell, David H; Sabroe, Ian; McGreal, Eamon P; Kotecha, Sailesh; Whyte, Moira K

    2014-01-01

    The etiology of persistent lung inflammation in preterm infants with chronic lung disease of prematurity (CLD) is poorly characterized, hampering efforts to stratify prognosis and treatment. Airway macrophages are important innate immune cells with roles in both the induction and resolution of tissue inflammation. To investigate airway innate immune cellular phenotypes in preterm infants with respiratory distress syndrome (RDS) or CLD. Bronchoalveolar lavage (BAL) fluid was obtained from term and preterm infants requiring mechanical ventilation. BAL cells were phenotyped by flow cytometry. Preterm birth was associated with an increase in the proportion of non-classical CD14(+)/CD16(+) monocytes on the day of delivery (58.9 ± 5.8% of total mononuclear cells in preterm vs 33.0 ± 6.1% in term infants, p = 0.02). Infants with RDS were born with significantly more CD36(+) macrophages compared with the CLD group (70.3 ± 5.3% in RDS vs 37.6 ± 8.9% in control, p = 0.02). At day 3, infants born at a low gestational age are more likely to have greater numbers of CD14(+) mononuclear phagocytes in the airway (p = 0.03), but fewer of these cells are functionally polarized as assessed by HLA-DR (p = 0.05) or CD36 (p = 0.05) positivity, suggesting increased recruitment of monocytes or a failure to mature these cells in the lung. These findings suggest that macrophage polarization may be affected by gestational maturity, that more immature macrophage phenotypes may be associated with the progression of RDS to CLD and that phenotyping mononuclear cells in BAL could predict disease outcome.

  15. Macrophage phenotype is associated with disease severity in preterm infants with chronic lung disease.

    Directory of Open Access Journals (Sweden)

    Lynne R Prince

    Full Text Available The etiology of persistent lung inflammation in preterm infants with chronic lung disease of prematurity (CLD is poorly characterized, hampering efforts to stratify prognosis and treatment. Airway macrophages are important innate immune cells with roles in both the induction and resolution of tissue inflammation.To investigate airway innate immune cellular phenotypes in preterm infants with respiratory distress syndrome (RDS or CLD.Bronchoalveolar lavage (BAL fluid was obtained from term and preterm infants requiring mechanical ventilation. BAL cells were phenotyped by flow cytometry.Preterm birth was associated with an increase in the proportion of non-classical CD14(+/CD16(+ monocytes on the day of delivery (58.9 ± 5.8% of total mononuclear cells in preterm vs 33.0 ± 6.1% in term infants, p = 0.02. Infants with RDS were born with significantly more CD36(+ macrophages compared with the CLD group (70.3 ± 5.3% in RDS vs 37.6 ± 8.9% in control, p = 0.02. At day 3, infants born at a low gestational age are more likely to have greater numbers of CD14(+ mononuclear phagocytes in the airway (p = 0.03, but fewer of these cells are functionally polarized as assessed by HLA-DR (p = 0.05 or CD36 (p = 0.05 positivity, suggesting increased recruitment of monocytes or a failure to mature these cells in the lung.These findings suggest that macrophage polarization may be affected by gestational maturity, that more immature macrophage phenotypes may be associated with the progression of RDS to CLD and that phenotyping mononuclear cells in BAL could predict disease outcome.

  16. Gender as a Modifying Factor Influencing Myotonic Dystrophy Type 1 Phenotype Severity and Mortality: A Nationwide Multiple Databases Cross-Sectional Observational Study.

    Directory of Open Access Journals (Sweden)

    Celine Dogan

    Full Text Available Myotonic Dystrophy type 1 (DM1 is one of the most heterogeneous hereditary disease in terms of age of onset, clinical manifestations, and severity, challenging both medical management and clinical trials. The CTG expansion size is the main factor determining the age of onset although no factor can finely predict phenotype and prognosis. Differences between males and females have not been specifically reported. Our aim is to study gender impact on DM1 phenotype and severity.We first performed cross-sectional analysis of main multiorgan clinical parameters in 1409 adult DM1 patients (>18 y from the DM-Scope nationwide registry and observed different patterns in males and females. Then, we assessed gender impact on social and economic domains using the AFM-Téléthon DM1 survey (n = 970, and morbidity and mortality using the French National Health Service Database (n = 3301.Men more frequently had (1 severe muscular disability with marked myotonia, muscle weakness, cardiac, and respiratory involvement; (2 developmental abnormalities with facial dysmorphism and cognitive impairment inferred from low educational levels and work in specialized environments; and (3 lonely life. Alternatively, women more frequently had cataracts, dysphagia, digestive tract dysfunction, incontinence, thyroid disorder and obesity. Most differences were out of proportion to those observed in the general population. Compared to women, males were more affected in their social and economic life. In addition, they were more frequently hospitalized for cardiac problems, and had a higher mortality rate.Gender is a previously unrecognized factor influencing DM1 clinical profile and severity of the disease, with worse socio-economic consequences of the disease and higher morbidity and mortality in males. Gender should be considered in the design of both stratified medical management and clinical trials.

  17. Genetic microheterogeneity and phenotypic variation of Helicobacter pylori arginase in clinical isolates

    Directory of Open Access Journals (Sweden)

    Spadafora Domenico

    2007-04-01

    Full Text Available Abstract Background Clinical isolates of the gastric pathogen Helicobacter pylori display a high level of genetic macro- and microheterogeneity, featuring a panmictic, rather than clonal structure. The ability of H. pylori to survive the stomach acid is due, in part, to the arginase-urease enzyme system. Arginase (RocF hydrolyzes L-arginine to L-ornithine and urea, and urease hydrolyzes urea to carbon dioxide and ammonium, which can neutralize acid. Results The degree of variation in arginase was explored at the DNA sequence, enzyme activity and protein expression levels. To this end, arginase activity was measured from 73 minimally-passaged clinical isolates and six laboratory-adapted strains of H. pylori. The rocF gene from 21 of the strains was cloned into genetically stable E. coli and the enzyme activities measured. Arginase activity was found to substantially vary (>100-fold in both different H. pylori strains and in the E. coli model. Western blot analysis revealed a positive correlation between activity and amount of protein expressed in most H. pylori strains. Several H. pylori strains featured altered arginase activity upon in vitro passage. Pairwise alignments of the 21 rocF genes plus strain J99 revealed extensive microheterogeneity in the promoter region and 3' end of the rocF coding region. Amino acid S232, which was I232 in the arginase-negative clinical strain A2, was critical for arginase activity. Conclusion These studies demonstrated that H. pylori arginase exhibits extensive genotypic and phenotypic variation which may be used to understand mechanisms of microheterogeneity in H. pylori.

  18. Screening program for Waardenburg syndrome in Colombia: clinical definition and phenotypic variability.

    Science.gov (United States)

    Tamayo, Marta L; Gelvez, Nancy; Rodriguez, Marcela; Florez, Silvia; Varon, Clara; Medina, David; Bernal, Jaime E

    2008-04-15

    A screening program to detect Waardenburg syndrome (WS) conducted between 2002 and 2005, among 1,763 deaf individuals throughout Columbia identified 95 affected individuals belonging to 95 families, giving a frequency of 5.38% of WS among the institutionalized deaf population. We confirmed the clinical diagnosis of WS in the 95 propositi and, through the family evaluation, we also identified 45 non-institutionalized affected relatives. Audiologic, ophthalmologic, and genetic studies were performed to confirm the diagnosis. Following the classification of the WS consortium, based on the Waardenburg Index (WI), to define the type of WS. We classified 62.1% of the propositi as WS2 and 37.9% as WS1. We present here the results of the study of clinical manifestations, analyzing the presence, severity, and symmetry of clinical findings among this affected population. Overall, among the 95 propositi, in addition to sensorineural deafness in all, the most frequent features were broad nasal root (58.9%), a first degree relative affected (37.9%), heterochromia irides (36.8%), skin hypopigmentation (31.6%), white forelock (28.0%), intense blue iris (27.4%), synophrys (12.6%), premature graying (10.5%), ptosis of the eyelids (9.5%), and hypoplasia alae nasi (1.1%). The majority of individuals had normal psychomotor development (87%), while the remaining 13% had developmental delay. Among the latter, 9.4% corresponded to WS2 and 3.6% to WS1. Our data confirm an interesting inter- and intrafamilial variability in the phenotypic manifestations as well as extremely variable expression. Copyright 2008 Wiley-Liss, Inc.

  19. Tourette syndrome in a longitudinal perspective. Clinical course of tics and comorbidities, coexisting psychopathologies, phenotypes and predictors.

    Science.gov (United States)

    Groth, Camilla

    2018-04-01

    Tourette syndrome (TS) is a childhood onset neurodevelopmental disorder characterised by motor and vocal tics and frequent associated comorbidities. The developmental trajectory of tic shows tic-onset in the age of 4-6, peak in the age of 10-12 and decline during adolescence, although only few and small longitudinal studies form the basis of this evidence. Recent studies suggest that comorbid obsessive-compulsive disorder (OCD), attention deficit-hyperactivity disorder (ADHD) and coexisting psychopathologies tend to persist and become more dominant in adolescence. This large prospective follow-up study want to examine the clinical course of TS: tic and comorbidities during adolescence, the prevalence of coexisting psychopathologies, the tic-related impairment, development in phenotype expression and find predictors for the expected course of TS. 
Method: This study is examining a large clinical cohort recruited at the Danish National Tourette Clinic during the period 2005-2007 and 2011-2013. At baseline, 314 participants aged 5-19 years were included and at follow-up 6 years later 227 participated, aged 11-26. All participants were uniformly clinically examined at basis and follow-up with a clinical interview and validated measurements to assess comorbidities. The Yale Global Tic Severity Scale was used to asses tic severity and tic-related impairment. At follow-up a cross-sectional diagnostic evaluation was made with the Development and Well-Being Assessment to assess coexisting psychopathologies.
 Results: A significant decline in tic and the most frequent comorbidities OCD and ADHD was found although some variation existed and some subclinical and partial remissions persisted. Tic-related impairment was not reflected in the tic-decline as expected but influenced by several parameters. The phenotype expression was found to be dynamic but overall changed toward TS without comorbidities. Several predictors were found to predict the clinical course of TS in

  20. Clinical phenotype in relation to the distance-to-index-patient in familial hypercholesterolemia

    NARCIS (Netherlands)

    Besseling, Joost; Huijgen, Roeland; Martin, Seth S.; Hutten, Barbara A.; Kastelein, John J. P.; Hovingh, G. Kees

    2016-01-01

    We evaluated whether the severity of the familial hypercholesterolemia (FH) phenotype, i.e. increased levels of low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (CVD) risk, decreases in more distantly related patients within one family. We included heterozygous FH patients

  1. Identification of Clinical Phenotypes in Idiopathic Interstitial Pneumonia with Pulmonary Emphysema.

    Science.gov (United States)

    Sato, Suguru; Tanino, Yoshinori; Misa, Kenichi; Fukuhara, Naoko; Nikaido, Takefumi; Uematsu, Manabu; Fukuhara, Atsuro; Wang, Xintao; Ishida, Takashi; Munakata, Mitsuru

    2016-01-01

    Objective Since the term "combined pulmonary fibrosis and emphysema" (CPFE) was first proposed, the co-existence of pulmonary fibrosis and pulmonary emphysema (PE) has drawn considerable attention. However, conflicting results on the clinical characteristics of patients with both pulmonary fibrosis and PE have been published because of the lack of an exact definition of CPFE. The goal of this study was thus to clarify the clinical characteristics and phenotypes of idiopathic interstitial pneumonia (IIP) with PE. Methods We retrospectively analyzed IIP patients who had been admitted to our hospital. Their chest high-resolution computed tomography images were classified into two groups according to the presence of PE. We then performed a cluster analysis to identify the phenotypes of IIP patients with PE. Results Forty-four (53.7%) out of 82 patients had at least mild emphysema in their bilateral lungs. The cluster analysis separated the IIP patients with PE into three clusters. The overall survival rate of one cluster that consisted of mainly idiopathic pulmonary fibrosis (IPF) patients was significantly worse than those of the other clusters. Conclusion Three different phenotypes can be identified in IIP patients with PE, and IPF with PE is a distinct clinical phenotype with a poor prognosis.

  2. Association of Immunological Cell Profiles with Specific Clinical Phenotypes of Scleroderma Disease

    Science.gov (United States)

    Calzada, David; Mayayo, Teodoro; González-Rodríguez, María Luisa; Rabasco, Antonio María; Lahoz, Carlos

    2014-01-01

    This study aimed to search the correlation among immunological profiles and clinical phenotypes of scleroderma in well-characterized groups of scleroderma patients, comparing forty-nine scleroderma patients stratified according to specific clinical phenotypes with forty-nine healthy controls. Five immunological cell subpopulations (B, CD4+ and CD8+ T-cells, NK, and monocytes) and their respective stages of apoptosis and activation were analyzed by flow cytometry, in samples of peripheral blood mononuclear cells (PBMCs). Analyses of results were stratified according to disease stage, time since the diagnosis, and visceral damage (pulmonary fibrosis, pulmonary hypertension, and cardiac affliction) and by time of treatment with corticosteroids. An increase in the percentages of monocytes and a decrease in the B cells were mainly related to the disease progression. A general apoptosis decrease was found in all phenotypes studied, except in localized scleroderma. An increase of B and NK cells activation was found in patients diagnosed more than 10 years ago. Specific cell populations like monocytes, NK, and B cells were associated with the type of affected organ. This study shows how, in a heterogeneous disease, proper patient's stratification according to clinical phenotypes allows finding specific cellular profiles. Our data may lead to improvements in the knowledge of prognosis factors and to aid in the analysis of future specific therapies. PMID:24818126

  3. Prediction of myotonic dystrophy clinical severity based on the number of intragenic [CTG]{sub n} trinucleotide repeats

    Energy Technology Data Exchange (ETDEWEB)

    Gennarelli, M.; Dallapiccola, B. [Universita Tor Vergata, Rome (Italy); Novelli, G. [Universita Cattolica del Sacro Cuore, Rome (Italy)] [and others

    1996-11-11

    We carried out a genotype-phenotype correlation study, based on clinical findings in 465 patients with myotonic dystrophy (DM), in order to assess [CTG] repeat number as a predictive test of disease severity. Our analysis showed that the DM subtypes defined by strict clinical criteria fall into three different classes with a log-normal distribution. This distribution is useful in predicting the probability of specific DM phenotypes based on triplet [CTG] number. This study demonstrates that measurement of triplet expansions in patients` lymphocyte DNA is highly valuable and accurate for prognostic assessment. 45 refs., 1 fig., 2 tabs.

  4. Palmoplantar psoriasis: a phenotypical and clinical review with introduction of a new quality-of-life assessment tool.

    Science.gov (United States)

    Farley, Elizabeth; Masrour, Shamin; McKey, Joanna; Menter, Alan

    2009-06-01

    Palmoplantar psoriasis is associated with significant quality-of-life issues. Its epidemiology and phenotypical expression remain ill defined. We reviewed the literature and our clinical experience and developed a new quality-of-life assessment tool. We conducted a retrospective review of 150 patients with palmoplantar psoriasis. In all, 78 (52%) patients displayed predominantly hyperkeratotic palmoplantar lesions, 24 (16%) pustular, 18 (12%) combination, and 30 (20%) had an indeterminate phenotype. In 27 (18%) patients, lesions were confined to the palms and soles. A new quality-of-life index was constructed to characterize disease severity. In all, 27 (18%) had mild, 72 (48%) moderate, and 51 (34%) severe disease involvement. Palmoplantar disease severity appeared independent from the degree of body surface area involvement. This was a retrospective review. The quality-of-life index remains to be statistically verified in prospective clinical studies. Defining morphologic subtypes together with the use of a specific quality-of-life assessment tool in patients with palmoplantar psoriasis will improve our understanding and treatment of this recalcitrant form of psoriasis.

  5. Is intrathoracic tracheal collapsibility correlated to clinical phenotypes and sex in patients with COPD?

    Directory of Open Access Journals (Sweden)

    Camiciottoli G

    2015-04-01

    Full Text Available Gianna Camiciottoli,1 Stefano Diciotti,2 Francesca Bigazzi,1 Simone Lombardo,3 Maurizio Bartolucci,4 Matteo Paoletti,1 Mario Mascalchi,3 Massimo Pistolesi1 1Section of Respiratory Medicine, Department of Clinical and Experimental Medicine, University of Florence, Florence, Italy; 2Department of Electrical, Electronic, and Information Engineering “Guglielmo Marconi,” University of Bologna, Cesena, Italy; 3Radiodiagnostic Section, Department of Clinical and Experimental Biomedical Sciences, University of Florence, Florence, Italy; 4Department of Diagnostic Imaging, Careggi University Hospital, Florence, Italy Abstract: A substantial proportion of patients with chronic obstructive pulmonary disease (COPD develops various degree of intrathoracic tracheal collapsibility. We studied whether the magnitude of intrathoracic tracheal collapsibility could be different across clinical phenotypes and sex in COPD. Intrathoracic tracheal collapsibility measured at paired inspiratory–expiratory low dose computed tomography (CT and its correlation with clinical, functional, and CT-densitometric data were investigated in 69 patients with COPD according to their predominant conductive airway or emphysema phenotypes and according to sex. Intrathoracic tracheal collapsibility was higher in patients with predominant conductive airway disease (n=28 and in females (n=27. Women with a predominant conductive airway phenotype (n=10 showed a significantly greater degree of collapsibility than women with predominant emphysema (28.9%±4% versus 11.6%±2%; P<0.001. Intrathoracic tracheal collapsibility was directly correlated with inspiratory–expiratory volume variation at CT and with forced expiratory volume (1 second, and inversely correlated with reduced CT lung density and functional residual capacity. Intrathoracic tracheal collapsibility was not correlated with cough and wheezing; however, intrathoracic tracheal collapsibility and clinical phenotypes of COPD

  6. Phenotyping of Chronic Obstructive Pulmonary Disease Based on the Integration of Metabolomes and Clinical Characteristics

    Directory of Open Access Journals (Sweden)

    Kalle Kilk

    2018-02-01

    Full Text Available Apart from the refined management-oriented clinical stratification of chronic obstructive pulmonary disease (COPD, the molecular pathologies behind this highly prevalent disease have remained obscure. The aim of this study was the characterization of patients with COPD, based on the metabolomic profiling of peripheral blood and exhaled breath condensate (EBC within the context of defined clinical and demographic variables. Mass-spectrometry-based targeted analysis of serum metabolites (mainly amino acids and lipid species, untargeted profiles of serum and EBC of patients with COPD of different clinical characteristics (n = 25 and control individuals (n = 21 were performed. From the combined clinical/demographic and metabolomics data, associations between clinical/demographic and metabolic parameters were searched and a de novo phenotyping for COPD was attempted. Adjoining the clinical parameters, sphingomyelins were the best to differentiate COPD patients from controls. Unsaturated fatty acid-containing lipids, ornithine metabolism and plasma protein composition-associated signals from the untargeted analysis differentiated the Global Initiative for COPD (GOLD categories. Hierarchical clustering did not reveal a clinical-metabolomic stratification superior to the strata set by the GOLD consensus. We conclude that while metabolomics approaches are good for finding biomarkers and clarifying the mechanism of the disease, there are no distinct co-variate independent clinical-metabolic phenotypes.

  7. Clinical phenotype and genetic mutation of one case with head tremor and cerebellar atrophy

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    Kun-ming XIE

    2017-07-01

    Full Text Available Objective To make the diagnosis for a patient presented with head tremor and cerebellar atrophy by integrating clinical features and accessory examination with genetic testing and to explore the interpretation of genetic testing results.  Methods A 30-year-old male patient's medical information, clinical pheontype, family history and accessory examinations were collected. The next?generation sequencing (NGS of exons in 3994 causative genes of Mendelian inheritance diseases and the family tree verification were carried out. China Human Phenotype Ontology (CHPO, Phenomizer, Ensembl and Online Mendelian Inheritance in Man (OMIM database were used to interpret the genetic test results.  Results The patient carried heterozygous mutation of spinocerebellar ataxia type 19 (SCA19 related KCND3 gene c.1057A > G (p. Ser353Gly, but his parents did not carry this mutation. The patient also carried heterozygous mutation of parkinsonism type 20 (PARK20 related SYNJ1 gene c.4436C > T (p.Thr1479Ile which was also seen in his mother. Phenotypic similarity analysis showed the patient's phenotype was correspond with the phenotype of SCA19, and the variation locus of KCND3 gene c.1057A > G was highly conservative with homologous gene in different species.  Conclusions By means of the integration of clinical phenotype with the result of genetic test, KCND3 gene c.1057A > G (p.Ser353Gly carried in the patient is the pathogenic mutation. DOI: 10.3969/j.issn.1672-6731.2017.07.007

  8. Clinical potentials of methylator phenotype in stage 4 high-risk neuroblastoma: an open challenge.

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    Barbara Banelli

    Full Text Available Approximately 20% of stage 4 high-risk neuroblastoma patients are alive and disease-free 5 years after disease onset while the remaining experience rapid and fatal progression. Numerous findings underline the prognostic role of methylation of defined target genes in neuroblastoma without taking into account the clinical and biological heterogeneity of this disease. In this report we have investigated the methylation of the PCDHB cluster, the most informative member of the "Methylator Phenotype" in neuroblastoma, hypothesizing that if this epigenetic mark can predict overall and progression free survival in high-risk stage 4 neuroblastoma, it could be utilized to improve the risk stratification of the patients, alone or in conjunction with the previously identified methylation of the SFN gene (14.3.3sigma that can accurately predict outcome in these patients. We have utilized univariate and multivariate models to compare the prognostic power of PCDHB methylation in terms of overall and progression free survival, quantitatively determined by pyrosequencing, with that of other markers utilized for the patients' stratification utilizing methylation thresholds calculated on neuroblastoma at stage 1-4 and only on stage 4, high-risk patients. Our results indicate that PCDHB accurately distinguishes between high- and intermediate/low risk stage 4 neuroblastoma in agreement with the established risk stratification criteria. However PCDHB cannot predict outcome in the subgroup of stage 4 patients at high-risk whereas methylation levels of SFN are suggestive of a "methylation gradient" associated with tumor aggressiveness as suggested by the finding of a higher threshold that defines a subset of patients with an extremely severe disease (OS <24 months. Because of the heterogeneity of neuroblastoma we believe that clinically relevant methylation markers should be selected and tested on homogeneous groups of patients rather than on patients at all stages.

  9. Alzheimer disease-like clinical phenotype in a family with FTDP-17 caused by a MAPT R406W mutation

    DEFF Research Database (Denmark)

    Lindquist, S.G.; Holm, I.E.; Schwartz, M.

    2008-01-01

    We report clinical, molecular, neuroimaging and neuropathological features of a Danish family with autosomal dominant inherited dementia, a clinical phenotype resembling Alzheimer's disease and a pathogenic mutation (R406W) in the microtubule associated protein tau (MAPT) gene. Pre-symptomatic an......We report clinical, molecular, neuroimaging and neuropathological features of a Danish family with autosomal dominant inherited dementia, a clinical phenotype resembling Alzheimer's disease and a pathogenic mutation (R406W) in the microtubule associated protein tau (MAPT) gene. Pre...

  10. Potential biomarkers for the clinical prognosis of severe dengue

    Directory of Open Access Journals (Sweden)

    Mayara Marques Carneiro da Silva

    2013-09-01

    Full Text Available Currently, several assays can confirm acute dengue infection at the point-of-care. However, none of these assays can predict the severity of the disease symptoms. A prognosis test that predicts the likelihood of a dengue patient to develop a severe form of the disease could permit more efficient patient triage and treatment. We hypothesise that mRNA expression of apoptosis and innate immune response-related genes will be differentially regulated during the early stages of dengue and might predict the clinical outcome. Aiming to identify biomarkers for dengue prognosis, we extracted mRNA from the peripheral blood mononuclear cells of mild and severe dengue patients during the febrile stage of the disease to measure the expression levels of selected genes by quantitative polymerase chain reaction. The selected candidate biomarkers were previously identified by our group as differentially expressed in microarray studies. We verified that the mRNA coding for CFD, MAGED1, PSMB9, PRDX4 and FCGR3B were differentially expressed between patients who developed clinical symptoms associated with the mild type of dengue and patients who showed clinical symptoms associated with severe dengue. We suggest that this gene expression panel could putatively serve as biomarkers for the clinical prognosis of dengue haemorrhagic fever.

  11. Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation

    Science.gov (United States)

    2011-01-01

    Background The kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA) (OMIM 225400) is a rare inheritable connective tissue disorder characterized by a deficiency of collagen lysyl hydroxylase 1 (LH1; EC 1.14.11.4) due to mutations in PLOD1. Biochemically this results in underhydroxylation of collagen lysyl residues and, hence, an abnormal pattern of lysyl pyridinoline (LP) and hydroxylysyl pyridinoline (HP) crosslinks excreted in the urine. Clinically the disorder is characterized by hypotonia and kyphoscoliosis at birth, joint hypermobility, and skin hyperelasticity and fragility. Severe hypotonia usually leads to delay in gross motor development, whereas cognitive development is reported to be normal. Methods We describe the clinical, biochemical and molecular characterisation, as well as electron microscopy findings of skin, in 15 patients newly diagnosed with this rare type of Ehlers-Danlos syndrome. Results Age at diagnosis ranged from 5 months to 27 years, with only 1/3 of the patients been diagnosed correctly in the first year of life. A similar disease frequency was found in females and males, however a broad disease severity spectrum (intra- and interfamilial), independent of molecular background or biochemical phenotype, was observed. Kyphoscoliosis, one of the main clinical features was not present at birth in 4 patients. Importantly we also noted the occurrence of vascular rupture antenatally and postnatally, as well as developmental delay in 5 patients. Conclusion In view of these findings we propose that EDS VIA is a highly variable clinical entity, presenting with a broad clinical spectrum, which may also be associated with cognitive delay and an increased risk for vascular events. Genotype/phenotype association studies and additional molecular investigations in more extended EDS VIA populations will be necessary to further elucidate the cause of the variability of the disease severity. PMID:21699693

  12. Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA: clinical, molecular and biochemical delineation

    Directory of Open Access Journals (Sweden)

    Kariminejad Ariana

    2011-06-01

    Full Text Available Abstract Background The kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA (OMIM 225400 is a rare inheritable connective tissue disorder characterized by a deficiency of collagen lysyl hydroxylase 1 (LH1; EC 1.14.11.4 due to mutations in PLOD1. Biochemically this results in underhydroxylation of collagen lysyl residues and, hence, an abnormal pattern of lysyl pyridinoline (LP and hydroxylysyl pyridinoline (HP crosslinks excreted in the urine. Clinically the disorder is characterized by hypotonia and kyphoscoliosis at birth, joint hypermobility, and skin hyperelasticity and fragility. Severe hypotonia usually leads to delay in gross motor development, whereas cognitive development is reported to be normal. Methods We describe the clinical, biochemical and molecular characterisation, as well as electron microscopy findings of skin, in 15 patients newly diagnosed with this rare type of Ehlers-Danlos syndrome. Results Age at diagnosis ranged from 5 months to 27 years, with only 1/3 of the patients been diagnosed correctly in the first year of life. A similar disease frequency was found in females and males, however a broad disease severity spectrum (intra- and interfamilial, independent of molecular background or biochemical phenotype, was observed. Kyphoscoliosis, one of the main clinical features was not present at birth in 4 patients. Importantly we also noted the occurrence of vascular rupture antenatally and postnatally, as well as developmental delay in 5 patients. Conclusion In view of these findings we propose that EDS VIA is a highly variable clinical entity, presenting with a broad clinical spectrum, which may also be associated with cognitive delay and an increased risk for vascular events. Genotype/phenotype association studies and additional molecular investigations in more extended EDS VIA populations will be necessary to further elucidate the cause of the variability of the disease severity.

  13. Genotypic Diversity Is Associated with Clinical Outcome and Phenotype in Cryptococcal Meningitis across Southern Africa.

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    Mathew A Beale

    Full Text Available Cryptococcal meningitis is a major cause of mortality throughout the developing world, yet little is known about the genetic markers underlying Cryptococcal virulence and patient outcome. We studied a cohort of 230 Cryptococcus neoformans (Cn isolates from HIV-positive South African clinical trial patients with detailed clinical follow-up using multi-locus sequence typing and in vitro phenotypic virulence assays, correlating these data with clinical and fungal markers of disease in the patient. South African Cn displayed high levels of genetic diversity and locus variability compared to globally distributed types, and we identified 50 sequence types grouped within the main molecular types VNI, VNII and VNB, with 72% of isolates typed into one of seven 'high frequency' sequence types. Spatial analysis of patients' cryptococcal genotype was not shown to be clustered geographically, which might argue against recent local acquisition and in favour of reactivation of latent infection. Through comparison of MLST genotyping data with clinical parameters, we found a relationship between genetic lineage and clinical outcome, with patients infected with the VNB lineage having significantly worse survival (n=8, HR 3.35, CI 1.51-7.20, p=0.003, and this was maintained even after adjustment for known prognostic indicators and treatment regimen. Comparison of fungal genotype with in vitro phenotype (phagocytosis, laccase activity and CSF survival performed on a subset of 89 isolates revealed evidence of lineage-associated virulence phenotype, with the VNII lineage displaying increased laccase activity (p=0.001 and ex vivo CSF survival (p=0.0001. These findings show that Cryptococcus neoformans is a phenotypically heterogeneous pathogen, and that lineage plays an important role in cryptococcal virulence during human infection. Furthermore, a detailed understanding of the genetic diversity in Southern Africa will support further investigation into how genetic

  14. Heterogeneity in phenotype of usher-congenital hyperinsulinism syndrome: hearing loss, retinitis pigmentosa, and hyperinsulinemic hypoglycemia ranging from severe to mild with conversion to diabetes.

    Science.gov (United States)

    Al Mutair, Angham N; Brusgaard, Klaus; Bin-Abbas, Bassam; Hussain, Khalid; Felimban, Naila; Al Shaikh, Adnan; Christesen, Henrik T

    2013-03-01

    To evaluate the phenotype of 15 children with congenital hyperinsulinism (CHI) and profound hearing loss, known as Homozygous 11p15-p14 Deletion syndrome (MIM #606528). Prospective clinical follow-up and genetic analysis by direct sequencing, multiplex ligation-dependent probe amplification, and microsatellite markers. Genetic testing identified the previous described homozygous deletion in 11p15, USH1C:c.(90+592)_ABCC8:c.(2694-528)del. Fourteen patients had severe CHI demanding near-total pancreatectomy. In one patient with mild, transient neonatal hypoglycemia and nonautoimmune diabetes at age 11 years, no additional mutations were found in HNF1A, HNF4A, GCK, INS, and INSR. Retinitis pigmentosa was found in two patients aged 9 and 13 years. No patients had enteropathy or renal tubular defects. Neuromotor development ranged from normal to severe delay with epilepsy. The phenotype of Homozygous 11p15-p14 Deletion syndrome, or Usher-CHI syndrome, includes any severity of neonatal-onset CHI and severe, sensorineural hearing loss. Retinitis pigmentosa and nonautoimmune diabetes may occur in adolescence.

  15. Adult siblings with homozygous G6PC3 mutations expand our understanding of the severe congenital neutropenia type 4 (SCN4 phenotype

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    Fernandez Bridget A

    2012-11-01

    Full Text Available Abstract Background Severe congenital neutropenia type 4 (SCN4 is an autosomal recessive disorder caused by mutations in the third subunit of the enzyme glucose-6-phosphatase (G6PC3. Its core features are congenital neutropenia and a prominent venous skin pattern, and affected individuals have variable birth defects. Oculocutaneous albinism type 4 (OCA4 is caused by autosomal recessive mutations in SLC45A2. Methods We report a sister and brother from Newfoundland, Canada with complex phenotypes. The sister was previously reported by Cullinane et al., 2011. We performed homozygosity mapping, next generation sequencing and conventional Sanger sequencing to identify mutations that cause the phenotype in this family. We have also summarized clinical data from 49 previously reported SCN4 cases with overlapping phenotypes and interpret the medical histories of these siblings in the context of the literature. Results The siblings’ phenotype is due in part to a homozygous mutation in G6PC3, [c.829C > T, p.Gln277X]. Their ages are 38 and 37 years respectively and they are the oldest SCN4 patients published to date. Both presented with congenital neutropenia and later developed Crohn disease. We suggest that the latter is a previously unrecognized SCN4 manifestation and that not all affected individuals have an intellectual disability. The sister also has a homozygous mutation in SLC45A2, which explains her severe oculocutaneous hypopigmentation. Her brother carried one SLC45A2 mutation and was diagnosed with “partial OCA” in childhood. Conclusions This family highlights that apparently novel syndromes can in fact be caused by two known autosomal recessive disorders.

  16. Severity of mutant phenotype in a series of chlorophyll-deficient wheat mutants depends on light intensity and the severity of the block in chlorophyll synthesis.

    Science.gov (United States)

    Falbel, T G; Meehl, J B; Staehelin, L A

    1996-10-01

    Analyses of a series of allelic chlorina mutants of wheat (Triticum aestivum L.), which have partial blocks in chlorophyll (Chl) synthesis and, therefore, a limited Chl supply, reinforce the principle that Chl is required for the stable accumulation of Chl-binding proteins and that only reaction centers accumulate when the supply of Chl is severely limited. Depending on the rate of Chl accumulation (determined by the severity of the mutation) and on the rate of turnover of Chl and its precursors (determined by the environment in which the plant is grown), the mutants each reach an equilibrium of Chl synthesis and degradation. Together these mutants generate a spectrum of phenotypes. Under the harshest conditions (high illumination), plants with moderate blocks in Chl synthesis have membranes with very little Chl and Chl-proteins and membrane stacks resembling the thylakoids of the lethal xantha mutants of barely grown at low to medium light intensities (which have more severe blocks). In contrast, when grown under low-light conditions the same plants with moderate blocks have thylakoids resembling those of the wild type. The wide range of phenotypes of Chl b-deficient mutants has historically produced more confusion than enlightenment, but incomparable growth conditions can now explain the discrepancies reported in the literature.

  17. A probabilistic model to predict clinical phenotypic traits from genome sequencing.

    Science.gov (United States)

    Chen, Yun-Ching; Douville, Christopher; Wang, Cheng; Niknafs, Noushin; Yeo, Grace; Beleva-Guthrie, Violeta; Carter, Hannah; Stenson, Peter D; Cooper, David N; Li, Biao; Mooney, Sean; Karchin, Rachel

    2014-09-01

    Genetic screening is becoming possible on an unprecedented scale. However, its utility remains controversial. Although most variant genotypes cannot be easily interpreted, many individuals nevertheless attempt to interpret their genetic information. Initiatives such as the Personal Genome Project (PGP) and Illumina's Understand Your Genome are sequencing thousands of adults, collecting phenotypic information and developing computational pipelines to identify the most important variant genotypes harbored by each individual. These pipelines consider database and allele frequency annotations and bioinformatics classifications. We propose that the next step will be to integrate these different sources of information to estimate the probability that a given individual has specific phenotypes of clinical interest. To this end, we have designed a Bayesian probabilistic model to predict the probability of dichotomous phenotypes. When applied to a cohort from PGP, predictions of Gilbert syndrome, Graves' disease, non-Hodgkin lymphoma, and various blood groups were accurate, as individuals manifesting the phenotype in question exhibited the highest, or among the highest, predicted probabilities. Thirty-eight PGP phenotypes (26%) were predicted with area-under-the-ROC curve (AUC)>0.7, and 23 (15.8%) of these were statistically significant, based on permutation tests. Moreover, in a Critical Assessment of Genome Interpretation (CAGI) blinded prediction experiment, the models were used to match 77 PGP genomes to phenotypic profiles, generating the most accurate prediction of 16 submissions, according to an independent assessor. Although the models are currently insufficiently accurate for diagnostic utility, we expect their performance to improve with growth of publicly available genomics data and model refinement by domain experts.

  18. Schwartz–jampel syndrome: Clinical and diagnostic phenotype of a rare genetic disorder

    Directory of Open Access Journals (Sweden)

    Bhaskara P Shelley

    2016-01-01

    Full Text Available The distinctive phenotypic, clinical, skeletal characteristics with the typical electrophysiological features of an 11-year-old male child who presented to the neurology outpatient service are described, with the objective of emphasizing the diagnostic awareness of chondrodystrophic myotonia or Schwartz–Jampel syndrome, a very rare genetic disorder. This autosomal recessive disorder due to mutations in the gene Perlecan leads to abnormal cartilage development and anomalous neuromuscular activity.

  19. Chronobiology differs between men and women with cluster headache, clinical phenotype does not

    DEFF Research Database (Denmark)

    Lund, Nunu; Barloese, Mads; Petersen, Anja

    2017-01-01

    OBJECTIVE: To describe differences between the sexes in the phenotype of cluster headache (CH) in a large, well-characterized clinical CH population. METHODS: Patients from the Danish CH survey aged 18-65 years, diagnosed with CH according to International Classification of Headache Disorders, se...... more often failed. Furthermore, women had chronic CH more frequently than men. A long diagnostic delay and frequent misdiagnosis emphasize the need for increased awareness of CH in both sexes....

  20. Comprehensive Clinical Phenotyping & Genetic Mapping for the Discovery of Autism Susceptibility Genes

    Science.gov (United States)

    2012-12-05

    teaching students with autism spectrum disorders 4.52 Learn strategies for incorporating IEP goals and district standard into daily teaching...W403 Columbus, OH 43205 Final Report Comprehensive Clinical Phenotyping & Genetic Mapping for the Discovery of Autism Susceptibility Genes...QFOXGHDUHDFRGH 1.0 Summary In 2006, the Central Ohio Registry for Autism (CORA) was initiated as a collaboration between Wright-Patterson Air

  1. Comprehensive Clinical Phenotyping and Genetic Mapping for the Discovery of Autism Susceptibility Genes

    Science.gov (United States)

    2013-03-14

    behavioral teaching strategies and best practice for teaching students with autism spectrum disorders 4.52 Learn strategies for incorporating IEP goals...AFRL-SA-WP-TR-2013-0013 Comprehensive Clinical Phenotyping and Genetic Mapping for the Discovery of Autism Susceptibility Genes...Genetic Mapping for the Discovery of Autism Susceptibility Genes 5a. CONTRACT NUMBER N/A 5b. GRANT NUMBER N/A 5c. PROGRAM ELEMENT NUMBER N/A 6

  2. Clinical profile and warning sign finding in children with severe dengue and non-severe dengue

    Science.gov (United States)

    Adam, A. S.; Pasaribu, S.; Wijaya, H.; Pasaribu, A. P.

    2018-03-01

    Dengue fever is one of the most important emerging vector-borne viral diseases. Approximately 500,000 out of 100 million cases develop to severe dengue infection. Patient with severe dengue (SD) can be predicted by clinical profile, laboratory and warning sign which could be saved by early interventions.This was a retrospective descriptive-analytic study to investigate clinical manifestations, laboratory and warning signs ofchildren with dengue infection in Haji Adam Malik hospital during January 2014–May 2016. Through medical records, we had selected 140 cases which fulfilled research criteria.Cases were classified as SD (n=28) and NSD (n=112). Most common clinical manifestations for NSD were abdominal pain (39.3%), myalgia (39.3%), headache (37.1%), mucosal bleeding (36.4%) while for SD were shock (15.7%), mucosal bleeding (15.7%), clinical fluid accumulation (15%), shortness of breath (14.3%). SGPT >1000IU/L (5 cases), SGOT >1000IU/L (9 cases), PT (10 cases) and aPTT (16 cases) were abnormal in SD. Severe dengue was frequently found in the range of white cell count 1000-4000/L and platelet count 20,000-50,000mm/uL. Clinical manifestations, warning sign, and laboratoryfinding, were different between SD and NSD.

  3. Characteristics of COPD patients according to GOLD classification and clinical phenotypes in the Russian Federation: the SUPPORT trial

    Directory of Open Access Journals (Sweden)

    Arkhipov V

    2017-11-01

    Full Text Available Vladimir Arkhipov,1 Daria Arkhipova,2 Marc Miravitlles,3 Andrey Lazarev,4 Ekaterina Stukalina5 1Clinical Pharmacology and Therapy Department, Russian Medical Academy of Postgraduate Education, Moscow, Russian Federation; 2Clinical Pharmacology and Propaedeutic Internal Diseases Department, First Moscow State Medical University, Moscow, Russian Federation; 3Pneumology Department, Hospital Universitari Vall d’Hebron, Ciber de Enfermedades Respiratorias (CIBERES, Barcelona, Spain; 4AstraZeneca Pharmaceuticals, Moscow, Russian Federation; 5AstraZeneca LP, Gaithersburg, MD, USA Background: The high prevalence of COPD in the Russian Federation has been demonstrated in several epidemiological studies. However, there are still no data on the clinical characteristics of these patients according to Global Initiative for Chronic Obstructive Lung Disease (GOLD groups and phenotypes, which could provide additional understanding of the burden of COPD, routine clinical practice, and ways to improve the treatment of patients with COPD in Russia.Patients and methods: SUPPORT was an observational multicenter study designed to obtain data about the distribution of patients with previously diagnosed COPD according to the severity of bronchial obstruction, symptom severity, risk of exacerbation, COPD phenotypes, and treatment of COPD. We included patients with a previous diagnosis of COPD who visited one of 33 primary-care centers for any reason in 23 cities in Russia.Results: Among the 1,505 patients with a previous diagnosis of COPD who attended the primary-care centers and were screened for the study, 1,111 had a spirometry-confirmed diagnosis and were included in the analysis. Up to 53% of the patients had severe or very severe COPD (GOLD stages III–IV, and 74.3% belonged to the GOLD D group. The majority of patients were frequent exacerbators (exacerbators with chronic bronchitis [37.3%], exacerbators without chronic bronchitis [14%], while 35.8% were

  4. Use of recombinant erythropoietin for the management of severe hemolytic disease of the newborn of a K0 phenotype mother.

    Science.gov (United States)

    Manoura, Antonia; Korakaki, Eftychia; Hatzidaki, Eleftheria; Saitakis, Emmanuel; Maraka, Sofia; Papamastoraki, Isabella; Matalliotakis, Emmanuel; Foundouli, Kaliopi; Giannakopoulou, Christine

    2007-01-01

    Very few people do not express any Kell antigens on their red blood cells (K0 phenotype). They can be immunized by transfusion or pregnancy and develop antibodies against Kell system antigens. These maternal antibodies can cause severe hemolytic disease of the fetus/newborn, as a result of the suppression of erythropoiesis and hemolysis. Multiple intrauterine transfusions in the management of severe hemolytic disease have been shown to cause erythropoietic suppression as well. Recombinant erythropoietin has been successfully used in the management of late anemia of infants with Rh hemolytic disease and in 1 case of KEL1 (Kell)-associated hemolytic disease. The authors present the case of severe hemolytic disease of a newborn due to KEL5 (Ku) isoimmunization of his K0 phenotype mother. Regular intrauterine transfusions were performed to manage the severe fetal anemia (Hb 3 g/dL). A male infant was born at the 36th week of gestation having normal hemoglobin (15.8 g/dL) and developed only mild hyperbilirubinemia. On the 15th day of life, the infant's hematocrit had fallen to 27.3%, with low reticulocyte count and low erythropoietin level. The infant was managed successfully with recombinant erythropoietin.

  5. NF1 truncating mutations associated to aggressive clinical phenotype with elephantiasis neuromatosa and solid malignancies.

    Science.gov (United States)

    Ponti, Giovanni; Martorana, Davide; Pellacani, Giovanni; Ruini, Cristel; Loschi, Pietro; Baccarani, Alessio; De Santis, Giorgio; Pollio, Annamaria; Neri, Tauro Maria; Mandel, Victor Desmond; Maiorana, Antonio; Maccio, Livia; Maccaferri, Monia; Tomasi, Aldo

    2014-06-01

    Von Recklinghausen disease is a syndrome characterized by a wide phenotypic variability giving rise to both, cutaneous and visceral benign and malignant neoplasms. The first include cutaneous neurofibromas, subcutaneous and plexiform neurofibromas. The latter can undergo malignant transformation and/or determine elephantiasis neuromatosa. Visceral tumors may include malignant peripheral nerve sheet tumors, gastrointestinal stromal tumors, cerebral gliomas and abdominal neurofibromas. In the present study, the authors discuss the clinical and biomolecular characterization of a cohort of 20 families with a diagnosis of type 1 neurofibromatosis. Clinically, the cohort includes three probands with elephantiasis neuromatosa and a peculiarly high incidence of breast and gastrointestinal cancer. Among the 14 NF1 mutations documented, 10 encoding for a truncated protein have been associated to particularly aggressive clinical phenotypes including elephantiasis neuromatosa, malignant peripheral nerve sheet tumors, breast cancer, gastrointestinal stromal tumors. This effect on protein synthesis, rather than the type of NF1 mutation, is the key to the explanation of the genotype-phenotype correlations in the context of neurofibromatosis type 1. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  6. Hotspots in clinical management of severe liver diseases

    Directory of Open Access Journals (Sweden)

    LYU Jiayu

    2017-09-01

    Full Text Available Severe liver diseases such as liver failure and acute decompensated cirrhosis have critical conditions and high mortality rates, and the prognosis of such patients is closely associated with early warning, timely dynamic assessment, and comprehensive and effective therapy. The patients require a series of effective clinical management measures for elimination of causative factors, organ support, and prevention and treatment of complications. Medical treatment-artificial liver-liver transplantation is an important modality for severe liver diseases. Granulocyte colony-stimulating factor, stem cell therapy, and bioartificial liver have a promising future, while there are still controversies over non-selective β-blocker. This article reviews the hotspots in the clinical management of severe liver diseases.

  7. Phenotypic and genotypic evaluation of 18 Nocardia isolates from human clinical samples in Mexico.

    Science.gov (United States)

    Sánchez-Herrera, K; Sandoval, H; Couble, A; Mouniee, D; Ramírez-Durán, N; Uzcategui de Morillo, M; Serrano, J A; Bergeron, E; Boiron, P; Rodríguez-Nava, V

    2012-03-01

    Mexico has the largest number of clinical cases of actinomycetoma in North and South America. Species originally identified by less specific methods have been recently reclassified as other known species or as new species. To assess, by 16S rRNA gene sequencing and phenotypic methods, the species distribution of 18 human clinical isolates originally identified as N. brasiliensis, some of them isolated between 1947 and 1959 in Mexico City. Clinical isolates came from the Hospital General, "Dr. Manuel Gea Gonzalez", and Instituto Nacional de Diagnóstico y Referencia Epidemiológica (INDRE) in Mexico, D.F. The strains used in this study included 15 clinical strains isolated between 1947 and 1959 that were originally identified as N. brasiliensis and three more strains obtained in 2007 identified as Nocardia spp. The isolates were identified genotypically by sequencing the 16S rRNA gene, and their phenotypic profiles were obtained with the API Coryne(®) system. Antibiotic susceptibility patterns were tested according to the protocol of the Comité de l'antibiogramme de la Société française de microbiologie[4]. According to 16S rRNA gene, sequencing were identified among 18 human clinical isolates as Nocardia farcinica (n=11) and Nocardia brasiliensis (n=7). A high number of the strains were susceptible to the majority of the antibiotics tested. The phenotypic profiles of the strains were quite uniform for N. farcinica and some variability was observed for N. brasiliensis strains. N. farcinica was the most prevalent species identified. Modern methodologies should be applied in clinical laboratories to accurately identify etiological agents. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  8. Partial clinical response to anakinra in severe palmoplantar pustular psoriasis.

    Science.gov (United States)

    Tauber, M; Viguier, M; Alimova, E; Petit, A; Lioté, F; Smahi, A; Bachelez, H

    2014-09-01

    Palmoplantar pustular psoriasis is a clinical psoriasis variant characterised by a high impact on quality of life and poor response to biologics approved for plaque type psoriasis.The recombinant interleukin-1 (IL-1) receptor antagonist anakinra has been recently used for the treatment of isolated refractory cases of generalised pustular psoriasis with contrasted results. To report the clinical response in two patients treated with anakinra as salvage therapy in two patients with severe palmoplantar pustular psoriasis refractory to currently available antipsoriatic systemic therapies. Anakinra was given subcutaneously at the daily dose of 100 mg, and clinical response was evaluated using the palmoplantar psoriasis area and severity index (PPPASI). Only partial and transient responses were observed in both patients, who had to stop anakinra due to lack of efficacy and to side effects. Anakinra appears to provide only partial clinical improvement in refractory palmoplantar pustular psoriasis. Prospective clinical studies on larger populations are warranted to investigate more accurately both efficacy and safety of IL-1-inhibiting strategies in pustular psoriasis. © 2014 British Association of Dermatologists.

  9. Characteristic cardiac phenotypes are detected by cardiovascular magnetic resonance in patients with different clinical phenotypes and genotypes of mitochondrial myopathy.

    Science.gov (United States)

    Florian, Anca; Ludwig, Anna; Stubbe-Dräger, Bianca; Boentert, Matthias; Young, Peter; Waltenberger, Johannes; Rösch, Sabine; Sechtem, Udo; Yilmaz, Ali

    2015-05-22

    Mitochondrial myopathies (MM) are a heterogeneous group of inherited conditions resulting from a primary defect in the mitochondrial respiratory chain with consecutively impaired cellular energy metabolism. Small sized studies using mainly electrocardiography (ECG) and echocardiography have revealed cardiac abnormalities ranging from conduction abnormalities and arrhythmias to hypertrophic or dilated cardiomyopathy in these patients. Recently, characteristic patterns of cardiac involvement were documented by cardiovascular magnetic resonance (CMR) in patients with chronic progressive external ophthalmoplegia (CPEO)/Kearns-Sayre syndrome (KSS) and with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS). The present study aimed to characterize the prevalence and pattern of cardiac abnormalities and to test the additional diagnostic value of CMR in this patient population. The hypothesis that different neuromuscular MM syndromes present with different cardiac disease phenotypes was evaluated. Sixty-four MM patients (50 ± 15 years, 44% male) and 25 matched controls (52 ± 14 years, 36% male) prospectively underwent cardiac evaluations including CMR (comprising cine- and late-gadolinium-enhancement (LGE) imaging). Based on the neuromuscular phenotype and genotype, the patients were grouped: (a) CPEO/KSS (N = 33); (b) MELAS/-like (N = 11); c) myoclonic epilepsy with ragged-red fibers (MERRF) (N = 3) and d) other non-specific MM forms (N = 17). Among the 64 MM patients, 34 (53%) had at least one abnormal CMR finding: 18 (28%) demonstrated an impaired left ventricular ejection-fraction (LV-EF patients showed significantly higher maximal wall thickness (10 ± 3 vs. 8 ± 2 mm, p = 0.005) and concentricity (LV mass to end-diastolic volume: 0.84 ± 0.27 vs. 0.67 ± 0.11, p patients showed the highest frequency of cardiac disease (in 10/11 (91%)), a mostly concentric LV hypertrophy (6/9; 67%) with or

  10. Variation in clinical phenotype of human infection among genetic groups of Blastomyces dermatitidis

    Science.gov (United States)

    Meece, Jennifer K.; Anderson, Jennifer L.; Gruszka, Sarah; Sloss, Brian L.; Sullivan, Bradley; Reed, Kurt D.

    2013-01-01

    Background. Blastomyces dermatitidis, the etiologic agent of blastomycosis, has 2 genetic groups and shows varied clinical presentation, ranging from silent infections to fulminant respiratory disease and dissemination. The objective of this study was to determine whether clinical phenotype and outcomes vary based on the infecting organism's genetic group.Methods. We used microsatellites to genotype 227 clinical isolates of B. dermatitidis from Wisconsin patients. For each isolate, corresponding clinical disease characteristics and patient demographic information were abstracted from electronic health records and Wisconsin Division of Health reportable disease forms and questionnaires.Results. In univariate analysis, group 1 isolates were more likely to be associated with pulmonary-only infections (P 1 month (P smoking status (P = .0001) remained predictors for group 2 infections.Conclusions. This study identified previously unknown associations between clinical phenotype of human infection and genetic groups of B. dermatitidis and provides a framework for further investigations of the genetic basis for virulence in B. dermatitidis.

  11. Histological Stratification of Thick and Thin Plaque Psoriasis Explores Molecular Phenotypes with Clinical Implications

    Science.gov (United States)

    Kim, Dong Joo; Brodmerkel, Carrie; Correa da Rosa, Joel; Krueger, James G.; Suárez-Fariñas, Mayte

    2015-01-01

    Psoriasis, which presents as red, scaly patches on the body, is a common, autoimmune skin disease that affects 2 to 3 percent of the world population. To leverage recent molecular findings into the personalized treatment of psoriasis, we need a strategy that integrates clinical stratification with molecular phenotyping. In this study, we sought to stratify psoriasis patients by histological measurements of epidermal thickness, and to compare their molecular characterizations by gene expression, serum cytokines, and response to biologics. We obtained histological measures of epidermal thickness in a cohort of 609 psoriasis patients, and identified a mixture of two subpopulations—thick and thin plaque psoriasis—from which they were derived. This stratification was verified in a subcohort of 65 patients from a previously published study with significant differences in inflammatory cell infiltrates in the psoriatic skin. Thick and thin plaque psoriasis shared 84.8% of the meta-analysis-derived psoriasis transcriptome, but a stronger dysregulation of the meta-analysis-derived psoriasis transcriptome was seen in thick plaque psoriasis on microarray. RT-PCR revealed that gene expression in thick and thin plaque psoriasis was different not only within psoriatic lesional skin but also in peripheral non-lesional skin. Additionally, differences in circulating cytokines and their changes in response to biologic treatments were found between the two subgroups. All together, we were able to integrate histological stratification with molecular phenotyping as a way of exploring clinical phenotypes with different expression levels of the psoriasis transcriptome and circulating cytokines. PMID:26176783

  12. Targeting neutrophilic inflammation in severe neutrophilic asthma : can we target the disease-relevant neutrophil phenotype?

    NARCIS (Netherlands)

    Bruijnzeel, Piet L B; Uddin, Mohib; Koenderman, Leo

    2015-01-01

    In severe, neutrophilic asthma, neutrophils are thought to have an important role in both the maintenance of the disease and during exacerbations. These patients often display excessive, mucosal airway inflammation with unresolving neutrophilia. Because this variant of asthma is poorly controlled by

  13. Cuticular Drusen: Clinical Phenotypes and Natural History Defined Using Multimodal Imaging.

    Science.gov (United States)

    Balaratnasingam, Chandrakumar; Cherepanoff, Svetlana; Dolz-Marco, Rosa; Killingsworth, Murray; Chen, Fred K; Mendis, Randev; Mrejen, Sarah; Too, Lay Khoon; Gal-Or, Orly; Curcio, Christine A; Freund, K Bailey; Yannuzzi, Lawrence A

    2018-01-01

    To define the range and life cycles of cuticular drusen phenotypes using multimodal imaging and to review the histologic characteristics of cuticular drusen. Retrospective, observational cohort study and experimental laboratory study. Two hundred forty eyes of 120 clinic patients with a cuticular drusen phenotype and 4 human donor eyes with cuticular drusen (n = 2), soft drusen (n = 1), and hard drusen (n = 1). We performed a retrospective review of clinical and multimodal imaging data of patients with a cuticular drusen phenotype. Patients had undergone imaging with various combinations of color photography, fluorescein angiography, indocyanine green angiography, near-infrared reflectance, fundus autofluorescence, high-resolution OCT, and ultrawide-field imaging. Human donor eyes underwent processing for high-resolution light and electron microscopy. Appearance of cuticular drusen in multimodal imaging and the topography of a cuticular drusen distribution; age-dependent variations in cuticular drusen phenotypes, including the occurrence of retinal pigment epithelium (RPE) abnormalities, choroidal neovascularization, acquired vitelliform lesions (AVLs), and geographic atrophy (GA); and ultrastructural and staining characteristics of druse subtypes. The mean age of patients at the first visit was 57.9±13.4 years. Drusen and RPE changes were seen in the peripheral retina, anterior to the vortex veins, in 21.8% of eyes. Of eyes with more than 5 years of follow-up, cuticular drusen disappeared from view in 58.3% of eyes, drusen coalescence was seen in 70.8% of eyes, and new RPE pigmentary changes developed in 56.2% of eyes. Retinal pigment epithelium abnormalities, AVLs, neovascularization, and GA occurred at a frequency of 47.5%, 24.2%, 12.5%, and 25%, respectively, and were significantly more common in patients older than 60 years of age (all P < 0.015). Occurrence of GA and neovascularization were important determinants of final visual acuity in eyes with the

  14. The Relation between Diverse Phenotypes of PCOS with Clinical Manifestations, Anthropometric Indices and Metabolic Characteristics.

    Science.gov (United States)

    Shahrami, Seyedeh Hajar; Abbasi Ranjbar, Zahra; Milani, Forozan; Kezem-Nejad, Ehsan; Hassanzadeh Rad, Afagh; Dalil Heirat, Seyedeh Fatemeh

    2016-02-01

    Critical issue regarding to variation of findings based on different phenotypes led investigators to define whether they are distinct features or overlapping ones. Therefore, we aimed to investigate the association between diverse phenotypes of PCOS (Poly Cystic Ovary Syndrome) with clinical manifestations, anthropometric indices, and metabolic characteristics. This was a descriptive cross-sectional study conducted in 15-39 years old women with PCOS referred to infertility clinics in the north part of Iran, Rasht during 2010-2011. Data were gathered through an interview by a form consisted of demographic characteristics, laboratory findings, ovarian volume and anthropometric indices. A total of 214 patients consisted of 161 PCOS (cases) and 53 normal women (controls) participated in this study. The most prevalent phenotype in PCOS population was IM/PCO/HA (54%), followed by IM/HA (28%) and IM/PCO (13%). PCO/HA was present only in 6 PCOS patients (5%). PCOS patients were significantly younger than controls (P=0.07). Results showed that increased ovarian volume were higher in PCOS group in comparison with controls and IM/PCO/HA, and IM/PCO had respectively the largest ovarian volumes. Also, a significant relation was observed based on Cholesterol, 17OHP, LH, TG, 2hpp, and LH/FSH between patients with PCOS and control groups. There were significant differences in demographic, anthropometric, hormonal and ultrasound findings between PCOS and controls. Therefore, it seems that classification of the characteristics of each phenotype could offer an appropriate guide for screening risks of PCOS and may facilitate performing most favorable treatment for these complications.

  15. The Relationship between the Broader Autism Phenotype, Child Severity, and Stress and Depression in Parents of Children with Autism Spectrum Disorders

    Science.gov (United States)

    Ingersoll, Brooke; Hambrick, David Z.

    2011-01-01

    This study examined the relationship between child symptom severity, parent broader autism phenotype (BAP), and stress and depression in parents of children with ASD. One hundred and forty-nine parents of children with ASD completed a survey of parenting stress, depression, broader autism phenotype, coping styles, perceived social support, and…

  16. The Importance of Clinical Phenotype in Understanding and Preventing Spontaneous Preterm Birth.

    Science.gov (United States)

    Esplin, M Sean

    2016-02-01

    Spontaneous preterm birth (SPTB) is a well-known cause of maternal and neonatal morbidity. The search for the underlying pathways, documentation of the genetic causes, and identification of markers of spontaneous PTB have been marginally successful due to the fact that it is highly complex, with numerous processes that lead to a final common pathway. There is a great need for a comprehensive, consistent, and uniform classification system, which will be useful in identifying mechanisms, assigning prognosis, aiding in clinical management, and can identify areas of interest for intervention and future study. Effective classification systems must overcome obstacles including the lack of widely accepted definitions and uncertainty about inclusion of classifying features (e.g., presentation at delivery and multiple gestations) and levels of detail of these features. The optimal classification system should be based on the clinical phenotype, including characteristics of the mother, fetus, placenta, and the presentation for delivery. We present a proposed phenotyping system for spontaneous PTB. Future classification systems must establish a universally accepted set of definitions and a standardized clinical workup for all PTBs including the minimum clinical data to be collected and the laboratory and pathologic evaluation that should be completed. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  17. Clinical indicators for severe prognosis of scrub typhus

    Directory of Open Access Journals (Sweden)

    Sriwongpan P

    2013-10-01

    Full Text Available Pamornsri Sriwongpan,1,2 Pornsuda Krittigamas,3 Pacharee Kantipong,4 Naowarat Kunyanone,5 Jayanton Patumanond,1 Sirianong Namwongprom1,61Clinical Epidemiology Program, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; 2Department of Social Medicine, Chiang Rai Prachanukroh Hospital, Chiang Rai, Thailand; 3Department of General Pediatrics, Nakornping Hospital, Chiang Mai, Thailand; 4Department of Internal Medicine, 5Department of Medical Technology, Chiang Rai Prachanukroh Hospital, Chiang Rai, Thailand; 6Department of Radiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, ThailandBackground: The study explored clinical risk characteristics that may be used to forecast scrub typhus severity under routine clinical practices.Methods: Retrospective data were collected from patients registered at two university-affiliated tertiary care hospitals in the north of Thailand, from 2004 to 2010. Key information was retrieved from in-patient records, out patient cards, laboratory reports and registers. Patients were classified into three severity groups: nonsevere, severe (those with at least one organ involvement, and deceased. Prognostic characteristics for scrub typhus severity were analyzed by a multivariable ordinal continuation ratio regression.Results: A total of 526 patients were classified into nonsevere (n = 357, severe (n = 100, and deceased (n = 69. The significant multivariable prognostic characteristics for scrub typhus severity were increased body temperature (odds ratio [OR] = 0.58, 95% confidence interval [CI] = 0.45–0.74, P < 0.001, increased pulse rate (OR = 1.03, 95% CI = 1.01–1.05, P < 0.001, presence of crepitation (OR = 3.25, 95% CI = 1.52–6.96, P = 0.001, increased percentage of lymphocytes (OR = 0.97, 95% CI = 0.95–0.98, P = 0.001, increased aspartate aminotransferase (every 10 IU/L (OR = 1.04, 95% CI = 1.02–1.06, P < 0.001, increased serum albumin (OR = 0.47, 95% CI = 0.27–0.80, P = 0

  18. A model for generating several adaptive phenotypes from a single genetic event

    DEFF Research Database (Denmark)

    Møller, Henrik D; Andersen, Kaj S; Regenberg, Birgitte

    2013-01-01

    Microbial populations adapt to environmental fluctuations through random switching of fitness-related traits in individual cells. This increases the likelihood that a subpopulation will be adaptive in a future milieu. However, populations are particularly challenged when several environment facto...... energy recruitment by trehalose mobilization, and in some cases, adherent biofilm growth. Our proposed model of a hub-switch locus enhances the bet-hedging model of population dynamics....

  19. Clinical experience using intranasal ketamine in the treatment of pediatric bipolar disorder/fear of harm phenotype.

    Science.gov (United States)

    Papolos, Demitri F; Teicher, Martin H; Faedda, Gianni L; Murphy, Patricia; Mattis, Steven

    2013-05-01

    Intravenous ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, has been shown to exert a rapid antidepressant effect in adults with treatment resistant depression. Children with bipolar disorder (BD) often respond poorly to pharmacotherapy, including polypharmacy. A pediatric-onset Fear of Harm (FOH) phenotype has been described, and is characterized by severe clinical features and resistance to accepted treatments for BD. The potential efficacy and safety of intranasal ketamine in children with BD with FOH-phenotype were assessed by a systematic retrospective chart review of a case series from the private practice of one of the authors, including cases with clear refractoriness to mood stabilizers, antipsychotics and benzodiazepines. A comparison was made between routinely collected symptom measures 1-2 weeks prior to and after the administration of ketamine, in 12 treatment-refractory youth, 10 males 2 females ages 6-19years. Ketamine administration was associated with a substantial reduction in measures of mania, fear of harm and aggression. Significant improvement was observed in mood, anxiety and behavioral symptoms, attention/executive functions, insomnia, parasomnias and sleep inertia. Treatment was generally well-tolerated. Intranasal ketamine administration in treatment-resistant youth with BD-FOH produced marked improvement in all symptomatic dimensions. A rapid, substantial therapeutic response, with only minimal side effects was observed. Formal clinical trials to assess safety and efficacy are warranted. Copyright © 2012 Elsevier B.V. All rights reserved.

  20. Characterization of Rod Function Phenotypes Across a Range of Age-Related Macular Degeneration Severities and Subretinal Drusenoid Deposits.

    Science.gov (United States)

    Flynn, Oliver J; Cukras, Catherine A; Jeffrey, Brett G

    2018-05-01

    To examine spatial changes in rod-mediated function in relationship to local structural changes across the central retina in eyes with a spectrum of age-related macular degeneration (AMD) disease severity. Participants were categorized into five AMD severity groups based on fundus features. Scotopic thresholds were measured at 14 loci spanning ±18° along the vertical meridian from one eye of each of 42 participants (mean = 71.7 ± 9.9 years). Following a 30% bleach, dark adaptation was measured at eight loci (±12°). Rod intercept time (RIT) was defined from the time to detect a -3.1 log cd/m2 stimulus. RITslope was defined from the linear fit of RIT with decreasing retinal eccentricity. The presence of subretinal drusenoid deposits (SDD), ellipsoid (EZ) band disruption, and drusen at the test loci was evaluated using optical coherence tomography. Scotopic thresholds indicated greater rod function loss in the macula, which correlated with increasing AMD group severity. RITslope, which captures the spatial change in the rate of dark adaptation, increased with AMD severity (P < 0.0001). Three rod function phenotypes emerged: RF1, normal rod function; RF2, normal scotopic thresholds but slowed dark adaptation; and RF3, elevated scotopic thresholds with slowed dark adaptation. Dark adaptation was slowed at all loci with SDD or EZ band disruption, and at 32% of loci with no local structural changes. Three rod function phenotypes were defined from combined measurement of scotopic threshold and dark adaptation. Spatial changes in dark adaptation across the macula were captured with RITslope, which may be a useful outcome measure for functional studies of AMD.

  1. The Ethics of Clinical Trials Research in Severe Mood Disorders.

    Science.gov (United States)

    Nugent, Allison C; Miller, Franklin G; Henter, Ioline D; Zarate, Carlos A

    2017-07-01

    Mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD), are highly prevalent, frequently disabling, and sometimes deadly. Additional research and more effective medications are desperately needed, but clinical trials research in mood disorders is fraught with ethical issues. Although many authors have discussed these issues, most do so from a theoretical viewpoint. This manuscript uses available empirical data to inform a discussion of the primary ethical issues raised in mood disorders research. These include issues of consent and decision-making capacity, including patients' motivations for participating in research. We also address drug withdrawals, placebo controls, and the overall safety of research. Finally, we examine the extant literature for studies discussing potential indirect benefits of clinical trials research to participants. Taken together, the evidence suggests that clinical trials research incorporating drug withdrawals and placebo controls can be conducted safely and ethically, even in patients with severe or treatment-resistant mood disorders. In fact, given the dearth of effective treatment options for this population, it is our opinion that a moral imperative exists to extend the offer of research participation to severely ill or treatment-resistant groups. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

  2. Improvement in pain severity category in clinical trials of pregabalin

    Directory of Open Access Journals (Sweden)

    Parsons B

    2016-10-01

    Full Text Available Bruce Parsons,1 Charles E Argoff,2 Andrew Clair,1 Birol Emir1 1Pfizer, New York, NY, USA; 2Albany Medical Center, Albany, NY, USA Background: Pregabalin is approved by the US Food and Drug Administration for the treatment of fibromyalgia (FM, diabetic peripheral neuropathy (DPN, postherpetic neuralgia (PHN, and neuropathic pain due to spinal cord injury (SCI. Approval was based on clinical trial data demonstrating statistically significant differences in pain scores versus placebo. However, statistically significant pain relief may not always equate to clinically meaningful pain relief. To further characterize the clinical benefit of pregabalin, this analysis examined shifts in pain severity categories in patients with FM, DPN/PHN (pooled in this analysis, and SCI treated with pregabalin.Methods: Data were pooled from 23 placebo-controlled trials in patients with FM (1,623 treated with pregabalin, 937 placebo, DPN/PHN (2,867 pregabalin, 1,532 placebo, or SCI (181 pregabalin, 175 placebo. Pain scores were assessed on an 11-point numeric rating scale and categorized as mild (0 to <4, moderate (4 to <7, or severe (7 to 10. Only patients with mean score ≥4 at baseline were randomized to treatment. The percentage of patients shifting pain category from baseline to endpoint for pregabalin and placebo was analyzed using a modified ridit transformation with the Cochran–Mantel–Haenszel procedure.Results: A higher proportion of patients shifted to a less severe pain category at endpoint with pregabalin compared with placebo. With flexible-dose pregabalin, the percentage of patients improving from: severe to mild (pregabalin versus placebo was 15.8 versus 13.4 in FM patients, 36.0 versus 16.6 in DPN/PHN patients, 14.3 versus 7.7 in SCI patients; severe to moderate was 28.7 versus 28.2 in FM patients, 32.5 versus 28.2 in DPN/PHN patients, 35.7 versus 28.2 in SCI patients; and moderate to mild was 38.3 versus 26.4 in FM patients, 59.5 versus 41.4 in

  3. Genotypic and Phenotypic Diversity of Cryptococcus gattii VGII Clinical Isolates and Its Impact on Virulence

    Directory of Open Access Journals (Sweden)

    Vanessa A. Barcellos

    2018-02-01

    Full Text Available The Cryptococcus gattii species complex harbors the main etiological agents of cryptococcosis in immunocompetent patients. C. gattii molecular type VGII predominates in the north and northeastern regions of Brazil, leading to high morbidity and mortality rates. C. gattii VGII isolates have a strong clinical relevance and phenotypic variations. These phenotypic variations among C. gattii species complex isolates suggest that some strains are more virulent than others, but little information is available related to the pathogenic properties of those strains. In this study, we analyzed some virulence determinants of C. gattii VGII strains (CG01, CG02, and CG03 isolated from patients in the state of Piauí, Brazil. The C. gattii R265 VGIIa strain, which was isolated from the Vancouver outbreak, differed from C. gattii CG01, CG02 and CG03 isolates (also classified as VGII when analyzed the capsular dimensions, melanin production, urease activity, as well as the glucuronoxylomannan (GXM secretion. Those differences directly reflected in their virulence potential. In addition, CG02 displayed higher virulence compared to R265 (VGIIa strain in a cryptococcal murine model of infection. Lastly, we examined the genotypic diversity of these strains through Multilocus Sequence Type (MLST and one new subtype was described for the CG02 isolate. This study confirms the presence and the phenotypic and genotypic diversity of highly virulent strains in the Northeast region of Brazil.

  4. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype.

    Directory of Open Access Journals (Sweden)

    Alvar Agustí

    Full Text Available Because chronic obstructive pulmonary disease (COPD is a heterogeneous condition, the identification of specific clinical phenotypes is key to developing more effective therapies. To explore if the persistence of systemic inflammation is associated with poor clinical outcomes in COPD we assessed patients recruited to the well-characterized ECLIPSE cohort (NCT00292552.Six inflammatory biomarkers in peripheral blood (white blood cells (WBC count and CRP, IL-6, IL-8, fibrinogen and TNF-α levels were quantified in 1,755 COPD patients, 297 smokers with normal spirometry and 202 non-smoker controls that were followed-up for three years. We found that, at baseline, 30% of COPD patients did not show evidence of systemic inflammation whereas 16% had persistent systemic inflammation. Even though pulmonary abnormalities were similar in these two groups, persistently inflamed patients during follow-up had significantly increased all-cause mortality (13% vs. 2%, p<0.001 and exacerbation frequency (1.5 (1.5 vs. 0.9 (1.1 per year, p<0.001 compared to non-inflamed ones. As a descriptive study our results show associations but do not prove causality. Besides this, the inflammatory response is complex and we studied only a limited panel of biomarkers, albeit they are those investigated by the majority of previous studies and are often and easily measured in clinical practice.Overall, these results identify a novel systemic inflammatory COPD phenotype that may be the target of specific research and treatment.

  5. Glioma CpG island methylator phenotype (G-CIMP): biological and clinical implications.

    Science.gov (United States)

    Malta, Tathiane M; de Souza, Camila F; Sabedot, Thais S; Silva, Tiago C; Mosella, Maritza S; Kalkanis, Steven N; Snyder, James; Castro, Ana Valeria B; Noushmehr, Houtan

    2018-04-09

    Gliomas are a heterogeneous group of brain tumors with distinct biological and clinical properties. Despite advances in surgical techniques and clinical regimens, treatment of high-grade glioma remains challenging and carries dismal rates of therapeutic success and overall survival. Challenges include the molecular complexity of gliomas, as well as inconsistencies in histopathological grading, resulting in an inaccurate prediction of disease progression and failure in the use of standard therapy. The updated 2016 World Health Organization (WHO) classification of tumors of the central nervous system reflects a refinement of tumor diagnostics by integrating the genotypic and phenotypic features, thereby narrowing the defined subgroups. The new classification recommends molecular diagnosis of isocitrate dehydrogenase (IDH) mutational status in gliomas. IDH-mutant gliomas manifest the cytosine-phosphate-guanine (CpG) island methylator phenotype (G-CIMP). Notably, the recent identification of clinically relevant subsets of G-CIMP tumors (G-CIMP-high and G-CIMP-low) provides a further refinement in glioma classification that is independent of grade and histology. This scheme may be useful for predicting patient outcome and may be translated into effective therapeutic strategies tailored to each patient. In this review, we highlight the evolution of our understanding of the G-CIMP subsets and how recent advances in characterizing the genome and epigenome of gliomas may influence future basic and translational research.

  6. Norrie-Warburg syndrome: two novel mutations in patients with classical clinical phenotype.

    Science.gov (United States)

    Gal, A; Veske, A; Jojart, G; Grammatico, B; Huber, B; Gu, S; del Porto, G; Senyi, K

    1996-01-01

    Norrie-Warburg syndrome (NWS) is a rare X-linked disorder characterized by blindness, which is invariable, deafness and mental disturbances, which are present occasionally. We describe here two novel mutations, a missense mutation (C126S) and a 1-base pair insertion (insT466/T467), together with a recurrent mutation (M1V), found in patients presenting with the classical clinical phenotype of NWS. All three mutations are likely to result in prominent structural changes of the norrin protein.

  7. Cortical sensorimotor alterations classify clinical phenotype and putative genotype of spasmodic dysphonia

    Science.gov (United States)

    Battistella, Giovanni; Fuertinger, Stefan; Fleysher, Lazar; Ozelius, Laurie J.; Simonyan, Kristina

    2017-01-01

    Background Spasmodic dysphonia (SD), or laryngeal dystonia, is a task-specific isolated focal dystonia of unknown causes and pathophysiology. Although functional and structural abnormalities have been described in this disorder, the influence of its different clinical phenotypes and genotypes remains scant, making it difficult to explain SD pathophysiology and to identify potential biomarkers. Methods We used a combination of independent component analysis and linear discriminant analysis of resting-state functional MRI data to investigate brain organization in different SD phenotypes (abductor vs. adductor type) and putative genotypes (familial vs. sporadic cases) and to characterize neural markers for genotype/phenotype categorization. Results We found abnormal functional connectivity within sensorimotor and frontoparietal networks in SD patients compared to healthy individuals as well as phenotype- and genotype-distinct alterations of these networks, involving primary somatosensory, premotor and parietal cortices. The linear discriminant analysis achieved 71% accuracy classifying SD and healthy individuals using connectivity measures in the left inferior parietal and sensorimotor cortex. When categorizing between different forms of SD, the combination of measures from left inferior parietal, premotor and right sensorimotor cortices achieved 81% discriminatory power between familial and sporadic SD cases, whereas the combination of measures from the right superior parietal, primary somatosensory and premotor cortices led to 71% accuracy in the classification of adductor and abductor SD forms. Conclusions Our findings present the first effort to identify and categorize isolated focal dystonia based on its brain functional connectivity profile, which may have a potential impact on the future development of biomarkers for this rare disorder. PMID:27346568

  8. Cortical sensorimotor alterations classify clinical phenotype and putative genotype of spasmodic dysphonia.

    Science.gov (United States)

    Battistella, G; Fuertinger, S; Fleysher, L; Ozelius, L J; Simonyan, K

    2016-10-01

    Spasmodic dysphonia (SD), or laryngeal dystonia, is a task-specific isolated focal dystonia of unknown causes and pathophysiology. Although functional and structural abnormalities have been described in this disorder, the influence of its different clinical phenotypes and genotypes remains scant, making it difficult to explain SD pathophysiology and to identify potential biomarkers. We used a combination of independent component analysis and linear discriminant analysis of resting-state functional magnetic resonance imaging data to investigate brain organization in different SD phenotypes (abductor versus adductor type) and putative genotypes (familial versus sporadic cases) and to characterize neural markers for genotype/phenotype categorization. We found abnormal functional connectivity within sensorimotor and frontoparietal networks in patients with SD compared with healthy individuals as well as phenotype- and genotype-distinct alterations of these networks, involving primary somatosensory, premotor and parietal cortices. The linear discriminant analysis achieved 71% accuracy classifying SD and healthy individuals using connectivity measures in the left inferior parietal and sensorimotor cortices. When categorizing between different forms of SD, the combination of measures from the left inferior parietal, premotor and right sensorimotor cortices achieved 81% discriminatory power between familial and sporadic SD cases, whereas the combination of measures from the right superior parietal, primary somatosensory and premotor cortices led to 71% accuracy in the classification of adductor and abductor SD forms. Our findings present the first effort to identify and categorize isolated focal dystonia based on its brain functional connectivity profile, which may have a potential impact on the future development of biomarkers for this rare disorder. © 2016 EAN.

  9. Severe paraquat poisoning: clinical and radiological findings in a survivor

    Energy Technology Data Exchange (ETDEWEB)

    Neves, Fabio Fernandes; Sousa, Romualdo Barroso; Pazin-Filho, Antonio; Cupo, Palmira; Elias Junior, Jorge; Nogueira-Barbosa, Marcello Henrique, E-mail: fabioneves@hcrp.usp.b [University of Sao Paulo (USP), Sao Paulo, SP (Brazil). Medical School

    2010-07-01

    Paraquat is a nonselective contact herbicide of great toxicological importance, being associated with high mortality rates, mainly due to respiratory failure. We report the case of a 22-year-old male admitted to the emergency room with a sore throat, dysphagia, hemoptysis, and retrosternal pain after the ingestion of 50 mL of a paraquat solution, four days prior to admission. Chest CT scans revealed pulmonary opacities, pneumomediastinum, pneumothorax, and subcutaneous emphysema. The patient was submitted to two cycles of immunosuppressive therapy with cyclophosphamide, methylprednisolone, and dexamethasone. The pulmonary gas exchange parameters gradually improved, and the patient was discharged four weeks later. The clinical and tomographic follow-up evaluations performed at four months after discharge showed that there had been further clinical improvement. We also present a brief review of the literature, as well as a discussion of the therapeutic algorithm for severe paraquat poisoning. (author)

  10. Severe hyperthyroidism: aetiology, clinical features and treatment outcome.

    Science.gov (United States)

    Iglesias, P; Dévora, O; García, J; Tajada, P; García-Arévalo, C; Díez, J J

    2010-04-01

    Severe hyperthyroidism (SH) is a serious medical disorder that can compromise life. There have not been systematic studies in which SH has been evaluated in detail. Here, our aims were: (1) to analyse both clinical and analytical features and outcome in patients with SH and (2) to compare these data with those found in more usual forms of hyperthyroidism. Patients and methods All patients diagnosed of SH (free thyroxine, FT4 > 100 pmol/l, NR: 11-23) seen in our endocrinology clinic in the last 15 years were studied and compared with a sample of patients with mild (mH; FT4, 23-50 pmol/l) and moderate (MH; FT4, 51-100 pmol/l) hyperthyroidism. Aetiology, clinical analytical and imaging data at diagnosis, therapeutic response and outcome were registered. Results A total of 107 patients with overt hyperthyroidism (81 females, mean age +/- SD 46.9 +/- 16.1 years) were evaluated. We studied a historic group with SH (n = 21; 14 females, 40.9 +/- 17.2 years) and, as a comparator group, we analyszed the data of 86 hyperthyroid patients (67 females, 48.4 +/- 15.5.6 years, NS) comparable in age and gender. The comparator group was classified in MH (n = 37, 26 females, 47.2 +/- 16.6 years) and mH (n = 49, 41 females, 49.4 +/- 14.8 years). In comparison with mH group, SH patients were significantly (P hyperthyroidism. FT4 was the only independent predictor of cure [OR 0.98 (CI 95%, 0.97-0.99), P hyperthyroidism is usually de novo and is accompanied by more clinical signs, symptoms, and analytical derangements, as well as higher titres of TRAb at diagnosis than milder forms of hyperthyroidism. The present data are not able to show differences in treatment modality, time to achieve cure, and remission rate among patients with mild, moderate and severe hyperthyroidism.

  11. Prediction of Long-Term Benefits of Inhaled Steroids by Phenotypic Markers in Moderate-to-Severe COPD: A Randomized Controlled Trial.

    Directory of Open Access Journals (Sweden)

    Jiska B Snoeck-Stroband

    Full Text Available The decline in lung function can be reduced by long-term inhaled corticosteroid (ICS treatment in subsets of patients with chronic obstructive pulmonary disease (COPD. We aimed to identify which clinical, physiological and non-invasive inflammatory characteristics predict the benefits of ICS on lung function decline in COPD.Analysis was performed in 50 steroid-naive compliant patients with moderate to severe COPD (postbronchodilator forced expiratory volume in one second (FEV1, 30-80% of predicted, compatible with GOLD stages II-III, age 45-75 years, >10 packyears smoking and without asthma. Patients were treated with fluticasone propionate (500 μg bid or placebo for 2.5 years. Postbronchodilator FEV1, dyspnea and health status were measured every 3 months; lung volumes, airway hyperresponsiveness (PC20, and induced sputum at 0, 6 and 30 months. A linear mixed effect model was used for analysis of this hypothesis generating study.Significant predictors of attenuated FEV1-decline by fluticasone treatment compared to placebo were: fewer packyears smoking, preserved diffusion capacity, limited hyperinflation and lower inflammatory cell counts in induced sputum (p<0.04.Long-term benefits of ICS on lung function decline in patients with moderate-to-severe COPD are most pronounced in patients with fewer packyears, and less severe emphysema and inflammation. These data generate novel hypotheses on phenotype-driven therapy in COPD.ClinicalTrials.gov NCT00158847.

  12. Early onset and severe clinical course associated with the m.5540G>A mutation in MT-TW

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    Jorge L. Granadillo

    2014-01-01

    Full Text Available We report a patient harboring a de novo m.5540G>A mutation affecting the MT-TW gene coding for the mitochondrial tryptophan-transfer RNA. This patient presented with atonic–myoclonic epilepsy, bilateral sensorineural hearing loss, ataxia, motor regression, ptosis, and pigmentary retinopathy. Our proband had an earlier onset and more severe phenotype than the first reported patient harboring the same mutation. We discuss her clinical presentation and compare it with the only previously published case.

  13. Phenotypic identification, frequency distribution and antibiogram of carbapenemase producing enterobacteriaceae in clinical isolates

    International Nuclear Information System (INIS)

    Ansari, M.; Saad, N.

    2018-01-01

    Objective:To differentiate between Ambler class A, B and D of carbapenemase-producing Enterobacteriaceae by using simple phenotypic methods that can be carried out in the laboratory without requiring any specialised techniques. Study Design:Cross-sectional study. Place and Duration of Study:Microbiology Department, Army Medical College, NUST, Islamabad, from November 2015 to November 2016. Methodology: Clinical specimens were subjected to identification of Enterobacteriaceae by colony morphology and API 20 E. Carbapenem resistance was detected by applying meropenem disc (10 mu g) by disc diffusion method according to CLSI (Clinical Laboratory Standard Institute) criteria. Carbapenemase production among Enterobacteriaceaewas detected by Modified Hodge test. Phenotypic methods, Phenylboronic acid (for Class A KPC producing Enterobacteriaceae) and EDTA inhibition tests (for Class B MBL producing Entrobacteriaceae) were applied. Presence of OXA 48 was detected by phenotypic method using imipenem 10 mu g, EDTA and PBA discs. Antibiotic susceptibility was determined by Kirby-Bauer disc diffusion method. Results:Forty-three out of 45 (95.45%) were carbapenemase producers. Thirty-eight out of 43 (88.3%) were KPC producers and 4 out of 43 (11.62%) were MBL producers. All KPC producers were Klebsiella pneumoniae. Among five MBL producers, one each (20%) was Enterobacter cloacae and Escherichia coli and 3 (60%) were Klebsiella pneumoniae. All MBL producers were resistant to aztreonam and amoxicillin/clavulanate. Two of the KPC producing Klebsiella pneumoniaewere pan-drug resistant (resistant to colistin and tigecycline). Two were non-carbapenemase producers. Conclusion:Enterobacteriaceaestrains producing KPC-type carbapenemase were the most prevalent (88.3%) in the studied healthcare setup. (author)

  14. Clinical neuropsychiatric symptoms in perpetrators of severe crimes against persons.

    Science.gov (United States)

    Söderström Anckarsäter, Henrik

    2005-01-01

    The objective of the study was to explore the possibility of common signs and symptoms of childhood-onset neuropsychiatric disorders and personality disorders, especially psychopathy, in a cohort of violent offenders. A structured neuropsychiatric status comprising features recorded in childhood-onset neuropsychiatric disorders and adult personality disorders was assessed in 89 perpetrators of severe crimes against other persons, analysed for factor structure, and compared to clinical diagnostics of neuropsychiatric disorders and independent assessments of psychopathy rated by the Psychopathy Checklist Revised (PCL-R). One or several childhood-onset neuropsychiatric disorders [autism, attention-deficit/hyperactivity disorder (AD/HD), tics and learning disability] affected the majority of adult offenders. A factor analysis yielded four higher-order problem constellations: Executive Dysfunction, Compulsivity, Social Interaction Problems and Superficiality. All four constellations were positively correlated with life histories of aggression, stressing the clinical importance of these problems in adult forensic psychiatry. Compulsivity and Social Interaction Problems were associated with autistic traits and tics, Executive Dysfunction with AD/HD, conduct disorder and psychopathic as well as autistic traits. Superficiality was a distinct aspect of AD/HD and psychopathic traits, especially the PCL-R factor reflecting interpersonal callousness. Neuropsychiatric disorders and personality disorders such as psychopathy share common symptoms. The various facets of psychopathy are associated with executive dysfunction and empathy deficits with superficial understanding of self, others and the rules of communication.

  15. Clinical heterogeneity among people with high functioning autism spectrum conditions: evidence favouring a continuous severity gradient

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    Woodbury-Smith Marc

    2008-02-01

    Full Text Available Abstract Background Autism Spectrum Conditions (ASCs are characterized by a high degree of clinical heterogeneity, but the extent to which this variation represents a severity gradient versus discrete phenotypes is unclear. This issue has complicated genetic studies seeking to investigate the genetic basis of the high hereditability observed clinically in those with an ASC. The aim of this study was to examine the possible clustering of symptoms associated with ASCs to determine whether the observed distribution of symptom type and severity supported either a severity or a symptom subgroup model to account for the phenotypic variation observed within the ASCs. Methods We investigated the responses of a group of adults with higher functioning ASCs on the fifty clinical features examined in the Autism Spectrum Quotient, a screening questionnaire used in the diagnosis of higher functioning ASCs. In contrast to previous studies we have used this instrument with no a priori assumptions about any underlying factor structure of constituent items. The responses obtained were analyzed using complete linkage hierarchical cluster analysis. For the members of each cluster identified the mean score on each Autism Spectrum Quotient question was calculated. Results Autism Spectrum Quotient responses from a total of 333 individuals between the ages of 16.6 and 78.0 years were entered into the hierarchical cluster analysis. The four cluster solution was the one that generated the largest number of clusters that did not also include very small cluster sizes, defined as a membership comprising 10 individuals or fewer. Examination of these clusters demonstrated that they varied in total Autism Spectrum Quotient but that the profiles across the symptoms comprising the Autism Spectrum Quotient did not differ independently of this severity factor. Conclusion These results are consistent with a unitary spectrum model, suggesting that the clinical heterogeneity observed

  16. Clinical and radiological analysis of severe acute respiratory syndrome

    International Nuclear Information System (INIS)

    Li Long; Li Zhi; Chi Xiaoyu; Huang Shupeng; Sheng Yan

    2003-01-01

    Objective: To study the X-ray features of severe acute respiratory syndrome (SARS). Methods: The clinical data and X-ray appearances of 29 cases with SARS were analyzed retrospectively. Results: Epidemic outbreak of SARS has occurred at this area. 29 cases of SARS in this group began with a fever. 15 cases (51.7%) experienced mild respiratory symptoms. In 10 patients (34.5%) the antibacterial medication showed inefficacy before hospitalization. Leucocyte counting was normal in 18 cases (62.1%) and decreased in 11 cases (37.9%). Platelet counting slightly decreased in 7 cases (24.1%). Hepatic function test was abnormal in 16 patients (55.2%), mostly with a decrease of serum enzymology. Obvious abnormalities were seen on the chest films, which were in sharp contrast with the mild clinical respiratory signs. Chest X-ray findings were as follows: Exaggerated and indistinct lung markings with reticular shadow in 7 cases (24.1%), ground-glass opacity in 3 cases (10.4%), small patchy and multi-patchy imaging in 12 cases (41.4%), and large patchy shadow in 7 cases (24.1%). X-ray abnormality was presented later and absorbed slower. Conclusion: SARS carries a variety of X-ray appearances. The combined use of epidemiologic history, clinical situation, laboratory tests, and imaging examinations can make a definite diagnosis

  17. Moyamoya Disease Clinical Course and Severity in Childhood

    Directory of Open Access Journals (Sweden)

    Ayse Kacar Bayram

    2016-01-01

    Full Text Available Aim: Moyamoya disease (MMD is a rare, progressive and oclusive cerebrovascular disorder, predominantly affecting the terminal segment of the internal carotid arteries (ICA and its main branches. The purpose of this study is to evaluate the clinical course and severity of MMD in pediatric patients. Material and Method: We examined 5 consecutive pediatric patients with MMD, focusing on clinical and radiological features, the therapy and outcome over the 58-month follow-up period. Results: The study population consisted of 3 boys and 2 girls. The mean age at diagnosis of patients was 7.2 ± 3.4 years (age range: 3-10 years. The mean duration of follow-up was 30.4 ± 17.4 months (follow-up interval: 12-58 months. Neurological findings at presentation included: motor deficit in 4 patients (80.0%, epileptic seizures in 2 patients (40.0%, movement disorders in 3 patients (60.0%, and headache in 1 patients (20.0%. There was areas of infarction on brain MRI in all patients. Angiographic findings included: internal carotid artery stenosis in all patients, anterior cerebral artery stenosis in 3 patients, middle cerebral artery stenosis in 3 patients, posterior cerebral artery stenosis in 2 patients, and vertebral artery stenosis in 1 patient. Enoxaparine therapy was started to all patients. Subdural hematoma developed in 1 patient during follow-up. Cerebral infarctions recurred despite medical treatment in 4 patients. Discussion: Although this disease is rare, it is an important cause of pediatric stroke. MMD shows different clinical course and disease severity in childhood. Early diagnosis and appropriate treatment are crucial.

  18. Clinical characteristics of Japanese patients with severe hypertriglyceridemia.

    Science.gov (United States)

    Tada, Hayato; Kawashiri, Masa-Aki; Nakahashi, Takuya; Yagi, Kunimasa; Chujo, Daisuke; Ohbatake, Azusa; Mori, Yukiko; Mori, Shunsuke; Kometani, Mitsuhiro; Fujii, Hiroshi; Nohara, Atsushi; Inazu, Akihiro; Mabuchi, Hiroshi; Yamagishi, Masakazu; Hayashi, Kenshi

    2015-01-01

    Although of interest, few data exist on the clinical characteristics of Japanese patients with an extremely high triglyceride level (≥ 1000 mg/dL). We assessed the clinical characteristics of Japanese patients with an extremely high triglyceride level. We investigated the presence of coronary artery disease, history of pancreatitis, the presence of fatty liver, and the potential causes of elevated triglyceride in Japanese subjects with an extremely high level of fasting triglyceride (≥ 1000 mg/dL) among 70,368 subjects whose serum triglyceride was measured for any reason at Kanazawa University Hospital from April 2004 to March 2014. We identified 215 (0.31%) subjects (mean age, 46 years; male, 170, mean body mass index, 25 kg/m(2)) with severe hypertriglyceridemia. Among them, 4 (1.9%) subjects were classified as type I, 97 (45.1%) subjects were type IV, and 114 (53.0%) subjects were type V hyperlipidemia, according to Fredrickson's classification. Among 215 subjects, 116 subjects (54.0%) drank alcohol, 58 (27.0%) showed heavy intake (≥ 60 g/d), and 64 (29.8%) subjects had diabetes. In total, 59 (27.4%) subjects had transient severe hypertriglyceridemia caused by corticosteroids (N = 19), antidepressant (N = 18), l-asparaginase and steroids for acute lymphoid leukemia (N = 15), hormone replacement therapy for breast cancer (N = 9), β-blocker (N = 5), hypothyroidism (N = 4), pregnancy (N = 4), and panhypopituitarism (N = 2). As many as 119 (55.3%) subjects exhibited fatty liver. Moreover, 12 (5.6%) and 17 (7.9%) subjects had a history of pancreatitis and coronary artery disease, respectively. A variety of situations can cause severe hypertriglyceridemia. We suggest that potential secondary causes should be carefully assessed for such patients. Copyright © 2015 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  19. Exome analysis in clinical practice: expanding the phenotype of Bartsocas-Papas syndrome.

    Science.gov (United States)

    Gripp, Karen W; Ennis, Sara; Napoli, Joseph

    2013-05-01

    Exome analysis has had a dramatic impact on genetic research. We present the application of such newly generated information to patient care. The patient was a female, born with normal growth parameters to nonconsanguineous parents after an uneventful pregnancy. She had bilateral cleft lip/palate and ankyloblepharon. Sparse hair, dysplastic nails and hypohidrosis were subsequently noted. With exception of speech related issues, her development was normal. A clinical diagnosis of ankyloblepharon-ectodermal defects-cleft lip/palate or Hay-Wells syndrome resulted in TP63 sequence analysis. TP63 sequence and deletion/duplication analysis of all coding exons had a normal result, as did chromosome and SNP array analysis. Diagnostic exome analysis revealed a heterozygous nonsense mutation in KRT83 categorized as deleterious and associated with monilethrix. In addition, a homozygous missense variant of unknown clinical significance was reported in RIPK4. Using research based exome analysis, RIPK4 had just a few months prior been identified as pathogenic for Bartsocas-Papas syndrome. While the clinical diagnostic report implied the KRT83 mutation as a more likely cause for the patient's phenotype, clinical correlation, literature review and use of computerized mutation analysis programs allowed us to identify the homozygous RIPK4 (c.488G > A; p.Gly163Asp) mutation as the underlying pathogenic change. Consequently, we expand the phenotype of Bartsocas-Papas syndrome to an attenuated presentation resembling Hay-Wells syndrome, lacking lethality and pterygia. In contrast to the autosomal dominant Hay-Wells syndrome, Bartsocas-Papas syndrome is autosomal recessive, implying a 25% recurrence risk. Copyright © 2013 Wiley Periodicals, Inc.

  20. Clinical events in a large prospective cohort of children with sickle cell disease in Nagpur, India: evidence against a milder clinical phenotype in India.

    Science.gov (United States)

    Jain, Dipty; Arjunan, Aishwarya; Sarathi, Vijaya; Jain, Harshwardhan; Bhandarwar, Amol; Vuga, Marike; Krishnamurti, Lakshmanan

    2016-10-01

    The clinical phenotype of sickle cell disease (SCD) has been reported to be milder in India than in the United States. The objective of this large single-center study was to examine the rate of complications to define the phenotype of SCD in India. The rate of complications per 100 person-years in 833 pediatric SCD patients for 1954 person-years in Nagpur, India including those diagnosed on newborn screen (NBS) and those presenting later in childhood (non-NBS) was compared to those reported in the cooperative study of sickle cell disease (CSSCD). Event rates were also compared between patients belonging to scheduled castes (SCs), scheduled tribes (STs), and other backward classes (OBC). Comparison of CSSCD versus Nagpur NBS versus Nagpur non-NBS for rates of pain (32.4 vs. 85.2 vs. 62.4), severe anemia (7.1 vs. 27 vs. 6.6), stroke (0.7 vs. 0.8 vs. 1.4), splenic sequestration (3.4 vs. 6.7 vs. 1.6), acute chest syndrome (24.5 vs. 23.6 vs. 1.0), and meningitis (0.8 vs. 0 vs. 0.1) revealed more frequent complications in Nagpur compared to CSSCD. Comparison of ST, SC, and OBC for rates of pain (84.6 vs. 71.9 vs. 63.5), acute chest syndrome (3.6 vs. 2.8 vs. 2.2), severe anemia (5.4 vs. 9.5 vs. 11.4), stroke (1.2 vs. 0.4 vs. 0.3), splenic sequestration (0.6 vs. 2.4 vs. 1.9), and meningitis (0.8 vs. 0 vs. 0.1) revealed significantly more frequent complications among ST. SCD-related complications are more frequent in Indian children than that observed in CSSCD. Further study is indicated to define SCD phenotype in India. © 2016 Wiley Periodicals, Inc.

  1. X-linked retinoschisis: RS1 mutation severity and age affect the ERG phenotype in a cohort of 68 affected male subjects.

    Science.gov (United States)

    Bowles, Kristen; Cukras, Catherine; Turriff, Amy; Sergeev, Yuri; Vitale, Susan; Bush, Ronald A; Sieving, Paul A

    2011-11-29

    To assess the effect of age and RS1 mutation on the phenotype of X-linked retinoschisis (XLRS) subjects using the clinical electroretinogram (ERG) in a cross-sectional analysis. Sixty-eight XLRS males 4.5 to 55 years of age underwent genotyping, and the retinoschisis (RS1) mutations were classified as less severe (27 subjects) or more severe (41 subjects) based on the putative impact on the protein. ERG parameters of retinal function were analyzed by putative mutation severity with age as a continuous variable. The a-wave amplitude remained greater than the lower limit of normal (mean, -2 SD) for 72% of XLRS males and correlated with neither age nor mutation class. However, b-wave and b/a-ratio amplitudes were significantly lower in the more severe than in the less severe mutation groups and in older than in younger subjects. Subjects up to 10 years of age with more severe RS1 mutations had significantly greater b-wave amplitudes and faster a-wave trough implicit times than older subjects in this group. RS1 mutation putative severity and age both had significant effects on retinal function in XLRS only in the severe mutation group, as judged by ERG analysis of the b-wave amplitude and the b/a-ratio, whereas the a-wave amplitude remained normal in most. A new observation was that increasing age (limited to those aged 55 and younger) caused a significant delay in XLRS b-wave onset (i.e., a-wave implicit time), even for those who retained considerable b-wave amplitudes. The delayed b-wave onset suggested that dysfunction of the photoreceptor synapse or of bipolar cells increases with age of XLRS subjects.

  2. PhenoTips: Patient Phenotyping Software for Clinical and Research Use.

    OpenAIRE

    Girdea, Marta; Dumitriu, Sergiu; Fiume, Marc; Buske, Orion; Bowdin, Sarah; Boycott, Kym M.; Chénier, Sébastien; Chitayat, David; Faghfoury, Hanna; Meyn, Stephen; Ray, Peter N.; So, Joyce; Stavropoulos, Dimitri J.; Brudno, Michael

    2014-01-01

    We have developed PhenoTips, a deep phenotyping tool and database, specifically designed for phenotyping patients with genetic disorders. Our tool closely mirrors clinician workflows so as to facilitate the recording of observations made during the patient encounter. Phenotypic information is represented using the Human Phenotype Ontology; however, the complexity of the ontology is hidden behind a user interface, which combines simple selection of common phenotypes with error-tolerant, predic...

  3. Clinics in diagnostic imaging (179). Severe rhabdomyolysis complicated by myonecrosis.

    Science.gov (United States)

    Kok, Shi Xian Shawn; Tan, Tien Jin

    2017-08-01

    A 32-year-old man presented to the emergency department with severe right lower limb pain and swelling of three days' duration. He had multiple prior admissions for recurrent seizures and suicide attempts. Markedly elevated serum creatine kinase levels and urine myoglobinuria were consistent with a diagnosis of rhabdomyolysis. Initial magnetic resonance imaging of the right lower limb revealed diffuse muscle oedema and features of myositis in the gluteal muscles and the adductor, anterior and posterior compartments of the thigh. Follow-up magnetic resonance imaging performed 11 days later showed interval development of areas of myonecrosis and haemorrhage. The causes, clinical presentation and imaging features of rhabdomyolysis are discussed. Copyright: © Singapore Medical Association.

  4. Clinical and molecular characterization of a novel INS mutation identified in patients with MODY phenotype.

    Science.gov (United States)

    Piccini, Barbara; Artuso, Rosangela; Lenzi, Lorenzo; Guasti, Monica; Braccesi, Giulia; Barni, Federica; Casalini, Emilio; Giglio, Sabrina; Toni, Sonia

    2016-11-01

    Correct diagnosis of Maturity-Onset Diabetes of the Young (MODY) is based on genetic tests requiring an appropriate subject selection by clinicians. Mutations in the insulin (INS) gene rarely occur in patients with MODY. This study is aimed at determining the genetic background and clinical phenotype in patients with suspected MODY. 34 patients with suspected MODY, negative for mutations in the GCK, HNF1α, HNF4α, HNF1β and PDX1 genes, were screened by next generation sequencing (NGS). A heterozygous INS mutation was identified in 4 members of the same family. First genetic tests performed identified two heterozygous silent nucleotide substitutions in MODY3/HNF1α gene. An ineffective attempt to suspend insulin therapy, administering repaglinide and sulphonylureas, was made. DNA was re-sequenced by NGS investigating a set of 102 genes. Genes implicated in the pathway of pancreatic β-cells, candidate genes for type 2 diabetes mellitus and genes causative of diabetes in mice were selected. A novel heterozygous variant in human preproinsulin INS gene (c.125T > C) was found in the affected family members. The new INS mutation broadens the spectrum of possible INS phenotypes. Screening for INS mutations is warranted not only in neonatal diabetes but also in MODYx patients and in selected patients with type 1 diabetes mellitus negative for autoantibodies. Subjects with complex diseases without a specific phenotype should be studied by NGS because Sanger sequencing is ineffective and time consuming in detecting rare variants. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  5. Pre-clinical cognitive phenotypes for Alzheimer disease: a latent profile approach.

    Science.gov (United States)

    Hayden, Kathleen M; Kuchibhatla, Maragatha; Romero, Heather R; Plassman, Brenda L; Burke, James R; Browndyke, Jeffrey N; Welsh-Bohmer, Kathleen A

    2014-11-01

    Cognitive profiles for pre-clinical Alzheimer disease (AD) can be used to identify groups of individuals at risk for disease and better characterize pre-clinical disease. Profiles or patterns of performance as pre-clinical phenotypes may be more useful than individual test scores or measures of global decline. To evaluate patterns of cognitive performance in cognitively normal individuals to derive latent profiles associated with later onset of disease using a combination of factor analysis and latent profile analysis. The National Alzheimer Coordinating Centers collect data, including a battery of neuropsychological tests, from participants at 29 National Institute on Aging-funded Alzheimer Disease Centers across the United States. Prior factor analyses of this battery demonstrated a four-factor structure comprising memory, attention, language, and executive function. Factor scores from these analyses were used in a latent profile approach to characterize cognition among a group of cognitively normal participants (N = 3,911). Associations between latent profiles and disease outcomes an average of 3 years later were evaluated with multinomial regression models. Similar analyses were used to determine predictors of profile membership. Four groups were identified; each with distinct characteristics and significantly associated with later disease outcomes. Two groups were significantly associated with development of cognitive impairment. In post hoc analyses, both the Trail Making Test Part B, and a contrast score (Delayed Recall - Trails B), significantly predicted group membership and later cognitive impairment. Latent profile analysis is a useful method to evaluate patterns of cognition in large samples for the identification of preclinical AD phenotypes; comparable results, however, can be achieved with very sensitive tests and contrast scores. Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

  6. Mutants of GABA transaminase (POP2 suppress the severe phenotype of succinic semialdehyde dehydrogenase (ssadh mutants in Arabidopsis.

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    Frank Ludewig

    Full Text Available BACKGROUND: The gamma-aminubutyrate (GABA shunt bypasses two steps of the tricarboxylic acid cycle, and is present in both prokaryotes and eukaryotes. In plants, the pathway is composed of the calcium/calmodulin-regulated cytosolic enzyme glutamate decarboxylase (GAD, the mitochondrial enzymes GABA transaminase (GABA-T; POP2 and succinic semialdehyde dehydrogenase (SSADH. We have previously shown that compromising the function of the GABA-shunt, by disrupting the SSADH gene of Arabidopsis, causes enhanced accumulation of reactive oxygen intermediates (ROIs and cell death in response to light and heat stress. However, to date, genetic investigations of the relationships between enzymes of the GABA shunt have not been reported. PRINCIPAL FINDINGS: To elucidate the role of succinic semialdehyde (SSA, gamma-hydroxybutyrate (GHB and GABA in the accumulation of ROIs, we combined two genetic approaches to suppress the severe phenotype of ssadh mutants. Analysis of double pop2 ssadh mutants revealed that pop2 is epistatic to ssadh. Moreover, we isolated EMS-generated mutants suppressing the phenotype of ssadh revealing two new pop2 alleles. By measuring thermoluminescence at high temperature, the peroxide contents of ssadh and pop2 mutants were evaluated, showing that only ssadh plants accumulate peroxides. In addition, pop2 ssadh seedlings are more sensitive to exogenous SSA or GHB relative to wild type, because GHB and/or SSA accumulate in these plants. SIGNIFICANCE: We conclude that the lack of supply of succinate and NADH to the TCA cycle is not responsible for the oxidative stress and growth retardations of ssadh mutants. Rather, we suggest that the accumulation of SSA, GHB, or both, produced downstream of the GABA-T transamination step, is toxic to the plants, resulting in high ROI levels and impaired development.

  7. Clinical value of computerized tomography scanning in severe head injury

    International Nuclear Information System (INIS)

    Kobayashi, Shiro; Yano, Masami; Otsuka, Toshibumi; Nakazawa, Shozo

    1982-01-01

    Serial computerized tomography (SCT) was performed on 138 patients suffering from severe head injuries (8 or less on the Glasgow Coma Scale). Standard practice called for scans to be done upon admission (within hours of the injury), and after 1, 3, 7 days and 1 month. Subsequent CT's depended on the patient's condition. Clinical results at the time of discharge were graded according to the Glasgow Outcome Scale. Patients who died, were in a persistent vegetative state, or were severely disabled were considered to have a ''bad outcome''. On the other hand, patients who were somewhat disabled or made good recoveries were considered to have a ''good outcome''. During the serial CT scan, there were new findings (not visualized on the initial CT but appearing on subsequent ones) in 91 of the 138 patients. These new findings were classified as follows; 1) decreased density collection in the subdural space (DDC), 2) ventricular dilation (VD), 3) intracerebral hematoma (ICH), 4) intraventricular hemorrhage (IVH), 5) extracerebral hematoma (ECH), 6) edema (E), 7) infarction (I). We defined ICH, IVH, ECH, E and I as new lesions. Of the 60 patients with new lesions 12 had good outcomes and 48 had poor outcomes. There were 78 patients who did not have any new lesions, 60 with good outcomes and 18 with poor outcomes. A significant correlation was found between good outcomes and the absence of new lesions, and between bad outcomes and the development of new lesions (p 2 = 44.038). We conclude that SCT can help predict the outcome with severe head injury patients and may be very important in their examination and care. (J.P.N.)

  8. Invited commentary: Personality phenotype and mortality--new avenues in genetic, social, and clinical epidemiology.

    Science.gov (United States)

    Chapman, Benjamin P

    2013-09-01

    In this issue of the Journal, Jokela et al. (Am J Epidemiol. 2013;178(5):667-675) scrutinize the association between personality phenotype and all-cause mortality in remarkable detail by using an "individual-participant meta-analysis" design. Across 7 large cohorts varying in demographics and methods of personality measurement, they find varying prospective associations for 4 dimensions of the five-factor (or "Big Five") model of personality, but robust and consistent prospective associations for Big Five dimension of "conscientiousness." Jokela et al. place an important exclamation point on a long era of study of this topic and hint directly and indirectly at new avenues for this line of research. I consider the following 3 areas particularly rife for further inquiry: the role of genetics in personality and health studies; the role of personality in social inequalities in health; and the health policy and clinical implications of work like that of Jokela et al., including the potential role of personality phenotype in the evolution of personalized medicine.

  9. Clinical phenotype of South-East Asian temporomandibular disorder patients with upper airway resistance syndrome.

    Science.gov (United States)

    Tay, D K L; Pang, K P

    2018-01-01

    Clinical and radiographic characteristics of a subset of South East Asian temporomandibular disorder (TMD) patients with comorbid upper airway resistance syndrome (UARS) were documented in a multi-center prospective series of 86 patients (26 men and 60 women / mean age 35.7 years). All had excessive daytime sleepiness, high arousal index and Apnoea-Hypopnoea Index (AHI) temporomandibular joint (TMJ) arthralgia while 90·7% reported sleep bruxism (SB). Unlike patients with obstructive sleep apnoea (OSA), hypertension was uncommon (4·7%) while depression was prevalent at 68·6% with short REM latency of 25% documented in 79·6% and 57·6% of these depressed patients, respectively. 65·1% displayed a posteriorly displaced condyle at maximum intercuspation with or without TMJ clicking. Most exhibited a forward head posture (FHP) characterised by loss of normal cervical lordosis (80·2%), C0-C1 narrowing (38·4%) or an elevated hyoid position (50%), and 91·9% had nasal congestion. We postulate the TMD-UARS phenotype may have originally developed as an adaptive response to 'awake' disordered breathing during growth. Patients with persistent TMD and/or reporting SB should be screened for UARS and chronic nasal obstruction, especially when they also present with FHP. The lateral cephalogram is a useful tool in the differentiation of UARS from other OSA phenotypes. © 2017 John Wiley & Sons Ltd.

  10. Multivariate Associations Among Behavioral, Clinical, and Multimodal Imaging Phenotypes in Patients With Psychosis.

    Science.gov (United States)

    Moser, Dominik A; Doucet, Gaelle E; Lee, Won Hee; Rasgon, Alexander; Krinsky, Hannah; Leibu, Evan; Ing, Alex; Schumann, Gunter; Rasgon, Natalie; Frangou, Sophia

    2018-04-01

    Alterations in multiple neuroimaging phenotypes have been reported in psychotic disorders. However, neuroimaging measures can be influenced by factors that are not directly related to psychosis and may confound the interpretation of case-control differences. Therefore, a detailed characterization of the contribution of these factors to neuroimaging phenotypes in psychosis is warranted. To quantify the association between neuroimaging measures and behavioral, health, and demographic variables in psychosis using an integrated multivariate approach. This imaging study was conducted at a university research hospital from June 26, 2014, to March 9, 2017. High-resolution multimodal magnetic resonance imaging data were obtained from 100 patients with schizophrenia, 40 patients with bipolar disorder, and 50 healthy volunteers; computed were cortical thickness, subcortical volumes, white matter fractional anisotropy, task-related brain activation (during working memory and emotional recognition), and resting-state functional connectivity. Ascertained in all participants were nonimaging measures pertaining to clinical features, cognition, substance use, psychological trauma, physical activity, and body mass index. The association between imaging and nonimaging measures was modeled using sparse canonical correlation analysis with robust reliability testing. Multivariate patterns of the association between nonimaging and neuroimaging measures in patients with psychosis and healthy volunteers. The analyses were performed in 92 patients with schizophrenia (23 female [25.0%]; mean [SD] age, 27.0 [7.6] years), 37 patients with bipolar disorder (12 female [32.4%]; mean [SD] age, 27.5 [8.1] years), and 48 healthy volunteers (20 female [41.7%]; mean [SD] age, 29.8 [8.5] years). The imaging and nonimaging data sets showed significant covariation (r = 0.63, P nonimaging variables examined, age (r = -0.53), IQ (r = 0.36), and body mass index (r = -0.25) were associated

  11. Hereditary rickets. How genetic alterations explain the biochemical and clinical phenotypes.

    Science.gov (United States)

    Papadopoulou, Anna; Gole, Evaggelia; Nicolaidou, Polyxeni

    2013-12-01

    The reemergence of vitamin D deficiency in the industrialized countries resurrects the "threat" of nutritional rickets, especially among pediatric populations, a fact that may lead to underdiagnosis of hereditary rickets. Today, hereditary rickets may be subdivided into two main groups according to their biochemical profile: the one associated with defects in vitamin D synthesis and action and the second associated with abnormal phosphorus metabolism. The classification of the patients in a particular group of hereditary rickets is determinative of the treatment to follow. This review, through the recent advances on vitamin D and P metabolism, discusses the molecular and biochemical defects associated to each group of inherited rickets, as well as the clinical phenotypes and the recommended therapeutic approaches.

  12. Severe scrub typhus infection: Clinical features, diagnostic challenges and management

    Science.gov (United States)

    Peter, John Victor; Sudarsan, Thomas I; Prakash, John Anthony J; Varghese, George M

    2015-01-01

    Scrub typhus infection is an important cause of acute undifferentiated fever in South East Asia. The clinical picture is characterized by sudden onset fever with chills and non-specific symptoms that include headache, myalgia, sweating and vomiting. The presence of an eschar, in about half the patients with proven scrub typhus infection and usually seen in the axilla, groin or inguinal region, is characteristic of scrub typhus. Common laboratory findings are elevated liver transaminases, thrombocytopenia and leukocytosis. About a third of patients admitted to hospital with scrub typhus infection have evidence of organ dysfunction that may include respiratory failure, circulatory shock, mild renal or hepatic dysfunction, central nervous system involvement or hematological abnormalities. Since the symptoms and signs are non-specific and resemble other tropical infections like malaria, enteric fever, dengue or leptospirosis, appropriate laboratory tests are necessary to confirm diagnosis. Serological assays are the mainstay of diagnosis as they are easy to perform; the reference test is the indirect immunofluorescence assay (IFA) for the detection of IgM antibodies. However in clinical practice, the enzyme-linked immuno-sorbent assay is done due to the ease of performing this test and a good sensitivity and sensitivity when compared with the IFA. Paired samples, obtained at least two weeks apart, demonstrating a ≥ 4 fold rise in titre, is necessary for confirmation of serologic diagnosis. The mainstay of treatment is the tetracycline group of antibiotics or chloramphenicol although macrolides are used alternatively. In mild cases, recovery is complete. In severe cases with multi-organ failure, mortality may be as high as 24%. PMID:26261776

  13. Genotypes and clinical phenotypes in children with cytochrome-c oxidase deficiency.

    Science.gov (United States)

    Darin, N; Moslemi, A-R; Lebon, S; Rustin, P; Holme, E; Oldfors, A; Tulinius, M

    2003-12-01

    Cytochrome c oxidase (COX) deficiency has been associated with a wide spectrum of clinical features and may be caused by mutations in different genes of both the mitochondrial and the nuclear DNA. In an attempt to correlate the clinical phenotype with the genotype in 16 childhood cases, mtDNA was analysed for deletion, depletion, and mutations in the three genes encoding COX subunits and the 22 tRNA genes. Furthermore, nuclear DNA was analysed for mutations in the SURF1, SCO2, COX10, and COX17 genes and cases with mtDNA depletion were analysed for mutations in the TK2 gene. SURF1-mutations were identified in three out of four cases with Leigh syndrome while a mutation in the mitochondrial tRNA (trp) gene was identified in the fourth. One case with mtDNA depletion had mutations in the TK2 gene. In two cases with leukoencephalopathy, one case with encephalopathy, five cases with fatal infantile myopathy and cardiomyopathy, two cases with benign infantile myopathy, and one case with mtDNA depletion, no mutations were identified. We conclude that COX deficiency in childhood should be suspected in a wide range of clinical settings and although an increasing number of genetic defects have been identified, the underlying mutations remain unclear in the majority of the cases.

  14. The importance of genotype-phenotype correlation in the clinical management of Marfan syndrome.

    Science.gov (United States)

    Becerra-Muñoz, Víctor Manuel; Gómez-Doblas, Juan José; Porras-Martín, Carlos; Such-Martínez, Miguel; Crespo-Leiro, María Generosa; Barriales-Villa, Roberto; de Teresa-Galván, Eduardo; Jiménez-Navarro, Manuel; Cabrera-Bueno, Fernando

    2018-01-22

    Marfan syndrome (MFS) is a disorder of autosomal dominant inheritance, in which aortic root dilation is the main cause of morbidity and mortality. Fibrillin-1 (FBN-1) gene mutations are found in more than 90% of MFS cases. The aim of our study was to summarise variants in FBN-1 and establish the genotype-phenotype correlation, with particular interest in the onset of aortic events, in a broad population of patients with an initial clinical suspicion of MFS. This single centre prospective cohort study included all patients presenting variants in the FBN-1 gene who visited a Hereditary Aortopathy clinic between September 2010 and October 2016. The study included 90 patients with FBN-1 variants corresponding to 58 non-interrelated families. Of the 57 FBN-1 variants found, 25 (43.9%) had previously been described, 23 of which had been identified as associated with MFS, while the the remainder are described for the first time. For 84 patients (93.3%), it was possible to give a definite diagnosis of Marfan syndrome in accordance with Ghent criteria. 44 of them had missense mutations, 6 of whom had suffered an aortic event (with either prophylactic surgery for aneurysm or dissection), whereas 20 of the 35 patients with truncating mutations had suffered an event (13.6% vs. 57.1%, p importance not only in the diagnosis, but also in risk stratification and clinical management of patients with suspected MFS.

  15. Severe hypertriglyceridemia in Norway: prevalence, clinical and genetic characteristics.

    Science.gov (United States)

    Retterstøl, Kjetil; Narverud, Ingunn; Selmer, Randi; Berge, Knut E; Osnes, Ingvild V; Ulven, Stine M; Halvorsen, Bente; Aukrust, Pål; Holven, Kirsten B; Iversen, Per O

    2017-06-12

    There is a lack of comprehensive patient-datasets regarding prevalence of severe hypertriglyceridemia (sHTG; triglycerides ≥10 mmol/L), frequency of co-morbidities, gene mutations, and gene characterization in sHTG. Using large surveys combined with detailed analysis of sub-cohorts of sHTG patients, we here sought to address these issues. We used data from several large Norwegian surveys that included 681,990 subjects, to estimate the prevalence. Sixty-five sHTG patients were investigated to obtain clinical profiles and candidate disease genes. We obtained peripheral blood mononuclear cells (PBMC) from six male patients and nine healthy controls and examined expression of mRNAs involved in lipid metabolism. The prevalence of sHTG was 0.13 (95% CI 0.12-0.14)%, and highest in men aged 40-49 years and in women 60-69 years. Among the 65 sHTG patients, a possible genetic cause was found in four and 11 had experienced acute pancreatitis. The mRNA expression levels of carnitine palmitoyltransferase (CPT)-1A, CPT2, and hormone-sensitive lipase, were significantly higher in patients compared to controls, whereas those of ATP-binding cassette, sub-family G, member 1 were significantly lower. In Norway, sHTG is present in 0.1%, carries considerable co-morbidity and is associated with an imbalance of genes involved in lipid metabolism, all potentially contributing to increased cardiovascular morbidity in sHTG.

  16. HIV-1 Promoter Single Nucleotide Polymorphisms Are Associated with Clinical Disease Severity.

    Directory of Open Access Journals (Sweden)

    Michael R Nonnemacher

    Full Text Available The large majority of human immunodeficiency virus type 1 (HIV-1 markers of disease progression/severity previously identified have been associated with alterations in host genetic and immune responses, with few studies focused on viral genetic markers correlate with changes in disease severity. This study presents a cross-sectional/longitudinal study of HIV-1 single nucleotide polymorphisms (SNPs contained within the viral promoter or long terminal repeat (LTR in patients within the Drexel Medicine CNS AIDS Research and Eradication Study (CARES Cohort. HIV-1 LTR SNPs were found to associate with the classical clinical disease parameters CD4+ T-cell count and log viral load. They were found in both defined and undefined transcription factor binding sites of the LTR. A novel SNP identified at position 108 in a known COUP (chicken ovalbumin upstream promoter/AP1 transcription factor binding site was significantly correlated with binding phenotypes that are potentially the underlying cause of the associated clinical outcome (increase in viral load and decrease in CD4+ T-cell count.

  17. Gastric electrical stimulation for treatment of clinically severe gastroparesis

    Directory of Open Access Journals (Sweden)

    Naga Venkatesh G Jayanthi

    2013-01-01

    Full Text Available Background: Severe, drug-resistant gastroparesis is a debilitating condition. Several, but not all, patients can get significant relief from nausea and vomiting by gastric electrical stimulation (GES. A trial of temporary, endoscopically delivered GES may be of predictive value to select patients for laparoscopic-implantation of a permanent GES device. Materials and Methods: We conducted a clinical audit of consecutive gastroparesis patients, who had been selected for GES, from May 2008 to January 2012. Delayed gastric emptying was diagnosed by scintigraphy of ≥50% global improvement in symptom-severity and well-being was a good response. Results: There were 71 patients (51 women, 72% with a median age of 42 years (range: 14-69. The aetiology of gastroparesis was idiopathic (43 patients, 61%, diabetes (15, 21%, or post-surgical (anti-reflux surgery, 6 patients; Roux-en-Y gastric bypass, 3; subtotal gastrectomy, 1; cardiomyotomy, 1; other gastric surgery, 2 (18%. At presentation, oral nutrition was supplemented by naso-jejunal tube feeding in 7 patients, surgical jejunostomy in 8, or parenterally in 1 (total 16 patients; 22%. Previous intervention included endoscopic injection of botulinum toxin (botox into the pylorus in 16 patients (22%, pyloroplasty in 2, distal gastrectomy in 1, and gastrojejunostomy in 1. It was decided to directly proceed with permanent GES in 4 patients. Of the remaining, 51 patients have currently completed a trial of temporary stimulation and 39 (77% had a good response and were selected for permanent GES, which has been completed in 35 patients. Outcome data are currently available for 31 patients (idiopathic, 21 patients; diabetes, 3; post-surgical, 7 with a median follow-up period of 10 months (1-28; 22 patients (71% had a good response to permanent GES, these included 14 (68% with idiopathic, 5 (71% with post-surgical, and remaining 3 with diabetic gastroparesis. Conclusions: Overall, 71% of well-selected patients

  18. Clinical utility of metabolic syndrome severity scores: considerations for practitioners

    Directory of Open Access Journals (Sweden)

    DeBoer MD

    2017-02-01

    Full Text Available Mark D DeBoer,1,2 Matthew J Gurka2 11Division of Pediatric Endocrinology, Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA, 2Department of Health Outcomes and Policy, College of Medicine, University of Florida, Gainesville, FL, USA Abstract: The metabolic syndrome (MetS is marked by abnormalities in central obesity, high blood pressure, high triglycerides, low high-density lipoprotein-cholesterol, and high fasting glucose and appears to be produced by underlying processes of inflammation, oxidative stress, and adipocyte dysfunction. MetS has traditionally been classified based on dichotomous criteria that deny that MetS-related risk likely exists as a spectrum. Continuous MetS scores provide a way to track MetS-related risk over time. We generated MetS severity scores that are sex- and race/ethnicity-specific, acknowledging that the way MetS is manifested may be different by sex and racial/ethnic subgroup. These scores are correlated with long-term risk for type 2 diabetes mellitus and cardiovascular disease. Clinical use of scores like these provide a potential opportunity to identify patients at highest risk, motivate patients toward lifestyle change, and follow treatment progress over time. Keywords: metabolic syndrome, insulin resistance, cardiovascular disease, type 2 diabetes, risk prediction

  19. Homology blocks of Plasmodium falciparum var genes and clinically distinct forms of severe malaria in a local population.

    Science.gov (United States)

    Rorick, Mary M; Rask, Thomas S; Baskerville, Edward B; Day, Karen P; Pascual, Mercedes

    2013-11-06

    The primary target of the human immune response to the malaria parasite Plasmodium falciparum, P. falciparum erythrocyte membrane protein 1 (PfEMP1), is encoded by the members of the hyper-diverse var gene family. The parasite exhibits antigenic variation via mutually exclusive expression (switching) of the ~60 var genes within its genome. It is thought that different variants exhibit different host endothelial binding preferences that in turn result in different manifestations of disease. Var sequences comprise ancient sequence fragments, termed homology blocks (HBs), that recombine at exceedingly high rates. We use HBs to define distinct var types within a local population. We then reanalyze a dataset that contains clinical and var expression data to investigate whether the HBs allow for a description of sequence diversity corresponding to biological function, such that it improves our ability to predict disease phenotype from parasite genetics. We find that even a generic set of HBs, which are defined for a small number of non-local parasites: capture the majority of local sequence diversity; improve our ability to predict disease severity from parasite genetics; and reveal a previously hypothesized yet previously unobserved parasite genetic basis for two forms of severe disease. We find that the expression rates of some HBs correlate more strongly with severe disease phenotypes than the expression rates of classic var DBLα tag types, and principal components of HB expression rate profiles further improve genotype-phenotype models. More specifically, within the large Kenyan dataset that is the focus of this study, we observe that HB expression differs significantly for severe versus mild disease, and for rosetting versus impaired consciousness associated severe disease. The analysis of a second much smaller dataset from Mali suggests that these HB-phenotype associations are consistent across geographically distant populations, since we find evidence suggesting

  20. Ablation of RIC8A function in mouse neurons leads to a severe neuromuscular phenotype and postnatal death.

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    Katrin Ruisu

    Full Text Available Resistance to inhibitors of cholinesterase 8 (RIC8 is a guanine nucleotide exchange factor required for the intracellular regulation of G protein signalling. RIC8 activates different Gα subunits via non-canonical pathway, thereby amplifying and prolonging the G protein mediated signal. In order to circumvent the embryonic lethality associated with the absence of RIC8A and to study its role in the nervous system, we constructed Ric8a conditional knockout mice using Cre/loxP technology. Introduction of a synapsin I promoter driven Cre transgenic mouse strain (SynCre into the floxed Ric8a (Ric8a (F/F background ablated RIC8A function in most differentiated neuron populations. Mutant SynCre (+/- Ric8 (lacZ/F mice were born at expected Mendelian ratio, but they died in early postnatal age (P4-P6. The mutants exhibited major developmental defects, like growth retardation and muscular weakness, impaired coordination and balance, muscular spasms and abnormal heart beat. Histological analysis revealed that the deficiency of RIC8A in neurons caused skeletal muscle atrophy and heart muscle hypoplasia, in addition, the sinoatrial node was misplaced and its size reduced. However, we did not observe gross morphological changes in brains of SynCre (+/- Ric8a (lacZ/F mutants. Our results demonstrate that in mice the activity of RIC8A in neurons is essential for survival and its deficiency causes a severe neuromuscular phenotype.

  1. Ablation of RIC8A function in mouse neurons leads to a severe neuromuscular phenotype and postnatal death.

    Science.gov (United States)

    Ruisu, Katrin; Kask, Keiu; Meier, Riho; Saare, Merly; Raid, Raivo; Veraksitš, Alar; Karis, Alar; Tõnissoo, Tambet; Pooga, Margus

    2013-01-01

    Resistance to inhibitors of cholinesterase 8 (RIC8) is a guanine nucleotide exchange factor required for the intracellular regulation of G protein signalling. RIC8 activates different Gα subunits via non-canonical pathway, thereby amplifying and prolonging the G protein mediated signal. In order to circumvent the embryonic lethality associated with the absence of RIC8A and to study its role in the nervous system, we constructed Ric8a conditional knockout mice using Cre/loxP technology. Introduction of a synapsin I promoter driven Cre transgenic mouse strain (SynCre) into the floxed Ric8a (Ric8a (F/F) ) background ablated RIC8A function in most differentiated neuron populations. Mutant SynCre (+/-) Ric8 (lacZ/F) mice were born at expected Mendelian ratio, but they died in early postnatal age (P4-P6). The mutants exhibited major developmental defects, like growth retardation and muscular weakness, impaired coordination and balance, muscular spasms and abnormal heart beat. Histological analysis revealed that the deficiency of RIC8A in neurons caused skeletal muscle atrophy and heart muscle hypoplasia, in addition, the sinoatrial node was misplaced and its size reduced. However, we did not observe gross morphological changes in brains of SynCre (+/-) Ric8a (lacZ/F) mutants. Our results demonstrate that in mice the activity of RIC8A in neurons is essential for survival and its deficiency causes a severe neuromuscular phenotype.

  2. Broad phenotypic spectrum in familial adenomatous polyposis; from early onset and severe phenotypes to late onset of attenuated polyposis with the first manifestation at age 72

    DEFF Research Database (Denmark)

    Nilbert, Mef; Kristoffersson, Ulf; Ericsson, Mats

    2008-01-01

    ABSTRACT: Background Familial adenomatous polyposis (FAP) is typically characterized by multiple colonic polyps and frequent extracolonic features. Whereas the number of colonic polyps has been linked to the APC gene mutation, possible genotype-phenotype correlations largely remain to be defined...... cancer at age 72 as the first manifestation of attenuated FAP. Conclusion With an increasing number of FAP families diagnosed, a broad and variable tumor spectrum and a high frequency of extracolonic manifestations are gradually recognized. We report novel APC mutations and present two FAP cases...

  3. A PEX6-defective peroxisomal biogenesis disorder with severe phenotype in an infant, versus mild phenotype resembling Usher syndrome in the affected parents.

    Science.gov (United States)

    Raas-Rothschild, Annick; Wanders, Ronald J A; Mooijer, Petra A W; Gootjes, Jeannette; Waterham, Hans R; Gutman, Alisa; Suzuki, Yasuyuki; Shimozawa, Nobuyuki; Kondo, Naomi; Eshel, Gideon; Espeel, Marc; Roels, Frank; Korman, Stanley H

    2002-04-01

    Sensorineural deafness and retinitis pigmentosa (RP) are the hallmarks of Usher syndrome (USH) but are also prominent features in peroxisomal biogenesis defects (PBDs); both are autosomal recessively inherited. The firstborn son of unrelated parents, who both had sensorineural deafness and RP diagnosed as USH, presented with sensorineural deafness, RP, dysmorphism, developmental delay, hepatomegaly, and hypsarrhythmia and died at age 17 mo. The infant was shown to have a PBD, on the basis of elevated plasma levels of very-long- and branched-chain fatty acids (VLCFAs and BCFAs), deficiency of multiple peroxisomal functions in fibroblasts, and complete absence of peroxisomes in fibroblasts and liver. Surprisingly, both parents had elevated plasma levels of VLCFAs and BCFAs. Fibroblast studies confirmed that both parents had a PBD. The parents' milder phenotypes correlated with relatively mild peroxisomal biochemical dysfunction and with catalase immunofluorescence microscopy demonstrating mosaicism and temperature sensitivity in fibroblasts. The infant and both of his parents belonged to complementation group C. PEX6 gene sequencing revealed mutations on both alleles, in the infant and in his parents. This unique family is the first report of a PBD with which the parents are themselves affected individuals rather than asymptomatic carriers. Because of considerable overlap between USH and milder PBD phenotypes, individuals suspected to have USH should be screened for peroxisomal dysfunction.

  4. Association of FLG single nucleotide variations with clinical phenotypes of atopic dermatitis.

    Directory of Open Access Journals (Sweden)

    Myungshin Kim

    Full Text Available FLG encodes a large protein called profilaggrin, which plays a key role in maintaining an effective skin barrier against the environment. In this study, we identified FLG single nucleotide variations (FLG-SNVs and evaluated the association of FLG-SNVs with clinical phenotypes including atopic dermatitis (AD-associated minor clinical features, presence of specific allergic sensitization, and serum parameters.Eighty-one Korean patients with AD were enrolled. AD-associated minor clinical features as well as allergic rhinitis and asthma were diagnosed by specialists. FLG-SNVs were identified by Sanger sequencing of entire exons through long-range PCR. Allergic sensitization to a specific allergen was evaluated by multiple allergen simultaneous test. Serologic parameters such as serum eosinophil cationic protein (ECP and eosinophil derived neurotoxin (EDN were measured.A total of seventy-three SNVs and 4 LOF mutations were successfully genotyped. rs71626704 and rs76413899 were significantly associated with a history of asthma and cheilitis (P = 0.002 and P = 0.033, respectively, however, the associations were not found statistically significant after adjustment by multiple comparisons. In addition, we detected haplotype blocks which were correlated with non-specific hand or foot dermatitis and scalp scale. We identified FLG-SNVs which were associated with sensitization to environmental allergens; rs62623409 and rs71625199 (P = 0.038 and P = 0.008, respectively. Patients with FLG P478S TT and history of allergic rhinitis showed a higher EDN level, and among those patients, the ones with asthma showed a higher ECP level.This study revealed the association of FLG-SNVs with AD-associated minor clinical features. We firstly identified rs71625199 which was associated with higher environmental allergic sensitization. We also suggest that FLG P478S is a kind of disease modifier which affects serologic parameters such as EDN and ECP.

  5. MANAGEMENT OF ACUTE SEVERE ULCERATIVE COLITIS: A CLINICAL UPDATE.

    Science.gov (United States)

    Sobrado, Carlos Walter; Sobrado, Lucas Faraco

    2016-01-01

    Acute severe colitis is a potentially lethal medical emergency and, even today, its treatment remains a challenge for clinicians and surgeons. Intravenous corticoid therapy, which was introduced into the therapeutic arsenal in the 1950s, continues to be the first-line treatment and, for patients who are refractory to this, the rescue therapy may consist of clinical measures or emergency colectomy. To evaluate the indications for and results from drug rescue therapy (cyclosporine, infliximab and tacrolimus), and to suggest a practical guide for clinical approaches. The literature was reviewed using the Medline/PubMed, Cochrane library and SciELO databases, and additional information from institutional websites of interest, by cross-correlating the following keywords: acute severe colitis, fulminating colitis and treatment. Treatments for acute severe colitis have avoided colectomy in 60-70% of the cases, provided that they have been started early on, with multidisciplinary follow-up. Despite the adverse effects of intravenous cyclosporine, this drug has been indicated in cases of greater severity with an imminent risk of colectomy, because of its fast action, short half-life and absence of increased risk of surgical complications. Therapy using infliximab has been reserved for less severe cases and those in which immunosuppressants are being or have been used (AZA/6-MP). Indication of biological agents has recently been favored because of their ease of therapeutic use, their good short and medium-term results, the possibility of maintenance therapy and also their action as a "bridge" for immunosuppressant action (AZA/6-MP). Colectomy has been reserved for cases in which there is still no response five to seven days after rescue therapy and in cases of complications (toxic megacolon, profuse hemorrhage and perforation). Patients with a good response to rescue therapy who do not undergo emergency operations should be considered for maintenance therapy using

  6. Simplified method of clinical phenotyping for older men and women using established field-based measures.

    Science.gov (United States)

    Fukuda, David H; Smith-Ryan, Abbie E; Kendall, Kristina L; Moon, Jordan R; Stout, Jeffrey R

    2013-12-01

    The purpose of this investigation was to determine body composition classification using field-based testing measurements in healthy elderly men and women. The use of isoperformance curves is presented as a method for this determination. Baseline values from 107 healthy Caucasian men and women, over the age of 65years old, who participated in a separate longitudinal study, were used for this investigation. Field-based measurements of age, height, weight, body mass index (BMI), and handgrip strength were recorded on an individual basis. Relative skeletal muscle index (RSMI) and body fat percentage (FAT%) were determined by dual-energy X-ray absorptiometry (DXA) for each participant. Sarcopenia cut-off values for RSMI of 7.26kg·m(-2) for men and 5.45kg·m(-2) for women and elderly obesity cut-off values for FAT% of 27% for men and 38% for women were used. Individuals above the RSMI cut-off and below the FAT% cut-off were classified in the normal phenotype category, while individuals below the RSMI cut-off and above the FAT% cut-off were classified in the sarcopenic-obese phenotype category. Prediction equations for RSMI and FAT% from sex, BMI, and handgrip strength values were developed using multiple regression analysis. The prediction equations were validated using double cross-validation. The final regression equation developed to predict FAT% from sex, BMI, and handgrip strength resulted in a strong relationship (adjusted R(2)=0.741) to DXA values with a low standard error of the estimate (SEE=3.994%). The final regression equation developed to predict RSMI from the field-based testing measures also resulted in a strong relationship (adjusted R(2)=0.841) to DXA values with a low standard error of the estimate (SEE=0.544kg·m(-2)). Isoperformance curves were developed from the relationship between BMI and handgrip strength for men and women with the aforementioned clinical phenotype classification criteria. These visual representations were used to aid in the

  7. Comparing deep learning and concept extraction based methods for patient phenotyping from clinical narratives.

    Science.gov (United States)

    Gehrmann, Sebastian; Dernoncourt, Franck; Li, Yeran; Carlson, Eric T; Wu, Joy T; Welt, Jonathan; Foote, John; Moseley, Edward T; Grant, David W; Tyler, Patrick D; Celi, Leo A

    2018-01-01

    In secondary analysis of electronic health records, a crucial task consists in correctly identifying the patient cohort under investigation. In many cases, the most valuable and relevant information for an accurate classification of medical conditions exist only in clinical narratives. Therefore, it is necessary to use natural language processing (NLP) techniques to extract and evaluate these narratives. The most commonly used approach to this problem relies on extracting a number of clinician-defined medical concepts from text and using machine learning techniques to identify whether a particular patient has a certain condition. However, recent advances in deep learning and NLP enable models to learn a rich representation of (medical) language. Convolutional neural networks (CNN) for text classification can augment the existing techniques by leveraging the representation of language to learn which phrases in a text are relevant for a given medical condition. In this work, we compare concept extraction based methods with CNNs and other commonly used models in NLP in ten phenotyping tasks using 1,610 discharge summaries from the MIMIC-III database. We show that CNNs outperform concept extraction based methods in almost all of the tasks, with an improvement in F1-score of up to 26 and up to 7 percentage points in area under the ROC curve (AUC). We additionally assess the interpretability of both approaches by presenting and evaluating methods that calculate and extract the most salient phrases for a prediction. The results indicate that CNNs are a valid alternative to existing approaches in patient phenotyping and cohort identification, and should be further investigated. Moreover, the deep learning approach presented in this paper can be used to assist clinicians during chart review or support the extraction of billing codes from text by identifying and highlighting relevant phrases for various medical conditions.

  8. Phenotype and Clinical Course of Inflammatory Bowel Disease with Co-Existent Celiac Disease.

    Science.gov (United States)

    Tse, Chung Sang; Deepak, Parakkal; De La Fuente, Jaime; Bledsoe, Adam C; Larson, Joseph J; Murray, Joseph A; Papadakis, Konstantinos A

    2018-05-07

    Inflammatory bowel diseases, principally Crohn's disease and ulcerative colitis, and celiac disease are among the most common immune-mediated gastrointestinal diseases. We aim to elucidate the clinical course and outcomes of patients with concomitant inflammatory bowel disease and celiac disease, a unique population that remains scarcely studied to date. A retrospective matched case-control study of adults with coexistent inflammatory bowel disease and celiac disease was performed at a tertiary referral institution in North America. Logistic regression and Kaplan-Meier curves compared disease characteristics and clinical outcomes of the two groups. A total of 342 inflammatory bowel disease patients were included in this study, of which 114 had coexistent celiac disease and 228 did not. Patients with coexistent inflammatory bowel disease and celiac disease had higher rates of primary sclerosing cholangitis (19.3% vs 5.7%; odds ratio, 4.4; 95% confidence interval, 2.1-9.4; pceliac disease (10.5% vs 3.5%; odds ratio 3.2; 95% confidence interval 1.3-8.2; p=0.01), compared to patients without concomitant celiac disease. Patients with inflammatory bowel disease with concomitant celiac disease have unique phenotypic features compared to non-celiac inflammatory bowel disease, with higher risks for colitis-related hospitalizations, extensive colitis, and primary sclerosing cholangitis. Increased recognition of coexistent IBD and celiac disease can prompt clinicians to investigate for concomitant disease sooner, particularly in patients with seemingly refractory disease.

  9. Outcomes of empirical eating disorder phenotypes in a clinical female sample: results from a latent class analysis.

    Science.gov (United States)

    Dechartres, Agnes; Huas, Caroline; Godart, Nathalie; Pousset, Maud; Pham, Alexandra; Divac, Snezana M; Rouillon, Frederic; Falissard, Bruno

    2011-01-01

    To empirically classify phenotypes of eating disorders (ED) using latent class analysis (LCA), and to validate this classification based on clinical outcomes. LCA was applied to 968 inpatients. The resultant classes were validated by clinical outcomes including mortality. A 5-class solution showed the best fit. The symptoms of latent class 1 (LC1; 26% of the sample) resembled anorexia nervosa (AN), bingeing-purging (AN-B/P) subtype; those of LC2 (23%) resembled bulimia nervosa; those of LC3 (11%) were close to AN-B/P without weight and body concerns; those of LC4 resembled restrictive anorexia nervosa (RAN) without weight and body concerns, and those of LC5 RAN. A history of hospitalization for ED was significantly more frequent for LC3 and LC4. The lowest BMI at admission were presented in LC4. LC1 showed the highest level of psychological disturbances and LC4 the lowest. LC3 and LC4 differed from LC1 and LC5 by higher percentages of treatment dropout (64.9 vs. 57.2 and 55.7 vs. 47.5%, respectively; overall p = 0.001). Survival rates tended to be different between the LC (p = 0.09). Subgroups of AN patients with low weight and body concerns seem more severe at hospitalization and more difficult to manage, with a higher rate of treatment dropout than the 'typical' AN patients. Copyright © 2010 S. Karger AG, Basel.

  10. Phenotypic and genotypic antimicrobial susceptibility pattern of Streptococcus spp. isolated from cases of clinical mastitis in dairy cattle in Poland.

    Science.gov (United States)

    Kaczorek, E; Małaczewska, J; Wójcik, R; Rękawek, W; Siwicki, A K

    2017-08-01

    Mastitis of dairy cattle is one of the most frequently diagnosed diseases worldwide. The main etiological agents of mastitis are bacteria of the genus Streptococcus spp., in which several antibiotic resistance mechanisms have been identified. However, detailed studies addressing this problem have not been conducted in northeastern Poland. Therefore, the aim of our study was to analyze, on phenotypic and genotypic levels, the antibiotic resistance pattern of Streptococcus spp. isolated from clinical cases of mastitis from dairy cattle in this region of Poland. The research was conducted using 135 strains of Streptococcus (Streptococcus uberis, n = 53; Streptococcus dysgalactiae, n = 41; Streptococcus agalactiae, n = 27; other streptococci, n = 14). The investigation of the antimicrobial susceptibility to 8 active substances applied in therapy in the analyzed region, as well as a selected bacteriocin (nisin), was performed using the minimum inhibitory concentration method. The presence of selected resistance genes (n = 14) was determined via PCR. We also investigated the correlation between the presence of resistance genes and the antimicrobial susceptibility of the examined strains in vitro. The highest observed resistance of Streptococcus spp. was toward gentamicin, kanamycin, and tetracycline, whereas the highest susceptibility occurred toward penicillin, enrofloxacin, and marbofloxacin. Additionally, the tested bacteriocin showed high efficacy. The presence of 13 analyzed resistance genes was observed in the examined strains [gene mef(A) was not detected]. In most strains, at least one resistance gene, mainly responsible for resistance to tetracyclines [tet(M), tet(K), tet(L)], was observed. However, a relationship between the presence of a given resistance gene and antimicrobial susceptibility on the phenotypic level was not always observed. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  11. Clinical experience with Omalizumab in a Portuguese severe asthma unit

    Directory of Open Access Journals (Sweden)

    S. Alfarroba

    2014-03-01

    Full Text Available Background: It is widely recognized that asthma control is not always possible in patients with very severe asthma despite available treatment. The aim of this study was to evaluate the efficacy of Omalizumab on asthma control as an add‐on therapy in patients from the “Severe Asthma Outpatient Service” of Pulido Valente Hospital in Lisbon, Portugal. Methods: A retrospective study was conducted to assess asthma control by the ACT score and by GINA classification, frequency and severity of exacerbations, medication use and pulmonary function in patients treated with Omalizumab. Clinical information was collected from medical records from the start of treatment and at 6‐, 12‐ and 24‐month follow‐ups. Results: 26 patients started the treatment with Omalizumab, and all (100% were classified by GINA with uncontrolled asthma prior to treatment. Mean ACT score was 11.5. All the patients had treatment with fixed‐dose ICS and LABA and 34.6% also had an anti‐cholinergic inhaler. 42.3% of patients were also treated with oral glucocorticosteroids for control. Patients reported an average of 1.8 moderate and 3.1 severe exacerbations/year. Statistical differences were found at 6‐month follow‐up in most end‐points: GINA score improved: 60.9% of patients with partially controlled asthma and only 39.1% with uncontrolled asthma (Wilcoxon 0.00; ACT score improved to 19.52 (Wilcoxon 0.00; mean FEV1 improved to 76.7% (Wilcoxon 0.025; the proportion of patients requiring oral glucocorticosteroid therapy reduced to 17.4% (Wilcoxon 0.014; and the number of moderate and severe exacerbations also decreased to 1.04 and 1.83 respectively (Wilcoxon 0.007; Wilcoxon 0.002 respectively. Conclusions: The current analysis shows evidence that omalizumab is successful in improving asthma control as an add‐on therapy GINA step 5 treatment. Resumo: Introdução: Está bem documentado que o controlo de asma nem

  12. Analysis of mammalian gene function through broad based phenotypic screens across a consortium of mouse clinics

    Science.gov (United States)

    Adams, David J; Adams, Niels C; Adler, Thure; Aguilar-Pimentel, Antonio; Ali-Hadji, Dalila; Amann, Gregory; André, Philippe; Atkins, Sarah; Auburtin, Aurelie; Ayadi, Abdel; Becker, Julien; Becker, Lore; Bedu, Elodie; Bekeredjian, Raffi; Birling, Marie-Christine; Blake, Andrew; Bottomley, Joanna; Bowl, Mike; Brault, Véronique; Busch, Dirk H; Bussell, James N; Calzada-Wack, Julia; Cater, Heather; Champy, Marie-France; Charles, Philippe; Chevalier, Claire; Chiani, Francesco; Codner, Gemma F; Combe, Roy; Cox, Roger; Dalloneau, Emilie; Dierich, André; Di Fenza, Armida; Doe, Brendan; Duchon, Arnaud; Eickelberg, Oliver; Esapa, Chris T; El Fertak, Lahcen; Feigel, Tanja; Emelyanova, Irina; Estabel, Jeanne; Favor, Jack; Flenniken, Ann; Gambadoro, Alessia; Garrett, Lilian; Gates, Hilary; Gerdin, Anna-Karin; Gkoutos, George; Greenaway, Simon; Glasl, Lisa; Goetz, Patrice; Da Cruz, Isabelle Goncalves; Götz, Alexander; Graw, Jochen; Guimond, Alain; Hans, Wolfgang; Hicks, Geoff; Hölter, Sabine M; Höfler, Heinz; Hancock, John M; Hoehndorf, Robert; Hough, Tertius; Houghton, Richard; Hurt, Anja; Ivandic, Boris; Jacobs, Hughes; Jacquot, Sylvie; Jones, Nora; Karp, Natasha A; Katus, Hugo A; Kitchen, Sharon; Klein-Rodewald, Tanja; Klingenspor, Martin; Klopstock, Thomas; Lalanne, Valerie; Leblanc, Sophie; Lengger, Christoph; le Marchand, Elise; Ludwig, Tonia; Lux, Aline; McKerlie, Colin; Maier, Holger; Mandel, Jean-Louis; Marschall, Susan; Mark, Manuel; Melvin, David G; Meziane, Hamid; Micklich, Kateryna; Mittelhauser, Christophe; Monassier, Laurent; Moulaert, David; Muller, Stéphanie; Naton, Beatrix; Neff, Frauke; Nolan, Patrick M; Nutter, Lauryl MJ; Ollert, Markus; Pavlovic, Guillaume; Pellegata, Natalia S; Peter, Emilie; Petit-Demoulière, Benoit; Pickard, Amanda; Podrini, Christine; Potter, Paul; Pouilly, Laurent; Puk, Oliver; Richardson, David; Rousseau, Stephane; Quintanilla-Fend, Leticia; Quwailid, Mohamed M; Racz, Ildiko; Rathkolb, Birgit; Riet, Fabrice; Rossant, Janet; Roux, Michel; Rozman, Jan; Ryder, Ed; Salisbury, Jennifer; Santos, Luis; Schäble, Karl-Heinz; Schiller, Evelyn; Schrewe, Anja; Schulz, Holger; Steinkamp, Ralf; Simon, Michelle; Stewart, Michelle; Stöger, Claudia; Stöger, Tobias; Sun, Minxuan; Sunter, David; Teboul, Lydia; Tilly, Isabelle; Tocchini-Valentini, Glauco P; Tost, Monica; Treise, Irina; Vasseur, Laurent; Velot, Emilie; Vogt-Weisenhorn, Daniela; Wagner, Christelle; Walling, Alison; Weber, Bruno; Wendling, Olivia; Westerberg, Henrik; Willershäuser, Monja; Wolf, Eckhard; Wolter, Anne; Wood, Joe; Wurst, Wolfgang; Yildirim, Ali Önder; Zeh, Ramona; Zimmer, Andreas; Zimprich, Annemarie

    2015-01-01

    The function of the majority of genes in the mouse and human genomes remains unknown. The mouse ES cell knockout resource provides a basis for characterisation of relationships between gene and phenotype. The EUMODIC consortium developed and validated robust methodologies for broad-based phenotyping of knockouts through a pipeline comprising 20 disease-orientated platforms. We developed novel statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no prior functional annotation. We captured data from over 27,000 mice finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. Novel phenotypes were uncovered for many genes with unknown function providing a powerful basis for hypothesis generation and further investigation in diverse systems. PMID:26214591

  13. Phenotypic and genotypic characterization of vancomycin-resistant Enterococcus faecium clinical isolates from two hospitals in Mexico: First detection of VanB phenotype-vanA genotype.

    Science.gov (United States)

    Bocanegra-Ibarias, Paola; Flores-Treviño, Samantha; Camacho-Ortiz, Adrián; Morfin-Otero, Rayo; Villarreal-Treviño, Licet; Llaca-Díaz, Jorge; Martínez-Landeros, Erik Alan; Rodríguez-Noriega, Eduardo; Calzada-Güereca, Andrés; Maldonado-Garza, Héctor Jesús; Garza-González, Elvira

    2016-01-01

    Enterococcus faecium has emerged as a multidrug-resistant nosocomial pathogen involved in outbreaks worldwide. Our aim was to determine the antimicrobial susceptibility, biofilm production, and clonal relatedness of vancomycin-resistant E. faecium (VREF) clinical isolates from two hospitals in Mexico. Consecutive clinical isolates (n=56) were collected in two tertiary care hospitals in Mexico from 2011 to 2014. VREF isolates were characterized by phenotypic and molecular methods including pulsed-field gel electrophoresis (PFGE). VREF isolates were highly resistant to vancomycin, erythromycin, norfloxacin, high-level streptomycin, and teicoplanin, and showed lower resistance to tetracycline, nitrofurantoin and quinupristin-dalfopristin. None of the isolates were resistant to linezolid. The vanA gene was detected in all isolates. Two VanB phenotype-vanA genotype isolates, highly resistant to vancomycin and susceptible to teicoplanin, were detected. Furthermore, 17.9% of the isolates were classified as biofilm producers, and the espfm gene was found in 98.2% of the isolates. A total of 37 distinct PFGE patterns and 6 clones (25% of the isolates as clone A, 5.4% as clone B, and 3.6% each as clone C, D, E, and F) were detected. Clone A was detected in 5 different wards of the same hospital during 14 months of surveillance. The high resistance to most antimicrobial agents and the moderate cross-transmission of VREF detected accentuates the need for continuous surveillance of E. faecium in the hospital setting. This is also the first reported incidence of the E. faecium VanB phenotype-vanA genotype in the Americas. Copyright © 2015 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  14. De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.

    Science.gov (United States)

    Reijnders, Margot R F; Miller, Kerry A; Alvi, Mohsan; Goos, Jacqueline A C; Lees, Melissa M; de Burca, Anna; Henderson, Alex; Kraus, Alison; Mikat, Barbara; de Vries, Bert B A; Isidor, Bertrand; Kerr, Bronwyn; Marcelis, Carlo; Schluth-Bolard, Caroline; Deshpande, Charu; Ruivenkamp, Claudia A L; Wieczorek, Dagmar; Baralle, Diana; Blair, Edward M; Engels, Hartmut; Lüdecke, Hermann-Josef; Eason, Jacqueline; Santen, Gijs W E; Clayton-Smith, Jill; Chandler, Kate; Tatton-Brown, Katrina; Payne, Katelyn; Helbig, Katherine; Radtke, Kelly; Nugent, Kimberly M; Cremer, Kirsten; Strom, Tim M; Bird, Lynne M; Sinnema, Margje; Bitner-Glindzicz, Maria; van Dooren, Marieke F; Alders, Marielle; Koopmans, Marije; Brick, Lauren; Kozenko, Mariya; Harline, Megan L; Klaassens, Merel; Steinraths, Michelle; Cooper, Nicola S; Edery, Patrick; Yap, Patrick; Terhal, Paulien A; van der Spek, Peter J; Lakeman, Phillis; Taylor, Rachel L; Littlejohn, Rebecca O; Pfundt, Rolph; Mercimek-Andrews, Saadet; Stegmann, Alexander P A; Kant, Sarina G; McLean, Scott; Joss, Shelagh; Swagemakers, Sigrid M A; Douzgou, Sofia; Wall, Steven A; Küry, Sébastien; Calpena, Eduardo; Koelling, Nils; McGowan, Simon J; Twigg, Stephen R F; Mathijssen, Irene M J; Nellaker, Christoffer; Brunner, Han G; Wilkie, Andrew O M

    2018-06-07

    Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  15. The clinical phenotype of Lynch syndrome due to germline PMS2 mutations

    Science.gov (United States)

    Senter, Leigha; Clendenning, Mark; Sotamaa, Kaisa; Hampel, Heather; Green, Jane; Potter, John D.; Lindblom, Annika; Lagerstedt, Kristina; Thibodeau, Stephen N.; Lindor, Noralane M.; Young, Joanne; Winship, Ingrid; Dowty, James G.; White, Darren M.; Hopper, John L.; Baglietto, Laura; Jenkins, Mark A.; de la Chapelle, Albert

    2009-01-01

    Background and Aims Although the clinical phenotype of Lynch syndrome (also known as Hereditary Nonpolyposis Colorectal Cancer) has been well described, little is known about disease in PMS2 mutation carriers. Now that mutation detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation carriers have been identified. Information about the clinical significance of PMS2 mutations is crucial for appropriate counseling. Here, we report the clinical characteristics of a large series of PMS2 mutation carriers. Methods We performed PMS2 mutation analysis using long range PCR and MLPA for 99 probands diagnosed with Lynch syndrome-associated tumors showing isolated loss of PMS2 by immunohistochemistry. Penetrance was calculated using a modified segregation analysis adjusting for ascertainment. Results Germline PMS2 mutations were detected in 62% of probands (n = 55 monoallelic; 6 biallelic). Among families with monoallelic PMS2 mutations, 65.5% met revised Bethesda guidelines. Compared with the general population, in mutation carriers, the incidence of colorectal cancer was 5.2 fold higher and the incidence of endometrial cancer was 7.5 fold higher. In North America, this translates to a cumulative cancer risk to age 70 of 15–20% for colorectal cancer, 15% for endometrial cancer, and 25–32% for any Lynch syndrome-associated cancer. No elevated risk for non-Lynch syndrome-associated cancers was observed. Conclusions PMS2 mutations contribute significantly to Lynch syndrome but the penetrance for monoallelic mutation carriers appears to be lower than that for the other mismatch repair genes. Modified counseling and cancer surveillance guidelines for PMS2 mutation carriers are proposed. PMID:18602922

  16. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations.

    Science.gov (United States)

    Senter, Leigha; Clendenning, Mark; Sotamaa, Kaisa; Hampel, Heather; Green, Jane; Potter, John D; Lindblom, Annika; Lagerstedt, Kristina; Thibodeau, Stephen N; Lindor, Noralane M; Young, Joanne; Winship, Ingrid; Dowty, James G; White, Darren M; Hopper, John L; Baglietto, Laura; Jenkins, Mark A; de la Chapelle, Albert

    2008-08-01

    Although the clinical phenotype of Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer) has been well described, little is known about disease in PMS2 mutation carriers. Now that mutation detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation carriers have been identified. Information about the clinical significance of PMS2 mutations is crucial for appropriate counseling. Here, we report the clinical characteristics of a large series of PMS2 mutation carriers. We performed PMS2 mutation analysis using long-range polymerase chain reaction and multiplex ligation-dependent probe amplification for 99 probands diagnosed with Lynch syndrome-associated tumors showing isolated loss of PMS2 by immunohistochemistry. Penetrance was calculated using a modified segregation analysis adjusting for ascertainment. Germ-line PMS2 mutations were detected in 62% of probands (n = 55 monoallelic; 6 biallelic). Among families with monoallelic PMS2 mutations, 65.5% met revised Bethesda guidelines. Compared with the general population, in mutation carriers, the incidence of colorectal cancer was 5.2-fold higher, and the incidence of endometrial cancer was 7.5-fold higher. In North America, this translates to a cumulative cancer risk to age 70 years of 15%-20% for colorectal cancer, 15% for endometrial cancer, and 25%-32% for any Lynch syndrome-associated cancer. No elevated risk for non-Lynch syndrome-associated cancers was observed. PMS2 mutations contribute significantly to Lynch syndrome, but the penetrance for monoallelic mutation carriers appears to be lower than that for the other mismatch repair genes. Modified counseling and cancer surveillance guidelines for PMS2 mutation carriers are proposed.

  17. Integrating precision medicine in the study and clinical treatment of a severely mentally ill person

    Directory of Open Access Journals (Sweden)

    Jason A. O’Rawe

    2013-10-01

    Full Text Available Background. In recent years, there has been an explosion in the number of technical and medical diagnostic platforms being developed. This has greatly improved our ability to more accurately, and more comprehensively, explore and characterize human biological systems on the individual level. Large quantities of biomedical data are now being generated and archived in many separate research and clinical activities, but there exists a paucity of studies that integrate the areas of clinical neuropsychiatry, personal genomics and brain-machine interfaces.Methods. A single person with severe mental illness was implanted with the Medtronic Reclaim® Deep Brain Stimulation (DBS Therapy device for Obsessive Compulsive Disorder (OCD, targeting his nucleus accumbens/anterior limb of the internal capsule. Programming of the device and psychiatric assessments occurred in an outpatient setting for over two years. His genome was sequenced and variants were detected in the Illumina Whole Genome Sequencing Clinical Laboratory Improvement Amendments (CLIA-certified laboratory.Results. We report here the detailed phenotypic characterization, clinical-grade whole genome sequencing (WGS, and two-year outcome of a man with severe OCD treated with DBS. Since implantation, this man has reported steady improvement, highlighted by a steady decline in his Yale-Brown Obsessive Compulsive Scale (YBOCS score from ∼38 to a score of ∼25. A rechargeable Activa RC neurostimulator battery has been of major benefit in terms of facilitating a degree of stability and control over the stimulation. His psychiatric symptoms reliably worsen within hours of the battery becoming depleted, thus providing confirmatory evidence for the efficacy of DBS for OCD in this person. WGS revealed that he is a heterozygote for the p.Val66Met variant in BDNF, encoding a member of the nerve growth factor family, and which has been found to predispose carriers to various psychiatric illnesses. He

  18. Streptococcus sanguinis isolate displaying a phenotype with cross-resistance to several rRNA-targeting agents.

    Science.gov (United States)

    Mendes, Rodrigo E; Deshpande, Lalitagauri M; Kim, Jihye; Myers, Debra S; Ross, James E; Jones, Ronald N

    2013-08-01

    This study describes a clinical case of a 71-year-old male with a history of ischemic cardiomyopathy after left ventricular assist device (LVAD) endocarditis caused by methicillin-resistant Staphylococcus epidermidis (MRSE) and a rare linezolid-resistant Streptococcus sanguinis strain (MIC, 32 μg/ml). The patient received courses of several antimicrobial agents, including linezolid for 79 days. The S. sanguinis strain had mutations in the 23S rRNA (T2211C, T2406C, G2576T, C2610T) and an amino acid substitution (N56D) in L22 and exhibited cross-resistance to ribosome-targeting agents.

  19. A Framework to Support the Sharing and Reuse of Computable Phenotype Definitions Across Health Care Delivery and Clinical Research Applications.

    Science.gov (United States)

    Richesson, Rachel L; Smerek, Michelle M; Blake Cameron, C

    2016-01-01

    The ability to reproducibly identify clinically equivalent patient populations is critical to the vision of learning health care systems that implement and evaluate evidence-based treatments. The use of common or semantically equivalent phenotype definitions across research and health care use cases will support this aim. Currently, there is no single consolidated repository for computable phenotype definitions, making it difficult to find all definitions that already exist, and also hindering the sharing of definitions between user groups. Drawing from our experience in an academic medical center that supports a number of multisite research projects and quality improvement studies, we articulate a framework that will support the sharing of phenotype definitions across research and health care use cases, and highlight gaps and areas that need attention and collaborative solutions. An infrastructure for re-using computable phenotype definitions and sharing experience across health care delivery and clinical research applications includes: access to a collection of existing phenotype definitions, information to evaluate their appropriateness for particular applications, a knowledge base of implementation guidance, supporting tools that are user-friendly and intuitive, and a willingness to use them. We encourage prospective researchers and health administrators to re-use existing EHR-based condition definitions where appropriate and share their results with others to support a national culture of learning health care. There are a number of federally funded resources to support these activities, and research sponsors should encourage their use.

  20. LINE-1 methylation in visceral adipose tissue of severely obese individuals is associated with metabolic syndrome status and related phenotypes

    Directory of Open Access Journals (Sweden)

    Turcot Valérie

    2012-07-01

    Full Text Available Abstract Background Epigenetic mechanisms may be involved in the regulation of genes found to be differentially expressed in the visceral adipose tissue (VAT of severely obese subjects with (MetS+ versus without (MetS- metabolic syndrome (MetS. Long interspersed nuclear element 1 (LINE-1 elements DNA methylation levels (%meth in blood, a marker of global DNA methylation, have recently been associated with fasting glucose, blood lipids, heart diseases and stroke. Aim To test whether LINE-1%meth levels in VAT are associated with MetS phenotypes and whether they can predict MetS risk in severely obese individuals. Methods DNA was extracted from VAT of 34 men (MetS-: n = 14, MetS+: n = 20 and 152 premenopausal women (MetS-: n = 84; MetS+: n = 68 undergoing biliopancreatic diversion for the treatment of obesity. LINE-1%meth levels were assessed by pyrosequencing of sodium bisulfite-treated DNA. Results The mean LINE-1%meth in VAT was of 75.8% (SD = 3.0%. Multiple linear regression analyses revealed that LINE-1%meth was negatively associated with fasting glucose levels (β = -0.04; P = 0.03, diastolic blood pressure (β =  -0.65; P = 0.03 and MetS status (β = -0.04; P = 0.004 after adjustments for the effects of age, sex, waist circumference (except for MetS status and smoking. While dividing subjects into quartiles based on their LINE-1%meth (Q1 to Q4: lower %meth to higher %meth levels, greater risk were observed in the first (Q1: odds ratio (OR = 4.37, P = 0.004 and the second (Q2: OR = 4.76, P = 0.002 quartiles compared to Q4 (1.00 when adjusting for age, sex and smoking. Conclusions These results suggest that lower global DNA methylation, assessed by LINE-1 repetitive elements methylation analysis, would be associated with a greater risk for MetS in the presence of obesity.

  1. Graduated clinical manifestations according to mutation type in patients with severe myoclonic epilepsy in infancy

    DEFF Research Database (Denmark)

    Brusgaard, Klaus; Møller, Rikke Steensbjerre; Dahl, Hans Atli

    . Later, patients also manifest other seizure types, including absence, myoclonic, and simple and complex partial seizures. Psychomotor development stagnates around the second year of life. SME is considered to be the most severe phenotype within the spectrum of GEFS+. SME is a malignant epileptic...... and intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC) at the severe end Patients and methods 87 infants representing GEFS+ were analyzed by bidirectional sequencing of all exons of the SCN1A, SCN2A, GABRG2 or SCN1B genes. Additionally, MLPA analysis of SCN1A was performed. Results...... to the SMEI phenotype represent de novo incidences....

  2. Evaluating the clinical management of severely malnourished children

    African Journals Online (AJOL)

    To assess the management of severely malnourished children in two rural district hospitals and to recommend improvements for their care. Methods. Based on draft World Health Organisation (WHO) guidelines for inpatient care of children with severe malnutrition, data collection instruments were developed in conjunction ...

  3. Molecular genetics of Turner syndrome: correlation with clinical phenotype and response to growth hormone therapy.

    Science.gov (United States)

    Tsezou, A; Hadjiathanasiou, C; Gourgiotis, D; Galla, A; Kavazarakis, E; Pasparaki, A; Kapsetaki, M; Sismani, C; Theodoridis, C; Patsalis, P C; Moschonas, N; Kitsiou, S

    1999-12-01

    To correlate the origin of the retained X in Turner syndrome with phenotype, pre-treatment height and response to recombinant human growth hormone (rhGH) therapy, systematic clinical assessment and molecular studies were carried out in 33 Greek children with Turner syndrome and their parents including 18 children with 45,X and 15 with X-mosaicism. Microsatellite markers on X chromosomes (DXS101 and DXS337) revealed that the intact X was paternal (Xp) in 15/30 and maternal (Xm) in 15/30 children, while 3/33 families were non-informative. No significant relationship was found between parental origin of the retained X and birth weight/length/gestational age, blepharoptosis, pterygium colli, webbed neck, low hairline, abnormal ears, lymphoedema, short 4th metacarpal, shield chest, widely spaced nipples, cubitus valgus, pigmented naevi, streak gonads, and cardiovascular/renal anomalies. With regard to the children's pre-treatment height, there was a significant correlation with maternal height and target height in both Xm and Xp groups. No differences were found between Xm and Xp groups and the improvement of growth velocity (GV) during the first and second year of rhGH administration, while for both groups GV significantly improved with rhGH by the end of the first and the second year. To our knowledge, this is the first attempt to correlate the parental origin of Turner syndrome with the response to rhGH therapy.

  4. Phenotypic and genotypic profile of clinical and animal multidrug-resistant Salmonella enterica isolates from Mexico.

    Science.gov (United States)

    Aguilar-Montes de Oca, S; Talavera-Rojas, M; Soriano-Vargas, E; Barba-León, J; Vázquez-Navarrete, J; Acosta-Dibarrat, J; Salgado-Miranda, C

    2018-01-01

    The objective of this study was to obtain a phenotypic and genotypic profile of Salmonella enterica including multidrug-resistant (MDR) isolates from food-producing animals and clinical isolates, as well as their genetic relatedness in two different States of Mexico (Jalisco and State of Mexico). A total of 243 isolates were evaluated in terms of antimicrobial resistance (AMR) and related genes through a disk diffusion method and PCR respectively; we found 16 MDR isolates, all of them harbouring the bla CMY gene but not qnr genes, these isolates represent less than 10% of the collection. The pulsed-field gel electrophoresis revealed a higher genotypic similitude within isolates of State of Mexico than Jalisco. A low percentage of Salmonella isolates were resistant to relevant antibiotics in human health, nevertheless, the AMR and involved genes were similar despite the different serovars and origin of the isolates. This investigation provided an insight of the current status of AMR of Salmonella isolates in two States of Mexico and pinpoint the genes involved in AMR and their epidemiological relationship, the information could help to determine an adequate therapy in human and veterinary medicine. © 2017 The Society for Applied Microbiology.

  5. Further Delineation of the Clinical Phenotype of Cerebellar Ataxia, Mental Retardation, and Disequilibrium Syndrome Type 4

    Directory of Open Access Journals (Sweden)

    Saud Alsahli

    2018-02-01

    Full Text Available Background: Cerebellar ataxia, mental retardation, and disequilibrium syndrome (CAMRQ is a heterogeneous group of genetic disorders that have been grouped by shared clinical features; all of these features are transmitted via an autosomal recessive mechanism. Four variants of this syndrome have been identified so far, and each one differs in terms of both clinical and genotypical features. CAMRQ4 is a rare genetic disorder characterized by mental retardation, ataxia or an inability to walk, dysarthria and, in some patients, quadrupedal gait. Methods: We investigated three Saudi families with CAMRQ4. Blood samples were collected from the affected patients, their parents, and healthy siblings. DNA was extracted from whole blood, and whole-exome sequencing was performed. Findings were confirmed by segregation analysis, which was performed on other family members. Results: Thus far, 17 patients have been affected by CAMRQ4. Genetic analysis of all patients, including our current patients, showed a mutation in the aminophospholipid transporter, class I, type 8A, member 2 gene ( ATP8A2 . A series of common phenotypical features have been reported in these patients, with few exceptions. Ataxia, mental retardation, and hypotonia were present in all patients, consanguinity in 90% and abnormal movements in 50%. Moreover, 40% achieved ambulation at least once in their lifetime, 40% had microcephaly, whereas 30% were mute. Magnetic resonance imaging (MRI of the brain was normal in 60% of patients. Conclusions: We described the largest cohort of patients with CAMRQ4 syndrome and identified three novel mutations. CAMRQ4 syndrome should be suspected in patients presenting with ataxia, intellectual disability, hypotonia, microcephaly, choreoathetoid movements, ophthalmoplegia, and global developmental delay, even if brain MRI appears normal.

  6. Further Delineation of the Clinical Phenotype of Cerebellar Ataxia, Mental Retardation, and Disequilibrium Syndrome Type 4.

    Science.gov (United States)

    Alsahli, Saud; Alrifai, Muhammad Talal; Al Tala, Saeed; Mutairi, Fuad Al; Alfadhel, Majid

    2018-01-01

    Cerebellar ataxia, mental retardation, and disequilibrium syndrome (CAMRQ) is a heterogeneous group of genetic disorders that have been grouped by shared clinical features; all of these features are transmitted via an autosomal recessive mechanism. Four variants of this syndrome have been identified so far, and each one differs in terms of both clinical and genotypical features. CAMRQ4 is a rare genetic disorder characterized by mental retardation, ataxia or an inability to walk, dysarthria and, in some patients, quadrupedal gait. We investigated three Saudi families with CAMRQ4. Blood samples were collected from the affected patients, their parents, and healthy siblings. DNA was extracted from whole blood, and whole-exome sequencing was performed. Findings were confirmed by segregation analysis, which was performed on other family members. Thus far, 17 patients have been affected by CAMRQ4. Genetic analysis of all patients, including our current patients, showed a mutation in the aminophospholipid transporter, class I, type 8A, member 2 gene ( ATP8A2 ). A series of common phenotypical features have been reported in these patients, with few exceptions. Ataxia, mental retardation, and hypotonia were present in all patients, consanguinity in 90% and abnormal movements in 50%. Moreover, 40% achieved ambulation at least once in their lifetime, 40% had microcephaly, whereas 30% were mute. Magnetic resonance imaging (MRI) of the brain was normal in 60% of patients. We described the largest cohort of patients with CAMRQ4 syndrome and identified three novel mutations. CAMRQ4 syndrome should be suspected in patients presenting with ataxia, intellectual disability, hypotonia, microcephaly, choreoathetoid movements, ophthalmoplegia, and global developmental delay, even if brain MRI appears normal.

  7. Elevated Serum IgG4 Defines Specific Clinical Phenotype of Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Le-Feng Chen

    2014-01-01

    Full Text Available Objectives. To explore the correlation of serum IgG4 (sIgG4 with clinical manifestations or therapeutic response in rheumatoid arthritis (RA. Methods. Consecutive 136 RA patients were recruited and followed up at regular interval. SIgG4 was detected by immunonephelometry. Serial synovial tissue sections from 46 RA patients were stained immunohistochemically for IgG4. Results. Forty-six percent of 136 RA patients had elevated sIgG4. Patients with elevated sIgG4 had higher sIgG4/sIgG ratio, C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor, and anticyclic citrullinated peptide antibodies than those with normal sIgG4 (all P<0.05. Among 45 patients who received methotrexate and leflunomide therapy, 50% (9/18 of patients with elevated sIgG4 and 85% (23/27 of patients with normal sIgG4 reached therapeutic target (disease activity score of 28 joints < 3.2 at 6-month visit (χ2=6.508, P=0.011. IgG4-positive plasma cell count correlated positively with sIgG4, total synovitis score, and CD3-, CD20-, and CD38-positive cell counts (all P<0.05. Conclusions. Our results showed that elevated sIgG4 in RA is common and disproportional to total IgG and RA with elevated sIgG4 may be a specific clinical phenotype with higher disease activity, higher level of autoantibodies, and poor response to methotrexate and leflunomide therapy.

  8. Clinical Significance of Immuno phenotypic Markers in Pediatric T-cell Acute Lymphoblastic Leukemia

    International Nuclear Information System (INIS)

    SIDHOM, I.; SHAABAN, Kh.; SOLIMAN, S.; HAMDY, N.; YASSIN, D.; SALEM, Sh.; HASSANEIN, H.; MANSOUR, M.T.; EZZAT, S.; EL-ANWAR, W.

    2008-01-01

    Background: Cell-marker profiling has led to conflicting conclusions about its prognostic significance in T-ALL. Aim: To investigate the prevalence of the expression of CD34, CD10 and myeloid associated antigens (CD13/ CD33) in childhood T-ALL and to relate their presence to initial clinical and biologic features and early response to therapy. Patients and Methods: This study included 67 consecutive patients with newly diagnosed T-ALL recruited from the Children's Cancer Hospital in Egypt during the time period from July 2007 to June 2008. Immuno phenotypic markers and minimal residual disease (MRD) were studied by five-color flow cytometry. Results: The frequency of CD34 was 34.9%, CD10 33.3%, while CD13/CD33 was 18.8%. No significant association was encountered between CD34, CD10 or myeloid antigen positivity and the presenting clinical features as age, sex, TLC and CNS leukemia. Only CD10+ expression had significant association with initial CNS involvement (p=0.039). CD34 and CD13/CD33 expression was significantly associated with T-cell maturation stages (p<0.05). No relationship was observed for age, TLC, gender, NCI risk or CNS involvement with early response to therapy illustrated by BM as well as MRD day 15 and day 42. CD34+, CD13/CD33+ and early T-cell stage had high MRD levels on day 15 that was statistically highly significant (p<0.01), but CD10+ had statistically significant lower MRD level on day 15 (p=0.049). However, only CD34 retained its significance at an MRD cut-off level of 0.01%. Conclusion: CD34, CD10, CD13/CD33 expression, as well as T-cell maturation stages, may have prognostic significance in pediatric T-ALL as they have a significant impact on early clearance of leukemic cells detected by MRD day 15.

  9. Novel Conserved Genotypes Correspond to Antibiotic Resistance Phenotypes of E. coli Clinical Isolates.

    Science.gov (United States)

    Swick, Michelle C; Evangelista, Michael A; Bodine, Truston J; Easton-Marks, Jeremy R; Barth, Patrick; Shah, Minita J; Bormann Chung, Christina A; Stanley, Sarah; McLaughlin, Stephen F; Lee, Clarence C; Sheth, Vrunda; Doan, Quynh; Hamill, Richard J; Steffen, David; Becnel, Lauren B; Sucgang, Richard; Zechiedrich, Lynn

    2013-01-01

    Current efforts to understand antibiotic resistance on the whole genome scale tend to focus on known genes even as high throughput sequencing strategies uncover novel mechanisms. To identify genomic variations associated with antibiotic resistance, we employed a modified genome-wide association study; we sequenced genomic DNA from pools of E. coli clinical isolates with similar antibiotic resistance phenotypes using SOLiD technology to uncover single nucleotide polymorphisms (SNPs) unanimously conserved in each pool. The multidrug-resistant pools were genotypically similar to SMS-3-5, a previously sequenced multidrug-resistant isolate from a polluted environment. The similarity was evenly spread across the entire genome and not limited to plasmid or pathogenicity island loci. Among the pools of clinical isolates, genomic variation was concentrated adjacent to previously reported inversion and duplication differences between the SMS-3-5 isolate and the drug-susceptible laboratory strain, DH10B. SNPs that result in non-synonymous changes in gyrA (encoding the well-known S83L allele associated with fluoroquinolone resistance), mutM, ligB, and recG were unanimously conserved in every fluoroquinolone-resistant pool. Alleles of the latter three genes are tightly linked among most sequenced E. coli genomes, and had not been implicated in antibiotic resistance previously. The changes in these genes map to amino acid positions in alpha helices that are involved in DNA binding. Plasmid-encoded complementation of null strains with either allelic variant of mutM or ligB resulted in variable responses to ultraviolet light or hydrogen peroxide treatment as markers of induced DNA damage, indicating their importance in DNA metabolism and revealing a potential mechanism for fluoroquinolone resistance. Our approach uncovered evidence that additional DNA binding enzymes may contribute to fluoroquinolone resistance and further implicate environmental bacteria as a reservoir for

  10. A severe form of Crouzon's Syndrome: clinical and radiological correlation

    International Nuclear Information System (INIS)

    Abdallah, Ahmad M.

    2003-01-01

    Craniofacial dysostosis (Crouzon's syndrome) is a well defined, dominantly inherited disorder, described by Crouzon in 1912. It is characterized by several deformities involving the skull,face and eyes. This case report details a rare form of Crouzon's syndrome in which proptosis was so severe that globes were completely proptotic outside the patient's extremely shallow orbits, and the eyelids were undeveloped bilaterally and replaced by small folds of skin. It appears that this is the first report of such a severe form of Crouzon's syndrome. (author)

  11. Two cases of RIT1 associated Noonan syndrome: Further delineation of the clinical phenotype and review of the literature

    NARCIS (Netherlands)

    Milosavljević, Doris; Overwater, Eline; Tamminga, Saskia; de Boer, Karin; Elting, Mariet W.; van Hoorn, Marion E.; Rinne, Tuula; Houweling, Arjan C.

    2016-01-01

    Mutations in RIT1, involved in the RAS-MAPK pathway, have recently been identified as a cause for Noonan syndrome. We present two patients with Noonan syndrome caused by a RIT1 mutation with novel phenotypic manifestations, severe bilateral lower limb lymphedema starting during puberty, and fetal

  12. Collagen VI glycine mutations : Perturbed assembly and a spectrum of clinical severity

    NARCIS (Netherlands)

    Pace, Rishika A.; Peat, Rachel A.; Baker, Naomi L.; Zamurs, Laura; Moergelin, Matthias; Irving, Melita; Adams, Naomi E.; Bateman, John F.; Mowat, David; Smith, Nicholas J. C.; Lamont, Phillipa J.; Moore, Steven A.; Mathews, Katherine D.; North, Kathryn N.; Lamande, Shireen R.

    Objective: The collagen VI muscular dystrophies, Bethlem myopathy and Ullrich congenital muscular dystrophy, form a continuum of clinical phenotypes. Glycine mutations in the triple helix have been identified in both Bethlem and Ullrich congenital muscular dystrophy, but it is not known why they

  13. Genotype-phenotype correlations in a mountain population community with high prevalence of Wilson's disease: genetic and clinical homogeneity.

    Directory of Open Access Journals (Sweden)

    Relu Cocoş

    Full Text Available Wilson's disease is an autosomal recessive disorder caused by more than 500 mutations in ATP7B gene presenting considerably clinical manifestations heterogeneity even in patients with a particular mutation. Previous findings suggested a potential role of additional genetic modifiers and environment factors on phenotypic expression among the affected patients. We conducted clinical and genetic investigations to perform genotype-phenotype correlation in two large families living in a socio-culturally isolated community with the highest prevalence of Wilson's disease ever reported of 1 ∶ 1130. Sequencing of ATP7B gene in seven affected individuals and 43 family members identified a common compound heterozygous genotype, H1069Q/M769H-fs, in five symptomatic and two asymptomatic patients and detected the presence of two out of seven identified single nucleotide polymorphisms in all affected patients. Symptomatic patients had similar clinical phenotype and age at onset (18 ± 1 years showing dysarthria and dysphagia as common clinical features at the time of diagnosis. Moreover, all symptomatic patients presented Kayser-Fleischer rings and lack of dystonia accompanied by unfavourable clinical outcomes. Our findings add value for understanding of genotype-phenotype correlations in Wilson's disease based on a multifamily study in an isolated population with high extent of genetic and environmental homogeneity as opposed to majority of reports. We observed an equal influence of presumed other genetic modifiers and environmental factors on clinical presentation and age at onset of Wilson's disease in patients with a particular genotype. These data provide valuable inferences that could be applied for predicting clinical management in asymptomatic patients in such communities.

  14. The Clinical Phenotype of Idiopathic Rapid Eye Movement Sleep Behavior Disorder at Presentation: A Study in 203 Consecutive Patients.

    Science.gov (United States)

    Fernández-Arcos, Ana; Iranzo, Alex; Serradell, Mónica; Gaig, Carles; Santamaria, Joan

    2016-01-01

    To describe the clinical phenotype of idiopathic rapid eye movement (REM) sleep behavior disorder (IRBD) at presentation in a sleep center. Clinical history review of 203 consecutive patients with IRBD identified between 1990 and 2014. IRBD was diagnosed by clinical history plus video-polysomnographic demonstration of REM sleep with increased electromyographic activity linked to abnormal behaviors. Patients were 80% men with median age at IRBD diagnosis of 68 y (range, 50-85 y). In addition to the already known clinical picture of IRBD, other important features were apparent: 44% of the patients were not aware of their dream-enactment behaviors and 70% reported good sleep quality. In most of these cases bed partners were essential to convince patients to seek medical help. In 11% IRBD was elicited only after specific questioning when patients consulted for other reasons. Seven percent did not recall unpleasant dreams. Leaving the bed occurred occasionally in 24% of subjects in whom dementia with Lewy bodies often developed eventually. For the correct diagnosis of IRBD, video-polysomnography had to be repeated in 16% because of insufficient REM sleep or electromyographic artifacts from coexistent apneas. Some subjects with comorbid obstructive sleep apnea reported partial improvement of RBD symptoms following continuous positive airway pressure therapy. Lack of therapy with clonazepam resulted in an increased risk of sleep related injuries. Synucleinopathy was frequently diagnosed, even in patients with mild severity or uncommon IRBD presentations (e.g., patients who reported sleeping well, onset triggered by a life event, nocturnal ambulation) indicating that the development of a neurodegenerative disease is independent of the clinical presentation of IRBD. We report the largest IRBD cohort observed in a single center to date and highlight frequent features that were not reported or not sufficiently emphasized in previous publications. Physicians should be aware of

  15. Clinical Correlates of Ambulatory Blood Pressure Phenotypes at a Tertiary Care Hospital in Turkey

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    Siyar Erdogmus

    2018-05-01

    Full Text Available Background/Aims: Hypertension and its complications are major public health issues worldwide due to their association with high cardiovascular morbidity and mortality. Despite significant progress in health, the prevalence of hypertension is increasing. Ambulatory blood pressure monitoring (ABPM is becoming increasingly important for the management of hypertension. In this study, we aimed to investigate the clinical and laboratory correlates of ambulatory blood pressure (ABP phenotypes at a tertiary care hospital in Turkey. Methods: The characteristics of 1053 patients were retrospectively obtained from the hospital database. Hypertension was defined as patients with office blood pressure (BP ≥140/90 mmHg and/or previously diagnosed hypertension and/or the use of antihypertensive medication. According to the office BP and ABPM results patients were identified namely: (1 sustained normotensive (SNT patients (both office BP and ABPM were normal, (2 sustained hypertensive (SHT patients (both office BP and ABPM were high, (3 masked hypertensive (MHT patients (office BP were normal, but ABPM were high, (4 white coat hypertensive (WCHT patients (office BP were above limits, but ABPM were normal. Results: A total of 1053 patients were included to the study (female/male: 608/445 and mean age 55 ± 15 years. The mean age of patients with hypertension was significantly higher than without hypertension (p< 0.0001. Hypertension was more frequent in females (p=0.009. The rates of history of diabetes mellitus (DM, hyperlipidemia (HL, and chronic kidney disease (CKD were higher in patients with hypertension (p< 0.0001. Among patients with hypertension (n=853, 81%, ABPM results showed that 388 (45% of patients had SHT, 92 (11% had MHT, and 144 (17% had WCHT, whereas 229 (27% had SNT. Patients with MHT were significantly older than patients with SNT (p=0.025. The prevalence of SHT was higher in men than in women, whereas the prevalence of WCHT was higher in

  16. Phenotypic Variation Is Almost Entirely Independent of the Host-Pathogen Relationship in Clinical Isolates of S. aureus.

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    Adrian D Land

    Full Text Available A key feature of Staphylococcus aureus biology is its ability to switch from an apparently benign colonizer of ~30% of the population to a cutaneous pathogen, to a deadly invasive pathogen. Little is known about the mechanisms driving this transition or the propensity of different S. aureus strains to engender different types of host-pathogen interactions. At the same time, significant weight has been given to the role of specific in vitro phenotypes in S. aureus virulence. Biofilm formation, hemolysis and pigment formation have all been associated with virulence in mice.To determine if there is a correlation between in vitro phenotype and the three types of host-pathogen relationships commonly exhibited by S. aureus in the context of its natural human host, we assayed 300 clinical isolates for phenotypes implicated in virulence including hemolysis, sensitivity to autolysis, and biofilm formation. For comparative purposes, we also assayed phenotype in 9 domesticated S. aureus strains routinely used for analysis of virulence determinants in laboratory settings.Strikingly, the clinical strains exhibited significant phenotypic uniformity in each of the assays evaluated in this study. One exception was a small, but significant, correlation between an increased propensity for biofilm formation and isolation from skin and soft tissue infections (SSTIs. In contrast, we observed a high degree of phenotypic variation between common laboratory strains that exhibit virulence in mouse models. These data suggest the existence of significant evolutionary pressure on the S. aureus genome and highlight a role for host factors as a strong determinant of the host-pathogen relationship. In addition, the high degree of variation between laboratory strains emphasizes the need for caution when applying data obtained in one lab strain to the analysis of another.

  17. Clinical Profile and Predictors of Severe Illness in young South ...

    African Journals Online (AJOL)

    Background. Most childhood deaths occur within the first 2 months of life. Simple symptoms and signs that reliably indicate the presence of severe illness that would warrant urgent hospital management are of major public health importance. Objectives. To describe the disease profile of sick young infants aged 0 - 59 days ...

  18. Clinical manifestations and outcomes of severe malaria among ...

    African Journals Online (AJOL)

    admitted children with severe malaria there is a need for health providers to deploy strategic management of fatal prognostic factors. In conclusion ..... Umulisa, N., Uwimana, A., Mokuolu, O.A., Adedoyin, O.T., Johnson, W.B.R.,. Tshefu, A.K. ...

  19. Complex phenotype linked to a mutation in exon 11 of the lamin A/C gene: Hypertrophic cardiomyopathy, atrioventricular block, severe dyslipidemia and diabetes.

    Science.gov (United States)

    Francisco, Ana Rita G; Santos Gonçalves, Inês; Veiga, Fátima; Mendes Pedro, Mónica; Pinto, Fausto J; Brito, Dulce

    2017-09-01

    The lamin A/C (LMNA) gene encodes lamins A and C, which have an important role in nuclear cohesion and chromatin organization. Mutations in this gene usually lead to the so-called laminopathies, the primary cardiac manifestations of which are dilated cardiomyopathy and intracardiac conduction defects. Some mutations, associated with lipodystrophy but not cardiomyopathy, have been linked to metabolic abnormalities such as diabetes and severe dyslipidemia. Herein we describe a new phenotype associated with a mutation in exon 11 of the LMNA gene: hypertrophic cardiomyopathy, atrioventricular block, severe dyslipidemia and diabetes. A 64-year-old woman with hypertrophic cardiomyopathy and a point mutation in exon 11 of the LMNA gene (c.1718C>T, Ser573Leu) presented with severe symptomatic ventricular hypertrophy and left ventricular outflow tract obstruction. She underwent septal alcohol ablation, followed by Morrow myectomy. The patient was also diagnosed with severe dyslipidemia, diabetes and obesity, and fulfilled diagnostic criteria for metabolic syndrome. No other characteristics of LMNA mutation-related phenotypes were identified. The development of type III atrioventricular block with no apparent cause, and mildly depressed systolic function, prompted referral for cardiac resynchronization therapy. In conclusion, the association between LMNA mutations and different phenotypes is complex and not fully understood, and can present with a broad spectrum of severity. Copyright © 2017 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

  20. New classification of geometric ventricular patterns in severe aortic stenosis: Could it be clinically useful?

    Science.gov (United States)

    Di Nora, Concetta; Cervesato, Eugenio; Cosei, Iulian; Ravasel, Andreea; Popescu, Bogdan A; Zito, Concetta; Carerj, Scipione; Antonini-Canterin, Francesco; Popescu, Andreea C

    2018-04-16

    In severe aortic stenosis, different left ventricle (LV) remodeling patterns as a response to pressure overload have distinct hemodynamic profiles, cardiac function, and outcomes. The most common classification considers LV relative wall thickness and LV mass index to create 4 different groups. A new classification including also end-diastolic volume index has been recently proposed. To describe the prevalence of the newly identified remodeling patterns in patients with severe aortic stenosis and to evaluate their clinical relevance according to symptoms. We analyzed 286 consecutive patients with isolated severe aortic stenosis. Current guidelines were used for echocardiographic evaluation. Symptoms were defined as the presence of angina, syncope, or NYHA class III-IV. The mean age was 75 ± 9 years, 156 patients (54%) were men, while 158 (55%) were symptomatic. According to the new classification, the most frequent remodeling pattern was concentric hypertrophy (57.3%), followed by mixed (18.9%) and dilated hypertrophy (8.4%). There were no patients with eccentric remodeling; only 4 patients had a normalLV geometry. Symptomatic patients showed significantly more mixed hypertrophy (P < .05), while the difference regarding the prevalence of the other patterns was not statistically significant. When we analyzed the distribution of the classic 4 patterns stratified by the presence of symptoms, however, we did not find a significant difference (P = .157). The new classification had refined the description of different cardiac geometric phenotypes that develop as a response to pressure overload. It might be superior to the classic 4 patterns in terms of association with symptoms. © 2018 Wiley Periodicals, Inc.

  1. Phenotypic and functional characteristics of blood natural killer cells from melanoma patients at different clinical stages.

    Directory of Open Access Journals (Sweden)

    Giulia Fregni

    Full Text Available Melanomas are aggressive skin tumors characterized by high metastatic potential. Immunotherapy is a valuable alternative for metastatic melanoma patients resistant to chemotherapy. Natural Killer (NK cells are efficient anti-tumor cytotoxic effectors. We previously showed that blood NK cells from stage IV metastatic melanoma patients display decreased NK receptors and that chemotherapy modifies the functional status of blood NK cells. To investigate the role of NK cells along melanoma progression, we have here studied NK cells from patients at different stages of the disease. First, we showed that ex vivo NK cells from certain stage III-IV patients displayed low degranulation potential. Using a dynamic label-free assay, we found that immunoselected IL-2 activated blood NK cells from patients efficiently lysed melanoma cells through NKp46 and NKG2D receptors, independently to the clinical stage. Moreover, the ex vivo phenotype of circulating NK cells from 33 patients (stage I to IV was extensively analyzed. NK cells from patients displayed higher variability in the percentages of Natural Cytotoxicity Receptors (NCR and Natural Killer Group 2D (NKG2D receptor expression compared to donor NK cells. The main defect was the decreased expression of NCR1 (NKp46 by NK cells from metastatic patients. Interestingly, we found a positive correlation between the NK cell percentages of NKp46 and the duration of stage IV in melanoma patients. Finally, we showed that NK cells infiltrated primary melanomas and displayed a predominant peritumoral distribution. These results are new arguments for the development of NK-based therapies in melanoma patients.

  2. A leprosy clinical severity scale for erythema nodosum leprosum: An international, multicentre validation study of the ENLIST ENL Severity Scale.

    Science.gov (United States)

    Walker, Stephen L; Sales, Anna M; Butlin, C Ruth; Shah, Mahesh; Maghanoy, Armi; Lambert, Saba M; Darlong, Joydeepa; Rozario, Benjamin Jewel; Pai, Vivek V; Balagon, Marivic; Doni, Shimelis N; Hagge, Deanna A; Nery, José A C; Neupane, Kapil D; Baral, Suwash; Sangma, Biliom A; Alembo, Digafe T; Yetaye, Abeba M; Hassan, Belaynesh A; Shelemo, Mohammed B; Nicholls, Peter G; Lockwood, Diana N J

    2017-07-01

    We wished to validate our recently devised 16-item ENLIST ENL Severity Scale, a clinical tool for measuring the severity of the serious leprosy associated complication of erythema nodosum leprosum (ENL). We also wished to assess the responsiveness of the ENLIST ENL Severity Scale in detecting clinical change in patients with ENL. Participants, recruited from seven centres in six leprosy endemic countries, were assessed using the ENLIST ENL Severity Scale by two researchers, one of whom categorised the severity of ENL. At a subsequent visit a further assessment using the scale was made and both participant and physician rated the change in ENL using the subjective categories of "Much better", "somewhat better", "somewhat worse" and "much worse" compared with "No change" or "about the same". 447 participants were assessed with the ENLIST ENL Severity Scale. The Cronbach alpha of the scale and each item was calculated to determine the internal consistency of the scale. The ENLIST ENL Severity Scale had good internal consistency and this improved following removal of six items to give a Cronbach's alpha of 0.77. The cut off between mild ENL and more severe disease was 9 determined using ROC curves. The minimal important difference of the scale was determined to be 5 using both participant and physician ratings of change. The 10-item ENLIST ENL Severity Scale is the first valid, reliable and responsive measure of ENL severity and improves our ability to assess and compare patients and their treatments in this severe and difficult to manage complication of leprosy. The ENLIST ENL Severity Scale will assist physicians in the monitoring and treatment of patients with ENL. The ENLIST ENL Severity Scale is easy to apply and will be useful as an outcome measure in treatment studies and enable the standardisation of other clinical and laboratory ENL research.

  3. Autoantibodies to N-terminally truncated GAD improve clinical phenotyping of individuals with adult-onset diabetes: Action LADA 12.

    Science.gov (United States)

    Achenbach, Peter; Hawa, Mohammed I; Krause, Stephanie; Lampasona, Vito; Jerram, Samuel T; Williams, Alistair J K; Bonifacio, Ezio; Ziegler, Anette G; Leslie, R David

    2018-04-04

    Adult-onset type 1 diabetes, in which the 65 kDa isoform of GAD (GAD65) is a major autoantigen, has a broad clinical phenotype encompassing variable need for insulin therapy. This study aimed to evaluate whether autoantibodies against N-terminally truncated GAD65 more closely defined a type 1 diabetes phenotype associated with insulin therapy. Of 1114 participants with adult-onset diabetes from the Action LADA (latent autoimmune diabetes in adults) study with sufficient sera, we selected those designated type 1 (n = 511) or type 2 diabetes (n = 603) and retested the samples in radiobinding assays for human full-length GAD65 autoantibodies (f-GADA) and N-terminally truncated (amino acids 96-585) GAD65 autoantibodies (t-GADA). Individuals' clinical phenotypes were analysed according to antibody binding patterns. Overall, 478 individuals were f-GADA-positive, 431 were t-GADA-positive and 628 were negative in both assays. Risk of insulin treatment was augmented in t-GADA-positive individuals (OR 4.69 [95% CI 3.57, 6.17]) compared with f-GADA-positive individuals (OR 3.86 [95% CI 2.95, 5.06]), irrespective of diabetes duration. Of 55 individuals who were f-GADA-positive but t-GADA-negative, i.e. with antibody binding restricted to the N-terminus of GAD65, the phenotype was similar to type 2 diabetes with low risk of progression to insulin treatment. Compared with these individuals with N-terminal GAD65-restricted GADA, t-GADA-positive individuals were younger at diagnosis (p = 0.005), leaner (p N-terminally truncated GAD65 autoantibodies is associated with the clinical phenotype of autoimmune type 1 diabetes and predicts insulin therapy.

  4. Exploring links between genotypes, phenotypes, and clinical predictors of response to early intensive behavioural intervention in Autism Spectrum Disorder

    Directory of Open Access Journals (Sweden)

    Valsamma eEapen

    2013-09-01

    Full Text Available Autism Spectrum Disorder (ASD is amongst the most familial of psychiatric disorders. Twin and family studies have demonstrated a monozygotic concordance rate of 70–90%, dizygotic concordance of around 10% and more than a 20-fold increase in risk for first-degree relatives. Despite major advances in the genetics of autism, the relationship between different aspects of the behavioural and cognitive phenotype and their underlying genetic liability is still unclear. This is complicated by the heterogeneity of autism, which exists at both genetic and phenotypic levels. Given this heterogeneity, one method to find homogeneous entities and link these with specific genotypes would be to pursue endophenotypes. Evidence from neuroimaging, eye tracking and electrophysiology studies supports the hypothesis that, building on genetic vulnerability, ASD emerges from a developmental cascade in which a deficit in attention to social stimuli leads to impaired interactions with primary caregivers. This results in abnormal development of the neurocircuitry responsible for social cognition, which in turn adversely affects later behavioural and functional domains dependent on these early processes, such as language development. Such a model begets a heterogeneous clinical phenotype, and is also supported by studies demonstrating better clinical outcomes with earlier treatment. Treatment response following intensive early behavioural intervention in ASD is also distinctly variable; however, relatively little is known about specific elements of the clinical phenotype that may predict response to current behavioural treatments. This paper overviews the literature regarding genotypes, phenotypes and predictors of response to behavioural intervention in ASD and presents suggestions for future research to explore linkages between these that would enable better identification of, and increased treatment efficacy for, ASD.

  5. Clinical experience using intranasal ketamine in the longitudinal treatment of juvenile bipolar disorder with fear of harm phenotype.

    Science.gov (United States)

    Papolos, Demitri; Frei, Mark; Rossignol, Daniel; Mattis, Steven; Hernandez-Garcia, Laura C; Teicher, Martin H

    2018-01-01

    Fear of Harm (FOH) is a pediatric onset phenotype of bipolar disorder (BD) characterized by BD plus treatment resistance, separation anxiety, aggressive obsessions, parasomnias, and thermal dysregulation. Intranasal ketamine (InK) in 12 youths with BD-FOH produced marked improvement during a two-week trial. Here we report on the open effectiveness and safety of InK in maintenance treatment of BD-FOH from the private practice of one author. As part of a chart review, patients 18 years or older and parents of younger children responded to a clinical effectiveness and safety survey. Effectiveness was assessed from analysis of responses to 49 questions on symptomatology plus qualitative content analyses of written reports and chart review. Adverse events (AEs) were analyzed by frequency, duration and severity. Peak InK doses ranged from 20 to 360mg per administration. Surveys were completed on 45 patients treated with InK for 3 months to 6.5 years. Almost all patients were "much" to "very much" improved clinically and in ratings of social function and academic performance. Significant reductions were reported in all symptom categories. There were 13 reports of persistent AEs, none of which resulted in discontinuation. Acute emergence reactions were sporadically observed in up to 75%, but were mild and of brief duration. Retrospective review from a single practice without placebo control with potential for response and recall bias. InK every 3-4 days at sub-anesthetic doses appeared to be a beneficial and well-tolerated treatment. Use of InK may be considered as a tertiary alternative in treatment refractory cases. Randomized control trials are warranted. Copyright © 2017. Published by Elsevier B.V.

  6. Cardiac Amyloidosis and its New Clinical Phenotype: Heart Failure with Preserved Ejection Fraction.

    Science.gov (United States)

    Mesquita, Evandro Tinoco; Jorge, Antonio José Lagoeiro; Souza, Celso Vale; Andrade, Thais Ribeiro de

    2017-07-01

    Heart failure with preserved ejection fraction (HFpEF) is now an emerging cardiovascular epidemic, being identified as the main phenotype observed in clinical practice. It is more associated with female gender, advanced age and comorbidities such as hypertension, diabetes, obesity and chronic kidney disease. Amyloidosis is a clinical disorder characterized by the deposition of aggregates of insoluble fibrils originating from proteins that exhibit anomalous folding. Recently, pictures of senile amyloidosis have been described in patients with HFpEF, demonstrating the need for clinical cardiologists to investigate this etiology in suspect cases. The clinical suspicion of amyloidosis should be increased in cases of HFPS where the cardio imaging methods are compatible with infiltrative cardiomyopathy. Advances in cardio imaging methods combined with the possibility of performing genetic tests and identification of the type of amyloid material allow the diagnosis to be made. The management of the diagnosed patients can be done in partnership with centers specialized in the study of amyloidosis, which, together with the new technologies, investigate the possibility of organ or bone marrow transplantation and also the involvement of patients in clinical studies that evaluate the action of the new emerging drugs. Resumo A insuficiência cardíaca com fração de ejeção preservada (ICFEP) é hoje uma epidemia cardiovascular emergente, sendo identificada como o principal fenótipo observado na prática clínica. Está mais associado ao sexo feminino, idade avançada e a comorbidades como hipertensão arterial, diabetes, obesidade e doença renal crônica. A amiloidose é uma desordem clínica caracterizada pelo depósito de agregados de fibrilas insolúveis originadas de proteínas que apresentam dobramento anômalo. Recentemente, têm sido descritos quadros de amiloidose senil em pacientes com ICFEP, demonstrando a necessidade de os cardiologistas clínicos investigarem

  7. The role of inflammation in hypoxic pulmonary hypertension: from cellular mechanisms to clinical phenotypes

    Science.gov (United States)

    Poth, Jens M.; Fini, Mehdi A.; Olschewski, Andrea; El Kasmi, Karim C.; Stenmark, Kurt R.

    2014-01-01

    Hypoxic pulmonary hypertension (PH) comprises a heterogeneous group of diseases sharing the common feature of chronic hypoxia-induced pulmonary vascular remodeling. The disease is usually characterized by mild to moderate pulmonary vascular remodeling that is largely thought to be reversible compared with the progressive irreversible disease seen in World Health Organization (WHO) group I disease. However, in these patients, the presence of PH significantly worsens morbidity and mortality. In addition, a small subset of patients with hypoxic PH develop “out-of-proportion” severe pulmonary hypertension characterized by pulmonary vascular remodeling that is irreversible and similar to that in WHO group I disease. In all cases of hypoxia-related vascular remodeling and PH, inflammation, particularly persistent inflammation, is thought to play a role. This review focuses on the effects of hypoxia on pulmonary vascular cells and the signaling pathways involved in the initiation and perpetuation of vascular inflammation, especially as they relate to vascular remodeling and transition to chronic irreversible PH. We hypothesize that the combination of hypoxia and local tissue factors/cytokines (“second hit”) antagonizes tissue homeostatic cellular interactions between mesenchymal cells (fibroblasts and/or smooth muscle cells) and macrophages and arrests these cells in an epigenetically locked and permanently activated proremodeling and proinflammatory phenotype. This aberrant cellular cross-talk between mesenchymal cells and macrophages promotes transition to chronic nonresolving inflammation and vascular remodeling, perpetuating PH. A better understanding of these signaling pathways may lead to the development of specific therapeutic targets, as none are currently available for WHO group III disease. PMID:25416383

  8. Interactions between the FTO and GNB3 genes contribute to varied clinical phenotypes in hypertension.

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    Rahul Kumar

    Full Text Available The genes FTO and GNB3 are implicated in essential hypertension but their interaction remains to be explored. This study investigates the role of interaction between the two genes in the pathophysiology of essential hypertension.In a case-control study comprising 750 controls and 550 patients, interaction between the polymorphisms of FTO and GNB3 was examined using multifactor dimensionality reduction (MDR. The influence of interaction on clinical phenotypes like systolic and diastolic blood pressure, mean arterial pressure and body mass index was also investigated. The 3-locus MDR model comprising FTO rs8050136C/A and GNB3 rs1129649T/C and rs5443C/T emerged as the best disease conferring model. Moreover, the interacted-genotypes having either 1, 2, 3, 4 or 5 risk alleles correlated with linearly increasing odds ratios of 1.91 (P = 0.027; 3.93 (P = 2.08E-06; 4.51 (P = 7.63E-07; 7.44 (P = 3.66E-08 and 11.57 (P = 1.18E-05, respectively, when compared with interacted-genotypes devoid of risk alleles. Furthermore, interactions among haplotypes of FTO (H1-9 and GNB3 (Ha-d differed by >1.5-fold for protective-haplotypes, CTGGC+TC [H2+Ha] and CTGAC+TC [H4+Ha] (OR = 0.39, P = 0.003; OR = 0.22, P = 6.86E-05, respectively and risk-haplotypes, AAAGC+CT [H3+Hc] and AAAGC+TT [H3+Hd] (OR = 2.91, P = 9.98E-06; OR = 2.50, P = 0.004, respectively compared to individual haplotypes. Moreover, the effectiveness of gene-gene interaction was further corroborated with a 1.29-, 1.25- and 1.38-fold higher SBP, MAP and BMI, respectively, in patients having risk interacted-haplotype H3+Hc and 2.48-fold higher SBP having risk interacted-haplotype H3+Hd compared to individual haplotypes.Interactions between genetic variants of FTO and GNB3 influence clinical parameters to augment hypertension.

  9. Human SOD1 ALS Mutations in a Drosophila Knock-In Model Cause Severe Phenotypes and Reveal Dosage-Sensitive Gain- and Loss-of-Function Components.

    Science.gov (United States)

    Şahin, Aslı; Held, Aaron; Bredvik, Kirsten; Major, Paxton; Achilli, Toni-Marie; Kerson, Abigail G; Wharton, Kristi; Stilwell, Geoff; Reenan, Robert

    2017-02-01

    Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset motor neuron disease and familial forms can be caused by numerous dominant mutations of the copper-zinc superoxide dismutase 1 (SOD1) gene. Substantial efforts have been invested in studying SOD1-ALS transgenic animal models; yet, the molecular mechanisms by which ALS-mutant SOD1 protein acquires toxicity are not well understood. ALS-like phenotypes in animal models are highly dependent on transgene dosage. Thus, issues of whether the ALS-like phenotypes of these models stem from overexpression of mutant alleles or from aspects of the SOD1 mutation itself are not easily deconvolved. To address concerns about levels of mutant SOD1 in disease pathogenesis, we have genetically engineered four human ALS-causing SOD1 point mutations (G37R, H48R, H71Y, and G85R) into the endogenous locus of Drosophila SOD1 (dsod) via ends-out homologous recombination and analyzed the resulting molecular, biochemical, and behavioral phenotypes. Contrary to previous transgenic models, we have recapitulated ALS-like phenotypes without overexpression of the mutant protein. Drosophila carrying homozygous mutations rendering SOD1 protein enzymatically inactive (G85R, H48R, and H71Y) exhibited neurodegeneration, locomotor deficits, and shortened life span. The mutation retaining enzymatic activity (G37R) was phenotypically indistinguishable from controls. While the observed mutant dsod phenotypes were recessive, a gain-of-function component was uncovered through dosage studies and comparisons with age-matched dsod null animals, which failed to show severe locomotor defects or nerve degeneration. We conclude that the Drosophila knock-in model captures important aspects of human SOD1-based ALS and provides a powerful and useful tool for further genetic studies. Copyright © 2017 by the Genetics Society of America.

  10. Clinical phenotypes of perinatal depression and time of symptom onset: analysis of data from an international consortium

    Science.gov (United States)

    Putnam, Karen T; Wilcox, Marsha; Robertson-Blackmore, Emma; Sharkey, Katherine; Bergink, Veerle; Munk-Olsen, Trine; Deligiannidis, Kristina M; Payne, Jennifer; Altemus, Margaret; Newport, Jeffrey; Apter, Gisele; Devouche, Emmanuel; Viktorin, Alexander; Magnusson, Patrik; Penninx, Brenda; Buist, Anne; Bilszta, Justin; O’Hara, Michael; Stuart, Scott; Brock, Rebecca; Roza, Sabine; Tiemeier, Henning; Guille, Constance; Epperson, C Neill; Kim, Deborah; Schmidt, Peter; Martinez, Pedro; Di Florio, Arianna; Wisner, Katherine L; Stowe, Zachary; Jones, Ian; Sullivan, Patrick F; Rubinow, David; Wildenhaus, Kevin; Meltzer-Brody, Samantha

    2018-01-01

    Summary Background The perinatal period is a time of high risk for onset of depressive disorders and is associated with substantial morbidity and mortality, including maternal suicide. Perinatal depression comprises a heterogeneous group of clinical subtypes, and further refinement is needed to improve treatment outcomes. We sought to empirically identify and describe clinically relevant phenotypic subtypes of perinatal depression, and further characterise subtypes by time of symptom onset within pregnancy and three post-partum periods. Methods Data were assembled from a subset of seven of 19 international sites in the Postpartum Depression: Action Towards Causes and Treatment (PACT) Consortium. In this analysis, the cohort was restricted to women aged 19–40 years with information about onset of depressive symptoms in the perinatal period and complete prospective data for the ten-item Edinburgh postnatal depression scale (EPDS). Principal components and common factor analysis were used to identify symptom dimensions in the EPDS. The National Institute of Mental Health research domain criteria functional constructs of negative valence and arousal were applied to the EPDS dimensions that reflect states of depressed mood, anhedonia, and anxiety. We used k-means clustering to identify subtypes of women sharing symptom patterns. Univariate and bivariate statistics were used to describe the subtypes. Findings Data for 663 women were included in these analyses. We found evidence for three underlying dimensions measured by the EPDS: depressed mood, anxiety, and anhedonia. On the basis of these dimensions, we identified five distinct subtypes of perinatal depression: severe anxious depression, moderate anxious depression, anxious anhedonia, pure anhedonia, and resolved depression. These subtypes have clear differences in symptom quality and time of onset. Anxiety and anhedonia emerged as prominent symptom dimensions with post-partum onset and were notably severe

  11. Identification and distribution of COPD phenotypes in clinical practice according to Spanish COPD Guidelines: the FENEPOC study

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    Calle Rubio M

    2017-08-01

    Full Text Available Myriam Calle Rubio,1,2 Ricard Casamor,3 Marc Miravitlles4 On behalf of the FENEPOC study group1Pulmonary Department, Hospital Clínico San Carlos, 2Department of Medicine, Faculty of Medicine, University Complutense of Madrid, Research Institute of Hospital Clínico San Carlos (IdISSC, Madrid, 3Medical Department, Novartis Farmaceutica, Barcelona, 4Pneumology Department, University Hospital Vall d’Hebron, CIBER de Enfermedades Respiratorias (CIBERES, Barcelona, SpainBackground: The Spanish Guidelines for COPD (GesEPOC describe four clinical phenotypes: non-exacerbator (NE, asthma-COPD overlap syndrome (ACO, frequent exacerbator with emphysema (EE, and exacerbator with chronic bronchitis (ECB. The objective of this study was to determine the frequency of COPD phenotypes, their clinical characteristics, and the availability of diagnostic tools to classify COPD phenotypes in clinical practice.Materials and methods: This study was an epidemiological, cross-sectional, and multicentered study. Patients ≥40 years old with a post-bronchodilator forced expiratory volume in 1 s (FEV1/forced vital capacity ratio of <0.7 and who were smokers or former smokers (with at least 10 pack-years were included. The availability of diagnostic tools to classify COPD phenotypes was assessed by an ad hoc questionnaire.Results: A total of 647 patients (294 primary care [PC], 353 pulmonology centers were included. Most patients were male (80.8%, with a mean age (SD of 68.2 (9.2 years, mean post-bronchodilator FEV1 was 53.2% (18.9% and they suffered a mean of 2.2 (2.1 exacerbations in the last year. NE was the most frequent phenotype (47.5% found, followed by ECB (29.1%, EE (17.0%, and ACO (6.5%. Significant differences between the four phenotypes were found regarding age; sex; body mass index; FEV1; body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE/body mass index, airflow obstruction, dyspnea and exacerbations (BODEx index; modified Medical

  12. Targeted next-generation sequencing reveals novel USH2A mutations associated with diverse disease phenotypes: implications for clinical and molecular diagnosis.

    Science.gov (United States)

    Chen, Xue; Sheng, Xunlun; Liu, Xiaoxing; Li, Huiping; Liu, Yani; Rong, Weining; Ha, Shaoping; Liu, Wenzhou; Kang, Xiaoli; Zhao, Kanxing; Zhao, Chen

    2014-01-01

    USH2A mutations have been implicated in the disease etiology of several inherited diseases, including Usher syndrome type 2 (USH2), nonsyndromic retinitis pigmentosa (RP), and nonsyndromic deafness. The complex genetic and phenotypic spectrums relevant to USH2A defects make it difficult to manage patients with such mutations. In the present study, we aim to determine the genetic etiology and to characterize the correlated clinical phenotypes for three Chinese pedigrees with nonsyndromic RP, one with RP sine pigmento (RPSP), and one with USH2. Family histories and clinical details for all included patients were reviewed. Ophthalmic examinations included best corrected visual acuities, visual field measurements, funduscopy, and electroretinography. Targeted next-generation sequencing (NGS) was applied using two sequence capture arrays to reveal the disease causative mutations for each family. Genotype-phenotype correlations were also annotated. Seven USH2A mutations, including four missense substitutions (p.P2762A, p.G3320C, p.R3719H, and p.G4763R), two splice site variants (c.8223+1G>A and c.8559-2T>C), and a nonsense mutation (p.Y3745*), were identified as disease causative in the five investigated families, of which three reported to have consanguineous marriage. Among all seven mutations, six were novel, and one was recurrent. Two homozygous missense mutations (p.P2762A and p.G3320C) were found in one individual family suggesting a potential double hit effect. Significant phenotypic divergences were revealed among the five families. Three families of the five families were affected with early, moderated, or late onset RP, one with RPSP, and the other one with USH2. Our study expands the genotypic and phenotypic variability relevant to USH2A mutations, which would help with a clear insight into the complex genetic and phenotypic spectrums relevant to USH2A defects, and is complementary for a better management of patients with such mutations. We have also

  13. Targeted next-generation sequencing reveals novel USH2A mutations associated with diverse disease phenotypes: implications for clinical and molecular diagnosis.

    Directory of Open Access Journals (Sweden)

    Xue Chen

    Full Text Available USH2A mutations have been implicated in the disease etiology of several inherited diseases, including Usher syndrome type 2 (USH2, nonsyndromic retinitis pigmentosa (RP, and nonsyndromic deafness. The complex genetic and phenotypic spectrums relevant to USH2A defects make it difficult to manage patients with such mutations. In the present study, we aim to determine the genetic etiology and to characterize the correlated clinical phenotypes for three Chinese pedigrees with nonsyndromic RP, one with RP sine pigmento (RPSP, and one with USH2. Family histories and clinical details for all included patients were reviewed. Ophthalmic examinations included best corrected visual acuities, visual field measurements, funduscopy, and electroretinography. Targeted next-generation sequencing (NGS was applied using two sequence capture arrays to reveal the disease causative mutations for each family. Genotype-phenotype correlations were also annotated. Seven USH2A mutations, including four missense substitutions (p.P2762A, p.G3320C, p.R3719H, and p.G4763R, two splice site variants (c.8223+1G>A and c.8559-2T>C, and a nonsense mutation (p.Y3745*, were identified as disease causative in the five investigated families, of which three reported to have consanguineous marriage. Among all seven mutations, six were novel, and one was recurrent. Two homozygous missense mutations (p.P2762A and p.G3320C were found in one individual family suggesting a potential double hit effect. Significant phenotypic divergences were revealed among the five families. Three families of the five families were affected with early, moderated, or late onset RP, one with RPSP, and the other one with USH2. Our study expands the genotypic and phenotypic variability relevant to USH2A mutations, which would help with a clear insight into the complex genetic and phenotypic spectrums relevant to USH2A defects, and is complementary for a better management of patients with such mutations. We have

  14. Cognitive flexibility and clinical severity in eating disorders.

    Directory of Open Access Journals (Sweden)

    Kate Tchanturia

    Full Text Available OBJECTIVES: The aim of this study was to explore cognitive flexibility in a large dataset of people with Eating Disorders and Healthy Controls (HC and to see how patient characteristics (body mass index [BMI] and length of illness are related to this thinking style. METHODS: A dataset was constructed from our previous studies using a conceptual shift test--the Brixton Spatial Anticipation Test. 601 participants were included, 215 patients with Anorexia Nervosa (AN (96 inpatients; 119 outpatients, 69 patients with Bulimia Nervosa (BN, 29 Eating Disorder Not Otherwise Specified (EDNOS, 72 in long-term recovery from AN (Rec AN and a comparison group of 216 HC. RESULTS: The AN and EDNOS groups had significantly more errors than the other groups on the Brixton Test. In comparison to the HC group, the effect size decrement was large for AN patients receiving inpatient treatment and moderate for AN outpatients. CONCLUSIONS: These findings confirm that patients with AN have poor cognitive flexibility. Severity of illness measured by length of illness does not fully explain the lack of flexibility and supports the trait nature of inflexibility in people with AN.

  15. Cognitive Flexibility and Clinical Severity in Eating Disorders

    Science.gov (United States)

    Tchanturia, Kate; Harrison, Amy; Davies, Helen; Roberts, Marion; Oldershaw, Anna; Nakazato, Michiko; Stahl, Daniel; Morris, Robin

    2011-01-01

    Objectives The aim of this study was to explore cognitive flexibility in a large dataset of people with Eating Disorders and Healthy Controls (HC) and to see how patient characteristics (body mass index [BMI] and length of illness) are related to this thinking style. Methods A dataset was constructed from our previous studies using a conceptual shift test - the Brixton Spatial Anticipation Test. 601 participants were included, 215 patients with Anorexia Nervosa (AN) (96 inpatients; 119 outpatients), 69 patients with Bulimia Nervosa (BN), 29 Eating Disorder Not Otherwise Specified (EDNOS), 72 in long-term recovery from AN (Rec AN) and a comparison group of 216 HC. Results The AN and EDNOS groups had significantly more errors than the other groups on the Brixton Test. In comparison to the HC group, the effect size decrement was large for AN patients receiving inpatient treatment and moderate for AN outpatients. Conclusions These findings confirm that patients with AN have poor cognitive flexibility. Severity of illness measured by length of illness does not fully explain the lack of flexibility and supports the trait nature of inflexibility in people with AN. PMID:21698277

  16. CDKL5 Gene-Related Epileptic Encephalopathy in Estonia: Four Cases, One Novel Mutation Causing Severe Phenotype in a Boy, and Overview of the Literature.

    Science.gov (United States)

    Lilles, Stella; Talvik, Inga; Noormets, Klari; Vaher, Ulvi; Õunap, Katrin; Reimand, Tiia; Sander, Valentin; Ilves, Pilvi; Talvik, Tiina

    2016-12-01

    Cyclin-dependent kinase-like 5 ( CDKL5 ) gene mutations have mainly been found in females with early infantile epileptic encephalopathy (EIEE), severe intellectual disability, and Rett-like features. To date, only 22 boys have been reported, presenting with far more severe phenotypic features. We report the first cases of CDKL5 gene-related EIEE in Estonia diagnosed using panels of epilepsy-associated genes and describe the phenotype-genotype correlations in three male and one female patient. One of the mutations, identified in a male patient, was a novel de novo hemizygous frameshift mutation (NM_003159.2:c.2225_2228del (p.Glu742Afs*41)) in exon 15 of CDKL5. All boys have a more severe phenotype than the female patient. In boys with early onset of seizures and poor development with absent or poor eye contact, CDKL5 gene-related EIEE can be suspected and epilepsy-associated genes should be analyzed for early etiological diagnosis. Early genetic diagnosis would be the cornerstone in personalized treatment in the future. Georg Thieme Verlag KG Stuttgart · New York.

  17. Childhood-onset systemic lupus erythematosus in Singapore: clinical phenotypes, disease activity, damage, and autoantibody profiles.

    Science.gov (United States)

    Tan, J H T; Hoh, S F; Win, M T M; Chan, Y H; Das, L; Arkachaisri, T

    2015-08-01

    Childhood-onset systemic lupus erythematosus (cSLE) is a multisystem autoimmune disease characterized by immune dysregulation affecting patients less than 18 years old. One-fifth of SLE cases are diagnosed during childhood. cSLE presents differently from adults and has a more severe and aggressive course. We describe the clinical and antibody profiles in our cSLE Singapore cohort. All cSLE patients who satisfied the 1997 American College of Rheumatology diagnostic criteria were captured in our lupus registry from January 2009 to January 2014. Data including demographic, cumulative clinical, serologic data, and damage indices were collected. Adjusted mean SLEDAI-2K (AMS) was used to summarize disease activity over multiple visits. Cluster analysis using non-hierarchical K-means procedure was performed on eight selected antibodies. The 64 patients (female:male ratio 5:1; Chinese 45.3%, Malay 28.1%, Indian 9.4%, and other races 17.2%) had a mean onset age of 11.5 years (range 2.1-16.7) and mean age at diagnosis was 11.9 years (range 2.6-18.0). Our study demonstrated differences in clinical manifestations for which hematologic involvement was the most common manifestation with less renal disease and uncommon neurologic manifestation as compared to other cSLE cohorts reported in our region. Antibody clusters were identified in our cohort but their clinical association/discrimination and outcome prediction required further validation study. Outcomes of our cohort in regard to disease activity after therapy and organ damages were comparable if not better to other cSLE cohorts elsewhere. Steroid-related damage, including symptomatic multifocal avascular necrosis and cataract, were not uncommon locally. Infection remains the major cause of death for the continent. Nevertheless, the five year survival rate of our cohort (98.4%) was high. © The Author(s) 2015.

  18. [Clinical and biological monitoring of nutritional status in severe burns].

    Science.gov (United States)

    Bargues, L; Cottez-Gacia, S; Jault, P; Renard, C; Vest, P

    2009-01-01

    Burn patients are subject to hypermetabolism and catabolic states. Aim was to evaluate our current practice in nutrition. Twenty-one severely burned patients were prospectively included during three months period. Body weight was measured at least two times in a week during all stay in burn ICU. Biological markers of inflammation (C-reactive protein, CRP) and nutrition (prealbumin) were performed weekly. Protocol included early nasogastric feeding, tolerated gastric stasis less than 250 mL at four hours nasogastric aspirations, caloric target value of 40 Kcal/kg per day and measurement of total daily calorie intakes. Patient demographics showed a mean percent total body surface burn of 51.1+/-27 % (range 20-90), age of 38.7+/-13.1 years (range 18-67) and 57.3 % of smoke inhalation. All patients were ventilated and 19 patients survived. Length of stay was 75.7+/-47 days (range 22-184). Patients received only 58.9+/-10 % of calorie intakes recommended by French burn society. Loss of body mass was 15.2+/-9 kg (range 3-31) or 19.1+/-10 % of admission weight (range 5-37). Erosion of body mass was not correlated with burned surface (p=0.08), calorie intakes (p=0.26), smoke inhalation (p=0.46), lengths of stay (p=0.53), lengths of ventilation (p=0.08) or nutrition (p=0.12), days of antibiotic (p=0.72), number of dressing changes (p=0.6) or surgery (p=0.64). Biological parameters showed CRP decreasing and prealbumin improving values. New strategies of nutrition are necessary to improve outcome and reduce body mass loss in burns.

  19. Frequently relapsing anti-glomerular basement membrane antibody disease with changing clinical phenotype and antibody characteristics over time

    OpenAIRE

    Gu, Bobby; Magil, Alex B.; Barbour, Sean J.

    2016-01-01

    Anti-glomerular basement membrane (GBM) antibody disease is a typically monophasic autoimmune disease with severe pulmonary and renal involvement. We report an atypical case of frequently relapsing anti-GBM antibody disease with both anti-GBM antibody?positive flares with pulmonary and renal involvement, and anti-GBM antibody?negative flares that were pulmonary limited with no histologic renal disease. This is the first report of alternating disease phenotype and anti-GBM antibody status over...

  20. Association of Calpain (CAPN) 10 (UCSNP-43, rs3792267) gene polymorphism with elevated serum androgens in young women with the most severe phenotype of polycystic ovary syndrome (PCOS).

    Science.gov (United States)

    Anastasia, Karela; Koika, Vasiliki; Roupas, Nikolaos D; Armeni, Anastasia; Marioli, Dimitra; Panidis, Dimitrios; George, Adonakis; Georgopoulos, Neoklis A

    2015-01-01

    To highlight a possible association of Calpain (CAPN 10) gene UCSNP-43 polymorphism with hormonal and metabolic traits of young women with different phenotypes of polycystic ovary syndrome (PCOS). PCOS women were genotyped for the CAPN 10 gene UCSNP-43 polymorphism. A comparison of clinical and biochemical features of women with PCOS stratified on the basis of the CAPN 10 gene UCSNP-43 variants was assessed. Anthropometric, hormonal and biochemical measurements were carried out in 668 PCOS women and 200 healthy controls. Subjects were also genotyped for the CAPN 10 gene UCSNP-43 polymorphism. The genotype frequency distributions between groups and controls were compared using the chi-square test. The association of the polymorphism with the clinical and biochemical features of the study cohort was estimated as well. No association of the frequency of CAPN 10 gene UCSNP-43 polymorphism with PCOS was detected. No association of the polymorphism with the anthropometric, biochemical and hormonal features was detected both in PCOS and control women. The polymorphism was associated with serum Δ4 androstenedione (p = 0.018), as well as with 17-OH progesterone (17-hydroxyprogesterone) among women with PCOS phenotype A (p = 0.012). CAPN 10 gene polymorphism UCSNP-43 is deprived of a metabolic contribution to cardiovascular disease (CVD). However, due to its association with androgen excess in phenotype A, CAPN 10 gene polymorphism UCSNP-43 could be used as a genetic marker for CVD in young PCOS women.

  1. Anthropometric, clinical, and metabolic comparisons of the four Rotterdam PCOS phenotypes: A prospective study of PCOS women

    Directory of Open Access Journals (Sweden)

    Sujata Kar

    2013-01-01

    Full Text Available Aims: 1. To study the distribution of various Rotterdam classified phenotypes of polycystic ovarian syndrome (PCOS women, in our population. 2. To compare the four phenotypes with respect to anthropometric, clinical, and metabolic parameters. 3. To report the prevalence of insulin resistance (IR and metabolic syndrome in these women. Settings and Design: Private practice, Prospective cross-sectional comparative study. Materials and Methods: Women attending gynecology outpatient with the primary complains of irregular menses and/or infertility were evaluated. Each of them underwent detailed clinical examination, transvaginal sonography, and biochemical and hormonal assays. Four hundred and ten women with a clinical diagnosis of PCOS based on Rotterdam criteria were included in the study. The four phenotypes were 1 PCO complete, that is oligo/anovulation (O + polycystic ovaries (P + hyperandrogenism (H 2 P + O, 3 P + H, and 4 O + H. All women were also evaluated for metabolic syndrome (American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI, modified Adult Treatment Panel (ATP III 2005 guidelines and IR (homeostatic model assessment-IR (HOMA-IR. Statistical Analysis: Statistical Package for Social Sciences (SPSS version 18. Results: Largest group was PCOS complete (65.6% followed by P + O (22.2%; H + O (11.2%; and P + H (0.9%. Overall prevalence of metabolic syndrome was 35.07%. Hyperandrogenic phenotyptes; H + O (50% and P + H + O (37.04%, had significantly higher prevalence of metabolic syndrome than normoandrogenic P + O phenotype (10% (P ≤ 0.001. Body mass index (BMI ≥ 25 (P = 0.0004; odds ratio (OR = 3.07 (1.6574-5.7108, 95% CI, waist circumference (WC ≥ 80 cm (P = 0.001; OR = 3.68 (1.6807-8.0737, 95% CI and family history of diabetes (P = 0.019; OR 1.82 (1.1008-3.0194, 95% CI, were strongly associated with the presence of metabolic syndrome. The overall prevalence of IR in PCOS women was 30.44% (HOMA-IR cutoff

  2. Anthropometric, clinical, and metabolic comparisons of the four Rotterdam PCOS phenotypes: A prospective study of PCOS women.

    Science.gov (United States)

    Kar, Sujata

    2013-07-01

    1. To study the distribution of various Rotterdam classified phenotypes of polycystic ovarian syndrome (PCOS) women, in our population. 2. To compare the four phenotypes with respect to anthropometric, clinical, and metabolic parameters. 3. To report the prevalence of insulin resistance (IR) and metabolic syndrome in these women. Private practice, Prospective cross-sectional comparative study. Women attending gynecology outpatient with the primary complains of irregular menses and/or infertility were evaluated. Each of them underwent detailed clinical examination, transvaginal sonography, and biochemical and hormonal assays. Four hundred and ten women with a clinical diagnosis of PCOS based on Rotterdam criteria were included in the study. The four phenotypes were 1) PCO complete, that is oligo/anovulation (O) + polycystic ovaries (P) + hyperandrogenism (H) 2) P + O, 3) P + H, and 4) O + H. All women were also evaluated for metabolic syndrome (American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI), modified Adult Treatment Panel (ATP) III 2005 guidelines) and IR (homeostatic model assessment-IR (HOMA-IR)). Statistical Package for Social Sciences (SPSS) version 18. Largest group was PCOS complete (65.6%) followed by P + O (22.2%); H + O (11.2%); and P + H (0.9%). Overall prevalence of metabolic syndrome was 35.07%. Hyperandrogenic phenotyptes; H + O (50%) and P + H + O (37.04%), had significantly higher prevalence of metabolic syndrome than normoandrogenic P + O phenotype (10%) (P ≤ 0.001). Body mass index (BMI) ≥ 25 (P = 0.0004; odds ratio (OR) = 3.07 (1.6574-5.7108, 95% CI)), waist circumference (WC) ≥ 80 cm (P = 0.001; OR = 3.68 (1.6807-8.0737, 95% CI)) and family history of diabetes (P = 0.019; OR 1.82 (1.1008-3.0194, 95% CI)), were strongly associated with the presence of metabolic syndrome. The overall prevalence of IR in PCOS women was 30.44% (HOMA-IR cutoff ≥ 3.8) and 34.94% (HOMA-IR cutoff ≥ 3.5). The prevalence of

  3. Extended phenotype and clinical subgroups in unilateral Meniere disease: A cross-sectional study with cluster analysis.

    Science.gov (United States)

    Frejo, L; Martin-Sanz, E; Teggi, R; Trinidad, G; Soto-Varela, A; Santos-Perez, S; Manrique, R; Perez, N; Aran, I; Almeida-Branco, M S; Batuecas-Caletrio, A; Fraile, J; Espinosa-Sanchez, J M; Perez-Guillen, V; Perez-Garrigues, H; Oliva-Dominguez, M; Aleman, O; Benitez, J; Perez, P; Lopez-Escamez, J A

    2017-12-01

    To define clinical subgroups by cluster analysis in patients with unilateral Meniere disease (MD) and to compare them with the clinical subgroups found in bilateral MD. A cross-sectional study with a two-step cluster analysis. A tertiary referral multicenter study. Nine hundred and eighty-eight adult patients with unilateral MD. best predictors to define clinical subgroups with potential different aetiologies. We established five clusters in unilateral MD. Group 1 is the most frequently found, includes 53% of patients, and it is defined as the sporadic, classic MD without migraine and without autoimmune disorder (AD). Group 2 is found in 8% of patients, and it is defined by hearing loss, which antedates the vertigo episodes by months or years (delayed MD), without migraine or AD in most of cases. Group 3 involves 13% of patients, and it is considered familial MD, while group 4, which includes 15% of patients, is linked to the presence of migraine in all cases. Group 5 is found in 11% of patients and is defined by a comorbid AD. We found significant differences in the distribution of AD in clusters 3, 4 and 5 between patients with uni- and bilateral MD. Cluster analysis defines clinical subgroups in MD, and it extends the phenotype beyond audiovestibular symptoms. This classification will help to improve the phenotyping in MD and facilitate the selection of patients for randomised clinical trials. © 2017 John Wiley & Sons Ltd.

  4. Searching for Tourette’s syndrome gene. Part 1. Heterogeneity of clinical phenotypes

    Directory of Open Access Journals (Sweden)

    Anna Kowalska

    2012-02-01

    Full Text Available The French neuropsychiatrist Georges Gilles de la Tourette described in 1885 the “Maladie des Tics” which later was named after him, as Gilles de la Tourette syndrome (GTS. Gilles de la Tourette syndrome is a neurodevelopmental disorder characterized by simple and complex motor and vocal tics with multiple neuropsychiatric comorbidities. GTS is often concurrent with obsessive-compulsive disorder (OCD and attention deficit hyperactivity disorder (ADHD. There are several clinical GTS subtypes: GTS only, GTS OCD, and GTS OCD ADHD. Additional clinical aspects of the disorder include occurrence of anger episodes, anxiety and mood disorders, and learning and sleeping disturbances. The genetics of GTS is complex and remains unclear. So far, no causative candidate genes have been identified. However, segregation studies in families and twins with GTS provide strong evidence for the existence of a genetic background associated with a multifactorial mode of inheritance. Progress in studies on genome variability among patients with GTS is necessary to improve pharmacotherapeutic strategies of the disorder.

  5. Carbapenem-resistant and cephalosporin-susceptible: a worrisome phenotype among Pseudomonas aeruginosa clinical isolates in Brazil.

    Science.gov (United States)

    Campana, Eloiza Helena; Xavier, Danilo Elias; Petrolini, Fernanda Villas-Boas; Cordeiro-Moura, Jhonatha Rodrigo; Araujo, Maria Rita Elmor de; Gales, Ana Cristina

    The mechanisms involved in the uncommon resistance phenotype, carbapenem resistance and broad-spectrum cephalosporin susceptibility, were investigated in 25 Pseudomonas aeruginosa clinical isolates that exhibited this phenotype, which were recovered from three different hospitals located in São Paulo, Brazil. The antimicrobial susceptibility profile was determined by CLSI broth microdilution. β-lactamase-encoding genes were investigated by PCR followed by DNA sequencing. Carbapenem hydrolysis activity was investigated by spectrophotometer and MALDI-TOF assays. The mRNA transcription level of oprD was assessed by qRT-PCR and the outer membrane proteins profile was evaluated by SDS-PAGE. Genetic relationship among P. aeruginosa isolates was assessed by PFGE. Carbapenems hydrolysis was not detected by carbapenemase assay in the carbapenem-resistant and cephalosporin-susceptible P. aueruginosa clinical isolates. OprD decreased expression was observed in all P. aeruginosa isolates by qRT-PCR. The outer membrane protein profile by SDS-PAGE suggested a change in the expression of the 46kDa porin that could correspond to OprD porin. The isolates were clustered into 17 genotypes without predominance of a specific PFGE pattern. These results emphasize the involvement of multiple chromosomal mechanisms in carbapenem-resistance among clinical isolates of P. aeruginosa, alert for adaptation of P. aeruginosa clinical isolates under antimicrobial selective pressure and make aware of the emergence of an uncommon phenotype among P. aeruginosa clinical isolates. Copyright © 2016 Sociedade Brasileira de Infectologia. Published by Elsevier Editora Ltda. All rights reserved.

  6. recA mediated spontaneous deletions of the icaADBC operon of clinical Staphylococcus epidermidis isolates : a new mechanism of phenotypic variations

    NARCIS (Netherlands)

    Nuryastuti, Titik; van der Mei, Henny C.; Busscher, Henk J.; Kuijer, Roel; Aman, Abu T.; Krom, Bastiaan P.

    Phenotypic variation of Staphylococcus epidermidis involving the slime related ica operon results in heterogeneity in surface characteristics of individual bacteria in axenic cultures. Five clinical S. epidermidis isolates demonstrated phenotypic variation, i.e. both black and red colonies on Congo

  7. The Urinary Microbiome Differs Significantly Between Patients With Chronic Prostatitis/Chronic Pelvic Pain Syndrome and Controls as Well as Between Patients With Different Clinical Phenotypes.

    Science.gov (United States)

    Shoskes, Daniel A; Altemus, Jessica; Polackwich, Alan S; Tucky, Barbara; Wang, Hannah; Eng, Charis

    2016-06-01

    To study the urinary microbiome of patients with Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) compared with controls. We identified 25 patients with CP/CPPS and 25 men who were either asymptomatic or only had urinary symptoms. Midstream urine was collected. Symptom severity was measured with the National Institutes of Health Chronic Prostatitis Symptom Index and clinical phenotype with UPOINT. Total DNA was extracted from the urine pellet and bacterial-specific 16Sr-DNA-capture identified by MiSeq sequencing. Taxonomic and functional bioinformatic analyses used principal coordinate analysis (PCoA)/MacQIIME, LEfSe, and PiCRUSt algorithms. Patients and controls were similar ages (52.3 vs 57.0 years, P = .27). For patients, median duration was 48 months, mean Chronic Prostatitis Symptom Index was 26.0, and mean UPOINT domains was 3.6. Weighted 3D UniFrac PCoA revealed tighter clustering of controls distinct from the wider clustering of cases (P = .001; α-diversity P = .005). Seventeen clades were overrepresented in patients, for example, Clostridia, and 5 were underrepresented, eg, Bacilli, resulting in predicted perturbations in functional pathways. PiCRUSt inferred differentially regulated pathways between cases and controls that may be of relevance including sporulation, chemotaxis, and pyruvate metabolism. PCoA-derived microbiomic differences were noted for neurologic/systemic domains (P = .06), whereas LEfSe identified differences associated with each of the 6 clinical features. Urinary microbiomes from patients with CP/CPPS have significantly higher alpha(phylogenetic) diversity which cluster differently from controls, and higher counts of Clostridia compared with controls, resulting in predicted perturbations of functional pathways which could suggest metabolite-specific targeted treatment. Several measures of severity and clinical phenotype have significant microbiome differences. Copyright © 2016 Elsevier Inc. All rights

  8. Normalization of Phenotypic Data from a Clinical Data Warehouse: Case Study of Heterogeneous Blood Type Data with Surprising Results.

    Science.gov (United States)

    Cimino, James J

    2015-01-01

    Clinical data warehouses often contain analogous data from disparate sources, resulting in heterogeneous formats and semantics. We have developed an approach that attempts to represent such phenotypic data in its most atomic form to facilitate aggregation. We illustrate this approach with human blood antigen typing (ABO-Rh) data drawn from the National Institutes of Health's Biomedical Translational Research Information System (BTRIS). In applying the method to actual patient data, we discovered a 2% incidence of changed blood types. We believe our approach can be applied to any institution's data to obtain comparable patient phenotypes. The actual discrepant blood type data will form the basis for a future study of the reasons for blood typing variation.

  9. Broad autism phenotype features of Chinese parents with autistic children and their associations with severity of social impairment in probands.

    Science.gov (United States)

    Shi, Li-Juan; Ou, Jian-Jun; Gong, Jing-Bo; Wang, Su-Hong; Zhou, Yuan-Yue; Zhu, Fu-Rong; Liu, Xu-Dong; Zhao, Jing-Ping; Luo, Xue-Rong

    2015-07-23

    Parents of children with autism have higher rates of broad autism phenotype (BAP) features than parents of typically developing children (TDC) in Western countries. This study was designed to examine the rate of BAP features in parents of children with autism and the relationship between parental BAP and the social impairment of their children in a Chinese sample. A total of 299 families with autistic children and 274 families with TDC participated in this study. Parents were assessed using the Broad Autism Phenotype Questionnaire (BAPQ), which includes self-report, informant-report, and best-estimate versions. Children were assessed using the Chinese version of the Social Responsiveness Scale (SRS). Parents of children with autism were significantly more likely to have BAP features than were parents of TDC; mothers and fathers in families with autistic children had various BAP features. The total scores of the informant and best-estimate BAPQ versions for fathers were significantly associated with their children's SRS total scores in the autism group, whereas the total scores of the three BAPQ versions for mothers were significantly associated with their children's SRS total scores in the TDC group. In the autism group, the total SRS scores of children with "BAP present" parents (informant and best-estimate) were higher than the total SRS scores of children with"BAP absent" parents. In the TDC group, the total SRS scores of children with "BAP present" parents were higher than the total SRS scores of children with"BAP absent" parents (best-estimate). Parents of autistic children were found to have higher rates of BAP than parents of TDC in a sample of Chinese parents. The BAP features of parents are associated with their children's social functioning in both autism families and TDC families, but the patterns of the associations are different.

  10. Two cases of RIT1 associated Noonan syndrome: Further delineation of the clinical phenotype and review of the literature.

    Science.gov (United States)

    Milosavljević, Doris; Overwater, Eline; Tamminga, Saskia; de Boer, Karin; Elting, Mariet W; van Hoorn, Marion E; Rinne, Tuula; Houweling, Arjan C

    2016-07-01

    Mutations in RIT1, involved in the RAS-MAPK pathway, have recently been identified as a cause for Noonan syndrome. We present two patients with Noonan syndrome caused by a RIT1 mutation with novel phenotypic manifestations, severe bilateral lower limb lymphedema starting during puberty, and fetal hydrops resulting in intrauterine fetal death, respectively. Including our patients, a total of 52 patients have been reported with Noonan syndrome caused by a RIT1 mutation. Our report contributes to the delineation of the phenotype associated with RIT1 mutations and underlines that lymphatic involvement is part of this spectrum. In addition, we provide an overview of the currently described Noonan syndrome patients with RIT1 mutations in literature. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  11. Dosha phenotype specific Ayurveda intervention ameliorates asthma symptoms through cytokine modulations: Results of whole system clinical trial.

    Science.gov (United States)

    Joshi, Kalpana S; Nesari, Tanuja M; Dedge, Amrish P; Dhumal, Vikram R; Shengule, Sushant A; Gadgil, Maithili S; Salvi, Sundeep; Valiathan, Marthanda Varma Sankaran

    2017-02-02

    Over the past few decades, there have been significant scientific advances leading to improved understanding of asthma as a disease and treatment providing immediate relief. However, prevention of recurrent attacks, exacerbations and disease cure remains a challenge. Ayurveda refers to bronchial asthma as Tamaka Swasa and it is well explained in Charaka Samhita. Management of asthma in Ayurveda includes removal of vitiated Kapha through Shodhana, Shamana procedures, herbal and herbomineral formulations in addition to advising a healthy lifestyle and diet. Several clinical trials on Ayurvedic formulations for treatment of asthma are reported, however, whole system management of asthma has rarely been studied in the manner in which it is actually being practiced. Ayurveda therapeutics provides Dosha specific approaches, which needs biological investigation. The objective of our study was to investigate lung functions and cytokine changes in Asthmatic individuals in response to Ayurvedic intervention. The study design was approved by the Institutional Ethics Committee of Tilak Ayurveda Mahavidyalaya (TAMV) & Sheth Tarachand Ramnath Charitable Ayurveda Hospital and followed guidelines of the Declaration of Helsinki and Tokyo for humans. It was conducted as a whole system individualized pragmatic clinical trial and written consent of patients was collected before enrollment. One hundred and fifteen patients with mild-to-moderate asthma were divided into 2 sub-groups depending on their disease subsets and administered phenotype specific ayurvedic interventions. Seventy six asthma patients completed the treatment. Serum IgE levels, blood eosinophil counts, spirometry and blood cytokine levels were measured before the start of treatment and six months at the end of treatment. Age and sex matched healthy participants (n=69) were recruited in the study for comparison of cytokines levels. Significant improvements in FEV1(% predicted) (p<0.0001) and FVC (% predicted) (p=0

  12. Point-of-care blood eosinophil count in a severe asthma clinic setting.

    Science.gov (United States)

    Heffler, Enrico; Terranova, Giovanni; Chessari, Carlo; Frazzetto, Valentina; Crimi, Claudia; Fichera, Silvia; Picardi, Giuseppe; Nicolosi, Giuliana; Porto, Morena; Intravaia, Rossella; Crimi, Nunzio

    2017-07-01

    One of the main severe asthma phenotypes is severe eosinophilic or eosinophilic refractory asthma for which novel biologic agents are emerging as therapeutic options. In this context, blood eosinophil counts are one of the most reliable biomarkers. To evaluate the performance of a point-of-care peripheral blood counter in a patients with severe asthma. The blood eosinophil counts of 76 patients with severe asthma were evaluated by point-of-care and standard analyzers. A significant correlation between blood eosinophils assessed by the 2 devices was found (R 2  = 0.854, P asthma and the ELEN index, a composite score useful to predict sputum eosinophilia. The results of our study contribute to the validation of a point-of-care device to assess blood eosinophils and open the possibility of using this device for the management of severe asthma management. Copyright © 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  13. Minireview: Clinical severity in sickle cell disease: the challenges of definition and prognostication.

    Science.gov (United States)

    Quinn, Charles T

    2016-04-01

    Sickle cell disease (SCD) is a monogenic, yet highly phenotypically variable disease with multisystem pathology. This manuscript provides an overview of many of the known determinants, modifiers, and correlates of disease severity in SCD. Despite this wealth of data, modeling the variable and multisystem pathology of SCD continues to be difficult. The current status of prediction of specific adverse outcomes and global disease severity in SCD is also reviewed, highlighting recent successes and ongoing challenges. © 2016 by the Society for Experimental Biology and Medicine.

  14. SPG7 Variant Escapes Phosphorylation-Regulated Processing by AFG3L2, Elevates Mitochondrial ROS, and Is Associated with Multiple Clinical Phenotypes

    Directory of Open Access Journals (Sweden)

    Naif A.M. Almontashiri

    2014-05-01

    Full Text Available Mitochondrial production of reactive oxygen species (ROS affects many processes in health and disease. SPG7 assembles with AFG3L2 into the mAAA protease at the inner membrane of mitochondria, degrades damaged proteins, and regulates the synthesis of mitochondrial ribosomes. SPG7 is cleaved and activated by AFG3L2 upon assembly. A variant in SPG7 that replaces arginine 688 with glutamine (Q688 is associated with several phenotypes, including toxicity of chemotherapeutic agents, type 2 diabetes mellitus, and (as reported here coronary artery disease. We demonstrate that SPG7 processing is regulated by tyrosine phosphorylation of AFG3L2. Carriers of Q688 bypass this regulation and constitutively process and activate SPG7 mAAA protease. Cells expressing Q688 produce higher ATP levels and ROS, promoting cell proliferation. Our results thus reveal an unexpected link between the phosphorylation-dependent regulation of the mitochondria mAAA protease affecting ROS production and several clinical phenotypes.

  15. Aberrant supracallosal longitudinal bundle: MR features, pathogenesis and associated clinical phenotype

    International Nuclear Information System (INIS)

    Arrigoni, Filippo; Peruzzo, Denis; Romaniello, Romina; Borgatti, Renato; Righini, Andrea; Parazzini, Cecilia; Colombo, Paola; Bassi, Maria Teresa; Triulzi, Fabio

    2016-01-01

    To describe the MRI and structural features of a peculiar malformation of the corpus callosum (CC) in a group of young patients with intellectual disability. We studied with conventional MRI and DTI a group of subjects showing an aberrant supracallosal bundle, characterized by the presence of a triangle-shaped bulging above the dorsal surface of CC on the midline. Clinical evaluations, CGH-array and instrumental analysis were also collected. Among 85 patients with malformed CC, we identified 15 subjects that showed the supracallosal bundle. The CC was thickened in five cases, long and thinned in three cases, short and thinned in three cases and it had a ''ribbon-like'' appearance in four subjects. Additional brain anomalies were present in eight cases. DTI colour maps and tractography showed that the bundle had an antero-posterior longitudinal orientation and that the tract bifurcated posteriorly, ending in the posterior hippocampi. Patients had different combinations of neurological symptoms, but all showed mild or severe intellectual disability. Combining radiological and genetic data with embryological knowledge of the development of cerebral commissures, we hypothesize that the supracallosal bundle represents a vestigial structure, the dorsal fornix, present during fetal life. Its persistence is associated with intellectual disability. (orig.)

  16. Hydrocephalus following severe traumatic brain injury in adults. Incidence, timing, and clinical predictors during rehabilitation

    DEFF Research Database (Denmark)

    Kammersgaard, Lars Peter; Linnemann, Mia; Tibæk, Maiken

    2013-01-01

    To investigate timing and clinical predictors that might predict hydrocephalus emerging during rehabilitation until 1 year following severe traumatic brain injury (TBI).......To investigate timing and clinical predictors that might predict hydrocephalus emerging during rehabilitation until 1 year following severe traumatic brain injury (TBI)....

  17. Sub-clinical assessment of atopic dermatitis severity using angiographic optical coherence tomography

    Science.gov (United States)

    Byers, Robert A.; Maiti, Raman; Danby, Simon G.; Pang, Elaine J.; Mitchell, Bethany; Carré, Matt J.; Lewis, Roger; Cork, Michael J.; Matcher, Stephen J.

    2018-01-01

    Measurement of sub-clinical atopic dermatitis (AD) is important for determining how long therapies should be continued after clinical clearance of visible AD lesions. An important biomarker of sub-clinical AD is epidermal hypertrophy, the structural measures of which often make optical coherence tomography (OCT) challenging due to the lack of a clearly delineated dermal-epidermal junction in AD patients. Alternatively, angiographic OCT measurements of vascular depth and morphology may represent a robust biomarker for quantifying the severity of clinical and sub-clinical AD. To investigate this, angiographic data sets were acquired from 32 patients with a range of AD severities. Deeper vascular layers within skin were found to correlate with increasing clinical severity. Furthermore, for AD patients exhibiting no clinical symptoms, the superficial plexus depth was found to be significantly deeper than healthy patients at both the elbow (p = 0.04) and knee (p<0.001), suggesting that sub-clinical changes in severity can be detected. Furthermore, the morphology of vessels appeared altered in patients with severe AD, with significantly different vessel diameter, length, density and fractal dimension. These metrics provide valuable insight into the sub-clinical severity of the condition, allowing the effects of treatments to be monitored past the point of clinical remission. PMID:29675335

  18. Als2 mRNA splicing variants detected in KO mice rescue severe motor dysfunction phenotype in Als2 knock-down zebrafish.

    Science.gov (United States)

    Gros-Louis, Francois; Kriz, Jasna; Kabashi, Edor; McDearmid, Jonathan; Millecamps, Stéphanie; Urushitani, Makoto; Lin, Li; Dion, Patrick; Zhu, Qinzhang; Drapeau, Pierre; Julien, Jean-Pierre; Rouleau, Guy A

    2008-09-01

    Recessive ALS2 mutations are linked to three related but slightly different neurodegenerative disorders: amyotrophic lateral sclerosis, hereditary spastic paraplegia and primary lateral sclerosis. To investigate the function of the ALS2 encoded protein, we generated Als2 knock-out (KO) mice and zAls2 knock-down zebrafish. The Als2(-/-) mice lacking exon 2 and part of exon 3 developed mild signs of neurodegeneration compatible with axonal transport deficiency. In contrast, zAls2 knock-down zebrafish had severe developmental abnormalities, swimming deficits and motor neuron perturbation. We identified, by RT-PCR, northern and western blotting novel Als2 transcripts in mouse central nervous system. These Als2 transcripts were present in Als2 null mice as well as in wild-type littermates and some rescued the zebrafish phenotype. Thus, we speculate that the newly identified Als2 mRNA species prevent the Als2 KO mice from developing severe neurodegenerative disease and might also regulate the severity of the motor neurons phenotype observed in ALS2 patients.

  19. Defining the Relationship Between Phenotypic and Genotypic Resistance Profiles of Multidrug-Resistant Enterobacterial Clinical Isolates.

    Science.gov (United States)

    Galal, Lamis; Abdel Aziz, Neveen A; Hassan, Walaa M

    2018-05-11

    Fluoroquinolones and aminoglycosides offer effective therapy for extended-spectrum beta-lactamase (ESBL)-producing enterobacterial infections, but their usefulness is threatened by increasing resistant strains. This study was conducted to demonstrate the phenotypic outcomes of the coexistence of genetic determinants mediating resistance to extended-spectrum cephalosporins and quinolones in enterobacterial isolates collected from patients with health-care-associated infections in Egypt. ESBL phenotype was determined using double-disk synergy test (DDST). The PCR technique was used to detect the presence of the genes mediating quinolone resistance (qnr and aac(6')-Ib-cr) and coexistence with ESBL genes. We also examined the association between the genetic makeup of the isolates and their resistance profiles including effect on MIC results. Phenotypically ESBLs were detected in 60-82% of the enterobacterial isolates. ESBL, qnr and aac(6')-Ib-cr genes were detected with the following percentages in Citrobacter isolates (69%, 69%, and 43%, respectively), E.coli isolates (65%, 70%, and 45%, respectively), Enterobacter isolates (56%, 67%, and 33%, respectively), and finally Klebsiella isolates (42%, 66%, and 25%, respectively). The coexistence of these multiresistant genetic elements significantly increased the MIC values of the tested antibiotics from different classes. We suggest using blaTEM, blaCTX-M-15, qnr, and aac(6')-Ib-cr genes for better and faster prediction of suitable antibiotic therapy with effective doses against ESBL-producing isolates harboring plasmid-mediated quinolone resistance (PMQR) determinants. Amikacin, meropenem, gentamicin, and imipenem seem to be better choices of treatment for such life-threatening infections, because of their remaining highest activity.

  20. Genotypic and Phenotypic Characteristics Associated with Biofilm Formation by Human Clinical Escherichia coli Isolates of Different Pathotypes.

    Science.gov (United States)

    Schiebel, Juliane; Böhm, Alexander; Nitschke, Jörg; Burdukiewicz, Michał; Weinreich, Jörg; Ali, Aamir; Roggenbuck, Dirk; Rödiger, Stefan; Schierack, Peter

    2017-12-15

    Bacterial biofilm formation is a widespread phenomenon and a complex process requiring a set of genes facilitating the initial adhesion, maturation, and production of the extracellular polymeric matrix and subsequent dispersal of bacteria. Most studies on Escherichia coli biofilm formation have investigated nonpathogenic E. coli K-12 strains. Due to the extensive focus on laboratory strains in most studies, there is poor information regarding biofilm formation by pathogenic E. coli isolates. In this study, we genotypically and phenotypically characterized 187 human clinical E. coli isolates representing various pathotypes (e.g., uropathogenic, enteropathogenic, and enteroaggregative E. coli ). We investigated the presence of biofilm-associated genes ("genotype") and phenotypically analyzed the isolates for motility and curli and cellulose production ("phenotype"). We developed a new screening method to examine the in vitro biofilm formation ability. In summary, we found a high prevalence of biofilm-associated genes. However, we could not detect a biofilm-associated gene or specific phenotype correlating with the biofilm formation ability. In contrast, we did identify an association of increased biofilm formation with a specific E. coli pathotype. Enteroaggregative E. coli (EAEC) was found to exhibit the highest capacity for biofilm formation. Using our image-based technology for the screening of biofilm formation, we demonstrated the characteristic biofilm formation pattern of EAEC, consisting of thick bacterial aggregates. In summary, our results highlight the fact that biofilm-promoting factors shown to be critical for biofilm formation in nonpathogenic strains do not reflect their impact in clinical isolates and that the ability of biofilm formation is a defined characteristic of EAEC. IMPORTANCE Bacterial biofilms are ubiquitous and consist of sessile bacterial cells surrounded by a self-produced extracellular polymeric matrix. They cause chronic and device

  1. Th1 and Th17 Cells and Associated Cytokines Discriminate among Clinically Isolated Syndrome and Multiple Sclerosis Phenotypes.

    Science.gov (United States)

    Arellano, Gabriel; Acuña, Eric; Reyes, Lilian I; Ottum, Payton A; De Sarno, Patrizia; Villarroel, Luis; Ciampi, Ethel; Uribe-San Martín, Reinaldo; Cárcamo, Claudia; Naves, Rodrigo

    2017-01-01

    Multiple sclerosis (MS) is a chronic, inflammatory, and demyelinating disease of the central nervous system. It is a heterogeneous pathology that can follow different clinical courses, and the mechanisms that underlie the progression of the immune response across MS subtypes remain incompletely understood. Here, we aimed to determine differences in the immunological status among different MS clinical subtypes. Blood samples from untreated patients diagnosed with clinically isolated syndrome (CIS) ( n  = 21), different clinical forms of MS ( n  = 62) [relapsing-remitting (RRMS), secondary progressive, and primary progressive], and healthy controls (HCs) ( n  = 17) were tested for plasma levels of interferon (IFN)-γ, IL-10, TGF-β, IL-17A, and IL-17F by immunoanalysis. Th1 and Th17 lymphocyte frequencies were determined by flow cytometry. Our results showed that IFN-γ levels and the IFN-γ/IL-10 ratio were higher in CIS patients than in RRMS patients and HC. Th1 cell frequencies were higher in CIS and RRMS than in progressive MS, and RRMS had a higher Th17 frequency than CIS. The Th1/Th17 cell ratio was skewed toward Th1 in CIS compared to MS phenotypes and HC. Receiver operating characteristic statistical analysis determined that IFN-γ, the IFN-γ/IL-10 ratio, Th1 cell frequency, and the Th1/Th17 cell ratio discriminated among CIS and MS subtypes. A subanalysis among patients expressing high IL-17F levels showed that IL-17F and the IFN-γ/IL-17F ratio discriminated between disease subtypes. Overall, our data showed that CIS and MS phenotypes displayed distinct Th1- and Th17-related cytokines and cell profiles and that these immune parameters discriminated between clinical forms. Upon validation, these parameters might be useful as biomarkers to predict disease progression.

  2. A proteomic network approach across the ALS-FTD disease spectrum resolves clinical phenotypes and genetic vulnerability in human brain.

    Science.gov (United States)

    Umoh, Mfon E; Dammer, Eric B; Dai, Jingting; Duong, Duc M; Lah, James J; Levey, Allan I; Gearing, Marla; Glass, Jonathan D; Seyfried, Nicholas T

    2018-01-01

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlap in clinical presentation, neuropathology, and genetic underpinnings. The molecular basis for the overlap of these disorders is not well established. We performed a comparative unbiased mass spectrometry-based proteomic analysis of frontal cortical tissues from postmortem cases clinically defined as ALS, FTD, ALS and FTD (ALS/FTD), and controls. We also included a subset of patients with the C9orf72 expansion mutation, the most common genetic cause of both ALS and FTD Our systems-level analysis of the brain proteome integrated both differential expression and co-expression approaches to assess the relationship of these differences to clinical and pathological phenotypes. Weighted co-expression network analysis revealed 15 modules of co-expressed proteins, eight of which were significantly different across the ALS-FTD disease spectrum. These included modules associated with RNA binding proteins, synaptic transmission, and inflammation with cell-type specificity that showed correlation with TDP-43 pathology and cognitive dysfunction. Modules were also examined for their overlap with TDP-43 protein-protein interactions, revealing one module enriched with RNA-binding proteins and other causal ALS genes that increased in FTD/ALS and FTD cases. A module enriched with astrocyte and microglia proteins was significantly increased in ALS cases carrying the C9orf72 mutation compared to sporadic ALS cases, suggesting that the genetic expansion is associated with inflammation in the brain even without clinical evidence of dementia. Together, these findings highlight the utility of integrative systems-level proteomic approaches to resolve clinical phenotypes and genetic mechanisms underlying the ALS-FTD disease spectrum in human brain. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

  3. Is Fetal Growth Restriction Associated with a More Severe Maternal Phenotype in the Setting of Early Onset Pre-Eclampsia? A Retrospective Study

    Science.gov (United States)

    Weiler, Jane; Tong, Stephen; Palmer, Kirsten R.

    2011-01-01

    Background Both pre-eclampsia and fetal growth restriction are thought to result from abnormal placental implantation in early pregnancy. Consistent with this shared pathophysiology, it is not uncommon to see growth restriction further confound the course of pre-eclampsia and vice versa. It has been previously suggested that superimposed growth restriction is associated with a more severe pre-eclamptic phenotype, however this has not been a consistent finding. Therefore, we set out to determine whether the presence of fetal growth restriction among women with severe early-onset pre-eclampsia was associated with more severe maternal disease compared to those without a growth-restricted fetus. Methods and Findings We undertook a retrospective cohort study of women presenting to a tertiary hospital with severe early-onset pre-eclampsia (restriction. However, no significant difference was seen in relation to the severity of pre-eclampsia between those with or without a growth-restricted baby. The presence of concomitant growth restriction was however associated with a significantly increased risk of stillbirth (p = 0.003) and total perinatal mortality (p = 0.02). Conclusions The presence of fetal growth restriction among women with severe early-onset pre-eclampsia is not associated with increased severity of maternal disease. However the incidence of stillbirth and perinatal death is significantly increased in this sub-population. PMID:22046419

  4. Multiple gene genealogies and phenotypic characters differentiate several novel species of Mycosphaerella and related anamorphs on banana

    NARCIS (Netherlands)

    Arzanlou, M.; Groenewald, J.Z.; Fullerton, R.A.; Abeln, E.C.A.; Carlier, J.; Zapater, M.-F.; Buddenhagen, I.W.; Viljoen, A.; Crous, P.W.

    2008-01-01

    Three species of Mycosphaerella, namely M. eumusae, M. fijiensis, and M. musicola are involved in the Sigatoka disease complex of bananas. Besides these three primary pathogens, several additional species of Mycosphaerella or their anamorphs have been described from Musa. However, very little is

  5. Association between severity of behavioral phenotype and comorbid attention deficit hyperactivity disorder symptoms in children with autism spectrum disorders

    OpenAIRE

    Rao, Patricia A; Landa, Rebecca J

    2013-01-01

    Autism spectrum disorder and attention deficit hyperactivity disorder are neurodevelopmental disorders that cannot be codiagnosed under existing diagnostic guidelines (Diagnostic and Statistical Manual of the American Psychiatric Association, 4th ed., text rev.). However, reports are emerging that attention deficit hyperactivity disorder is sometimes comorbid with autism spectrum disorder. In the current study, we examined rates of parent-reported clinically significant symptoms of attention ...

  6. Heteroresistance to Fluconazole Is a Continuously Distributed Phenotype among Candida glabrata Clinical Strains Associated with In Vivo Persistence

    Directory of Open Access Journals (Sweden)

    Ronen Ben-Ami

    2016-08-01

    Full Text Available Candida glabrata causes persistent infections in patients treated with fluconazole and often acquires resistance following exposure to the drug. Here we found that clinical strains of C. glabrata exhibit cell-to-cell variation in drug response (heteroresistance. We used population analysis profiling (PAP to assess fluconazole heteroresistance (FLCHR and to ask if it is a binary trait or a continuous phenotype. Thirty (57.6% of 52 fluconazole-sensitive clinical C. glabrata isolates met accepted dichotomous criteria for FLCHR. However, quantitative grading of FLCHR by using the area under the PAP curve (AUC revealed a continuous distribution across a wide range of values, suggesting that all isolates exhibit some degree of heteroresistance. The AUC correlated with rhodamine 6G efflux and was associated with upregulation of the CDR1 and PDH1 genes, encoding ATP-binding cassette (ABC transmembrane transporters, implying that HetR populations exhibit higher levels of drug efflux. Highly FLCHRC. glabrata was recovered more frequently than nonheteroresistant C. glabrata from hematogenously infected immunocompetent mice following treatment with high-dose fluconazole (45.8% versus 15%, P = 0.029. Phylogenetic analysis revealed some phenotypic clustering but also variations in FLCHR within clonal groups, suggesting both genetic and epigenetic determinants of heteroresistance. Collectively, these results establish heteroresistance to fluconazole as a graded phenotype associated with ABC transporter upregulation and fluconazole efflux. Heteroresistance may explain the propensity of C. glabrata for persistent infection and the emergence of breakthrough resistance to fluconazole.

  7. Distribution of clinical phenotypes in patients with chronic obstructive pulmonary disease caused by biomass and tobacco smoke.

    Science.gov (United States)

    Golpe, Rafael; Sanjuán López, Pilar; Cano Jiménez, Esteban; Castro Añón, Olalla; Pérez de Llano, Luis A

    2014-08-01

    Exposure to biomass smoke is a risk factor for chronic obstructive pulmonary disease (COPD). It is unknown whether COPD caused by biomass smoke has different characteristics to COPD caused by tobacco smoke. To determine clinical differences between these two types of the disease. Retrospective observational study of 499 patients with a diagnosis of COPD due to biomass or tobacco smoke. The clinical variables of both groups were compared. There were 122 subjects (24.4%) in the biomass smoke group and 377 (75.5%) in the tobacco smoke group. In the tobacco group, the percentage of males was higher (91.2% vs 41.8%, P<.0001) and the age was lower (70.6 vs 76.2 years, P<.0001). Body mass index and FEV1% values were higher in the biomass group (29.4±5.7 vs 28.0±5.1, P=.01, and 55.6±15.6 vs 47.1±17.1, P<.0001, respectively). The mixed COPD-asthma phenotype was more common in the biomass group (21.3% vs 5%, P<.0001), although this difference disappeared when corrected for gender. The emphysema phenotype was more common in the tobacco group (45.9% vs 31.9%, P=.009). The prevalence of the chronic bronchitis and exacerbator phenotypes, the comorbidity burden and the rate of hospital admissions were the same in both groups. Differences were observed between COPD caused by biomass and COPD caused by tobacco smoke, although these may be attributed in part to uneven gender distribution between the groups. Copyright © 2013 SEPAR. Published by Elsevier Espana. All rights reserved.

  8. PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature

    NARCIS (Netherlands)

    Reijnders, Margot R. F.; Janowski, Robert; Alvi, Mohsan; Self, Jay E.; van Essen, Ton J.; Vreeburg, Maaike; Rouhl, Rob P. W.; Stevens, Servi J. C.; Stegmann, Alexander P. A.; Schieving, Jolanda; Pfundt, Rolph; van Dijk, Katinke; Smeets, Eric; Stumpel, Connie T. R. M.; Bok, Levinus A.; Cobben, Jan Maarten; Engelen, Marc; Mansour, Sahar; Whiteford, Margo; Chandler, Kate E.; Douzgou, Sofia; Cooper, Nicola S.; Tan, Ene-Choo; Foo, Roger; Lai, Angeline H. M.; Rankin, Julia; Green, Andrew; Lönnqvist, Tuula; Isohanni, Pirjo; Williams, Shelley; Ruhoy, Ilene; Carvalho, Karen S.; Dowling, James J.; Lev, Dorit L.; Sterbova, Katalin; Lassuthova, Petra; Neupauerová, Jana; Waugh, Jeff L.; Keros, Sotirios; Clayton-Smith, Jill; Smithson, Sarah F.; Brunner, Han G.; van Hoeckel, Ceciel; Anderson, Mel; Clowes, Virginia E.; Siu, Victoria Mok; Selber, Paulo; Leventer, Richard J.; Nellaker, Christoffer; Niessing, Dierk; Hunt, David; Baralle, Diana

    2018-01-01

    Background De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. Objectives T o delineate the clinical spectrum of PURA syndrome and

  9. Etiology, clinical profile, severity and outcome of acute pancreatitis in relation to bed side index for severity of acute pancreatitis bisap and CT severity index [CTSI] scores

    Directory of Open Access Journals (Sweden)

    Bezwada Srinivasa Rao, Matta SreeVani, V.Sarat Chandra

    2014-11-01

    Full Text Available Background: Acute pancreatitis is an inflammatory process of the pancreas with involvement of regional tissues or remote organ systems and with potentially devastating consequences. Early prediction of outcome of acute pancreatitis within 24 hrs by clinically based bed Side Index of Severity of Acute Pancreatitis [BISAP] Score and radiological based CT Severity Index [CTSI] later on being useful in initiation of early treatment, assessing severity, to prevent morbidity and mortality. In those who survive, it can progress to chronic pancreatitis resulting in malabsorption and permanent diabetes. Aim: The aim was to study aetiology, clinical profile, severity, outcome of acute pancreatitis in relation to BISAP Score and CTSI. Materials and Methods: This was an observational and prospective study. The present study enrolled 55 patients who were diagnosed as acute pancreatitis and patients with chronic pancreatitis were excluded from the study. Vital data like pulse rate, blood Pressure, temperature, respiratory rate, conscious level using Glasgow coma scale, serum amylase, lipase, Chest x-ray, US abdomen and CT abdomen [both CECT & NCCT] were done. BISAP Score was obtained at the time of presentation or within 24 hours of presentation and radiological based CT Severity Index [CTSI] was calculated using the Balthazar grading system and Necrosis Scoring system to assess the severity, morbidity and mortality. The results: In this study, the most common aetiology being alcohol intake followed by gall stones. BISAP Score 3 had organ dysfunction and Score 4 had 100% mortality. The relation between CTSI score and Organ dysfunction showed increased organic dysfunction and higher mortality with higher CTSI Scores. p value < 0.0001 was calculated using Pearson Chi-square test and found to be statistically significant. Conclusions: Both BISAP and CTSI scores had positive correlation with morbidity and mortality.

  10. Phenotypic changes of methicillin-resistant Staphylococcus aureus during vancomycin therapy for persistent bacteraemia and related clinical outcome.

    Science.gov (United States)

    Kim, T; Kim, E S; Park, S Y; Sung, H; Kim, M-N; Kim, S-H; Lee, S-O; Choi, S-H; Jeong, J-Y; Woo, J H; Chong, Y P; Kim, Y S

    2017-08-01

    Persistent bacteraemia (PB) due to methicillin-resistant Staphylococcus aureus (MRSA) that fails to respond to glycopeptide therapy is a well-documented clinical problem. There are limited data on changes in agr functionality, vancomycin susceptibility and heteroresistance during MRSA PB. Thus, the frequency of these changes and their clinical significance remain unclear. Only patients with MRSA PB (≥7 days) from a prospective cohort of S. aureus bacteraemia were included. We collected isogenic paired strains and compared vancomycin MIC, vancomycin heteroresistance, and agr functionality between initial and final blood isolates. We also assessed the clinical outcome. A total of 49 patients had MRSA PB over 22 months. Bacteraemia persisted for a median of 13 days and most patients (98%) received glycopeptide as initial therapy. Among 49 isogenic pairs, only one pair showed a vancomycin MIC increase ≥2-fold by broth microdilution method, and only seven (14%) by E-test. Significant portions of initial isolates had vancomycin heteroresistance (49%) and agr dysfunction (76%). Development of vancomycin heteroresistance during PB occurred in four (16%) among 25 initial vancomycin-susceptible isolates, and acquisition of agr dysfunction occurred in two (16%) among 12 initial agr-functional isolates. Changes in the opposite direction occasionally occurred. These phenotypic changes during PB were not associated with mortality, whereas agr dysfunction of the initial isolates was significantly associated with mortality. During MRSA PB, phenotypic changes of MRSA isolates occurred occasionally under prolonged vancomycin exposure but were not significantly associated with clinical outcome. In contrast, initial agr dysfunction could be a predictor for mortality in MRSA PB.

  11. Clinical penetrance in hereditary hemochromatosis: estimates of the cumulative incidence of severe liver disease among HFE C282Y homozygotes.

    Science.gov (United States)

    Grosse, Scott D; Gurrin, Lyle C; Bertalli, Nadine A; Allen, Katrina J

    2018-04-01

    Iron overload (hemochromatosis) can cause serious, symptomatic disease that is preventable if detected early and managed appropriately. The leading cause of hemochromatosis in populations of predominantly European ancestry is homozygosity of the C282Y variant in the HFE gene. Screening of adults for iron overload or associated genotypes is controversial, largely because of a belief that severe phenotypes are uncommon, although cascade testing of first-degree relatives of patients is widely endorsed. We contend that severe liver disease (cirrhosis or hepatocellular cancer) is not at all uncommon among older males with hereditary hemochromatosis. Our review of the published data from a variety of empirical sources indicates that roughly 1 in 10 male HFE C282Y homozygotes is likely to develop severe liver disease during his lifetime unless iron overload is detected early and treated. New evidence from a randomized controlled trial of treatment allows for evidence-based management of presymptomatic patients. Although population screening for HFE C282Y homozygosity faces multiple barriers, a potentially effective strategy for increasing the early detection and prevention of clinical iron overload and severe disease is to include HFE C282Y homozygosity in lists of medically actionable gene variants when reporting the results of genome or exome sequencing.

  12. [Clinical presentation of different severities of hemorrhagic fever with renal syndrome: how to recognise it].

    Science.gov (United States)

    Lausević, Mirjana; Lausević, Zeljko; Stojimirović, Biljana

    2012-07-01

    Besides viral serotype, HLA haplotype and cytokine genes polymorphism are associated with clinical presentation of hemorrhagic fever with renal syndrome. Since these analyses are unavailable in routine clinical practice, the aim of this study was to assess clinical, laboratory and radiographic findings associated with clinical presentation of disease severity. A total of 30 patients (27 men and 3 women), average age 40 +/- 14.9 years, treated for hemorrhagic fever with renal syndrome from January 1, 1999 to December 31, 2009 in Clinical Center of Serbia, were included in the study. Nine patients (30%) had mild, 14 (46.7%) moderate and 7 (23.3%) severe form of the disease; 24 (800%) recovered, 6 (20%) died in the acute phase of the illness, and 19 patients (63.3%) required hemodialysis. The average titer of antiviral antibodies in patients infected with Belgrade serotype virus were significantly higher in those with severe clinical presentation. Hypotension, anuria, macrohaematuria, pulmonary infiltration, pleural effusion, hepatomegalia and positive meningeal signs were more frequent in the patients with severe form of the disease. Statistically significant differences between groups with mild, moderate and severe clinical picture were found in serum total protein, albumin, calcium, glutamate pyruvate and glutamate oxaloacetate transaminase on admittance; serum creatinine and phosphorus concentration on day 14 and day 21; serum sodium and calciums on day 14; hemoglobine concentration on day 21. A statistically significant correlation was found between clinical presentation of the disease severity and platelet count, white blood cell count, hemoglobine concentration, serum calcium and serum transaminases on admittance. Multivariate analysis identified variables' combinations associated with clinical presentation of the disease. Our study confirmed that we can distinguish patients who will manifest different severities of the disease on the basis of careful

  13. Clinical presentation of different severities of hemorrhagic fever with renal syndrome: How to recognize it

    Directory of Open Access Journals (Sweden)

    Laušević Mirjana

    2012-01-01

    Full Text Available Background/Aim. Besides viral serotype, HLA haplotype and cytokine genes polymorphism are associated with clinical presentation of hemorrhagic fever with renal syndrome. Since these analyses are unavailable in routine clinical practice, the aim of this study was to assess clinical, laboratory and radiographic findings associated with clinical presentation of disease severity. Methods. A total of 30 patients (27 men and 3 women, average age 40 ± 14.9 years, treated for hemorrhagic fever with renal syndrome from January 1, 1999 to December 31, 2009 in Clinical Center of Serbia, were included in the study. Nine patients (30% had mild, 14 (46.7% moderate and 7 (23.3% severe form of the disease; 24 (80% recovered, 6 (20% died in the acute phase of the illness, and 19 patients (63.3% required hemodialysis. Results. The average titer of antiviral antibodies in patients infected with Belgrade serotype virus were significantly higher in those with severe clinical presentation. Hypotension, anuria, macrohaematuria, pulmonary infiltration, pleural effusion, hepatomegalia and positive meningeal signs were more frequent in the patients with severe form of the disease. Statistically significant differences between groups with mild, moderate and severe clinical picture were found in serum total protein, albumin, calcium, glutamate pyruvate and glutamate oxaloacetate transaminase on admittance; serum creatinine and phosphorus concentration on day 14 and day 21; serum sodium and calciums on day 14; hemoglobine concentration on day 21. A statistically significant correlation was found between clinical presentation of the disease severity and platelet count, white blood cell count, hemoglobine concentration, serum calcium and serum transaminases on admittance. Multivariate analysis identified variables` combinations associated with clinical presentation of the disease. Conclusion. Our study confirmed that we can distinguish patients who will manifest different

  14. Improvement of neuromuscular synaptic phenotypes without enhanced survival and motor function in severe spinal muscular atrophy mice selectively rescued in motor neurons.

    Directory of Open Access Journals (Sweden)

    Ximena Paez-Colasante

    Full Text Available In the inherited childhood neuromuscular disease spinal muscular atrophy (SMA, lower motor neuron death and severe muscle weakness result from the reduction of the ubiquitously expressed protein survival of motor neuron (SMN. Although SMA mice recapitulate many features of the human disease, it has remained unclear if their short lifespan and motor weakness are primarily due to cell-autonomous defects in motor neurons. Using Hb9(Cre as a driver, we selectively raised SMN expression in motor neurons in conditional SMAΔ7 mice. Unlike a previous study that used choline acetyltransferase (ChAT(Cre+ as a driver on the same mice, and another report that used Hb9(Cre as a driver on a different line of conditional SMA mice, we found no improvement in survival, weight, motor behavior and presynaptic neurofilament accumulation. However, like in ChAT(Cre+ mice, we detected rescue of endplate size and mitigation of neuromuscular junction (NMJ denervation status. The rescue of endplate size occurred in the absence of an increase in myofiber size, suggesting endplate size is determined by the motor neuron in these animals. Real time-PCR showed that the expression of spinal cord SMN transcript was sharply reduced in Hb9(Cre+ SMA mice relative to ChAT(Cre+ SMA mice. This suggests that our lack of overall phenotypic improvement is most likely due to an unexpectedly poor recombination efficiency driven by Hb9(Cre . Nonetheless, the low levels of SMN were sufficient to rescue two NMJ structural parameters indicating that these motor neuron cell autonomous phenotypes are very sensitive to changes in motoneuronal SMN levels. Our results directly suggest that even those therapeutic interventions with very modest effects in raising SMN in motor neurons may provide mitigation of neuromuscular phenotypes in SMA patients.

  15. Evaluation of Acne Quality of Life and Clinical Severity in Acne Female Adults

    Directory of Open Access Journals (Sweden)

    Amal Kokandi

    2010-01-01

    Full Text Available Acne is a common disease especially among teenagers. It has a considerable psychological impact on affected individuals. The aim of this paper was to assess if the effect of acne on acne-related quality of life is correlated to acne clinical severity. 112 university female students attending the university medical clinics with acne complaints were examined. Cardiff Acne Disability Index (CADI was used to assess acne-related quality of life, and global acne grading system (GAGS was used to assess clinical severity of acne. There was no correlation between acne severity (GAGS scoring system and quality of life impairment as assessed by CADI score (=0.145, =.127. Additionally, CADI score did not correlate with disease duration or age of patients. We therefore conclude that acne clinical severity alone does not affect acne-related quality of life changes. Many other factors might play a role.

  16. Study of phenotype evolution during childhood in Marfan syndrome to improve clinical recognition.

    Science.gov (United States)

    Stheneur, Chantal; Tubach, Florence; Jouneaux, Marlène; Roy, Carine; Benoist, Gregoire; Chevallier, Bertrand; Boileau, Catherine; Jondeau, Guillaume

    2014-03-01

    Because diagnosis of Marfan syndrome is difficult during infancy, we used a large cohort of children to describe the evolution of the Marfan syndrome phenotype with age. Two hundred and fifty-nine children carrying an FBN1 gene mutation and fulfilling Ghent criteria were compared with 474 non-Marfan syndrome children. Prevalence of skeletal features changed with aging: prevalence of pectus deformity increased from 43% at 0-6 years to 62% at 15-17 years, wrist signs increased from 28 to 67%, and scoliosis increased from 16 to 59%. Hypermobility decreased from 67 to 47% and pes planus decreased from 73 to 65%. Striae increased from 2 to 84%. Prevalence of ectopia lentis remained stable, varying from 66 to 72%, similar to aortic root dilatation (varying from 75 to 80%). Aortic root dilatation remained stable during follow-up in this population receiving β-blocker therapy. When comparing Marfan syndrome children with non-Marfan syndrome children, height appeared to be a simple and discriminant criterion when it was >3.3 SD above the mean. Ectopia lentis and aortic dilatation were both similarly discriminating. Ectopia lentis and aortic dilatation are the best-discriminating features, but height remains a simple discriminating variable for general practitioners when >3.3 SD above the mean. Mean aortic dilatation remains stable in infancy when children receive a β-blocker.

  17. Multiple gene genealogies and phenotypic characters differentiate several novel species of Mycosphaerella and related anamorphs on banana.

    Science.gov (United States)

    Arzanlou, M; Groenewald, J Z; Fullerton, R A; Abeln, E C A; Carlier, J; Zapater, M-F; Buddenhagen, I W; Viljoen, A; Crous, P W

    2008-06-01

    Three species of Mycosphaerella, namely M. eumusae, M. fijiensis, and M. musicola are involved in the Sigatoka disease complex of bananas. Besides these three primary pathogens, several additional species of Mycosphaerella or their anamorphs have been described from Musa. However, very little is known about these taxa, and for the majority of these species no culture or DNA is available for study. In the present study, we collected a global set of Mycosphaerella strains from banana, and compared them by means of morphology and a multi-gene nucleotide sequence data set. The phylogeny inferred from the ITS region and the combined data set containing partial gene sequences of the actin gene, the small subunit mitochondrial ribosomal DNA and the histone H3 gene revealed a rich diversity of Mycosphaerella species on Musa. Integration of morphological and molecular data sets confirmed more than 20 species of Mycosphaerella (incl. anamorphs) to occur on banana. This study reconfirmed the previously described presence of Cercospora apii, M. citri and M. thailandica, and also identified Mycosphaerella communis, M. lateralis and Passalora loranthi on this host. Moreover, eight new species identified from Musa are described, namely Dissoconium musae, Mycosphaerella mozambica, Pseudocercospora assamensis, P. indonesiana, P. longispora, Stenella musae, S. musicola, and S. queenslandica.

  18. Clinical and laboratory assessment of dehydration severity in children with acute gastroenteritis.

    Science.gov (United States)

    Parkin, Patricia C; Macarthur, Colin; Khambalia, Amina; Goldman, Ran D; Friedman, Jeremy N

    2010-03-01

    To evaluate clinical and laboratory assessment of dehydration severity in children, 1 to 36 months, with acute gastroenteritis. Clinical and laboratory measures and weight change following rehydration were collected for enrolled children. Pediatric emergency department. Likelihood ratio (LR+) and 95% confidence interval (CI): for a clinical score of 0, the LR+ was 2.2 (95% CI = 0.9-5.3); for a clinical score of 1 to 4, the LR+ was 1.3 (95% CI = 0.90-1.74); for a clinical score of 5 to 8, the LR+ was 5.2 (95% CI = 2.2-12.8); for a venous pH Dehydration Scale and laboratory measures into clinical decision-making algorithms to assess dehydration severity in children with acute gastroenteritis.

  19. Comparison of clinical associations and laboratory abnormalities in children with moderate and severe dehydration.

    Science.gov (United States)

    Hayajneh, Wail A; Jdaitawi, Hussein; Al Shurman, Abdullah; Hayajneh, Yaseen A

    2010-03-01

    To search for possible early clinical associations and laboratory abnormalities in children with severe dehydration in northern Jordan. We prospectively evaluated 251 children with acute gastroenteritis. Dehydration assessment was done following a known clinical scheme. Probable clinical associations and laboratory abnormalities were examined against the preassigned dehydration status. Children with severe dehydration had significantly more hypernatremia and hyperkalemia, less isonatremia, and higher mean levels of urea, creatinine, and glucose (P dehydration. Historic clinical characteristics of patients did not correlate to dehydration degree. Serum urea, creatinine, sodium, potassium, and glucose were useful independently in augmenting clinical examination to diagnose the degree of dehydration status among children presenting with gastroenteritis. Serum urea performed the best among all. On the contrary, none of the examined historical clinical patterns could be correlated to the dehydration status. Larger and multicenter studies are needed to validate our results and to examine their impact on final outcomes.

  20. Correlation between clinical severity and type and degree of pectus excavatum in twelve brachycephalic dogs.

    Science.gov (United States)

    Hassan, Elham A; Hassan, Marwa H; Torad, Faisal A

    2018-05-18

    The aim of the study was to correlate the clinical severity of pectus excavatum with its type and degree based on objective radiographic evaluation. Twelve brachycephalic dogs were included. Grading of the clinical severity was done based on a 6-point grading score. Thoracic radiographs were used to calculate the frontosagittal and vertebral indices at the tenth thoracic vertebra and the vertebra overlying the excavatum. Correlation between the clinical severity score and frontosagittal and vertebral indices was evaluated using Pearson's correlation coefficient. Typical pectus excavatum was recorded in the caudal sternum in seven dogs, with a mean clinical severity score of 1.7 ± 1.4, whereas in five dogs, atypical mid-sternal deviation was recorded with a mean clinical severity score of 3.8 ± 0.7. A strong correlation (r=0.7) was recorded between the clinical severity score and vertebral index in the atypical form, whereas a weak correlation (r=0.02) was recorded in the typical form (Pcorrelated (r=0.3) in the typical form of pectus excavatum, whereas it was strongly correlated (r=0.9) in the atypical form. Pectus excavatum in dogs is associated with compressive cardiopulmonary dysfunction, which depends mainly on the site/type of deviation rather than the degree of deviation.

  1. Comorbid personality disorders in subjects with panic disorder: which personality disorders increase clinical severity?

    OpenAIRE

    Mustafa Ozkan; Abdurrahman Altindag

    2003-01-01

    Personality disorders are common in subjects with panic disorder. Personality disorders have shown to affect the course of panic disorder. The purpose of this study was to examine which personality disorders effect clinical severity in subjects with panic disorder. This study included 122 adults (71 female, 41 male), who met DSM-IV criteria for panic disorder (with or without agoraphobia). Clinical assessment was conducted by using the Structured Clinical Interview for DSM-IV Axis I Disorders...

  2. Clinical phenotype associations with various types of anti-dsDNA antibodies in patients with recent onset of rheumatic symptoms. Results from a multicentre observational study

    DEFF Research Database (Denmark)

    Compagno, Michele; Rekvig, Ole P; Bengtsson, Anders A

    2014-01-01

    UNLABELLED: Despite anti-dsDNA antibodies constitute a wide range of specificities, they are considered as the hallmark for systemic lupus erythematosus (SLE). OBJECTIVE: To identify clinical phenotypes associated with anti-dsDNA antibodies, independently of any clinical diagnoses. METHODS...

  3. Identifying novel phenotypes of acute heart failure using cluster analysis of clinical variables.

    Science.gov (United States)

    Horiuchi, Yu; Tanimoto, Shuzou; Latif, A H M Mahbub; Urayama, Kevin Y; Aoki, Jiro; Yahagi, Kazuyuki; Okuno, Taishi; Sato, Yu; Tanaka, Tetsu; Koseki, Keita; Komiyama, Kota; Nakajima, Hiroyoshi; Hara, Kazuhiro; Tanabe, Kengo

    2018-07-01

    Acute heart failure (AHF) is a heterogeneous disease caused by various cardiovascular (CV) pathophysiology and multiple non-CV comorbidities. We aimed to identify clinically important subgroups to improve our understanding of the pathophysiology of AHF and inform clinical decision-making. We evaluated detailed clinical data of 345 consecutive AHF patients using non-hierarchical cluster analysis of 77 variables, including age, sex, HF etiology, comorbidities, physical findings, laboratory data, electrocardiogram, echocardiogram and treatment during hospitalization. Cox proportional hazards regression analysis was performed to estimate the association between the clusters and clinical outcomes. Three clusters were identified. Cluster 1 (n=108) represented "vascular failure". This cluster had the highest average systolic blood pressure at admission and lung congestion with type 2 respiratory failure. Cluster 2 (n=89) represented "cardiac and renal failure". They had the lowest ejection fraction (EF) and worst renal function. Cluster 3 (n=148) comprised mostly older patients and had the highest prevalence of atrial fibrillation and preserved EF. Death or HF hospitalization within 12-month occurred in 23% of Cluster 1, 36% of Cluster 2 and 36% of Cluster 3 (p=0.034). Compared with Cluster 1, risk of death or HF hospitalization was 1.74 (95% CI, 1.03-2.95, p=0.037) for Cluster 2 and 1.82 (95% CI, 1.13-2.93, p=0.014) for Cluster 3. Cluster analysis may be effective in producing clinically relevant categories of AHF, and may suggest underlying pathophysiology and potential utility in predicting clinical outcomes. Copyright © 2018 Elsevier B.V. All rights reserved.

  4. Automated interpretable computational biology in the clinic: a framework to predict disease severity and stratify patients from clinical data

    Directory of Open Access Journals (Sweden)

    Soumya Banerjee

    2017-10-01

    Full Text Available We outline an automated computational and machine learning framework that predicts disease severity and stratifies patients. We apply our framework to available clinical data. Our algorithm automatically generates insights and predicts disease severity with minimal operator intervention. The computational framework presented here can be used to stratify patients, predict disease severity and propose novel biomarkers for disease. Insights from machine learning algorithms coupled with clinical data may help guide therapy, personalize treatment and help clinicians understand the change in disease over time. Computational techniques like these can be used in translational medicine in close collaboration with clinicians and healthcare providers. Our models are also interpretable, allowing clinicians with minimal machine learning experience to engage in model building. This work is a step towards automated machine learning in the clinic.

  5. Educational paper: The expanding clinical and immunological spectrum of severe combined immunodeficiency

    NARCIS (Netherlands)

    M. van der Burg (Mirjam); A.R. Gennery (Andy R.)

    2011-01-01

    textabstractSevere combined immunodeficiency (SCID) is one of the most severe forms of primary immunodeficiency characterized by absence of functional T lymphocytes. It is a paediatric emergency, which is life-threatening when recognized too late. The clinical presentation varies from the classical

  6. The connective tissue phenotype of glaucomatous cupping in the monkey eye - Clinical and research implications.

    Science.gov (United States)

    Yang, Hongli; Reynaud, Juan; Lockwood, Howard; Williams, Galen; Hardin, Christy; Reyes, Luke; Stowell, Cheri; Gardiner, Stuart K; Burgoyne, Claude F

    2017-07-01

    In a series of previous publications we have proposed a framework for conceptualizing the optic nerve head (ONH) as a biomechanical structure. That framework proposes important roles for intraocular pressure (IOP), IOP-related stress and strain, cerebrospinal fluid pressure (CSFp), systemic and ocular determinants of blood flow, inflammation, auto-immunity, genetics, and other non-IOP related risk factors in the physiology of ONH aging and the pathophysiology of glaucomatous damage to the ONH. The present report summarizes 20 years of technique development and study results pertinent to the characterization of ONH connective tissue deformation and remodeling in the unilateral monkey experimental glaucoma (EG) model. In it we propose that the defining pathophysiology of a glaucomatous optic neuropathy involves deformation, remodeling, and mechanical failure of the ONH connective tissues. We view this as an active process, driven by astrocyte, microglial, fibroblast and oligodendrocyte mechanobiology. These cells, and the connective tissue phenomena they propagate, have primary and secondary effects on retinal ganglion cell (RGC) axon, laminar beam and retrolaminar capillary homeostasis that may initially be "protective" but eventually lead to RGC axonal injury, repair and/or cell death. The primary goal of this report is to summarize our 3D histomorphometric and optical coherence tomography (OCT)-based evidence for the early onset and progression of ONH connective tissue deformation and remodeling in monkey EG. A second goal is to explain the importance of including ONH connective tissue processes in characterizing the phenotype of a glaucomatous optic neuropathy in all species. A third goal is to summarize our current efforts to move from ONH morphology to the cell biology of connective tissue remodeling and axonal insult early in the disease. A final goal is to facilitate the translation of our findings and ideas into neuroprotective interventions that target

  7. Fasciola hepatica reinfection potentiates a mixed Th1/Th2/Th17/Treg response and correlates with the clinical phenotypes of anemia

    Science.gov (United States)

    Perez-Crespo, Ignacio; Chillón-Marinas, Carlos; Khoubbane, Messaoud; Quesada, Carla; Reguera-Gomez, Marta; Mas-Coma, Santiago; Fresno, Manuel; Gironès, Núria

    2017-01-01

    Background Fascioliasis is a severe zoonotic disease of worldwide extension caused by liver flukes. In human fascioliasis hyperendemic areas, reinfection and chronicity are the norm and anemia is the main sign. Herein, the profile of the Th1/Th2/Th17/Treg expression levels is analyzed after reinfection, correlating them with their corresponding hematological biomarkers of morbidity. Methodology/Principal findings The experimental design reproduces the usual reinfection/chronicity conditions in human fascioliasis endemic areas and included Fasciola hepatica primo-infected Wistar rats (PI) and rats reinfected at 8 weeks (R8), and at 12 weeks (R12), and negative control rats. In a cross-sectional study, the expression of the genes associated with Th1 (Ifng, Il12a, Il12b, Nos2), Th2 (Il4, Arg1), Treg (Foxp3, Il10, Tgfb, Ebi3), and Th17 (Il17) in the spleen and thymus was analyzed. After 20 weeks of primary infection, PI did not present significant changes in the expression of those genes when compared to non-infected rats (NI), but an increase of Il4, Arg1 and Ifng mRNA in the spleen was observed in R12, suggesting the existence of an active mixed Th1/Th2 systemic immune response in reinfection. Foxp3, Il10, Tgfb and Ebi3 levels increased in the spleen in R12 when compared to NI and PI, indicating that the Treg gene expression levels are potentiated in chronic phase reinfection. Il17 gene expression levels in R12 in the spleen increased when compared to NI, PI and R8. Gene expression levels of Il10 in the thymus increased when compared to NI and PI in R12. Ifng expression levels in the thymus increased in all reinfected rats, but not in PI. The clinical phenotype was determined by the fluke burden, the rat body weight and the hemogram. Multivariate mathematical models were built to describe the Th1/Th2/Th17/Treg expression levels and the clinical phenotype. In reinfection, two phenotypic patterns were detected: i) one which includes only increased splenic Ifng

  8. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype

    NARCIS (Netherlands)

    Toubiana, Julie; Okada, Satoshi; Hiller, Julia; Oleastro, Matias; Lagos Gomez, Macarena; Aldave Becerra, Juan Carlos; Ouachée-Chardin, Marie; Fouyssac, Fanny; Girisha, Katta Mohan; Etzioni, Amos; van Montfrans, Joris M.; Camcioglu, Yildiz; Kerns, Leigh Ann; Belohradsky, Bernd; Blanche, Stéphane; Bousfiha, Aziz; Rodriguez-Gallego, Carlos; Meyts, Isabelle; Kisand, Kai; Reichenbach, Janine; Renner, Ellen D; Rosenzweig, Sergio; Grimbacher, Bodo; van de Veerdonk, Frank L; Traidl-Hoffmann, Claudia; Picard, Capucine; Marodi, Laszlo; Morio, Tomohiro; Kobayashi, Masao; Lilic, Desa; Milner, Joshua D; Holland, Steven; Casanova, Jean-Laurent; Puel, Anne

    2016-01-01

    Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274

  9. Kraepelin’s description of chronic mania: a clinical picture that meets the behavioral variant frontotemporal dementia phenotype

    Directory of Open Access Journals (Sweden)

    Leandro Boson Gambogi

    Full Text Available ABSTRACT Chronic mania is an under-investigated condition and few reports have associated this disorder with an organic background. The present work examines Kraepelin’s reliable description of chronic mania from a current behavioral neurology viewpoint. Kraepelin had described a cluster of symptoms that are now recognized as core manifestations of the behavioral variant frontotemporal dementia (bvFTD clinical phenotype. We also carried out additional reviews of original manuscripts from Kraepelin’s peers, in order to find any case reports that might fulfill the current diagnostic proposal for bvFTD. Even though we failed to find an ideal case, we found some scholars who seemed to agree that chronic mania should be considered a special form of dementia. The present work highlights, through historical data, the possible overlapping features between primary psychiatric disorders and neuropsychiatric symptoms secondary to neurodegenerative conditions.

  10. Moving into a new era of periodontal genetic studies: relevance of large case-control samples using severe phenotypes for genome-wide association studies.

    Science.gov (United States)

    Vaithilingam, R D; Safii, S H; Baharuddin, N A; Ng, C C; Cheong, S C; Bartold, P M; Schaefer, A S; Loos, B G

    2014-12-01

    Studies to elucidate the role of genetics as a risk factor for periodontal disease have gone through various phases. In the majority of cases, the initial 'hypothesis-dependent' candidate-gene polymorphism studies did not report valid genetic risk loci. Following a large-scale replication study, these initially positive results are believed to be caused by type 1 errors. However, susceptibility genes, such as CDKN2BAS (Cyclin Dependend KiNase 2B AntiSense RNA; alias ANRIL [ANtisense Rna In the Ink locus]), glycosyltransferase 6 domain containing 1 (GLT6D1) and cyclooxygenase 2 (COX2), have been reported as conclusive risk loci of periodontitis. The search for genetic risk factors accelerated with the advent of 'hypothesis-free' genome-wide association studies (GWAS). However, despite many different GWAS being performed for almost all human diseases, only three GWAS on periodontitis have been published - one reported genome-wide association of GLT6D1 with aggressive periodontitis (a severe phenotype of periodontitis), whereas the remaining two, which were performed on patients with chronic periodontitis, were not able to find significant associations. This review discusses the problems faced and the lessons learned from the search for genetic risk variants of periodontitis. Current and future strategies for identifying genetic variance in periodontitis, and the importance of planning a well-designed genetic study with large and sufficiently powered case-control samples of severe phenotypes, are also discussed. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Cortical thickness in de novo patients with Parkinson disease and mild cognitive impairment with consideration of clinical phenotype and motor laterality.

    Science.gov (United States)

    Danti, S; Toschi, N; Diciotti, S; Tessa, C; Poletti, M; Del Dotto, P; Lucetti, C

    2015-12-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder with motor and non-motor symptoms, including cognitive deficits. Several magnetic resonance imaging approaches have been applied to investigate brain atrophy in PD. The aim of this study was to detect early structural cortical and subcortical changes in de novo PD whilst distinguishing cognitive status, clinical phenotype and motor laterality. Eighteen de novo PD with mild cognitive impairment (PD-MCI), 18 de novo PD without MCI (PD-NC) and 18 healthy control subjects were evaluated. In the PD-MCI group, nine were tremor dominant and nine were postural instability gait disorder (PIGD) phenotype; 11 had right-sided symptom dominance and seven had left-sided symptom dominance. FreeSurfer was used to measure cortical thickness/folding, subcortical structures and to study group differences as well as the association with clinical and neuropsychological data. Parkinson's disease with MCI showed regional thinning in the right frontal, right middle temporal areas and left insula compared to PD-NC. A reduction of the volume of the left and right thalamus and left hippocampus was found in PD-MCI compared to PD-NC. PD-MCI PIGD showed regional thinning in the right inferior parietal area compared to healthy controls. A decreased volume of the left thalamus was reported in PD-MCI with right-sided symptom dominance compared to PD-NC and PD-MCI with left-sided symptom dominance. When MCI was present, PD patients showed a fronto-temporo-parietal pattern of cortical thinning. This cortical pattern does not appear to be influenced by motor laterality, although one-sided symptom dominance may contribute to volumetric reduction of specific subcortical structures. © 2015 EAN.

  12. Noise Maps for Quantitative and Clinical Severity Towards Long-Term ECG Monitoring.

    Science.gov (United States)

    Everss-Villalba, Estrella; Melgarejo-Meseguer, Francisco Manuel; Blanco-Velasco, Manuel; Gimeno-Blanes, Francisco Javier; Sala-Pla, Salvador; Rojo-Álvarez, José Luis; García-Alberola, Arcadi

    2017-10-25

    Noise and artifacts are inherent contaminating components and are particularly present in Holter electrocardiogram (ECG) monitoring. The presence of noise is even more significant in long-term monitoring (LTM) recordings, as these are collected for several days in patients following their daily activities; hence, strong artifact components can temporarily impair the clinical measurements from the LTM recordings. Traditionally, the noise presence has been dealt with as a problem of non-desirable component removal by means of several quantitative signal metrics such as the signal-to-noise ratio (SNR), but current systems do not provide any information about the true impact of noise on the ECG clinical evaluation. As a first step towards an alternative to classical approaches, this work assesses the ECG quality under the assumption that an ECG has good quality when it is clinically interpretable. Therefore, our hypotheses are that it is possible (a) to create a clinical severity score for the effect of the noise on the ECG, (b) to characterize its consistency in terms of its temporal and statistical distribution, and (c) to use it for signal quality evaluation in LTM scenarios. For this purpose, a database of external event recorder (EER) signals is assembled and labeled from a clinical point of view for its use as the gold standard of noise severity categorization. These devices are assumed to capture those signal segments more prone to be corrupted with noise during long-term periods. Then, the ECG noise is characterized through the comparison of these clinical severity criteria with conventional quantitative metrics taken from traditional noise-removal approaches, and noise maps are proposed as a novel representation tool to achieve this comparison. Our results showed that neither of the benchmarked quantitative noise measurement criteria represent an accurate enough estimation of the clinical severity of the noise. A case study of long-term ECG is reported

  13. Coffee consumption, metabolic syndrome and clinical severity of psoriasis: good or bad stuff?

    Science.gov (United States)

    Barrea, Luigi; Muscogiuri, Giovanna; Di Somma, Carolina; Annunziata, Giuseppe; Megna, Matteo; Falco, Andrea; Balato, Anna; Colao, Annamaria; Savastano, Silvia

    2018-05-01

    Despite the wide consumption of coffee, its anti-inflammatory effect on clinical severity of psoriasis is still debatable. The aim of this study was to evaluate the association between the coffee consumption and clinical severity of psoriasis in a sample of patients stratified according to the presence of the metabolic syndrome (MetS) and smoking. This cross-sectional case-control observational study was conducted on 221 treatment-naïve psoriatic patients. Lifestyle habits, anthropometric measures, clinical and biochemical evaluations were obtained. Clinical severity of psoriasis was assessed by Psoriasis Area and Severity Index (PASI) score. Data on energy caloric intake and coffee consumption were collected using a 7-day food diary record. The coffee consumption was analyzed as coffee intake (consumers and non-consumers) and daily servings (range 0-4 servings/day). Coffee consumers have a lower PASI score vs non-consumers (p < 0.001). The lowest PASI score and MetS prevalence were found in patients consuming 3 cups of coffee/day (p < 0.001), which was also the most common daily serving (34.8%), whereas the highest PASI score was found among those drinking ≥ 4 cups/day. Grouping the case patients according to smoking and MetS, the best odds of PASI score was observed in those drinking 3 cups of coffee per day and no smokers, after adjusting for total energy intake (OR 74.8; p < 0.001). As a novel finding, we reported a negative association between coffee intake, MetS prevalence and clinical severity of psoriasis. The evaluation of the anti-inflammatory effect of coffee on clinical severity of psoriasis, whose metabolic risk increases along with its clinical severity, could be of great importance from a public health perspective.

  14. Association between maternal comorbidity and preterm birth by severity and clinical subtype: retrospective cohort study.

    Science.gov (United States)

    Auger, Nathalie; Le, Thi Uyen Nhi; Park, Alison L; Luo, Zhong-Cheng

    2011-10-04

    Preterm birth (PTB) is a major cause of infant morbidity and mortality, but the relationship between comorbidity and PTB by clinical subtype and severity of gestational age remains poorly understood. We evaluated associations between maternal comorbidities and PTB by clinical subtype and gestational age. We conducted a retrospective cohort study of 1,329,737 singleton births delivered in hospitals in the province of Québec, Canada, 1989-2006. PTB was classified by clinical subtype (medically indicated, preterm premature rupture of membranes (PPROM), spontaneous preterm labour) and gestational age (PTBs across all gestational ages (OR > 2.0). At the population level, several major comorbidities (placental abruption, chorioamnionitis, oliogohydramnios, structural abnormality, cervical incompetence) were key contributors to all clinical subtypes of PTB, especially at PTBs. The relationship between comorbidity and clinical subtypes of PTB depends on gestational age. Prevention of PPROM and spontaneous PTB may benefit from greater attention to preeclampsia, anemia and comorbidities localized to the reproductive system.

  15. Different phenotypic and molecular mechanisms associated with multidrug resistance in Gram-negative clinical isolates from Egypt

    Directory of Open Access Journals (Sweden)

    Helmy OM

    2017-12-01

    Full Text Available Omneya M Helmy, Mona T Kashef Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt Objectives: We set out to investigate the prevalence, different mechanisms, and clonal relatedness of multidrug resistance (MDR among third-generation cephalosporin-resistant Gram-negative clinical isolates from Egypt.Materials and methods: A total of 118 third-generation cephalosporin-resistant Gram-negative clinical isolates were included in this study. Their antimicrobial susceptibility pattern was determined using Kirby–Bauer disk diffusion method. Efflux pump-mediated resistance was tested by the efflux-pump inhibitor-based microplate assay using chlorpromazine. Detection of different aminoglycoside-, β-lactam-, and quinolone-resistance genes was done using polymerase chain reaction. The genetic diversity of MDR isolates was investigated using random amplification of polymorphic DNA.Results: Most of the tested isolates exhibited MDR phenotypes (84.75%. The occurrence of efflux pump-mediated resistance in the different MDR species tested was 40%–66%. Acinetobacter baumannii isolates showed resistance to most of the tested antibiotics, including imipenem. The blaOXA-23-like gene was detected in 69% of the MDR A. baumannii isolates. The MDR phenotype was detected in 65% of Pseudomonas aeruginosa isolates, of which only 23% exhibited efflux pump-mediated resistance. On the contrary, efflux-mediated resistance to piperacillin and gentamicin was recorded in 47.5% of piperacillin-resistant and 25% of gentamicin-resistant MDR Enterobacteriaceae. Moreover, the plasmid-mediated quinolone-resistance genes (aac(6’-Ib-cr, qnrB, and qnrS were detected in 57.6% and 83.33% of quinolone-resistant MDR Escherichia coli and Klebsiella pneumoniae isolates, respectively. The β-lactamase-resistance gene blaSHV-31 was detected for the first time in one MDR K. pneumoniae isolate from an endotracheal tube specimen in Egypt

  16. Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function

    NARCIS (Netherlands)

    Lacbawan, F.; Solomon, B. D.; Roessler, E.; El-Jaick, K.; Domené, S.; Vélez, J. I.; Zhou, N.; Hadley, D.; Balog, J. Z.; Long, R.; Fryer, A.; Smith, W.; Omar, S.; McLean, S. D.; Clarkson, K.; Lichty, A.; Clegg, N. J.; Delgado, M. R.; Levey, E.; Stashinko, E.; Potocki, L.; VanAllen, M. I.; Clayton-Smith, J.; Donnai, D.; Bianchi, D. W.; Juliusson, P. B.; Njølstad, P. R.; Brunner, H. G.; Carey, J. C.; Hehr, U.; Müsebeck, J.; Wieacker, P. F.; Postra, A.; Hennekam, R. C. M.; van den Boogaard, M.-J. H.; van Haeringen, A.; Paulussen, A.; Herbergs, J.; Schrander-Stumpel, C. T. R. M.; Janecke, A. R.; Chitayat, D.; Hahn, J.; McDonald-McGinn, D. M.; Zackai, E. H.; Dobyns, W. B.; Muenke, M.

    2009-01-01

    BACKGROUND: Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain. There are several important HPE mutational target genes, including the transcription factor SIX3, which encodes an early regulator of Shh, Wnt, Bmp and Nodal signalling expressed in the developing

  17. Clinical classification of cancer cachexia: phenotypic correlates in human skeletal muscle.

    Directory of Open Access Journals (Sweden)

    Neil Johns

    Full Text Available BACKGROUND: Cachexia affects the majority of patients with advanced cancer and is associated with a reduction in treatment tolerance, response to therapy, and duration of survival. One impediment towards the effective treatment of cachexia is a validated classification system. METHODS: 41 patients with resectable upper gastrointestinal (GI or pancreatic cancer underwent characterisation for cachexia based on weight-loss (WL and/or low muscularity (LM. Four diagnostic criteria were used >5%WL, >10%WL, LM, and LM+>2%WL. All patients underwent biopsy of the rectus muscle. Analysis included immunohistochemistry for fibre size and type, protein and nucleic acid concentration, Western blots for markers of autophagy, SMAD signalling, and inflammation. FINDINGS: Compared with non-cachectic cancer patients, patients with LM or LM+>2%WL, mean muscle fibre diameter was reduced by about 25% (p = 0.02 and p = 0.001 respectively. No significant difference in fibre diameter was observed if patients had WL alone. Regardless of classification, there was no difference in fibre number or proportion of fibre type across all myosin heavy chain isoforms. Mean muscle protein content was reduced and the ratio of RNA/DNA decreased in patients with either >5%WL or LM+>2%WL. Compared with non-cachectic patients, SMAD3 protein levels were increased in patients with >5%WL (p = 0.022 and with >10%WL, beclin (p = 0.05 and ATG5 (p = 0.01 protein levels were increased. There were no differences in phospho-NFkB or phospho-STAT3 levels across any of the groups. CONCLUSION: Muscle fibre size, biochemical composition and pathway phenotype can vary according to whether the diagnostic criteria for cachexia are based on weight loss alone, a measure of low muscularity alone or a combination of the two. For intervention trials where the primary end-point is a change in muscle mass or function, use of combined diagnostic criteria may allow identification of a more

  18. Clinical trials in hospitalized heart failure patients: targeting interventions to optimal phenotypic subpopulations.

    Science.gov (United States)

    Vaduganathan, Muthiah; Butler, Javed; Roessig, Lothar; Fonarow, Gregg C; Greene, Stephen J; Metra, Marco; Cotter, Gadi; Kupfer, Stuart; Zalewski, Andrew; Sato, Naoki; Filippatos, Gerasimos; Gheorghiade, Mihai

    2015-07-01

    With one possible exception, the last decade of clinical trials in hospitalized heart failure (HHF) patients has failed to demonstrate improvement in long-term clinical outcomes. This trend necessitates a need to evaluate optimal drug development strategies and standards of trial conduct. It has become increasingly important to recognize the heterogeneity among HHF patients and the differential characterization of novel drug candidates. Targeting these agents to specific subpopulations may afford optimal net response related to the particular mode of action of the drug. Analyses of previous trials demonstrate profound differences in the baseline characteristics of patients enrolled across global regions and participating sites. Such differences may influence risks for events and interpretation of results. Therefore, the actual execution of trials and the epidemiology of HHF populations at the investigative sites must be taken into consideration. Collaboration among participating sites including the provision of registry data tailored to the planned development program will optimize trial conduct. Observational data prior to study initiation may enable sites to feedback and engage in protocol development to allow for feasible and valid clinical trial conduct. This site-centered, epidemiology-based network environment may facilitate studies in specific patient populations and promote optimal data collection and clear interpretation of drug safety and efficacy. This review summarizes the roundtable discussion held by a multidisciplinary team of representatives from academia, National Institutes of Health, industry, regulatory agencies, payers, and contract and academic research organizations to answer the question: Who should be targeted for novel therapies in HHF?

  19. Omics AnalySIs System for PRecision Oncology (OASISPRO): A Web-based Omics Analysis Tool for Clinical Phenotype Prediction.

    Science.gov (United States)

    Yu, Kun-Hsing; Fitzpatrick, Michael R; Pappas, Luke; Chan, Warren; Kung, Jessica; Snyder, Michael

    2017-09-12

    Precision oncology is an approach that accounts for individual differences to guide cancer management. Omics signatures have been shown to predict clinical traits for cancer patients. However, the vast amount of omics information poses an informatics challenge in systematically identifying patterns associated with health outcomes, and no general-purpose data-mining tool exists for physicians, medical researchers, and citizen scientists without significant training in programming and bioinformatics. To bridge this gap, we built the Omics AnalySIs System for PRecision Oncology (OASISPRO), a web-based system to mine the quantitative omics information from The Cancer Genome Atlas (TCGA). This system effectively visualizes patients' clinical profiles, executes machine-learning algorithms of choice on the omics data, and evaluates the prediction performance using held-out test sets. With this tool, we successfully identified genes strongly associated with tumor stage, and accurately predicted patients' survival outcomes in many cancer types, including mesothelioma and adrenocortical carcinoma. By identifying the links between omics and clinical phenotypes, this system will facilitate omics studies on precision cancer medicine and contribute to establishing personalized cancer treatment plans. This web-based tool is available at http://tinyurl.com/oasispro ;source codes are available at http://tinyurl.com/oasisproSourceCode . © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

  20. Association of sputum and blood eosinophil concentrations with clinical measures of COPD severity: an analysis of the SPIROMICS cohort.

    Science.gov (United States)

    Hastie, Annette T; Martinez, Fernando J; Curtis, Jeffrey L; Doerschuk, Claire M; Hansel, Nadia N; Christenson, Stephanie; Putcha, Nirupama; Ortega, Victor E; Li, Xingnan; Barr, R Graham; Carretta, Elizabeth E; Couper, David J; Cooper, Christopher B; Hoffman, Eric A; Kanner, Richard E; Kleerup, Eric; O'Neal, Wanda K; Paine, Richard; Peters, Stephen P; Alexis, Neil E; Woodruff, Prescott G; Han, MeiLan K; Meyers, Deborah A; Bleecker, Eugene R

    2017-12-01

    Increased concentrations of eosinophils in blood and sputum in chronic obstructive pulmonary disease (COPD) have been associated with increased frequency of exacerbations, reduced lung function, and corticosteroid responsiveness. We aimed to assess whether high eosinophil concentrations in either sputum or blood are associated with a severe COPD phenotype, including greater exacerbation frequency, and whether blood eosinophils are predictive of sputum eosinophils. We did a multicentre observational study analysing comprehensive baseline data from SPIROMICS in patients with COPD aged 40-80 years who had a smoking history of at least 20 pack-years, recruited from six clinical sites and additional subsites in the USA between Nov 12, 2010, and April 21, 2015. Inclusion criteria for this analysis were SPIROMICS baseline visit data with complete blood cell counts and, in a subset, acceptable sputum counts. We stratified patients on the basis of blood and sputum eosinophil concentrations and compared their demographic characteristics, as well as results from questionnaires, clinical assessments, and quantitative CT (QCT). We also analysed whether blood eosinophil concentrations reliably predicted sputum eosinophil concentrations. This study is registered with ClinicalTrials.gov (NCT01969344). Of the 2737 patients recruited to SPIROMICS, 2499 patients were smokers and had available blood counts, and so were stratified by mean blood eosinophil count: 1262 patients with low (George Respiratory Questionnaire symptom scores (p=0·037), and increased wheezing (p=0·018), but no evidence of an association with COPD exacerbations (p=0·35) or the other indices of COPD severity, such as emphysema measured by CT density, COPD assessment test scores, Body-mass index, airflow Obstruction, Dyspnea, and Exercise index, or Global Initiative for Chronic Obstructive Lung Disease stage. Blood eosinophil counts showed a weak but significant association with sputum eosinophil counts

  1. A rule-based electronic phenotyping algorithm for detecting clinically relevant cardiovascular disease cases.

    Science.gov (United States)

    Esteban, Santiago; Rodríguez Tablado, Manuel; Ricci, Ricardo Ignacio; Terrasa, Sergio; Kopitowski, Karin

    2017-07-14

    The implementation of electronic medical records (EMR) is becoming increasingly common. Error and data loss reduction, patient-care efficiency increase, decision-making assistance and facilitation of event surveillance, are some of the many processes that EMRs help improve. In addition, they show a lot of promise in terms of data collection to facilitate observational epidemiological studies and their use for this purpose has increased significantly over the recent years. Even though the quantity and availability of the data are clearly improved thanks to EMRs, still, the problem of the quality of the data remains. This is especially important when attempting to determine if an event has actually occurred or not. We sought to assess the sensitivity, specificity, and agreement level of a codes-based algorithm for the detection of clinically relevant cardiovascular (CaVD) and cerebrovascular (CeVD) disease cases, using data from EMRs. Three family physicians from the research group selected clinically relevant CaVD and CeVD terms from the international classification of primary care, Second Edition (ICPC-2), the ICD 10 version 2015 and SNOMED-CT 2015 Edition. These terms included both signs, symptoms, diagnoses and procedures associated with CaVD and CeVD. Terms not related to symptoms, signs, diagnoses or procedures of CaVD or CeVD and also those describing incidental findings without clinical relevance were excluded. The algorithm yielded a positive result if the patient had at least one of the selected terms in their medical records, as long as it was not recorded as an error. Else, if no terms were found, the patient was classified as negative. This algorithm was applied to a randomly selected sample of the active patients within the hospital's HMO by 1/1/2005 that were 40-79 years old, had at least one year of seniority in the HMO and at least one clinical encounter. Thus, patients were classified into four groups: (1) Negative patients (2) Patients with Ca

  2. Clinical aspects of a multicenter clinical trial of implant-retained mandibular overdentures in patients with severely resorbed mandibles

    NARCIS (Netherlands)

    Geertman, ME; Boerrigter, EM; VanWaas, MAJ; vanOort, RP

    In a multicenter clinical trial treatment, the effects of overdentures on different implant systems in patients with severely resorbed mandibles were compared 1 year after the insertion of new dentures. The implant systems used were the transmandibular implant (TMI), the IMZ (IMZ), and the Branemark

  3. Spontaneously Reported Symptoms by Informants Are Associated with Clinical Severity in Dementia Help-Seekers.

    Science.gov (United States)

    Xu, Jia-Qi; Choy, Jacky C P; Tang, Jennifer Y M; Liu, Tian-Yin; Luo, Hao; Lou, Vivian W Q; Lum, Terry Y S; Wong, Gloria H Y

    2017-09-01

    To investigate the predictive value of symptoms of dementia that the person or an informant noticed spontaneously in determining the clinical severity of dementia. Cross-sectional. Community-based open-referral dementia assessment service in Hong Kong between 2005 and 2013. Help-seekers for dementia assessment service and their informants (N = 965 dyads). Participants underwent a clinical dementia interview based on the Clinical Dementia Rating. Spontaneous complaints that the person and the informant made that had prompted their help-seeking of groups with interview results suggestive of no impairment, mild cognitive impairment, and dementia were compared. Logistic regression was used to evaluate the predictive value of spontaneous complaints for clinical severity. Independent raters blinded to clinical results coded spontaneously reported symptoms into theoretical themes: memory, executive function, language, time and place orientation, neuropsychiatric, mood, and avolition. Memory problems were the most frequently reported complaints for participants (87.7%) and their informants (95.5%), followed by self-reported language (33.0%) and informant-reported orientation (33.0%) difficulties. Informant-reported but not self-reported symptoms predicted clinical severity. Compared with the persons themselves, informants reported more pervasive symptoms corresponding to clinical severity. Persons with dementia self-reported fewer types of symptoms than their healthy or mildly impaired counterparts. Spontaneously reported language and orientation symptoms by the informant distinguished persons with mild or worse dementia (P < .001, Nagelkerke coefficient of determination = 29.7%, percentage correct 85.6%). The type and pervasiveness of symptoms spontaneously that informants reported predicted clinical severity. This may provide a quick reference for triage. © 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.

  4. [Gene mutation and clinical phenotype analysis of patients with Noonan syndrome and hypertrophic cardiomyopathy].

    Science.gov (United States)

    Liu, X H; Ding, W W; Han, L; Liu, X R; Xiao, Y Y; Yang, J; Mo, Y

    2017-10-02

    Objective: To analyze the gene mutations and clinical features of patients with Noonan syndrome and hypertrophic cardiomyopathy. Method: Determined the mutation domain in five cases diagnosed with Noonan syndrome and hypertrophic cardiomyopathy and identified the relationship between the mutant domain and hypertrophic cardiomyopathy by searching relevant articles in pubmed database. Result: Three mutant genes (PTPN11 gene in chromosome 12, RIT1 gene in chromosome 1 and RAF1 gene in chromosome 3) in five cases all had been reported to be related to hypertrophic cardiomyopathy. The reported hypertrophic cardiomyopathy relevant genes MYPN, MYH6 and MYBP3 had also been found in case 1 and 2. Patients with same gene mutation had different clinical manifestations. Both case 4 and 5 had RAF1 mutation (c.770C>T). However, case 4 had special face, low IQ, mild pulmonary artery stenosis, and only mild ventricular hypertrophy. Conclusion: Noonan syndrome is a genetic heterogeneity disease. Our study identified specific gene mutations that could result in Noonan syndrome with hypertrophic cardiomyopathy through molecular biology methods. The results emphasize the importance of gene detection in the management of Noonan syndrome.

  5. MAX to MYCN intracellular ratio drives the aggressive phenotype and clinical outcome of high risk neuroblastoma.

    Science.gov (United States)

    Ferrucci, Francesca; Ciaccio, Roberto; Monticelli, Sara; Pigini, Paolo; di Giacomo, Simone; Purgato, Stefania; Erriquez, Daniela; Bernardoni, Roberto; Norris, Murray; Haber, Michelle; Milazzo, Giorgio; Perini, Giovanni

    2018-03-01

    Childhood neuroblastoma, a disease of the sympathetic nervous system, is the most common solid tumour of infancy, remarkably refractory to therapeutic treatments. One of the most powerful independent prognostic indicators for this disease is the amplification of the MYCN oncogene, which occurs at high levels in approximately 25% of neuroblastomas. Interestingly, amplification and not just expression of MYCN has a strong prognostic value, although this fact appears quite surprising as MYCN is a transcription factor that requires dimerising with its partner MAX, to exert its function. This observation greatly suggests that the role of MYCN in neuroblastoma should be examined in the context of MAX expression. In this report, we show that, in contrast to what is found in normal cells, MAX expression is significantly different among primary NBs, and that its level appears to correlate with the clinical outcome of the disease. Importantly, controlled modulation of MAX expression in neuroblastoma cells with different extents of MYCN amplification, demonstrates that MAX can instruct gene transcription programs that either reinforce or weaken the oncogenic process enacted by MYCN. In general, our work illustrates that it is the MAX to MYCN ratio that can account for tumour progression and clinical outcome in neuroblastoma and proposes that such a ratio should be considered as an important criterion to the design and development of anti-MYCN therapies. Copyright © 2018 Elsevier B.V. All rights reserved.

  6. Clinical phenotype and genetic mutation of fatty acid hydroxylase - associated neurodegeneration: analysis of four cases

    Directory of Open Access Journals (Sweden)

    Xiao-jun HUANG

    2017-07-01

    Full Text Available Objective To report 4 cases of fatty acid hydroxylase - associated neurodegeneration (FAHN and to summarize the clinical and genetic characteristics of FAHN by literatures review.  Methods Four cases of FAHN patients' clinical and family data were collected in detail. The gDNA of patients and their parents were extracted from peripheral blood. FA2H gene was conducted and followed by Sanger sequencing.  Results Among the 4 cases, 3 cases (Case 2, Case 3, Case 4 presented typical manifestations of FAHN while the other (Case 1 was atypical. Genetic sequencing showed FA2H gene mutation in all affected patients. Compound heterozygous mutation c.461G > A (p.Arg154His and c.794T > G (p.Phe265Cys were seen in Case 1. In Case 2, only one documented heterozygous mutation c.703C > T (p.Arg235Cys was found, and dificit mutation was not found in single nucleotide polymorphism (SNP chip test of the patient and her mother. Compound heterozygous mutation c.688G > A (p.Glu230Lys and insertion mutation c.172_173insGGGCCAGGAC (p.Ile58ArgfsX47 were presented in Case 3. In Case 4, compound heterozygous mutation c.688G > A (p.Glu230Lys, c.968C > A (p.Pro323Gln and c.976G > A (p. Gly326Asp were seen, while his father was the carrier of c.688G > A (p.Glu230Lys mutation and his mother was the carrier of c.968C > A (p.Pro323Gln and c.976G > A (p.Gly326Asp mutation. According to the standard of American College of Medical Genetics and Genomics (ACMG, c.461G > A (p.Arg154His and c.794T > G (p.Phe265Cys in Case 1, and c.703C > T (p.Arg235Cys in Case 2 were considered as "likely pathogenic", while FA2H gene compound heterozygous mutation c.688G > A (p.Glu230Lys, insertion mutation c.172_173insGGGCCAGGAC (p.Ile58ArgfsX47 in Case 3 was as "pathogenic", and in Case 4, the FA2H gene mutation c.688G > A (p.Glu230Lys and c.968C > A (p.Pro323Gln were "pathogenic" and c.976G > A (p.Gly326Asp was "likely pathogenic".  Conclusions FAHN has highly clinical and genetic

  7. PASI (Psoriasis Area and Severity Index in the evaluation of the clinical manifestations of psoriasis

    Directory of Open Access Journals (Sweden)

    A. A. Kubanov

    2016-01-01

    Full Text Available Psoriasis is one of the most prevalent chronic inflammatory skin diseases. The severity of its clinical manifestations can vary greatly. Objective assessment of psoriasis severity is required to select an adequate therapy. One of the simplest and most consistent methods used to determine psoriasis severity is to calculate the PASI (Psoriasis Area and Severity Index. This index is based on the doctor’s determination of the sum of indices showing the intensity of the main symptoms of psoriasis: erythema, infiltration and peeling in view of the affected skin area. The PASI can also be used to assess the efficacy of treatment for psoriasis patients.

  8. [Analysis of clinical phenotype and mode of inheritance in retinitis pigmentosa patients with consanguineous marriage].

    Science.gov (United States)

    Rong, Wei-ning; Sheng, Xun-lun; Liu, Ya-ni

    2012-10-01

    To analyse the mode of inheritance and clinical characteristics of retinitis pigmentosa (RP) patients with consanguineous marriage. RP patients were recruited for this study in Ningxia Eye Hospital from September 2009 to July 2011. All patients received complete ophthalmic examination. The mode of inheritance were determined based on family history and marriage history. Clinical features were characterized by complete ophthalmic examinations including visual acuity, macular OCT, visual field and electroretinogram (ERG). A total of 143 individuals with RP (33 families) were recruited. Based on analysis of family history and marriage history, 20 RP families (23 patients) had consanguineous marriage history accounted for 60.6% RP families (16.1% RP patients). There were 4 patients (from 4 families) diagnosed as Usher syndrome. In 20 RP families with consanguineous marriage history, 7 families (35.0%) were Hui ethnicity and 13 families (65%) were Han ethnicity. The marriages of 15 families were between first cousins and 3 families were between second cousins, only 2 families were between half cousins matrimony. Of 23 RP patients, 12 were males and 11 were females. The average age of onset was 11.4 ± 6.8 years and the average age of recruitment was (32.0 ± 13.5) years. The best-corrected visual acuity was less than 0.6 in 78.2% patients. According to the features of the fundus, 13 patients were classical retinitis pigmentosa and 10 patients were retinitis pigmentosa sine pigmento. Visual field examination showed that all patients had varying degrees of peripheral visual field defect. Retinal neuroepithelial layer of macular and peripheral retina became thinner and retinal photoreceptors were disappeared. The average thickness of macular fovea was (186.1 ± 78.7) µm on right eyes and (187.4 ± 76.3) µm on left eyes. The incidence of RP with consanguineous marriages was high in Ningxia Region. The mode of inheritance of RP patients with consanguinity is autosomal

  9. Pain modulatory phenotypes differentiate subgroups with different clinical and experimental pain sensitivity

    DEFF Research Database (Denmark)

    Vaegter, Henrik B.; Graven-Nielsen, Thomas

    2016-01-01

    between subgroups. Cuff algometry was performed on lower legs in 400 chronic pain patients to assess pressure pain threshold (cPPT), pressure pain tolerance (cPTT), temporal summation of pain (TSP: increase in pain scores to ten repeated stimulations), and conditioned pain modulation (CPM: increase in c......PPT during cuff pain conditioning on the contralateral leg). Heat detection (HDT) and heat pain thresholds (HPT) at clinical painful and non-painful body areas were assessed. Based on TSP and CPM four distinct groups were formed: Group 1 (n=85) had impaired CPM and facilitated TSP. Group 2 (n=148) had...... impaired CPM and normal TSP. Group 3 (n=45) had normal CPM and facilitated TSP. Group 4 (n=122) had normal CPM and normal TSP. Group 1 showed more pain regions compared with the other three groups (PCPM and facilitated TSP plays an important role in widespread pain. Group 1...

  10. Overexpression of AtDREB1A causes a severe dwarf phenotype by decreasing endogenous gibberellin levels in soybean [Glycine max (L. Merr].

    Directory of Open Access Journals (Sweden)

    Haicui Suo

    Full Text Available Gibberellic acids (GAs are plant hormones that play fundamental roles in plant growth and developmental processes. Previous studies have demonstrated that three key enzymes of GA20ox, GA3ox, and GA2ox are involved in GA biosynthesis. In this study, the Arabidopsis DREB1A gene driven by the CaMV 35S promoter was introduced into soybean plants by Agrobacterium- mediated transformation. The results showed that the transgenic soybean plants exhibited a typical phenotype of GA-deficient mutants, such as severe dwarfism, small and dark-green leaves, and late flowering compared to those of the non-transgenic plants. The dwarfism phenotype was rescued by the application of exogenous GA(3 once a week for three weeks with the concentrations of 144 µM or three times in one week with the concentrations of 60 µM. Quantitative RT-PCR analysis revealed that the transcription levels of the GA synthase genes were higher in the transgenic soybean plants than those in controls, whereas GA-deactivated genes except GmGA2ox4 showed lower levels of expression. The transcript level of GmGA2ox4 encoding the only deactivation enzyme using C(20-GAs as the substrates in soybean was dramatically enhanced in transgenic plants compared to that of wide type. Furthermore, the contents of endogenous bioactive GAs were significantly decreased in transgenic plants than those of wide type. The results suggested that AtDREB1A could cause dwarfism mediated by GA biosynthesis pathway in soybean.

  11. Motor neuronal repletion of the NMJ organizer, Agrin, modulates the severity of the spinal muscular atrophy disease phenotype in model mice.

    Science.gov (United States)

    Kim, Jeong-Ki; Caine, Charlotte; Awano, Tomoyuki; Herbst, Ruth; Monani, Umrao R

    2017-07-01

    Spinal muscular atrophy (SMA) is a common and often fatal neuromuscular disorder caused by low levels of the Survival Motor Neuron (SMN) protein. Amongst the earliest detectable consequences of SMN deficiency are profound defects of the neuromuscular junctions (NMJs). In model mice these synapses appear disorganized, fail to mature and are characterized by poorly arborized nerve terminals. Given one role of the SMN protein in orchestrating the assembly of spliceosomal snRNP particles and subsequently regulating the alternative splicing of pre-mRNAs, a plausible link between SMN function and the distal neuromuscular SMA phenotype is an incorrectly spliced transcript or transcripts involved in establishing or maintaining NMJ structure. In this study, we explore the effects of one such transcript-Z+Agrin-known to be a critical organizer of the NMJ. We confirm that low SMN protein reduces motor neuronal levels of Z+Agrin. Repletion of this isoform of Agrin in the motor neurons of SMA model mice increases muscle fiber size, enhances the post-synaptic NMJ area, reduces the abnormal accumulation of intermediate filaments in nerve terminals of the neuromuscular synapse and improves the innervation of muscles. While these effects are independent of changes in SMN levels or increases in motor neuron numbers they nevertheless have a significant effect on the overall disease phenotype, enhancing mean survival in severely affected SMA model mice by ∼40%. We conclude that Agrin is an important target of the SMN protein and that mitigating NMJ defects may be one strategy in treating human spinal muscular atrophy. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  12. Overexpression of AtDREB1A causes a severe dwarf phenotype by decreasing endogenous gibberellin levels in soybean [Glycine max (L.) Merr].

    Science.gov (United States)

    Suo, Haicui; Ma, Qibin; Ye, Kaixin; Yang, Cunyi; Tang, Yujuan; Hao, Juan; Zhang, Zhanyuan J; Chen, Mingluan; Feng, Yuqi; Nian, Hai

    2012-01-01

    Gibberellic acids (GAs) are plant hormones that play fundamental roles in plant growth and developmental processes. Previous studies have demonstrated that three key enzymes of GA20ox, GA3ox, and GA2ox are involved in GA biosynthesis. In this study, the Arabidopsis DREB1A gene driven by the CaMV 35S promoter was introduced into soybean plants by Agrobacterium- mediated transformation. The results showed that the transgenic soybean plants exhibited a typical phenotype of GA-deficient mutants, such as severe dwarfism, small and dark-green leaves, and late flowering compared to those of the non-transgenic plants. The dwarfism phenotype was rescued by the application of exogenous GA(3) once a week for three weeks with the concentrations of 144 µM or three times in one week with the concentrations of 60 µM. Quantitative RT-PCR analysis revealed that the transcription levels of the GA synthase genes were higher in the transgenic soybean plants than those in controls, whereas GA-deactivated genes except GmGA2ox4 showed lower levels of expression. The transcript level of GmGA2ox4 encoding the only deactivation enzyme using C(20)-GAs as the substrates in soybean was dramatically enhanced in transgenic plants compared to that of wide type. Furthermore, the contents of endogenous bioactive GAs were significantly decreased in transgenic plants than those of wide type. The results suggested that AtDREB1A could cause dwarfism mediated by GA biosynthesis pathway in soybean.

  13. Phenotypic methods for detection of various β-lactamases in Gram-negative clinical isolates: Need of the hour

    Directory of Open Access Journals (Sweden)

    Neena V Nagdeo

    2012-01-01

    Full Text Available Background: Many clinical laboratories have problems detecting various β-lactamases. Confusion exists about the importance of these resistance mechanisms, optimal test methods, and appropriate reporting conventions. It is more imperative to use various phenotypic methods for detection of various β-lactamases in routine microbiology laboratory on day-to-day basis to prevent antimicrobial resistance by evidence-based judicious use of antimicrobials. Aims: In view of the multidrug-resistant organisms being reported world over, we planned a cross-sectional prospective analytical study to determine resistance mechanism by various β-lactamases in Gram-negative clinical isolates using various phenotypic methods. Materials and Methods: All nonrepeat, nonenteric clinical isolates of Gram-negative bacilli, resistant to at least two third-generation cephalosporins, were first screened by Novel disc placement method, and isolates showing multiple mechanisms of resistance and reduced zone of inhibition for imipenem were further confirmed for AmpC and metallo β-lactamases. Statistical Analysis: All the data was managed and analyzed in Microsoft Excel. Results: Out of 807 isolates tested, as many as 795 (98.51% revealed the presence of extended-spectrum β-lactamases (ESBLs. Only 10 isolates of Escherichia coli and 2 of Klebsiella pneumoniae did not show production of ESBL. A total of 450 (55.76% isolates produced single enzyme,while 345 (42.75% strains revealed multiple enzyme production simultaneously. Only ESBL production was seen in 315 (39.03% strains, only AmpC in 75 (9.29% and only MBL in 60 (7.44% strains, while ESBL and AmpC together were seen in 219 (27.14% and AmpC plus MBL in 92 (11.40% strains. However, ESBL plus MBL were never observed together. All three enzymes were simultaneously detected in 34 (4.21% strains. Conclusion: This innovative method of disc placement makes it easy, affordable, and reliable method for routine use by basic

  14. Clinical decision making and mental health service use in people with severe mental illness across Europe

    OpenAIRE

    Cosh, S.; Zentner, N.; Ay, E.; Loos, S.; Slade, Mike; Maj, Mario; Salzano, A.; Berecz, R.; Glaub, T.; Munk-Jørgensen, Povl; Krogsgaard Bording, M.; Rössler, Wulf; Kawohl, Wolfram; Puschner, Bernd

    2017-01-01

    Objective: This study aims to explore relationships between preferred and experienced clinical decision making with service use, and associated costs, by people with severe mental illness.\\ud Methods: Prospective observational study of mental healthcare in six European countries: Germany, UK, Italy Hungary, Denmark and Switzerland. Patients (N = 588) and treating clinicians (N = 213) reported preferred and experienced decision making at baseline using the Clinical Decision Making Style Scale ...

  15. Cigarette smoking in male patients with chronic schizophrenia in a Chinese population: prevalence and relationship to clinical phenotypes.

    Directory of Open Access Journals (Sweden)

    Xiang Yang Zhang

    Full Text Available The high prevalence of smoking in schizophrenia of European background may be related to smoking's reducing clinical symptoms and medication side effects. Because smoking prevalence and its associations with clinical phenotypes are less well characterized in Chinese than European patients with schizophrenia, we assessed these smoking behaviors using clinician-administered questionnaires and the Fagerstrom Test for Nicotine Dependence (FTND in 776 Chinese male schizophrenia and 560 control subjects. Patients also were rated on the Positive and Negative Symptom Scale (PANSS, the Simpson and Angus Extrapyramidal Symptom Rating Scale (SAES, and the Abnormal Involuntary Movement Scale (AIMS. We found that the schizophrenia patients had a higher lifetime incidence of smoking (79% vs 63%, were more likely to be heavy smokers (61% vs 31%, and had lower smoking cessation rates (4% vs 9% (all p0.05 than the non-smoking patients. These results suggest that Chinese males with schizophrenia smoke more frequently than the general population. Further, smokers with schizophrenia may display fewer negative symptoms and possibly less parkinsonism than non-smokers with schizophrenia.

  16. Evaluation of different phenotypic methods for detection of amp c beta-lactamase producing bacteria in clinical isolates

    International Nuclear Information System (INIS)

    Hassan, A.; Usman, J.; Kalim, F.; Gill, M.M.; Khalid, A.; Iqbal, M.; Ingram, P.

    2013-01-01

    To compare the sensitivity and specificity of different phenotypic methods for detection of Amp C betalactamase producing bacteria. Study Design: Analytical study. Place and Duration of Study: Department of Microbiology, Army Medical College / National University of Sciences and Technology (NUST), Islamabad, Pakistan, from June 2010 to December 2010. Methodology: A total of 150 clinical isolates were screened for presence of Amp C beta-lactamase by using the cefoxitin disc. The confirmatory methods evaluated were inhibitor based assay (boronic acid), Amp C disc test and Amp C Etest. Three dimensional enzyme extract assay was used as the reference method for determining the sensitivity and specificity. Results: Among the total isolates tested, 62.8% bacteria showed the presence of Amp C beta-lactamase by standard three dimensional enzyme extract assay. Among the three methods compared, boronic acid disk test found out to be highly sensitive (88%) and specific (92%) for the detection of Amp C beta-lactamase producing bacteria. Conclusion: Detection of Amp C production is crucial in order to establish the antibiotic therapy and to attain the favourable clinical outcomes. Implementation of simple tests like boronic acid disk tests in the laboratories will help to alleviate the spread of Amp C beta-lactamase harboring organisms. (author)

  17. Animal models of polycystic ovary syndrome: a focused review of rodent models in relationship to clinical phenotypes and cardiometabolic risk.

    Science.gov (United States)

    Shi, Danni; Vine, Donna F

    2012-07-01

    To review rodent animal models of polycystic ovary syndrome (PCOS), with a focus on those associated with the metabolic syndrome and cardiovascular disease risk factors. Review. Rodent models of PCOS. Description and comparison of animal models. Comparison of animal models to clinical phenotypes of PCOS. Animals used to study PCOS include rodents, mice, rhesus monkeys, and ewes. Major methods to induce PCOS in these models include subcutaneous injection or implantation of androgens, estrogens, antiprogesterone, letrozole, prenatal exposure to excess androgens, and exposure to constant light. In addition, transgenic mice models and spontaneous PCOS-like rodent models have also been developed. Rodents are the most economical and widely used animals to study PCOS and ovarian dysfunction. The model chosen to study the development of PCOS and other metabolic parameters remains dependent on the specific etiologic hypotheses being investigated. Rodent models have been shown to demonstrate changes in insulin metabolism, with or without induction of hyperandrogenemia, and limited studies have investigated cardiometabolic risk factors for type 2 diabetes and cardiovascular disease. Given the clinical heterogeneity of PCOS, the utilization of different animal models may be the best approach to further our understanding of the pathophysiologic mechanisms associated with the early etiology of PCOS and cardiometabolic risk. Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  18. Short communication: Phenotypic protease inhibitor resistance and cross-resistance in the clinic from 2006 to 2008 and mutational prevalences in HIV from patients with discordant tipranavir and darunavir susceptibility phenotypes.

    Science.gov (United States)

    Bethell, Richard; Scherer, Joseph; Witvrouw, Myriam; Paquet, Agnes; Coakley, Eoin; Hall, David

    2012-09-01

    To test tipranavir (TPV) or darunavir (DRV) as treatment options for patients with phenotypic resistance to protease inhibitors (PIs), including lopinavir, saquinavir, atazanavir, and fosamprenavir, the PhenoSense GT database was analyzed for susceptibility to DRV or TPV among PI-resistant isolates. The Monogram Biosciences HIV database (South San Francisco, CA) containing 7775 clinical isolates (2006-2008) not susceptible to at least one first-generation PI was analyzed. Phenotypic responses [resistant (R), partially susceptible (PS), or susceptible (S)] were defined by upper and lower clinical cut-offs to each PI. Genotypes were screened for amino acid substitutions associated with TPV-R/DRV-S and TPV-S/DRV-R phenotypes. In all, 4.9% (378) of isolates were resistant to all six PIs and 31.0% (2407) were resistant to none. Among isolates resistant to all four first-generation PIs, DRV resistance increased from 21.2% to 41.9% from 2006 to 2008, respectively, and resistance to TPV remained steady (53.9 to 57.3%, respectively). Higher prevalence substitutions in DRV-S/TPV-R isolates versus DRV-R/TPV-S isolates, respectively, were 82L/T (44.4% vs. 0%) and 83D (5.8% vs. 0%). Higher prevalence substitutions in DRV-R/TPV-S virus were 50V (0.0% vs. 28.9%), 54L (1.0% vs. 36.1%), and 76V (0.4% vs. 15.5%). Mutations to help predict discordant susceptibility to DRV and TPV in isolates with reduced susceptibility to other PIs were identified. DRV resistance mutations associated with improved virologic response to TPV were more prevalent in DRV-R/TPV-S isolates. TPV resistance mutations were more prevalent in TPV-R and DRV-S isolates. These results confirm the impact of genotype on phenotype, illustrating how HIV genotype and phenotype data assist regimen optimization.

  19. Effect of severe weather events on the shedding of Shiga toxigenic Escherichia coli in slaughter cattle and phenotype of serogroup O157 isolates.

    Science.gov (United States)

    Stanford, Kim; Reuter, Tim; Bach, Susan J; Chui, Linda; Ma, Angela; Conrad, Cheyenne C; Tostes, Renata; McAllister, Tim A

    2017-09-01

    High-event periods (HEPs) occur sporadically when beef carcasses and meat have episodes of acute contamination with Shiga toxin-producing Escherichia coli (STEC). In this study, severe weather events were investigated as catalysts for HEPs based on PCR and isolate prevalence of seven E. coli serogroups in slaughter cattle feces. Winter ambient temperatures with daily means 10.5oC warmer or 12.3°C colder than seasonal norms (-10.4°C) most altered STEC shedding. Fecal samples yielded increased proportions (P  10 min and one also had strong biofilm-forming potential. However, this isolate lacked eae and stx genes. Severe weather can influence STEC shedding, particularly of O157, and could possibly trigger HEPs. However, our data suggest that it is unlikely for isolates to carry virulence genes and possess phenotypes capable of evading post-harvest microbiological interventions. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  20. Two Thai families with Norrie disease (ND): association of two novel missense mutations with severe ND phenotype, seizures, and a manifesting carrier.

    Science.gov (United States)

    Yamada, K; Limprasert, P; Ratanasukon, M; Tengtrisorn, S; Yingchareonpukdee, J; Vasiknanonte, P; Kitaoka, T; Ghadami, M; Niikawa, N; Kishino, T

    2001-04-15

    We describe two Thai families with Norrie disease (ND) in three generations, including 10 affected males and one manifesting female. All affected males in each family had severely defective eye development with complete loss of vision. In addition, three male patients (one from family 1 and two from family 2) suffered from epilepsy, and one female carrier from one family manifested blindness with phthisis bulbi in her right eye. Mutation analysis of the ND gene (NDP) revealed two different novel missense mutations (L16P and S75P) that co-segregated with ND in each family, suggesting that the newly appearing proline at codon 16 or codon 75 alters the conformation of the ND protein and contributes to the severe phenotype of ND in each family. Other studies suggest that epileptic seizures or growth retardation that is associated with ND is the consequence of loss of contiguous genes, because most such patients had deletions extending beyond the Norrie locus. Our finding that the three affected males in the two families with the missense mutations had epilepsy does not support a contiguous gene effect, but favors the pleiotropism of NDP, at least as far as the epileptic manifestation is concerned. The unilateral blindness in the female carrier may have been due to non-random X-inactivation. Copyright 2001 Wiley-Liss, Inc.

  1. Refining clinical phenotypes by contrasting ethnically different populations with schizophrenia from Australia, India and Sarawak.

    Science.gov (United States)

    McLean, Duncan; John, Sujit; Barrett, Robert; McGrath, John; Loa, Peter; Thara, Rangaswamy; Mowry, Bryan

    2012-04-30

    We contrasted demographic and clinical characteristics in transethnic schizophrenia populations from Australia (n=821), India (n=520) and Sarawak, Malaysia (n=298) and proposed cultural explanations for identified site differences. From these we aimed to identify candidate variables free from significant cultural confounding that are hence suitable for inclusion in genetic analyses. We observed five phenomena: (1) more individuals were living alone in Australia than India or Sarawak; (2) drug use was lower in India than Australia or Sarawak; (3) duration of untreated psychosis (DUP) was longer in India than Australia or Sarawak; (4) the rate of schizoaffective disorder was lower in India than Australia or Sarawak; and (5) age at psychosis onset (AAO) was older in Sarawak than Australia or India. We suggest that site differences for living arrangements, drug use and DUP are culturally confounded. The schizoaffective site difference likely results from measurement bias. The AAO site difference, however, has no obvious cultural or measurement bias explanation. Therefore, this may be an ideal candidate for use in genetic studies, given that genetic variants affecting AAO have already been proposed. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  2. Evaluation of the DSM-5 severity indicator for binge eating disorder in a clinical sample

    Science.gov (United States)

    Grilo, Carlos M.; Ivezaj, Valentina; White, Marney A.

    2015-01-01

    Objective This study tested the new DSM-5 severity criterion for binge eating disorder (BED) based on frequency of binge-eating in a clinical sample. This study also tested overvaluation of shape/weight as an alternative severity specifier. Method Participants were 834 treatment-seeking adults diagnosed with DSM-5 BED using semistructured diagnostic and eating-disorder interviews. Participants sub-grouped based on DSM-5 severity levels and on overvaluation of shape/weight were compared on demographic and clinical variables. Results Based on DSM-5 severity definitions, 331 (39.7%) participants were categorized as mild, 395 (47.5%) as moderate, 83 (10.0%) as severe, and 25 (3.0%) as extreme. Analyses comparing three (mild, moderate, and severe/extreme) severity groups revealed no significant differences in demographic variables or body mass index (BMI). Analyses revealed significantly higher eating-disorder psychopathology in the severe/extreme than moderate and mild groups and higher depression in moderate and severe/extreme groups than the mild group; effect sizes were small. Participants characterized with overvaluation (N = 449; 54%) versus without overvaluation (N = 384; 46%) did not differ significantly in age, sex, BMI, or binge-eating frequency, but had significantly greater eating-disorder psychopathology and depression. The robustly greater eating-disorder psychopathology and depression levels (medium-to-large effect sizes) in the overvaluation group was observed without attenuation of effect sizes after adjusting for ethnicity/race and binge-eating severity/frequency. Conclusions Our findings provide support for overvaluation of shape/weight as a severity specifier for BED as it provides stronger information about the severity of homogeneous groupings of patients than the DSM-5 rating based on binge-eating. PMID:26114779

  3. Women with congenital factor VII deficiency: clinical phenotype and treatment options from two international studies.

    Science.gov (United States)

    Napolitano, M; Di Minno, M N D; Batorova, A; Dolce, A; Giansily-Blaizot, M; Ingerslev, J; Schved, J-F; Auerswald, G; Kenet, G; Karimi, M; Shamsi, T; Ruiz de Sáez, A; Dolatkhah, R; Chuansumrit, A; Bertrand, M A; Mariani, G

    2016-09-01

    A paucity of data exists on the incidence, diagnosis and treatment of bleeding in women with inherited factor VII (FVII) deficiency. Here we report results of a comprehensive analysis from two international registries of patients with inherited FVII deficiency, depicting the clinical picture of this disorder in women and describing any gender-related differences. A comprehensive analysis of two fully compatible, international registries of patients with inherited FVII deficiency (International Registry of Factor VII deficiency, IRF7; Seven Treatment Evaluation Registry, STER) was performed. In our cohort (N = 449; 215 male, 234 female), the higher prevalence of mucocutaneous bleeds in females strongly predicted ensuing gynaecological bleeding (hazard ratio = 12.8, 95% CI 1.68-97.6, P = 0.014). Menorrhagia was the most prevalent type of bleeding (46.4% of patients), and was the presentation symptom in 12% of cases. Replacement therapies administered were also analysed. For surgical procedures (n = 50), a receiver operator characteristic analysis showed that the minimal first dose of rFVIIa to avoid postsurgical bleeding during the first 24 hours was 22 μg kg(-1) , and no less than two administrations. Prophylaxis was reported in 25 women with excellent or effective outcomes when performed with a total weekly rFVIIa dose of 90 μg kg(-1) (divided as three doses). Women with FVII deficiency have a bleeding disorder mainly characterized by mucocutaneous bleeds, which predicts an increased risk of ensuing gynaecological bleeding. Systematic replacement therapy or long-term prophylaxis with rFVIIa may reduce the impact of menorrhagia on the reproductive system, iron loss and may avoid unnecessary hysterectomies. © 2016 John Wiley & Sons Ltd.

  4. Clinical and Cognitive Phenotype of Mild Cognitive Impairment Evolving to Dementia with Lewy Bodies

    Directory of Open Access Journals (Sweden)

    Annachiara Cagnin

    2015-11-01

    Full Text Available Objective: The aim of this study was to determine which characteristics could better distinguish dementia with Lewy bodies (DLB from Alzheimer's disease (AD at the mild cognitive impairment (MCI stage, with particular emphasis on visual space and object perception abilities. Methods: Fifty-three patients with mild cognitive deficits that were eventually diagnosed with probable DLB (MCI-DLB: n = 25 and AD (MCI-AD: n = 28 at a 3-year follow-up were retrospectively studied. At the first visit, the patients underwent cognitive assessment including the Qualitative Scoring Mini Mental State Examination Pentagon Test and the Visual Object and Space Perception Battery. The Neuropsychiatric Inventory Questionnaire, Unified Parkinson's Disease Rating Scale (UPDRS and questionnaires for cognitive fluctuations and sleep disorders were also administered. Results: The best clinical predictor of DLB was the presence of soft extrapyramidal signs (mean UPDRS score: 4.04 ± 5.9 detected in 72% of patients, followed by REM sleep behavior disorder (60% and fluctuations (60%. Wrong performances in the pentagon's number of angles were obtained in 44% of DLB and 3.7% of AD patients and correlated with speed of visual attention. Executive functions, visual attention and visuospatial abilities were worse in DLB, while verbal episodic memory impairment was greater in AD. Deficits in the visual-perceptual domain were present in both MCI-DLB and AD. Conclusions: Poor performance in the pentagon's number of angles is specific of DLB and correlates with speed of visual attention. The dorsal visual stream seems specifically more impaired in MCI-DLB with respect to the ventral visual stream, the latter being involved in both DLB and AD. These cognitive features, associated with subtle extrapyramidal signs, should alert clinicians to a diagnostic hypothesis of DLB.

  5. Ketosis-prone atypical diabetes in Cameroonian people with hyperglycaemic crisis: frequency, clinical and metabolic phenotypes.

    Science.gov (United States)

    Lontchi-Yimagou, E; Nguewa, J L; Assah, F; Noubiap, J J; Boudou, P; Djahmeni, E; Balti, E V; Atogho-Tiedeu, B; Gautier, J F; Mbanya, J C; Sobngwi, E

    2017-03-01

    It is unclear whether ketosis-prone diabetes is a specific type or a subtype of Type 2 diabetes. We aimed to describe the clinical and metabolic features of ketosis-prone diabetes in a sub-Saharan population. We consecutively enrolled and characterized 173 people with non-autoimmune diabetes admitted for hyperglycaemic crisis at the Yaoundé Central Hospital, Cameroon. Blood samples were collected for fasting glucose, HbA 1c , lipid profile and C-peptide assays with insulin resistance and secretion estimation by homeostasis model assessment. People were classified as having Type 2 diabetes (n = 124) or ketosis-prone diabetes (n = 49). Ketosis-prone diabetes was sub-classified as new-onset ketotic phase (n = 34) or non-ketotic phase (n = 15). Ketosis-prone diabetes was found in 28.3% of the hyperglycaemic crises. Age at diabetes diagnosis was comparable in Type 2 and ketosis-prone diabetes [48 ± 14 vs 47 ± 11 years; P = 0.13] with a similar sex distribution. Overall BMI was 27.7 ± 13.4 kg/m 2 and was ≥ 25 kg/m 2 in 55.8% of those taking part, however, 73.5% of those with ketosis-prone diabetes reported weight loss of > 5% at diagnosis. Blood pressure and lipid profile were comparable in both types. Ketosis-prone diabetes in the ketotic phase was characterized by lower insulin secretion and higher serum triglycerides compared with non-ketotic ketosis prone and Type 2 diabetes. Type 2 and ketosis prone diabetes in the non-ketotic phase were comparable in terms of lipid profile, blood pressure, waist-to-hip ratio, BMI and fat mass, insulin secretion and insulin resistance indices. Ketosis-prone diabetes is likely to be a subtype of Type 2 diabetes with the potential to develop acute insulinopenic episodes. © 2016 Diabetes UK.

  6. Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics.

    Science.gov (United States)

    de Angelis, Martin Hrabě; Nicholson, George; Selloum, Mohammed; White, Jacqui; Morgan, Hugh; Ramirez-Solis, Ramiro; Sorg, Tania; Wells, Sara; Fuchs, Helmut; Fray, Martin; Adams, David J; Adams, Niels C; Adler, Thure; Aguilar-Pimentel, Antonio; Ali-Hadji, Dalila; Amann, Gregory; André, Philippe; Atkins, Sarah; Auburtin, Aurelie; Ayadi, Abdel; Becker, Julien; Becker, Lore; Bedu, Elodie; Bekeredjian, Raffi; Birling, Marie-Christine; Blake, Andrew; Bottomley, Joanna; Bowl, Mike; Brault, Véronique; Busch, Dirk H; Bussell, James N; Calzada-Wack, Julia; Cater, Heather; Champy, Marie-France; Charles, Philippe; Chevalier, Claire; Chiani, Francesco; Codner, Gemma F; Combe, Roy; Cox, Roger; Dalloneau, Emilie; Dierich, André; Di Fenza, Armida; Doe, Brendan; Duchon, Arnaud; Eickelberg, Oliver; Esapa, Chris T; El Fertak, Lahcen; Feigel, Tanja; Emelyanova, Irina; Estabel, Jeanne; Favor, Jack; Flenniken, Ann; Gambadoro, Alessia; Garrett, Lilian; Gates, Hilary; Gerdin, Anna-Karin; Gkoutos, George; Greenaway, Simon; Glasl, Lisa; Goetz, Patrice; Da Cruz, Isabelle Goncalves; Götz, Alexander; Graw, Jochen; Guimond, Alain; Hans, Wolfgang; Hicks, Geoff; Hölter, Sabine M; Höfler, Heinz; Hancock, John M; Hoehndorf, Robert; Hough, Tertius; Houghton, Richard; Hurt, Anja; Ivandic, Boris; Jacobs, Hughes; Jacquot, Sylvie; Jones, Nora; Karp, Natasha A; Katus, Hugo A; Kitchen, Sharon; Klein-Rodewald, Tanja; Klingenspor, Martin; Klopstock, Thomas; Lalanne, Valerie; Leblanc, Sophie; Lengger, Christoph; le Marchand, Elise; Ludwig, Tonia; Lux, Aline; McKerlie, Colin; Maier, Holger; Mandel, Jean-Louis; Marschall, Susan; Mark, Manuel; Melvin, David G; Meziane, Hamid; Micklich, Kateryna; Mittelhauser, Christophe; Monassier, Laurent; Moulaert, David; Muller, Stéphanie; Naton, Beatrix; Neff, Frauke; Nolan, Patrick M; Nutter, Lauryl Mj; Ollert, Markus; Pavlovic, Guillaume; Pellegata, Natalia S; Peter, Emilie; Petit-Demoulière, Benoit; Pickard, Amanda; Podrini, Christine; Potter, Paul; Pouilly, Laurent; Puk, Oliver; Richardson, David; Rousseau, Stephane; Quintanilla-Fend, Leticia; Quwailid, Mohamed M; Racz, Ildiko; Rathkolb, Birgit; Riet, Fabrice; Rossant, Janet; Roux, Michel; Rozman, Jan; Ryder, Ed; Salisbury, Jennifer; Santos, Luis; Schäble, Karl-Heinz; Schiller, Evelyn; Schrewe, Anja; Schulz, Holger; Steinkamp, Ralf; Simon, Michelle; Stewart, Michelle; Stöger, Claudia; Stöger, Tobias; Sun, Minxuan; Sunter, David; Teboul, Lydia; Tilly, Isabelle; Tocchini-Valentini, Glauco P; Tost, Monica; Treise, Irina; Vasseur, Laurent; Velot, Emilie; Vogt-Weisenhorn, Daniela; Wagner, Christelle; Walling, Alison; Weber, Bruno; Wendling, Olivia; Westerberg, Henrik; Willershäuser, Monja; Wolf, Eckhard; Wolter, Anne; Wood, Joe; Wurst, Wolfgang; Yildirim, Ali Önder; Zeh, Ramona; Zimmer, Andreas; Zimprich, Annemarie; Holmes, Chris; Steel, Karen P; Herault, Yann; Gailus-Durner, Valérie; Mallon, Ann-Marie; Brown, Steve Dm

    2015-09-01

    The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.

  7. Anti-protein C antibodies are associated with resistance to endogenous protein C activation and a severe thrombotic phenotype in antiphospholipid syndrome.

    Science.gov (United States)

    Arachchillage, D R J; Efthymiou, M; Mackie, I J; Lawrie, A S; Machin, S J; Cohen, H

    2014-11-01

    Antiphospholipid antibodies may interfere with the anticoagulant activity of activated protein C (APC) to induce acquired APC resistance (APCr). To investigate the frequency and characteristics of APCr by using recombinant human APC (rhAPC) and endogenous protein C activation in antiphospholipid syndrome (APS). APCr was assessed in APS and non-APS venous thromboembolism (VTE) patients on warfarin and normal controls with rhAPC or Protac by thrombin generation. IgG anti-protein C and anti-protein S antibodies and avidity were assessed by ELISA. APS patients showed greater resistance to both rhAPC and Protac than non-APS patients and normal controls (median normalized endogenous thrombin potential inhibition): APS patients with rhAPC, 81.3% (95% confidence interval [CI] 75.2-88.3%; non-APS patients with rhAPC, 97.7% (95% CI 93.6-101.8%; APS patients with Protac, 66.0% (95% CI 59.5-72.6%); and non-APS patients with Protac, 80.7 (95% CI 74.2-87.2%). APS patients also had a higher frequency and higher levels of anti-protein C antibodies, with 60% (15/25) high-avidity antibodies. High-avidity anti-protein C antibodies were associated with greater APCr and with a severe thrombotic phenotype (defined as the development of recurrent VTE while patients were receiving therapeutic anticoagulation or both venous and arterial thrombosis). Twelve of 15 (80%) patients with high-avidity anti-protein C antibodies were classified as APS category I. Thrombotic APS patients showed greater APCr to both rhAPC and activation of endogenous protein C by Protac. High-avidity anti-protein C antibodies, associated with greater APCr, may provide a marker for a severe thrombotic phenotype in APS. However, in patients with category I APS, it remains to be established whether anti-protein C or anti-β2 -glycoprotein I antibodies are responsible for APCr. © 2014 International Society on Thrombosis and Haemostasis.

  8. Biomarker-driven phenotyping in Parkinson disease: a translational missing link in disease-modifying clinical trials

    Science.gov (United States)

    Espay, Alberto J.; Schwarzschild, Michael A.; Tanner, Caroline M.; Fernandez, Hubert H; Simon, David K.; Leverenz, James B.; Merola, Aristide; Chen-Plotkin, Alice; Brundin, Patrik; Kauffman, Marcelo A.; Erro, Roberto; Kieburtz, Karl; Woo, Daniel; Macklin, Eric A.; Standaert, David G.; Lang, Anthony E.

    2016-01-01

    Past clinical trials of putative neuroprotective therapies have targeted Parkinson disease (PD) as a single pathogenic disease entity. From an Oslerian clinico-pathologic perspective, the wide complexity of PD converges into Lewy bodies and justifies a reductionist approach to PD: a single-mechanism therapy can affect most of those sharing the classic pathologic hallmark. From a systems-biology perspective, PD is a group of disorders that, while related by sharing the feature of nigral dopamine-neuron degeneration, exhibit unique genetic, biological and molecular abnormalities, which probably respond differentially to a given therapeutic approach, particularly for strategies aimed at neuroprotection. Under this model, only biomarker-defined, homogenous subtypes of PD are likely to respond optimally to therapies proven to affect the biological processes within each subtype. Therefore, we suggest that precision medicine applied to PD requires a reevaluation of the biomarker-discovery effort. This effort is currently centered on correlating biological measures to clinical features of PD and on identifying factors that predict whether various prodromal states will convert into the classical movement disorder. We suggest, instead, that subtyping of PD requires the reverse view, where abnormal biological signals (i.e., biomarkers) rather than clinical definitions are used to define disease phenotypes. Successful development of disease-modifying strategies will depend on how relevant the specific biological processes addressed by an intervention are to the pathogenetic mechanisms in the subgroup of targeted patients. This precision-medicine approach will likely yield smaller but well-defined subsets of PD amenable to successful neuroprotection. PMID:28233927

  9. The frequency of Listeria monocytogenes strains recovered from clinical and non-clinical samples using phenotypic methods and confirmed by PCR

    Directory of Open Access Journals (Sweden)

    abazar pournajaf

    2013-09-01

    Full Text Available Background: Listeria monocytogenes is a facultative intracellular pathogen that causes listeriosis which has extensive clinical manifestations. Infections with L. monocytogenes are a serious threat to immunocompromised persons. The aim of this study was to determine the frequency of L. monocytogenes strains recovered from clinical and non-clinical samples using phenotypic methods and confirmed by PCR. Materials and Methods: In this study, 617 specimens were analyzed. All specimens were cultured in the specific PALCAM agar. Colonies were initially identified by routine biochemical tests. Finally, PCR assays using primers specific for inlA gene were performed. Results: In all, 46 (8.2% L. monocytogenes isolates were recovered from 617 specimens. Fourteen (8.2% strains, including 4 (7.5%, 2 (5.7%, 5 (14.2% and 3 (8.5% isolates were obtained from placental tissue, urine, vaginal and rectal swabs, respectively. In addition, 9 (7.4% strains of L. monocytogenes which were isolated from 107 different dairy products originated from cheese 5 (7.1%, cream 2 (10% and kashk 2 (11.7%, respectively. Among 11 (5.2% strains isolated from 210 different meat products, 5 (5.5%, 4 (7.2% and 2 (3% strains belonged to sausage, meat and poultry extracts, respectively. Finally, 12 (9.2% Listeria strains were recovered from 130 animal specimens that included 6 (10%, 4 (8% and 2 (10% strains from goat, sheep and cattle, respectively. Furthermore, all Listeria isolates (100% were found to be carriers of  inlA gene in PCR assay. Conclusion: The present study showed that the clinical and non-clinical specimens were contaminated with L. monocytogenes. So, it seems necessary to use a simple and standard technique such as PCR for rapid detection of this organism from various sources.

  10. Apoptosis and clinical severity in patients with psoriasis and HCV infection

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    Sami A Gabr

    2014-01-01

    Full Text Available Background: It has been proposed that hepatitis C virus (HCV antigens are involved in the pathogenesis of psoriasis and may contribute to severity of the disease. Increased expression of the apoptosis-regulating proteins p53 and tTG and decreased levels of bcl-2 in the keratinocytes of the skin of psoriatic patients have been reported. Aim: This study aims to identify the serum levels of apoptosis-regulating proteins in patients with psoriasis and without HCV infection and to study the relation between clinical severity of psoriasis and the presence of HCV infection. Materials and Methods: Disease severity was assessed by psoriasis area severity index score (PASI of 90 patients with psoriasis grouped as mild (n = 30, moderate (n = 30 and severe (n = 30; 20 healthy individuals were used as controls. All groups were subjected for complete history taking, clinical examination, and tests for liver function and HCV infection. The serum levels of apoptosis related proteins: p53, tTG and bcl-2 were estimated by enzyme linked immune sorbent assay (ELISA. Results: There was a statistically significant (P < 0.001 correlation between clinical severity of psoriasis and presence of HCV antibodies and HCV-mRNA. In addition, significantly (P < 0.001 raised serum p53 and tTG, and reduced bcl-2 were observed among HCV-positive patients as compared to HCV-negative patients and control patients. Conclusion: These results conclude that clinical severity of psoriasis is affected by the presence of HCV antibodies and overexpression of apoptotic related proteins. In addition, altered serum levels of apoptosis-regulating proteins could be useful prognostic markers and therapeutic targets of psoriatic disease.

  11. Severity variation of clinical E.coli mastitis in cows: where do we stand?

    Science.gov (United States)

    Neutrophils are key effector cells that underpin both defence and severity of clinical coliform mastitis. Increased turnover and viability of neutrophils in the lumen of the bovine mammary gland facilitate the physiological response and acute inflammation that fuel this effective mammary defence mec...

  12. Impact of Parental Severe Mental Illness: Ethical and Clinical Issues for Counselors

    Science.gov (United States)

    Spiegelhoff, Sarah F.; Ahia, C. Emmanuel

    2011-01-01

    This article draws attention to the issue of parental severe mental illness and the ethical and clinical implications for counselors who work with this population. Parents with mental illness face a multitude of life challenges including, but not limited to, parenting difficulties, medication and hospitalization, custody and placement of their…

  13. Severe bacterial infections in patients with non-transfusion-dependent thalassemia: prevalence and clinical risk factors

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    Nattiya Teawtrakul

    2015-10-01

    Conclusion: The prevalence of bacterial infection in patients with NTDT was found to be moderate. Time after splenectomy >10 years, deferoxamine therapy, and iron overload may be clinical risk factors for severe bacterial infection in patients with NTDT. Bacterial infection should be recognized in splenectomized patients with NTDT, particularly those who have an iron overload.

  14. Association between maternal comorbidity and preterm birth by severity and clinical subtype: retrospective cohort study

    Directory of Open Access Journals (Sweden)

    Le Thi

    2011-10-01

    Full Text Available Abstract Background Preterm birth (PTB is a major cause of infant morbidity and mortality, but the relationship between comorbidity and PTB by clinical subtype and severity of gestational age remains poorly understood. We evaluated associations between maternal comorbidities and PTB by clinical subtype and gestational age. Methods We conducted a retrospective cohort study of 1,329,737 singleton births delivered in hospitals in the province of Québec, Canada, 1989-2006. PTB was classified by clinical subtype (medically indicated, preterm premature rupture of membranes (PPROM, spontaneous preterm labour and gestational age ( Results PTB rates were higher among mothers with comorbidity (10.9% compared to those without comorbidity (4.7%. Several comorbidities were associated with greater odds of medically indicated PTB compared with no comorbidity, but only comorbidities localized to the reproductive system were associated with spontaneous PTB. Drug dependence and mental disorders were strongly associated with PPROM and spontaneous PTBs across all gestational ages (OR > 2.0. At the population level, several major comorbidities (placental abruption, chorioamnionitis, oliogohydramnios, structural abnormality, cervical incompetence were key contributors to all clinical subtypes of PTB, especially at Conclusions The relationship between comorbidity and clinical subtypes of PTB depends on gestational age. Prevention of PPROM and spontaneous PTB may benefit from greater attention to preeclampsia, anemia and comorbidities localized to the reproductive system.

  15. Upper gastrointestinal bleeding caused by severe esophagitis: a unique clinical syndrome.

    Science.gov (United States)

    Guntipalli, Prathima; Chason, Rebecca; Elliott, Alan; Rockey, Don C

    2014-12-01

    We have recognized a unique clinical syndrome in patients with upper gastrointestinal bleeding who are found to have severe esophagitis. We aimed to more clearly describe the clinical entity of upper gastrointestinal bleeding in patients with severe esophagitis. We conducted a retrospective matched case-control study designed to investigate clinical features in patients with carefully defined upper gastrointestinal bleeding and severe esophagitis. Patient data were captured prospectively via a Gastrointestinal Bleeding Healthcare Registry, which collects data on all patients admitted with gastrointestinal bleeding. Patients with endoscopically documented esophagitis (cases) were matched with randomly selected controls that had upper gastrointestinal bleeding caused by other lesions. Epidemiologic features in patients with esophagitis were similar to those with other causes of upper gastrointestinal bleeding. However, hematemesis was more common in patients with esophagitis 86% (102/119) than in controls 55% (196/357) (p bleeding than those without cirrhosis. We have described a unique clinical syndrome in patients with upper gastrointestinal bleeding who have erosive esophagitis. This syndrome is manifest by typical clinical features and is associated with favorable outcomes.

  16. [Clinical and neurophysiological aspects of severe forms of autism in children].

    Science.gov (United States)

    Simashkova, N V; Iakupova, L P; Bashina, V M

    2006-01-01

    The aim of the study was to elucidate fundamentals for the phenomenon of universality of childhood autism by comparison of clinical and neurophysiological features of its severest forms--children endogenous autism (CEA) and Rett's syndrome (RS). Each group included 20 patients. Both groups were similar by age-at-disease-onset, clinical appearances during the disease course and dynamics of psychopathological syndromes. The theta-rhythm is common for CEA and RS at the disease stage with marked signs of disease acuity, autism, regress and, therefore, may be regarded as a marker of severity and development delay. The universality of autism phenomenon in its severe forms was confirmed both at the clinical and neurophysiological levels.

  17. Influenza and other respiratory viruses: standardizing disease severity in surveillance and clinical trials.

    Science.gov (United States)

    Rath, Barbara; Conrad, Tim; Myles, Puja; Alchikh, Maren; Ma, Xiaolin; Hoppe, Christian; Tief, Franziska; Chen, Xi; Obermeier, Patrick; Kisler, Bron; Schweiger, Brunhilde

    2017-06-01

    Influenza-Like Illness is a leading cause of hospitalization in children. Disease burden due to influenza and other respiratory viral infections is reported on a population level, but clinical scores measuring individual changes in disease severity are urgently needed. Areas covered: We present a composite clinical score allowing individual patient data analyses of disease severity based on systematic literature review and WHO-criteria for uncomplicated and complicated disease. The 22-item ViVI Disease Severity Score showed a normal distribution in a pediatric cohort of 6073 children aged 0-18 years (mean age 3.13; S.D. 3.89; range: 0 to 18.79). Expert commentary: The ViVI Score was correlated with risk of antibiotic use as well as need for hospitalization and intensive care. The ViVI Score was used to track children with influenza, respiratory syncytial virus, human metapneumovirus, human rhinovirus, and adenovirus infections and is fully compliant with regulatory data standards. The ViVI Disease Severity Score mobile application allows physicians to measure disease severity at the point-of care thereby taking clinical trials to the next level.

  18. [Clinical analysis of acute encephalocele during operation in 21 patients with severe craniocerebral injury].

    Science.gov (United States)

    Zhuang, Qiang; Qu, Chun-cheng; Liang, Wen-zhi; Qin, Hao; Yu, Rui

    2011-03-08

    To analyze the clinical features of acute intra-operative encephalocele and the proper prophylactic-therapeutic measures for severe craniocerebral injury. The clinical data were collected and analyzed for 21 patients with severe head injuries who suffered acute intra-operative encephalocele from June 2008 to May 2010. There were 12 males and 9 females with an age range of 18 - 69 years old. Among these patients, 6 died with a mortality rate of 28.5%. It was lower than that reported in literatures. One patient died post-operatively of severe brain swelling and intracranial infection secondary to leakage of cerebrospinal fluid. Four patients died of severe craniocerebral injury, brain swelling and brain stem failure. And 1 patient died after his guardian abandoned the treatment. The follow-up period for the remaining 15 surviving patients was 3 - 6 months. According to the Glasgow outcome score (GOS), there were a favorable prognosis (n = 9), moderate disabilities (n = 5) and severe disability (n = 1). The probability of acute intra-operative encephalocele may be predicted in advance with a combination of clinical features and computed tomographic scans. The therapeutic success rate of acute encephalocele will be boosted by taking protective and therapeutic measures pre- and intra-operatively.

  19. Childhood asthma-predictive phenotype.

    Science.gov (United States)

    Guilbert, Theresa W; Mauger, David T; Lemanske, Robert F

    2014-01-01

    Wheezing is a fairly common symptom in early childhood, but only some of these toddlers will experience continued wheezing symptoms in later childhood. The definition of the asthma-predictive phenotype is in children with frequent, recurrent wheezing in early life who have risk factors associated with the continuation of asthma symptoms in later life. Several asthma-predictive phenotypes were developed retrospectively based on large, longitudinal cohort studies; however, it can be difficult to differentiate these phenotypes clinically as the expression of symptoms, and risk factors can change with time. Genetic, environmental, developmental, and host factors and their interactions may contribute to the development, severity, and persistence of the asthma phenotype over time. Key characteristics that distinguish the childhood asthma-predictive phenotype include the following: male sex; a history of wheezing, with lower respiratory tract infections; history of parental asthma; history of atopic dermatitis; eosinophilia; early sensitization to food or aeroallergens; or lower lung function in early life. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  20. Retroillumination photography analysis enhances clinical definition of severe Fuchs Corneal Dystrophy

    Science.gov (United States)

    Eghrari, Allen O.; Garrett, Brian S.; Mumtaz, Aisha A.; Edalati, Armand E.; Meadows, Danielle N.; McGlumphy, Elyse J.; Iliff, Benjamin W.; Gottsch, John D.

    2015-01-01

    Purpose Retroillumination photography analysis (RPA) provides objective assessment of the number and distribution of guttae in Fuchs Corneal Dystrophy. Here, we assess its correlation with clinical grading using slit-lamp biomicroscopy across varying levels of severity. Methods Retroillumination photographs were conducted of 95 affected corneas with slit-lamp flash photography after pupillary dilation. Individual guttae were counted manually and the position of individual points recorded. Clinical grading using the Krachmer scale was documented for each eye during examination, and regression analyses were performed to identify the strength of association with number of guttae. We assessed range at each stage of clinical grading, and utilized the Mann-Whitney U test to assess whether clinical grading levels demonstrated successively higher numbers of guttae. Results Krachmer score ranged from 1 to 5, with mean of 2.6. Mean numbers of guttae at each level of severity were 289 (1+), 999 (2+), 2669 (3+), 5474 (4+), and 7133 (5+). Each stage demonstrated significantly higher numbers of guttae than its preceding level except from 4+ to 5+ (p=0.30), consistent with the definition of 4+ as the highest level defined by presence of guttae. Higher levels of clinical grading were associated with larger ranges of guttae (p<0.01). A linear regression model resulted in a strong fit between RPA and Krachmer score (r=0.81). Conclusion In this largest study of RPA data and comparison with subjective clinical grading of FCD severity, RPA correlates strongly and demonstrates enhanced definition of severity at advanced stages of disease. PMID:26488628

  1. Gender differences in the T-cell profiles of the airways in COPD patients associated with clinical phenotypes

    Directory of Open Access Journals (Sweden)

    Forsslund H

    2016-12-01

    Full Text Available Helena Forsslund,1 Mingxing Yang,1 Mikael Mikko,1 Reza Karimi,1 Sven Nyrén,2 Benita Engvall,1 Johan Grunewald,1 Heta Merikallio,1,3 Riitta Kaarteenaho,3–5 Jan Wahlström,1 Åsa M Wheelock,1 C Magnus Sköld1 1Department of Medicine Solna and Centre for Molecular Medicine, Respiratory Medicine Unit, 2Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden; 3Respiratory Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland; 4Unit of Medicine and Clinical Research, Pulmonary Division, University of Eastern Finland, 5Center for Medicine and Clinical Research, Division of Respiratory Medicine, Kuopio University Hospital, Kuopio, Finland Abstract: T lymphocytes are believed to play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD. How T cells are recruited to the lungs and contribute to the inflammatory process is largely unknown. COPD is a heterogeneous disease, and discriminating disease phenotypes based on distinct molecular and cellular pathways may provide new approaches for individualized diagnosis and therapies. Bronchoalveolar lavage (BAL and blood samples were obtained from 40 never-smokers, 40 smokers with normal lung function, and 38 COPD patients. T-cell chemokine receptor expression was analyzed with flow cytometry, and soluble BAL cytokines and chemokines were measured using a cytokine multiplex assay. Correlations with gender and clinical characteristics including lung imaging were investigated using multivariate modeling. Th1/Tc1- and Th2/Tc2-associated soluble analytes and T-cell chemokine receptors were analyzed as cumulative Th1/Tc1 and Th2/Tc2 immune responses. A higher expression of chemokine receptor CCR5 on CD8+ T cells in BAL and higher percentage of CXCR3+CD8+ T cells in blood was found in female smokers with COPD compared to those without COPD. CCR5 expression

  2. Social, dietary and clinical correlates of oedema in children with severe acute malnutrition

    DEFF Research Database (Denmark)

    Rytter, Maren Johanne Heilskov; Namusoke, Hanifa; Babirekere-Iriso, Esther

    2015-01-01

    BACKGROUND: Severe acute malnutrition is a serious public health problem, and a challenge to clinicians. Why some children with malnutrition develop oedema (kwashiorkor) is not well understood. The objective of this study was to investigate socio-demographic, dietary and clinical correlates...... of oedema, in children hospitalised with severe acute malnutrition. METHODS: We recruited children with severe acute malnutrition admitted to Mulago Hospital, Uganda. Data was collected using questionnaires, clinical examination and measurement of blood haemoglobin, plasma c-reactive protein and α1-acid...... glycoprotein. Correlates of oedema were identified using multiple logistic regression analysis. RESULTS: Of 120 children included, 77 (64%) presented with oedematous malnutrition. Oedematous children were slightly older (17.7 vs. 15.0 months, p = 0.006). After adjustment for age and sex, oedematous children...

  3. Comorbid personality disorders in subjects with panic disorder: which personality disorders increase clinical severity?

    Directory of Open Access Journals (Sweden)

    Mustafa Ozkan

    2003-03-01

    Full Text Available Personality disorders are common in subjects with panic disorder. Personality disorders have shown to affect the course of panic disorder. The purpose of this study was to examine which personality disorders effect clinical severity in subjects with panic disorder. This study included 122 adults (71 female, 41 male, who met DSM-IV criteria for panic disorder (with or without agoraphobia. Clinical assessment was conducted by using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I, the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II and the Panic and Agoraphobia Scale (PAS, Global Assessment Functioning Scale (GAF, Beck Depression Inventory (BDI, and State-Trait Anxiety Inventory (STAI. Patients who had a history of sexual abuse were assessed with Sexual Abuse Severity Scale. Logistic regressions were used to identify predictors of suicide attempts, suicidal ideation, agoraphobia, different panic attack symptoms, sexual abuse, and early onset of disorders. The rates of comorbid Axis I and Axis II psychiatric disorders were 80.3% and 33.9%, consecutively, in patients with panic disorder. Panic disorder patients with comorbid personality disorders had more severe anxiety, depression and agoraphobia symptoms, and had earlier ages of onset, and lower levels of functioning. The rates of suicidal ideation and suicide attempts were 34.8% and 9.8%, consecutively, in subjects with panic disorder. The rate of patients with panic disorder had a history of childhood sexual abuse was 12.5%. The predictor of sexual abuse was more than one comorbid Axis II diagnosis. The predictors of suicide attempt were comorbid paranoid and borderline personality disorders, and the predictor of suicidal ideation was major depressive disorder in subjects with panic disorder. In conclusion, this study documents that comorbid personality disorders increase the clinical severity of panic disorder. Patients with more than one

  4. Hydatidiform mole: age-related clinical presentation and high rate of severe complications in older women.

    Science.gov (United States)

    Mangili, Giorgia; Giorgione, Veronica; Gentile, Cinzia; Bergamini, Alice; Pella, Francesca; Almirante, Giada; Candiani, Massimo

    2014-05-01

    The purpose of this study was to demonstrate differences in clinical presentation of hydatidiform mole between women ≥40 years and younger women. Retrospective study. A tertiary referral unit in northern Italy. Three hundred and sixty-five women with hydatidiform mole were divided into group A (Clinical presentation between groups A and B was analyzed, also considering partial hydatidiform mole and complete hydatidiform mole. Differences in clinical presentation according to woman's age. In group B the diagnosis of hydatidiform mole at ≥12 gestational weeks was more frequent (p presented with vaginal bleeding (p clinical features of hydatidiform mole in women ≥40 years are different from those seen in younger women. Failures in the early detection of hydatidiform mole in older women may expose them to a higher rate of severe complications. © 2014 Nordic Federation of Societies of Obstetrics and Gynecology.

  5. Brief report: genotype, phenotype, and clinical course in five patients with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne).

    Science.gov (United States)

    Demidowich, Andrew P; Freeman, Alexandra F; Kuhns, Douglas B; Aksentijevich, Ivona; Gallin, John I; Turner, Maria L; Kastner, Daniel L; Holland, Steven M

    2012-06-01

    To describe the genotypes, phenotypes, immunophenotypes, and treatments of PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne), a rare autoinflammatory disease, in 5 patients. Clinical information was gathered from medical records and through interviews with 5 patients from 4 kindreds. PSTPIP1 (CD2BP1) exon 10 and exon 11 sequencing was performed in each patient. Neutrophil granule content and cytokine levels were determined in plasma and stimulated peripheral blood mononuclear cells (PBMCs) from patients and controls. We identified 2 previously described PAPA syndrome-associated PSTPIP1 mutations, A230T and E250Q, and a novel change, E250K. Disease penetrance was incomplete, with variable expressivity. The cutaneous manifestations included pathergy, cystic acne, and pyoderma gangrenosum. Interleukin-1β (IL-1β) and circulating neutrophil granule enzyme levels were markedly elevated in patients compared to those in controls. PBMC stimulation studies demonstrated impaired production of IL-10 and enhanced production of granulocyte-macrophage colony-stimulating factor. Good resolution of pyoderma gangrenosum was achieved in 3 patients with tumor necrosis factor α (TNFα) blockade treatment. This analysis of 5 patients demonstrates that mutations in PSTPIP1 are incompletely penetrant and variably expressed in the PAPA syndrome. Neutrophil granule proteins are markedly elevated ex vivo and in the plasma, and elevated levels might be compatible with a diagnosis of PAPA syndrome. TNFα blockade appears to be effective in treating the cutaneous manifestations of PAPA syndrome. Copyright © 2012 by the American College of Rheumatology.

  6. Virulence phenotypes of low-passage clinical isolates of Nontypeable Haemophilus influenzae assessed using the chinchilla laniger model of otitis media

    Directory of Open Access Journals (Sweden)

    Hogg Justin

    2007-06-01

    Full Text Available Abstract Background The nontypeable Haemophilus influenzae (NTHi are associated with a spectrum of respiratory mucosal infections including: acute otitis media (AOM; chronic otitis media with effusion (COME; otorrhea; locally invasive diseases such as mastoiditis; as well as a range of systemic disease states, suggesting a wide range of virulence phenotypes. Genomic studies have demonstrated that each clinical strain contains a unique genic distribution from a population-based supragenome, the distributed genome hypothesis. These diverse clinical and genotypic findings suggest that each NTHi strain possesses a unique set of virulence factors that contributes to the course of the disease. Results The local and systemic virulence patterns of ten genomically characterized low-passage clinical NTHi strains (PittAA – PittJJ obtained from children with COME or otorrhea were stratified using the chinchilla model of otitis media (OM. Each isolate was used to bilaterally inoculate six animals and thereafter clinical assessments were carried out daily for 8 days by blinded observers. There was no statistical difference in the time it took for any of the 10 NTHi strains to induce otologic (local disease with respect to any or all of the other strains, however the differences in time to maximal local disease and the severity of local disease were both significant between the strains. Parameters of systemic disease indicated that the strains were not all equivalent: time to development of the systemic disease, maximal systemic scores and mortality were all statistically different among the strains. PittGG induced 100% mortality while PittBB, PittCC, and PittEE produced no mortality. Overall Pitt GG, PittII, and Pitt FF produced the most rapid and most severe local and systemic disease. A post hoc determination of the clinical origins of the 10 NTHi strains revealed that these three strains were of otorrheic origin, whereas the other 7 were from patients

  7. Comparison of an expert system with other clinical scores for the evaluation of severity of asthma.

    Science.gov (United States)

    Gautier, V; Rédier, H; Pujol, J L; Bousquet, J; Proudhon, H; Michel, C; Daurès, J P; Michel, F B; Godard, P

    1996-01-01

    "Asthmaexpert" was produced at the special request of several clinicians in order to obtain a better understanding of the medical decisions taken by clinical experts in the management of asthmatic patients. In order to assess the severity of asthma, a new score called Artificial Intelligence score (AI score), produced by Asthmaexpert, was compared with three other scores (Aas, Hargreave and Brooks). One hundred patients were enrolled prospectively in the study during their first consultation in the out-patient clinic. Distribution of severity level according to the different scores was studied, and the reliability between AI and other scores was evaluated by Kappa and MacNemar tests. Correlations with functional parameters were performed. The AI score assessed higher levels of severity than the other scores (Kappa = 18, 28 and 10% for Aas, Hargreave and Brooks, respectively) with significant MacNemar test in all cases. There was a significant correlation between AI score and forced expiratory volume in one second (FEV1) (r = 0.73). These data indicate that the AI score is a severity score which defines higher levels of severity than the chosen scores. Correlations for functional parameters are good. This score appears easy to use for the first consultation of an asthmatic patient.

  8. A Multi-Center Prospective Derivation and Validation of a Clinical Prediction Tool for Severe Clostridium difficile Infection.

    LENUS (Irish Health Repository)

    Na, Xi

    2015-04-23

    Prediction of severe clinical outcomes in Clostridium difficile infection (CDI) is important to inform management decisions for optimum patient care. Currently, treatment recommendations for CDI vary based on disease severity but validated methods to predict severe disease are lacking. The aim of the study was to derive and validate a clinical prediction tool for severe outcomes in CDI.

  9. Severe visceral leishmaniasis in children: the relationship between cytokine patterns and clinical features

    Directory of Open Access Journals (Sweden)

    Monica Elinor Alves Gama

    2013-12-01

    Full Text Available Introduction The relationship between severe clinical manifestations of visceral leishmaniasis (VL and immune response profiles has not yet been clarified, despite numerous studies on the subject. This study aimed to investigate the relationship between cytokine profiles and the presence of immunological markers associated with clinical manifestations and, particularly, signs of severity, as defined in a protocol drafted by the Ministry of Health (Brazil. Methods We conducted a prospective, descriptive study between May 2008 and December 2009. This study was based on an assessment of all pediatric patients with VL who were observed in a reference hospital in Maranhão. Results Among 27 children, 55.5% presented with more than one sign of severity or warning sign. Patients without signs of severity or warning signs and patients with only one warning sign had the highest interferon-gamma (IFN-γ levels, although their interleukin 10 (IL-10 levels were also elevated. In contrast, patients with the features of severe disease had the lowest IFN-γ levels. Three patients who presented with more than two signs of severe disease died; these patients had undetectable interleukin 2 (IL-2 and IFN-γ levels and low IL-10 levels, which varied between 0 and 36.8pg/mL. Conclusions Our results showed that disease severity was associated with low IFN-γ levels and elevated IL-10 levels. However, further studies with larger samples are needed to better characterize the relationship between disease severity and cytokine levels, with the aim of identifying immunological markers of active-disease severity.

  10. [Value of nutritional risk screening in evaluating adverse clinical outcomes in children with severe pneumonia].

    Science.gov (United States)

    Guo, Xiao-Hui; Sun, Yan-Feng; Wang, Jiang-Bo; Han, Shu-Zhen; Miao, Jing; Cui, Min

    2017-03-01

    To investigate the nutritional risk in children with severe pneumonia using the Screening Tool for the Assessment of Malnutrition in Paediatrics (STAMP) and the association between nutritional risk and adverse clinical outcomes. According to the STAMP score, 216 children with severe pneumonia were classified into high nutritional risk group (HR group; n=98), moderate nutritional risk group (MR group; n=65), and low nutritional risk group (LR group; n=53). Fasting blood samples were collected to measure the levels of insulin-like growth factor-1 (IGF-1), adiponectin, leptin, non-esterified fatty acid (NEFA), albumin, transferrin, prealbumin, and retinol binding protein (RBP). The adverse clinical outcomes were recorded. Compared with the MR and LR groups, the HR group had significantly lower serum levels of IGF-1, leptin, adiponectin, prealbumin, and RBP, as well as a significantly higher serum level of NEFA (Prisk screening has an important value in evaluating the clinical outcome of children with severe pneumonia, and children at a higher nutritional risk tend to have more adverse clinical outcomes.

  11. Intrapulmonary arteriovenous anastomoses in dogs with severe Angiostrongylus vasorum infection: clinical, radiographic, and echocardiographic evaluation.

    Science.gov (United States)

    Novo Matos, J; Malbon, A; Dennler, M; Glaus, T

    2016-06-01

    In both humans and dogs the pulmonary vasculature is able to recruit large-diameter anatomical intrapulmonary arteriovenous anastomoses (IPAVAs). In healthy people the opening of these anastomoses affects the degree of exercise-induced increase in pulmonary arterial pressure. The presence of these IPAVAs can be demonstrated using saline contrast echocardiography. The aims of the present study were to characterize severely affected, naturally infected dogs with Angiostrongylus vasorum, to evaluate if these dogs can open IPAVAs, and to assess if the recruitment of such anastomoses affects the severity of pulmonary hypertension (PH). Eight client-owned dogs with severe A. vasorum infection were recruited. Dogs with A. vasorum infection that presented with severe dyspnea and/or syncope were prospectively screened by echocardiography for the presence of PH and IPAVAs. Only severely affected dogs, based on a combination of clinical, radiographic and echocardiographic abnormalities, were enrolled. Opening of IPAVAs could be demonstrated in three dogs with no to moderate PH, and could not be demonstrated in five dogs with severe PH. In two dogs thoracic radiographs showed only mild interstitial changes, while computer tomography and postmortem examination revealed severe pulmonary interstitial and vascular disease. These results suggest that dogs may open IPAVAs and that opening of such anastomoses may play a regulatory role in the development of PH. There may be a marked discrepancy between radiographic changes and disease severity in A. vasorum. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Eating disorder severity and functional impairment: moderating effects of illness duration in a clinical sample.

    Science.gov (United States)

    Davidsen, Annika Helgadóttir; Hoyt, William T; Poulsen, Stig; Waaddegaard, Mette; Lau, Marianne

    2017-09-01

    The aim was to examine duration of illness and body mass index as possible moderators of the relationship between eating disorder severity and functional impairment, as well as psychological distress as a possible mediator of this relationship. The study included 159 patients diagnosed with bulimia nervosa, binge eating disorder or eating disorder not otherwise specified. Regression analysis was applied to assess the effect of the hypothesized moderators and mediators. Eating disorder severity was measured with the Eating Disorder Examination Questionnaire, functional impairment was measured with the Sheehan Disability Scale, and psychological distress was measured with the Symptom Check List-90-R. Duration of illness and body mass index were assessed clinically. Duration of illness significantly moderated the relationship between eating disorder severity and functional impairment; the relationship was strongest for patients with a shorter duration of illness. Psychological distress partly mediated the relationship between eating disorder severity and functional impairment. Duration of illness significantly moderated the relationship between psychological distress and functional impairment; the strongest relationship was seen for patients with a shorter duration of illness. Body mass index was not a significant moderator of the relationship between ED severity and functional impairment. Overall, this study established a link between ED severity, psychological distress and functional impairment indicating that both eating disorder severity and psychological distress are more strongly related to impaired role functioning for patients with more recent onset of an eating disorder. More research in the complex relationship between ED severity and functional impairment is needed.

  13. Studying Different Clinical Syndromes Of Paediatric Severe Malaria Using Plasma Proteomics

    KAUST Repository

    Ramaprasad, Abhinay

    2012-08-01

    Background- Severe Plasmodium falciparum malaria remains one of the major causes of childhood morbidity and mortality in Africa. Severe malaria manifests itself as three main clinical syndromes-impaired consciousness (cerebral malaria), respiratory distress and severe malarial anaemia. Cerebral malaria and respiratory distress are major contributors to malaria mortality but their pathophysiology remains unclear. Motivation/Objectives- Most children with severe malaria die within the first 24 hours of admission to a hospital because of their pathophysiological conditions. Thus, along with anti-malarial drugs, various adjuvant therapies such as fluid bolus (for hypovolaemia) and anticonvulsants (for seizures) are given to alleviate the sick child’s condition. But these therapies can sometimes have adverse effects. Hence, a clear understanding of severe malaria pathophysiology is essential for making an informed decision regarding adjuvant therapies. Methodology- We used mass spectrometry-based shotgun proteomics to study plasma samples from Gambian children with severe malaria. We compared the proteomic profiles of different severe malaria syndromes and generated hypotheses regarding the underlying disease mechanisms. Results/Conclusions- The main challenges of studying the severe malaria syndromes using proteomics were the high complexity and variability among the samples. We hypothesized that hepatic injury and nitric oxide play roles in the pathophysiology of cerebral malaria and respiratory distress.

  14. Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype

    Directory of Open Access Journals (Sweden)

    Johnathan Cooper-Knock

    2017-11-01

    consistent with an oligogenic model of ALS. We provide evidence for a number of entirely novel genetic variants of ALS caused by mutations in RNA-binding proteins. Moreover we show that these mutations act synergistically with each other and with C9ORF72 expansions to modify the clinical phenotype of ALS. A key finding is that this synergy is present only between functionally interacting variants. This work has significant implications for ALS therapy development.

  15. Patient profiles and clinical utility of mepolizumab in severe eosinophilic asthma

    Directory of Open Access Journals (Sweden)

    Haldar P

    2017-06-01

    Full Text Available Pranabashis Haldar Respiratory Biomedical Research Unit, Glenfield Hospital, University of Leicester, Leicester, UK Abstract: Mepolizumab (Nucala® is an effective and specific anti-eosinophil molecular therapy that has recently been approved as add-on therapy for the management of severe eosinophilic asthma by the US Food and Drug Administration (FDA, European Medicines Agency (EMA; European Union and more recently National Institute for Health and Care Excellence (NICE; UK. It is one of several molecular therapies in development for this indication and is illustrative of the strategic trajectory for pharmaceutical drug development taken over the past decade in several disease areas. Molecular therapies offer the prospect of improved specificity and effectiveness of biological effect. However, this necessitates a clear understanding of the underlying mechanistic pathways underpinning pathological processes, to inform drug development that yields novel more efficacious treatment options with a better clinical profile than existing agents. For the first time, utilization of molecular therapies in clinical trials is providing a novel in vivo model to characterize the association between specific pathways and clinical disease expression. It is increasingly recognized that asthma exhibits both clinical and pathological heterogeneity. It follows that a one-size-fits-all approach will not be appropriate and cost-effectiveness may only be achieved by identifying responder subgroups. This so-called personalized approach to therapy is being supported by the parallel development of companion biomarkers for clinical application. In this review, the author summarizes the clinical studies, their interpretation and the lessons learnt with mepolizumab that have informed our understanding of the approach to personalized molecular therapy in asthma. Keywords: IL-5, Nucala, exacerbations 

  16. Evaluation of the DSM-5 severity ratings for anorexia nervosa in a clinical sample.

    Science.gov (United States)

    Dakanalis, Antonios; Alix Timko, C; Colmegna, Fabrizia; Riva, Giuseppe; Clerici, Massimo

    2018-04-01

    We examined the validity and utility of the DSM-5 severity ratings for anorexia nervosa (AN) in a clinical (treatment-seeking) sample (N = 273; 95.6% women). Participants classified with mild, moderate, severe, and extreme severity of AN based on their measured body mass index, differed significantly from each other in eating disorder features, putative maintenance factors, and illness-specific functional impairment (medium effect sizes). However, they were statistically indistinguishable in psychiatric-disorder comorbidity and distress, demographics, and age-of-AN onset. The implications of our findings, providing limited support for the DSM-5 severity ratings for AN, and directions for future research are outlined. Copyright © 2018 Elsevier B.V. All rights reserved.

  17. Clinical Trial of Imipenem/Cilastatin in Severely Burned and Infected Patients

    Science.gov (United States)

    1987-07-01

    34"OT FILE CO.Y CLINICAL TRIAL OF IMIPENEM /CILASTATIN IN SEVERELY BURNED AND INFECTED PATIENTS Gary R. Culbertson, M.D., Albert T. McManus, PH.D., D T...NOV 1 3 1987 San Antonio, Texas b H Imipenem /cilastatin was examined for safety and effi- ,-;Opportunistic organisms causing infections in cacy in a...All of the clinical failures were in the pulmonary in ec- imipenem /cilastatin, a novel thienamycin alti- tion group. No serious toxicity or side

  18. Clinical relevance and discriminatory value of elevated liver aminotransferase levels for dengue severity.

    Science.gov (United States)

    Lee, Linda K; Gan, Victor C; Lee, Vernon J; Tan, Adriana S; Leo, Yee Sin; Lye, David C

    2012-01-01

    Elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) is prominent in acute dengue illness. The World Health Organization (WHO) 2009 dengue guidelines defined AST or ALT ≥ 1000 units/liter (U/L) as a criterion for severe dengue. We aimed to assess the clinical relevance and discriminatory value of AST or ALT for dengue hemorrhagic fever (DHF) and severe dengue. We retrospectively studied and classified polymerase chain reaction positive dengue patients from 2006 to 2008 treated at Tan Tock Seng Hospital, Singapore according to WHO 1997 and 2009 criteria for dengue severity. Of 690 dengue patients, 31% had DHF and 24% severe dengue. Elevated AST and ALT occurred in 86% and 46%, respectively. Seven had AST or ALT ≥ 1000 U/L. None had acute liver failure but one patient died. Median AST and ALT values were significantly higher with increasing dengue severity by both WHO 1997 and 2009 criteria. However, they were poorly discriminatory between non-severe and severe dengue (e.g., AST area under the receiver operating characteristic [ROC] curve=0.62; 95% confidence interval [CI]: 0.57-0.67) and between dengue fever (DF) and DHF (AST area under the ROC curve=0.56; 95% CI: 0.52-0.61). There was significant overlap in AST and ALT values among patients with dengue with or without warning signs and severe dengue, and between those with DF and DHF. Although aminotransferase levels increased in conjunction with dengue severity, AST or ALT values did not discriminate between DF and DHF or non-severe and severe dengue.

  19. Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel.

    Science.gov (United States)

    Santos, Raul D; Gidding, Samuel S; Hegele, Robert A; Cuchel, Marina A; Barter, Philip J; Watts, Gerald F; Baum, Seth J; Catapano, Alberico L; Chapman, M John; Defesche, Joep C; Folco, Emanuela; Freiberger, Tomas; Genest, Jacques; Hovingh, G Kees; Harada-Shiba, Mariko; Humphries, Steve E; Jackson, Ann S; Mata, Pedro; Moriarty, Patrick M; Raal, Frederick J; Al-Rasadi, Khalid; Ray, Kausik K; Reiner, Zelijko; Sijbrands, Eric J G; Yamashita, Shizuya

    2016-10-01

    Familial hypercholesterolaemia is common in individuals who had a myocardial infarction at a young age. As many as one in 200 people could have heterozygous familial hypercholesterolaemia, and up to one in 300 000 individuals could be homozygous. The phenotypes of heterozygous and homozygous familial hypercholesterolaemia overlap considerably; the response to treatment is also heterogeneous. In this Review, we aim to define a phenotype for severe familial hypercholesterolaemia and identify people at highest risk for cardiovascular disease, based on the concentration of LDL cholesterol in blood and individuals' responsiveness to conventional lipid-lowering treatment. We assess the importance of molecular characterisation and define the role of other cardiovascular risk factors and advanced subclinical coronary atherosclerosis in risk stratification. Individuals with severe familial hypercholesterolaemia might benefit in particular from early and more aggressive cholesterol-lowering treatment (eg, with PCSK9 inhibitors). In addition to better tailored therapy, more precise characterisation of individuals with severe familial hypercholesterolaemia could improve resource use. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Characteristics associated with clinical severity and inflammatory phenotype of naturally occurring virus-induced exacerbations of asthma in adults

    DEFF Research Database (Denmark)

    Bjerregaard, Asger; Laing, Ingrid A; Poulsen, Nadia

    2017-01-01

    BACKGROUND: In experimental studies viral infections have been shown to induce type 2 inflammation in asthmatics, but whether this is a feature of naturally occurring virus-induced asthma exacerbations is unknown. Thymic stromal lymphopoietin (TSLP) released from the airway epithelium in response...... occurring virus-induced exacerbations of asthma and whether TSLP is associated with this type 2 inflammation. METHODS: Patients presenting to hospital with acute asthma were examined during the exacerbation, and after 4 weeks recovery. The assessments included spirometry, FeNO and induced sputum...... in patients during virus-induced asthma exacerbations, to the same degree as non-viral exacerbations, and correlate negatively with FEV1. However, in virus-positive patients, high TSLP expression during exacerbation was associated with low sputum eosinophils, suggesting that the effect of TSLP in vivo...

  1. Diagnosing and management of iatrogenic moderate and severe ovarian hyperstymulation syndrome (OHSS in clinical material.

    Directory of Open Access Journals (Sweden)

    Anna Fritz

    2008-04-01

    Full Text Available Severe ovarian hyperstymulation syndrome is a rare but potentially life-threatening complication in patients undergoing assisted reproductive techniques (ART. The pathogenesis of this condition is likely to be multifactorial. The aim of the retrospective study was to present management in moderate and severe iatrogenic ovarian hyperstymulation syndrome (OHSS in clinical material. The study group was 19 women, admitted to the Department of Obstetrics and Gynecology in Central Clinical Hospital of Ministry of Interior and Administration in Warsaw from large outpatient infertility center "Novum" in Warsaw with moderate and severe OHSS between 14.07.2004 and 8.11.2005. Laboratory tests and ultrasound examination of the ovarian size and ascites were performed, abdominal circumference was measured. Patients were treated with rehydration with intravenous crystalloids and colloids, diuretics, antibiotics, anticoagulants and ultrasound-guided paracentesis if symptoms of ascites become severe (ascites causes pain and compromised pulmonary function. Oral intake of water was restricted, monitoring of fluid intake and output, and daily monitoring of body weight was performed. During treatment controlled laboratory tests were done. In one patient occurred intra-abdominal hemorrhage from ovarian rupture and laparotomy with oophorectomy was performed. The ovarian hyperstimulation syndrome is still a difficult diagnostic and therapeutic problem and more studies are required to elucidate pathophysiology of OHSS. Because of still unknown etiology treatment is empirical and in most of cases bases on experience of medical team. Thus, the management in individual patients varies according to the severity of ovarian hyperstymulation syndrome and its complications.

  2. Severe myoclonic epilepsy of infancy (Dravet syndrome: Clinical and genetic features of nine Turkish patients

    Directory of Open Access Journals (Sweden)

    Meral Özmen

    2011-01-01

    Full Text Available Purpose: Mutations of the a-1 subunit sodium channel gene (SCN1A cause severe myoclonic epilepsy of infancy (SMEI. To date, over 300 mutations related to SMEI have been described. In the present study, we report new SCN1A mutations and the clinical features of SMEI cases. Materials and Methods: We studied the clinical and genetic features of nine patients diagnosed with SMEI at the Pediatric Neurology Department of Istanbul Medical Faculty. Results: Five patients had nonsense mutations, two had missense mutations, one had a splice site mutation and one had a deletion mutation of the SCN1A gene. Mutations at c.3705+5G splice site, p.trip153X nonsense mutation and deletion at c.2416_2946 have not been previously described. The seizures started following whole cell pertussis vaccination in all patients. The seizures ceased in one patient and continued in the other eight patients. Developmental regression was severe in three patients, with frequent status epilepticus. The type of mutation was not predictive for the severity of the disease. Two of the three patients with severe regression had nonsense and missense mutations. Conclusions : Dravet syndrome can be result of several different types of mutation in SCN1A gene. Onset of the seizures after pertussis vaccination is an important clue for the diagnosis and neuro- developmental delay should be expected in all patients.

  3. Distinct Niemann-Pick Disease Type C Clinical, Cytological, and Biochemical Phenotype in an Adult Patient With 1 Mutated, Overexpressed Allele

    Directory of Open Access Journals (Sweden)

    Julia Jecel MD

    2015-11-01

    Full Text Available Niemann-Pick disease type C (NP-C is a rare autosomal-recessive neurovisceral lysosomal storage disease. We report on a juvenile onset, now 25-year-old female patient with typical neurologic symptoms, including vertical gaze palsy, of NP-C. The diagnosis was supported by a positive filipin test (“variant biochemical phenotype” of cholesterol accumulation in cultured fibroblasts, high numbers of “Niemann-Pick cells” in the bone marrow, and 1 positive out of 3 NP-C biomarkers tested, but NP-C was not definitely confirmed genetically. She showed only 1 known NPC1 variant (3 bp deletion in exon 18; p.N916del; this allele, however, being distinctly overexpressed at the messenger RNA level as compared to the wild-type allele, as a not as yet clarified (copathogenic? phenomenon. The patient’s mother, also carrying the p.N916del allele but without overexpression, has a chronic inflammatory disease of the central nervous system classified as multiple sclerosis. However, her severe clinical phenotype includes some signs also consistent with NP-C. The laboratory diagnosis of NP-C can be challenging in detecting novel disease constellations.

  4. Natural History and Genotype–Phenotype Correlation in Female X-Linked Alport Syndrome

    Directory of Open Access Journals (Sweden)

    Tomohiko Yamamura

    2017-09-01

    Discussion: This study revealed that phenotypes in female XLAS patients may be severe, but genotype does not help to predict the disease severity. Clinicians must therefore pay careful attention to the clinical course and appropriate treatment in females with XLAS.

  5. Using thermographic cameras to investigate eye temperature and clinical severity in depression

    Science.gov (United States)

    Maller, Jerome J.; George, Shefin Sam; Viswanathan, Rekha Puzhavakkathumadom; Fitzgerald, Paul B.; Junor, Paul

    2016-02-01

    Previous studies suggest that altered corneal temperature may be a feature of schizophrenia, but the association between major depressive disorder (MDD) and corneal temperature has yet to be assessed. The aim of this study is to investigate whether eye temperature is different among MDD patients than among healthy individuals. We used a thermographic camera to measure and compare the temperature profile across the corneas of 16 patients with MDD and 16 age- and sex-matched healthy subjects. We found that the average corneal temperature between the two groups did not differ statistically, although clinical severity correlated positively with right corneal temperature. Corneal temperature may be an indicator of clinical severity in psychiatric disorders, including depression.

  6. A Clinical Prediction Algorithm to Stratify Pediatric Musculoskeletal Infection by Severity

    Science.gov (United States)

    Benvenuti, Michael A; An, Thomas J; Mignemi, Megan E; Martus, Jeffrey E; Mencio, Gregory A; Lovejoy, Stephen A; Thomsen, Isaac P; Schoenecker, Jonathan G; Williams, Derek J

    2016-01-01

    Objective There are currently no algorithms for early stratification of pediatric musculoskeletal infection (MSKI) severity that are applicable to all types of tissue involvement. In this study, the authors sought to develop a clinical prediction algorithm that accurately stratifies infection severity based on clinical and laboratory data at presentation to the emergency department. Methods An IRB-approved retrospective review was conducted to identify patients aged 0–18 who presented to the pediatric emergency department at a tertiary care children’s hospital with concern for acute MSKI over a five-year period (2008–2013). Qualifying records were reviewed to obtain clinical and laboratory data and to classify in-hospital outcomes using a three-tiered severity stratification system. Ordinal regression was used to estimate risk for each outcome. Candidate predictors included age, temperature, respiratory rate, heart rate, C-reactive protein, and peripheral white blood cell count. We fit fully specified (all predictors) and reduced models (retaining predictors with a p-value ≤ 0.2). Discriminatory power of the models was assessed using the concordance (c)-index. Results Of the 273 identified children, 191 (70%) met inclusion criteria. Median age was 5.8 years. Outcomes included 47 (25%) children with inflammation only, 41 (21%) with local infection, and 103 (54%) with disseminated infection. Both the full and reduced models accurately demonstrated excellent performance (full model c-index 0.83, 95% CI [0.79–0.88]; reduced model 0.83, 95% CI [0.78–0.87]). Model fit was also similar, indicating preference for the reduced model. Variables in this model included C-reactive protein, pulse, temperature, and an interaction term for pulse and temperature. The odds of a more severe outcome increased by 30% for every 10-unit increase in C-reactive protein. Conclusions Clinical and laboratory data obtained in the emergency department may be used to accurately

  7. Severe Maternal or Near Miss Morbidity: Implications for Public Health Surveillance and Clinical Audit.

    Science.gov (United States)

    Kuklina, Elena V; Goodman, David A

    2018-06-01

    This chapter reviews the historical development of indicators to identify severe maternal morbidity/maternal near miss (SMM/MNM), and their use for public health surveillance, research, and clinical audit. While there has been progress toward identifying standard definitions for SMM/MNM within countries, there remain inconsistencies in the definition of SMM/MNM indicators and their application between countries. Using these indicators to screen for events that then trigger a clinical audit may both under identify select SMM/MNM (false negative)and over identify select SMM/MNM (false positive). Thus, indicators which support the efficient identification of SMM/MNM for the purpose of facility-based clinical audits are still needed.

  8. Rectal dihydroartemisinin versus intravenous quinine in the treatment of severe malaria: a randomised clinical trial.

    Science.gov (United States)

    Esamai, F; Ayuo, P; Owino-Ongor, W; Rotich, J; Ngindu, A; Obala, A; Ogaro, F; Quoqiao, L; Xingbo, G; Guangqian, L

    2000-05-01

    To compare the clinical efficacy and safety of rectal dihydroartemisinin (DATM--Cotecxin) and intravenous quinine in the treatment of severe malaria in children and adults. Moi Teaching and Referral Hospital, Eldoret, Kenya between July and November 1998. A total of sixty seven patients aged two to sixty years with severe malaria were studied. This was an open randomised comparative clinical trial. These were parasite clearance time, fever clearance time, efficacy and the side effect profile of the two drugs. The two groups were comparable on admission on the clinical and laboratory parameters. The parasite clearance time was shorter in the rectal DATM group than quinine group. There was no statistical difference on the fever clearance time and cure rates in the two groups. The adverse reaction profile was better with rectal DATM than with quinine, tinnitus observed more in the quinine group. Rectal DATM is faster in parasite clearance than quinine and is a safe and convenient alternative to quinine in the treatment of severe malaria.

  9. Sleep Disruption in Hematopoietic Cell Transplant Recipients: Prevalence, Severity, and Clinical Management

    Science.gov (United States)

    Jim, Heather S.L.; Evans, Bryan; Jeong, Jiyeon M.; Gonzalez, Brian D.; Johnston, Laura; Nelson, Ashley M.; Kesler, Shelli; Phillips, Kristin M.; Barata, Anna; Pidala, Joseph; Palesh, Oxana

    2014-01-01

    Sleep disruption is common among hematopoietic cell transplant (HCT) recipients, with over 50% of patients experiencing sleep disruption pre-transplant, up to 82% experiencing moderate to severe sleep disruption during hospitalization for transplant, and up to 43% in the post-transplant period. These rates of sleep disruption are substantially higher than the general population. Although sleep disruption can be distressing to patients and contribute to diminished quality of life, it is rarely discussed during clinical visits. The goal of the current review is to draw attention to sleep disruption as a clinical problem in HCT in order to facilitate patient education, intervention, and research. The review opens with a discussion of sleep disruption measurement and clinical diagnosis of sleep disorders. An overview of the prevalence, severity, and chronicity of sleep disruption and disorders in patients receiving HCT follows. Current evidence regarding sociodemographic and clinical predictors of sleep disruption and disorders is summarized. The review concludes with suggestions for behavioral and pharmacologic management of sleep disruption and disorders as well as directions for future research. PMID:24747335

  10. Acne severity grading: determining essential clinical components and features using a Delphi consensus.

    Science.gov (United States)

    Tan, Jerry; Wolfe, Barat; Weiss, Jonathan; Stein-Gold, Linda; Bikowski, Joseph; Del Rosso, James; Webster, Guy F; Lucky, Anne; Thiboutot, Diane; Wilkin, Jonathan; Leyden, James; Chren, Mary-Margaret

    2012-08-01

    There are multiple global scales for acne severity grading but no singular standard. Our objective was to determine the essential clinical components (content items) and features (property-related items) for an acne global grading scale for use in research and clinical practice using an iterative method, the Delphi process. Ten acne experts were invited to participate in a Web-based Delphi survey comprising 3 iterative rounds of questions. In round 1, the experts identified the following clinical components (primary acne lesions, number of lesions, extent, regional involvement, secondary lesions, and patient experiences) and features (clinimetric properties, ease of use, categorization of severity based on photographs or text, and acceptance by all stakeholders). In round 2, consensus for inclusion in the scale was established for primary lesions, number, sites, and extent; as well as clinimetric properties and ease of use. In round 3, consensus for inclusion was further established for categorization and acceptance. Patient experiences were excluded and no consensus was achieved for secondary lesions. The Delphi panel consisted solely of the United States (U.S.)-based acne experts. Using an established method for achieving consensus, experts in acne vulgaris concluded that an ideal acne global grading scale would comprise the essential clinical components of primary acne lesions, their quantity, extent, and facial and extrafacial sites of involvement; with features of clinimetric properties, categorization, efficiency, and acceptance. Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  11. Cluster headache - clinical pattern and a new severity scale in a Swedish cohort.

    Science.gov (United States)

    Steinberg, Anna; Fourier, Carmen; Ran, Caroline; Waldenlind, Elisabet; Sjöstrand, Christina; Belin, Andrea Carmine

    2018-06-01

    Background The aim of this study was to investigate clinical features of a cluster headache cohort in Sweden and to construct and test a new scale for grading severity. Methods Subjects were identified by screening medical records for the ICD 10 code G44.0, that is, cluster headache. Five hundred participating research subjects filled in a questionnaire including personal, demographic and medical aspects. We constructed a novel scale for grading cluster headache in this cohort: The Cluster Headache Severity Scale, which included number of attacks per day, attack and period duration. The lowest total score was three and the highest 12, and we used the Cluster Headache Severity Scale to grade subjects suffering from cluster headache. We further implemented the scale by defining a cluster headache maximum severity subgroup with a high Cluster Headache Severity Scale score ≥ 9. Results A majority (66.7%) of the patients reported that attacks appear at certain time intervals. In addition, cluster headache patients who were current tobacco users or had a history of tobacco consumption had a later age of disease onset (31.7 years) compared to non-tobacco users (28.5 years). The Cluster Headache Severity Scale score was higher in the patient group reporting sporadic or no alcohol intake than in the groups reporting an alcohol consumption of three to four standard units per week or more. Maximum severity cluster headache patients were characterised by higher age at disease onset, greater use of prophylactic medication, reduced hours of sleep, and lower alcohol consumption compared to the non-cluster headache maximum severity group. Conclusion There was a wide variation of severity grade among cluster headache patients, with a very marked impact on daily living for the most profoundly affected.

  12. Quality of life in acne vulgaris: Relationship to clinical severity and demographic data.

    Science.gov (United States)

    Gupta, Aayush; Sharma, Yugal Kishor; Dash, Kedar Nath; Chaudhari, Nitin Dinkar; Jethani, Sumit

    2016-01-01

    Acne vulgaris is known to impair many aspects of quality of life. However, the correlation of this impairment with clinical severity remains equivocal despite various school, community and hospital-based studies. A hospital-based study was undertaken to measure the impairment of quality of life of patients of acne vulgaris and correlate it with the severity of lesions. This was a cross-sectional, questionnaire-based study in a cohort of 100 patients of acne vulgaris attending the outpatient department of our referral hospital. A physician measured the severity of lesions using the global acne grading system, and patients assessed quality of life by completing a questionnaire (Cardiff acne disability index). A correlation of these two was done; some additional correlations were brought out through demographic data collected from the patients. There was no correlation between the severity of acne vulgaris and an impaired quality of life. Patients who consumed alcohol and/or smoked cigarettes were found to have an impaired quality of life. While the severity of acne progressively lessened in older patients, the impact on quality of life increased. The sample size was small and there was a lack of guaranteed reliability on the self-reported quality of life. The severity of acne vulgaris does not correlate with impairment in quality of life.

  13. Clinical and socioeconomic impact of moderate-to-severe versus mild influenza in children.

    Science.gov (United States)

    Heikkinen, T; Silvennoinen, H; Heinonen, S; Vuorinen, T

    2016-07-01

    Some studies have assessed the efficacy of influenza vaccination in children separately for moderate-to-severe and any influenza, but the definition used for identifying children with moderate-to-severe illness has not been validated. We analyzed clinical and socioeconomic data from two prospective cohort studies of respiratory infections among children aged ≤13 years (four influenza seasons, 3,416 child-seasons of follow-up). We categorized children with laboratory-confirmed influenza into two mutually exclusive groups of moderate-to-severe and mild influenza using the previously proposed criteria. We obtained the data for the analyses from structured medical records filled out by the study physicians and from daily symptom cards filled out by the parents. Of 434 cases of influenza, 217 (50 %) were classified as moderate-to-severe and 217 (50 %) as mild. The mean duration of fever was 4.0 days in children with moderate-to-severe influenza and 3.1 days in those with milder illness (P socioeconomic impact of influenza is highest. Illness severity should be considered when assessing influenza vaccine effectiveness in children.

  14. Frequency of the HFE C282Y and H63D mutations in Danish patients with clinical haemochromatosis initially diagnosed by phenotypic methods

    DEFF Research Database (Denmark)

    Milman, Nils; Koefoed, Pernille; Pedersen, Palle

    2003-01-01

    AIM: To assess the frequency of the C282Y and H63D mutations on the HFE gene in Danish patients with clinical hereditary haemochromatosis initially diagnosed by phenotypic methods. METHODS: In the period 1950-1985, an epidemiological survey in Denmark identified 179 patients with clinical...... diagnosis of clinical idiopathic haemochromatosis was made before blood samples were taken for HFE genotyping. The total series consisted of 58 patients (40 men and 18 women) with a median age of 60 yrs (range 18-74). HFE genotyping was performed by the polymerase chain reaction (PCR) technique. RESULTS...

  15. Genotypic and phenotypic diversity of Ralstonia pickettii and Ralstonia insidiosa isolates from clinical and environmental sources including High-purity Water.

    LENUS (Irish Health Repository)

    Ryan, Michael P

    2011-08-30

    Abstract Background Ralstonia pickettii is a nosocomial infectious agent and a significant industrial contaminant. It has been found in many different environments including clinical situations, soil and industrial High Purity Water. This study compares the phenotypic and genotypic diversity of a selection of strains of Ralstonia collected from a variety of sources. Results Ralstonia isolates (fifty-nine) from clinical, industrial and environmental origins were compared genotypically using i) Species-specific-PCR, ii) PCR and sequencing of the 16S-23S rRNA Interspatial region (ISR) iii) the fliC gene genes, iv) RAPD and BOX-PCR and v) phenotypically using biochemical testing. The species specific-PCR identified fifteen out of fifty-nine designated R. pickettii isolates as actually being the closely related species R. insidiosa. PCR-ribotyping of the 16S-23S rRNA ISR indicated few major differences between the isolates. Analysis of all isolates demonstrated different banding patterns for both the RAPD and BOX primers however these were found not to vary significantly. Conclusions R. pickettii species isolated from wide geographic and environmental sources appear to be reasonably homogenous based on genotypic and phenotypic characteristics. R. insidiosa can at present only be distinguished from R. pickettii using species specific PCR. R. pickettii and R. insidiosa isolates do not differ significantly phenotypically or genotypically based on environmental or geographical origin.

  16. Comparison of the accuracy of two conventional phenotypic methods and two MALDI-TOF MS systems with that of DNA sequencing analysis for correctly identifying clinically encountered yeasts.

    Science.gov (United States)

    Chao, Qiao-Ting; Lee, Tai-Fen; Teng, Shih-Hua; Peng, Li-Yun; Chen, Ping-Hung; Teng, Lee-Jene; Hsueh, Po-Ren

    2014-01-01

    We assessed the accuracy of species-level identification of two commercially available matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) systems (Bruker Biotyper and Vitek MS) and two conventional phenotypic methods (Phoenix 100 YBC and Vitek 2 Yeast ID) with that of rDNA gene sequencing analysis among 200 clinical isolates of commonly encountered yeasts. The correct identification rates of the 200 yeast isolates to species or complex (Candida parapsilosis complex, C. guilliermondii complex and C. rugosa complex) levels by the Bruker Biotyper, Vitek MS (using in vitro devices [IVD] database), Phoenix 100 YBC and Vitek 2 Yeast ID (Sabouraud's dextrose agar) systems were 92.5%, 79.5%, 89%, and 74%, respectively. An additional 72 isolates of C. parapsilosis complex and 18 from the above 200 isolates (30 in each of C. parapsilosis, C. metapsilosis, and C. orthopsilosis) were also evaluated separately. Bruker Biotyper system could accurately identify all C. parapsilosis complex to species level. Using Vitek 2 MS (IVD) system, all C. parapsilosis but none of C. metapsilosis, or C. orthopsilosis could be accurately identified. Among the 89 yeasts misidentified by the Vitek 2 MS (IVD) system, 39 (43.8%), including 27 C. orthopsilosis isolates, could be correctly identified Using the Vitek MS Plus SARAMIS database for research use only. This resulted in an increase in the rate of correct identification of all yeast isolates (87.5%) by Vitek 2 MS. The two species in C. guilliermondii complex (C. guilliermondii and C. fermentati) isolates were correctly identified by cluster analysis of spectra generated by the Bruker Biotyper system. Based on the results obtained in the current study, MALDI-TOF MS systems present a promising alternative for the routine identification of yeast species, including clinically commonly and rarely encountered yeast species and several species belonging to C. parapsilosis complex, C. guilliermondii complex

  17. Comparison of the accuracy of two conventional phenotypic methods and two MALDI-TOF MS systems with that of DNA sequencing analysis for correctly identifying clinically encountered yeasts.

    Directory of Open Access Journals (Sweden)

    Qiao-Ting Chao

    Full Text Available We assessed the accuracy of species-level identification of two commercially available matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS systems (Bruker Biotyper and Vitek MS and two conventional phenotypic methods (Phoenix 100 YBC and Vitek 2 Yeast ID with that of rDNA gene sequencing analysis among 200 clinical isolates of commonly encountered yeasts. The correct identification rates of the 200 yeast isolates to species or complex (Candida parapsilosis complex, C. guilliermondii complex and C. rugosa complex levels by the Bruker Biotyper, Vitek MS (using in vitro devices [IVD] database, Phoenix 100 YBC and Vitek 2 Yeast ID (Sabouraud's dextrose agar systems were 92.5%, 79.5%, 89%, and 74%, respectively. An additional 72 isolates of C. parapsilosis complex and 18 from the above 200 isolates (30 in each of C. parapsilosis, C. metapsilosis, and C. orthopsilosis were also evaluated separately. Bruker Biotyper system could accurately identify all C. parapsilosis complex to species level. Using Vitek 2 MS (IVD system, all C. parapsilosis but none of C. metapsilosis, or C. orthopsilosis could be accurately identified. Among the 89 yeasts misidentified by the Vitek 2 MS (IVD system, 39 (43.8%, including 27 C. orthopsilosis isolates, could be correctly identified Using the Vitek MS Plus SARAMIS database for research use only. This resulted in an increase in the rate of correct identification of all yeast isolates (87.5% by Vitek 2 MS. The two species in C. guilliermondii complex (C. guilliermondii and C. fermentati isolates were correctly identified by cluster analysis of spectra generated by the Bruker Biotyper system. Based on the results obtained in the current study, MALDI-TOF MS systems present a promising alternative for the routine identification of yeast species, including clinically commonly and rarely encountered yeast species and several species belonging to C. parapsilosis complex, C. guilliermondii

  18. A novel splice variant in the N-propeptide of COL5A1 causes an EDS phenotype with severe kyphoscoliosis and eye involvement.

    Directory of Open Access Journals (Sweden)

    Sofie Symoens

    Full Text Available BACKGROUND: The Ehlers-Danlos Syndrome (EDS is a heritable connective tissue disorder characterized by hyperextensible skin, joint hypermobility and soft tissue fragility. The classic subtype of EDS is caused by mutations in one of the type V collagen genes (COL5A1 and COL5A2. Most mutations affect the type V collagen helical domain and lead to a diminished or structurally abnormal type V collagen protein. Remarkably, only two mutations were reported to affect the extended, highly conserved N-propeptide domain, which plays an important role in the regulation of the heterotypic collagen fibril diameter. We identified a novel COL5A1 N-propeptide mutation, resulting in an unusual but severe classic EDS phenotype and a remarkable splicing outcome. METHODOLOGY/PRINCIPAL FINDINGS: We identified a novel COL5A1 N-propeptide acceptor-splice site mutation (IVS6-2A>G, NM_000093.3_c.925-2A>G in a patient with cutaneous features of EDS, severe progressive scoliosis and eye involvement. Two mutant transcripts were identified, one with an exon 7 skip and one in which exon 7 and the upstream exon 6 are deleted. Both transcripts are expressed and secreted into the extracellular matrix, where they can participate in and perturb collagen fibrillogenesis, as illustrated by the presence of dermal collagen cauliflowers. Determination of the order of intron removal and computational analysis showed that simultaneous skipping of exons 6 and 7 is due to the combined effect of delayed splicing of intron 7, altered pre-mRNA secondary structure, low splice site strength and possibly disturbed binding of splicing factors. CONCLUSIONS/SIGNIFICANCE: We report a novel COL5A1 N-propeptide acceptor-splice site mutation in intron 6, which not only affects splicing of the adjacent exon 7, but also causes a splicing error of the upstream exon 6. Our findings add further insights into the COL5A1 splicing order and show for the first time that a single COL5A1 acceptor-splice site

  19. A novel Ile1455Thr variant in the skeletal muscle sodium channel alpha-subunit in a patient with a severe adult-onset proximal myopathy with electrical myotonia and a patient with mild paramyotonia phenotype

    NARCIS (Netherlands)

    Bednarz, M.; Stunnenberg, B.C.; Kusters, B.; Kamsteeg, E.J.; Saris, C.G.J.; Groome, J.; Winston, V.; Meola, G.; Jurkat-Rott, K.; Voermans, N.C.

    2017-01-01

    In sodium channelopathies, a severe fixed myopathy caused by a dominant mutation is rare. We describe two unrelated patients with a novel variant, p.Ile1455Thr, with phenotypes of paramyotonia in one case and fixed proximal myopathy with latent myotonia in another. In-vitro whole cell patch-clamp

  20. Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy.

    Directory of Open Access Journals (Sweden)

    Olga Gorlova

    2011-07-01

    Full Text Available The aim of this study was to determine, through a genome-wide association study (GWAS, the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc. We considered limited (lcSSc and diffuse (dcSSc cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA, and anti-topoisomerase I (ATA. Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32×10(-12, OR = 0.75. Also, rs12540874 in GRB10 gene (P = 1.27 × 10(-6, OR = 1.15 and rs11047102 in SOX5 gene (P = 1.39×10(-7, OR = 1.36 showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79×10(-61, OR = 2.48, in the HLA-DPA1/B1 loci with ATA (P = 4.57×10(-76, OR = 8.84, and in NOTCH4 with ACA P = 8.84×10(-21, OR = 0.55 and ATA (P = 1.14×10(-8, OR = 0.54. We have identified three new non-HLA genes (IRF8, GRB10, and SOX5 associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.

  1. Diagnostic Challenges in Retinitis Pigmentosa: Genotypic Multiplicity and Phenotypic Variability

    Science.gov (United States)

    Chang, Susie; Vaccarella, Leah; Olatunji, Sunday; Cebulla, Colleen; Christoforidis, John

    2011-01-01

    Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal disorders. Diagnosis can be challenging as more than 40 genes are known to cause non-syndromic RP and phenotypic expression can differ significantly resulting in variations in disease severity, age of onset, rate of progression, and clinical findings. We describe the clinical manifestations of RP, the more commonly known causative gene mutations, and the genotypic-phenotypic correlation of RP. PMID:22131872

  2. Correlation between the severity of critically ill patients and clinical predictors of bronchial aspiration

    Science.gov (United States)

    de Medeiros, Gisele Chagas; Sassi, Fernanda Chiarion; Zambom, Lucas Santos; de Andrade, Claudia Regina Furquim

    2016-01-01

    Objective: To determine whether the severity of non-neurological critically ill patients correlates with clinical predictors of bronchial aspiration. Methods: We evaluated adults undergoing prolonged orotracheal intubation (> 48 h) and bedside swallowing assessment within the first 48 h after extubation. We collected data regarding the risk of bronchial aspiration performed by a speech-language pathologist, whereas data regarding the functional level of swallowing were collected with the American Speech-Language-Hearing Association National Outcome Measurement System (ASHA NOMS) scale and those regarding health status were collected with the Sequential Organ Failure Assessment (SOFA). Results: The study sample comprised 150 patients. For statistical analyses, the patients were grouped by ASHA NOMS score: ASHA1 (levels 1 and 2), ASHA2 (levels 3 to 5); and ASHA3 (levels 6 and 7). In comparison with the other patients, those in the ASHA3 group were significantly younger, remained intubated for fewer days, and less severe overall clinical health status (SOFA score). The clinical predictors of bronchial aspiration that best characterized the groups were abnormal cervical auscultation findings and cough after swallowing. None of the patients in the ASHA 3 group presented with either of those signs. Conclusions: Critically ill patients 55 years of age or older who undergo prolonged orotracheal intubation (≥ 6 days), have a SOFA score ≥ 5, have a Glasgow Coma Scale score ≤ 14, and present with abnormal cervical auscultation findings or cough after swallowing should be prioritized for a full speech pathology assessment. PMID:27167432

  3. The Clinical Impression of Severity Index for Parkinson's Disease: international validation study.

    Science.gov (United States)

    Martínez-Martín, Pablo; Rodríguez-Blázquez, Carmen; Forjaz, Maria João; de Pedro, Jesús

    2009-01-30

    This study sought to provide further information about the psychometric properties of the Clinical Impression of Severity Index for Parkinson's Disease (CISI-PD), in a large, international, cross-culturally diverse sample. Six hundred and fourteen patients with PD participated in the study. Apart from the CISI-PD, assessments were based on Hoehn & Yahr (HY) staging, the Scales for Outcomes in PD-Motor (SCOPA-M), -Cognition (SCOPA-COG) and -Psychosocial (SCOPA-PS), the Cumulative Illness Rating Scale-Geriatrics, and the Hospital Anxiety and Depression Scale. The total CISI-PD score displayed no floor or ceiling effects. Internal consistency was 0.81, the test-retest intraclass correlation coefficient was 0.84, and item homogeneity was 0.52. Exploratory and confirmatory factor analysis (CFI = 0.99, RMSEA = 0.07) confirmed CISI-PD's unifactorial structure. The CISI-PD showed adequate convergent validity with SCOPA-COG and SCOPA-M (r(S) = 0.46-0.85, respectively) and discriminative validity for HY stages and disease duration (P validation study, thus showing that the CISI-PD is a valid instrument to measure clinical impression of severity in PD. Its simplicity and easy application make it an attractive and useful tool for clinical practice and research.

  4. Inferring gene dependency network specific to phenotypic alteration based on gene expression data and clinical information of breast cancer.

    Science.gov (United States)

    Zhou, Xionghui; Liu, Juan

    2014-01-01

    Although many methods have been proposed to reconstruct gene regulatory network, most of them, when applied in the sample-based data, can not reveal the gene regulatory relations underlying the phenotypic change (e.g. normal versus cancer). In this paper, we adopt phenotype as a variable when constructing the gene regulatory network, while former researches either neglected it or only used it to select the differentially expressed genes as the inputs to construct the gene regulatory network. To be specific, we integrate phenotype information with gene expression data to identify the gene dependency pairs by using the method of conditional mutual information. A gene dependency pair (A,B) means that the influence of gene A on the phenotype depends on gene B. All identified gene dependency pairs constitute a directed network underlying the phenotype, namely gene dependency network. By this way, we have constructed gene dependency network of breast cancer from gene expression data along with two different phenotype states (metastasis and non-metastasis). Moreover, we have found the network scale free, indicating that its hub genes with high out-degrees may play critical roles in the network. After functional investigation, these hub genes are found to be biologically significant and specially related to breast cancer, which suggests that our gene dependency network is meaningful. The validity has also been justified by literature investigation. From the network, we have selected 43 discriminative hubs as signature to build the classification model for distinguishing the distant metastasis risks of breast cancer patients, and the result outperforms those classification models with published signatures. In conclusion, we have proposed a promising way to construct the gene regulatory network by using sample-based data, which has been shown to be effective and accurate in uncovering the hidden mechanism of the biological process and identifying the gene signature for

  5. Current concepts of severe asthma

    Science.gov (United States)

    Raundhal, Mahesh; Oriss, Timothy B.; Ray, Prabir; Wenzel, Sally E.

    2016-01-01

    The term asthma encompasses a disease spectrum with mild to very severe disease phenotypes whose traditional common characteristic is reversible airflow limitation. Unlike milder disease, severe asthma is poorly controlled by the current standard of care. Ongoing studies using advanced molecular and immunological tools along with improved clinical classification show that severe asthma does not identify a specific patient phenotype, but rather includes patients with constant medical needs, whose pathobiologic and clinical characteristics vary widely. Accordingly, in recent clinical trials, therapies guided by specific patient characteristics have had better outcomes than previous therapies directed to any subject with a diagnosis of severe asthma. However, there are still significant gaps in our understanding of the full scope of this disease that hinder the development of effective treatments for all severe asthmatics. In this Review, we discuss our current state of knowledge regarding severe asthma, highlighting different molecular and immunological pathways that can be targeted for future therapeutic development. PMID:27367183

  6. Clinical significance of C-reactive protein for assessment and outcomes of severe acute pancreatitis

    Directory of Open Access Journals (Sweden)

    REN Linan

    2015-05-01

    Full Text Available ObjectiveTo study the change in serum CRP level in patients with severe acute pancreatitis (SAP, and to explore its clinical significance in predicting outcomes and assessing the severity of SAP. MethodsA retrospective analysis was performed on 52 SAP patients with complete case data and admitted to General Hospital of Shenyang Military Area Command from September 2013 to September 2014. Blood drawing was performed and serum CRP concentration was determined on admission and at 24, 48, 72, 96, 120, and 144 hours after admission. The pattern of its dynamic change was observed. ResultsSerum CRP level in SAP patients significantly increased, and had a positive correlation with clinical outcomes. Forty-two cases (80.77% gradually recovered with aggressive treatment and the serum CRP levels were also slowly reduced (P<0.05. The serum CRP levels in four death cases (7.7% had no significant decrease and was maintained at a high level (P<0.05. Six patients (11.53% had aggravated conditions and recovered after aggressive treatment; meanwhile, the serum CRP levels first increased and then decreased (P<0.05. ConclusionFor SAP patients, serum CRP level fluctuates as their conditions change and can be considered as an important reference index for evaluating the severity and judging the outcomes of SAP.

  7. Augmentative and alternative communication in adolescents with severe intellectual disability: a clinical experience.

    Science.gov (United States)

    Uliano, D; Falciglia, G; Del Viscio, C; Picelli, A; Gandolfi, M; Passarella, A

    2010-06-01

    Augmentative and alternative communication devices proved to be effective in patients with severe intellectual disability to overcome their communication impairments. In order to give a contribution for design of augmentative and alternative communication systems that better meet the needs of beginning communicators we decided to report our clinical experience about using augmentative and alternative communication in adolescents with severe intellectual disability. Five patients who underwent a long time traditional speech rehabilitation program (at least 5 years) with scant improvements in linguistic function were recruited and evaluated by means of the Vineland Adaptive Behaviour Scale before and after a three years augmentative and alternative communication intervention carried out by a multidisciplinary team. After the rehabilitative intervention patients showed an improvement in communication, daily living skills and socialization as measured by the Vineland Adaptive Behaviour Scale. Augmentative and alternative communication is an effective rehabilitation approach to people with severe intellectual disability and impairments in linguistic expression. Moreover augmentative and alternative communication is a useful tool allowing these patients to increase their social participation also enhancing their self-esteem. Our clinical experience confirmed these topics also in adolescents who underwent a long time traditional speech rehabilitation program with scant improvements, providing practical information to clinicians.

  8. Novel RSPO1 mutation causing 46,XX testicular disorder of sex development with palmoplantar keratoderma: A review of literature and expansion of clinical phenotype.

    Science.gov (United States)

    Tallapaka, Karthik; Venugopal, Vineeth; Dalal, Ashwin; Aggarwal, Shagun

    2018-04-01

    Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and sex reversal (MIM # 610644) is a clinically distinctive form of SRY-negative 46,XX disorder of sex development. It is a rare autosomal recessive disorder caused due to biallelic loss of function mutations in RSPO1 gene. RSPO1 acts by activating the canonical β-catenin pathway and is one of the most important genes controlling female gonadal differentiation. RSPO1-associated disorders of sex development have been described only in three instances in the past. We report fourth such case with additional findings and perform a comparative review of previous phenotypic descriptions, thereby expanding the clinical phenotype of this syndrome. © 2018 Wiley Periodicals, Inc.

  9. Different clinical features of anaphylaxis according to cause and risk factors for severe reactions.

    Science.gov (United States)

    Kim, Sang-Yoon; Kim, Min-Hye; Cho, Young-Joo

    2018-01-01

    Anaphylaxis is a life-threatening allergic reaction. Several studies reported different anaphylactic reactions according to the causative substances. However, a comparison of anaphylaxis for each cause has not been done. This study was conducted to identify common causes of anaphylaxis, characteristics of anaphylactic reaction for each cause and to analyze the factors related to the severity of the reaction. Medical records of patients who visited the emergency room of Ewha Womans University Mokdong Hospital from March 2003 to April 2016 and diagnosed with anaphylactic shock were retrospectively reviewed. We compared the clinical features of anaphylaxis according to the cause. In addition, the severity of anaphylaxis was analyzed and contributing factors for severe anaphylaxis were reviewed. A total of 199 patients with anaphylaxis were analyzed. Food was the most common cause (49.7%), followed by drug reaction (36.2%), bee venom (10.1%), and unknown cause (4.0%). Cardiovascular symptoms of syncope and hypotension were more common in drug-induced anaphylaxis. The incidence of severe anaphylaxis was the highest in anaphylaxis due to drugs (54.2%). Urticaria and other skin symptoms were significantly more common in food-induced anaphylaxis. Risk factors for severe anaphylaxis included older age, male, and drug-induced one. Epinephrine treatment of anaphylaxis was done for 69.7% and 56.9% of patients with food-induced and drug-induced anaphylaxis, respectively. More severe anaphylaxis developed with drug treatment and in males. Low rate of epinephrine prescription was also observed. Male patients with drug induced anaphylaxis should be paid more attention. Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

  10. Clinical and Laboratory Potential Predictors of Blood Culture Positivity in Under Five Children with Clinically Severe Pneumonia - Khartoum -Sudan.

    Science.gov (United States)

    Salih, Karimeldin Mohamed Ali; El-Samani, El-Fatih; Bilal, Jalal Ali; Eldouch, Widad; Ibrahim, Salah Ahmed

    2015-08-01

    Blood culture is necessary for appropriate management of clinically severe pneumonia in children under five years of age. However, in limited resource countries it might be unduly costly and waste of valuable time because of the high negative culture rate. This study aims to identify clinical and laboratory parameters that potentially predict a positive blood culture in cases of severe pneumonia. A hospital based study, enrolled 189 cases satisfying the WHO definition of severe pneumonia. Age, gender, clinical history, physical examination, temperature, complete blood count, C-reactive protein, blood culture and Chest X Ray for all the patients were recorded. Forty one patients had positive blood culture giving a prevalence of 21.7%. All variables were used in a dichotomous manner. White Blood Count (WBC) more than 20 000, very high C-reactive protein (C-RP ≥8mg/L) and Temperature more than 40(o)C, had a positive predictive value of 46.1%, 44.3% and 40.0% respectively for a positive culture as well as a Negative Predictive Value of 91.1%, 91.6% and 91.7% respectively. The WBC more than 20 000 and temperature above 40(o)C had a significant association with a positive blood culture. Their adjusted Odds Ratios were 3.9 (95% CI: 1.4-10.90) and 3.1 (95% CI: 1.2-8.4) respectively. This was not the case for C-RP (Odds Ratio=2.2, 95% CI: 0.7-2.2) or positive Chest X Ray (Odds Ratio=1.5, 95% CI: 0.6-3.6). Temperature of more than 40(o)C, Very high C-RP and WBC of more than 20 000 are good indicators of a potential positive blood culture. It is therefore recommended that further research be undertaken to refine these predictors as screening tools before resorting to blood culture. It is also recommended that antibiotic treatment may be initiated on the basis of the high temperature and WBC, while waiting for the culture results.

  11. Computed tomography and clinical outcome in patients with severe traumatic brain injury.

    Science.gov (United States)

    Stenberg, Maud; Koskinen, Lars-Owe D; Jonasson, Per; Levi, Richard; Stålnacke, Britt-Marie

    2017-01-01

    To study: (i) acute computed tomography (CT) characteristics and clinical outcome; (ii) clinical course and (iii) Corticosteroid Randomisation after Significant Head Injury acute calculator protocol (CRASH) model and clinical outcome in patients with severe traumatic brain injury (sTBI). Initial CT (CT i ) and CT 24 hours post-trauma (CT 24 ) were evaluated according to Marshall and Rotterdam classifications. Rancho Los Amigos Cognitive Scale-Revised (RLAS-R) and Glasgow Outcome Scale Extended (GOSE) were assessed at three months and one year post-trauma. The prognostic value of the CRASH model was evaluated. Thirty-seven patients were included. Marshall CT i and CT 24 were significantly correlated with RLAS-R at three months. Rotterdam CT 24 was significantly correlated with GOSE at three months. RLAS-R and the GOSE improved significantly from three months to one year. CRASH predicted unfavourable outcome at six months for 81% of patients with bad outcome and for 85% of patients with favourable outcome according to GOSE at one year. Neither CT nor CRASH yielded clinically useful predictions of outcome at one year post-injury. The study showed encouragingly many instances of significant recovery in this population of sTBI. The combination of lack of reliable prognostic indicators and favourable outcomes supports the case for intensive acute management and rehabilitation as the default protocol in the cases of sTBI.

  12. Molecular genetic analysis of the calcium sensing receptor gene in patients clinically suspected to have familial hypocalciuric hypercalcemia: phenotypic variation and mutation spectrum in a Danish population

    DEFF Research Database (Denmark)

    Nissen, Peter H; Christensen, Signe E; Heickendorff, Lene

    2007-01-01

    CONTEXT: The autosomal dominantly inherited condition familial hypocalciuric hypercalcemia (FHH) is characterized by elevated plasma calcium levels, relative or absolute hypocalciuria, and normal to moderately elevated plasma PTH. The condition is difficult to distinguish clinically from primary...... hyperparathyroidism and is caused by inactivating mutations in the calcium sensing receptor (CASR) gene. OBJECTIVE: We sought to define the mutation spectrum of the CASR gene in a Danish FHH population and to establish genotype-phenotype relationships regarding the different mutations. DESIGN AND PARTICIPANTS...

  13. World Endometriosis Research Foundation Endometriosis Phenome and biobanking harmonization project: II. Clinical and covariate phenotype data collection in endometriosis research

    Science.gov (United States)

    Vitonis, Allison F.; Vincent, Katy; Rahmioglu, Nilufer; Fassbender, Amelie; Buck Louis, Germaine M.; Hummelshoj, Lone; Giudice, Linda C.; Stratton, Pamela; Adamson, G. David; Becker, Christian M.; Zondervan, Krina T.; Missmer, Stacey A.

    2014-01-01

    Objective To harmonize the collection of nonsurgical clinical and epidemiologic data relevant to endometriosis research, allowing large-scale collaboration. Design An international collaboration involving 34 clinical/academic centers and three industry collaborators from 16 countries on five continents. Setting In 2013, two workshops followed by global consultation, bringing together 54 leaders in endometriosis research. Patients None. Intervention(s) Development of a self-administered endometriosis patient questionnaire (EPQ), based on [1] systematic comparison of questionnaires from eight centers that collect data from endometriosis cases (and controls/comparison women) on a medium to large scale (publication on >100 cases); [2] literature evidence; and [3] several global consultation rounds. Main Outcome Measure(s) Standard recommended and minimum required questionnaires to capture detailed clinical and covariate data. Result(s) The standard recommended (EPHect EPQ-S) and minimum required (EPHect EPQ-M) questionnaires contain questions on pelvic pain, subfertility and menstrual/reproductive history, hormone/medication use, medical history, and personal information. Conclusion(s) The EPQ captures the basic set of patient characteristics and exposures considered by the WERF EPHect Working Group to be most critical for the advancement of endometriosis research, but is also relevant to other female conditions with similar risk factors and/or symptomatology. The instruments will be reviewed based on feedback from investigators, and–after a first review after 1 year–triannually through systematic follow-up surveys. Updated versions will be made available through http://endometriosisfoundation.org/ephect. PMID:25256930

  14. Asthma phenotypes in childhood.

    Science.gov (United States)

    Reddy, Monica B; Covar, Ronina A

    2016-04-01

    This review describes the literature over the past 18 months that evaluated childhood asthma phenotypes, highlighting the key aspects of these studies, and comparing these studies to previous ones in this area. Recent studies on asthma phenotypes have identified new phenotypes on the basis of statistical analyses (using cluster analysis and latent class analysis methodology) and have evaluated the outcomes and associated risk factors of previously established early childhood asthma phenotypes that are based on asthma onset and patterns of wheezing illness. There have also been investigations focusing on immunologic, physiologic, and genetic correlates of various phenotypes, as well as identification of subphenotypes of severe childhood asthma. Childhood asthma remains a heterogeneous condition, and investigations into these various presentations, risk factors, and outcomes are important since they can offer therapeutic and prognostic relevance. Further investigation into the immunopathology and genetic basis underlying childhood phenotypes is important so therapy can be tailored accordingly.

  15. Relationship of activin A levels with clinical presentation, extent, and severity of coronary artery disease.

    Science.gov (United States)

    Bouzidi, Nadia; Betbout, Fethi; Maatouk, Faouzi; Gamra, Habib; Miled, Abdelhedi; Ferchichi, Salima

    2017-12-01

    We aimed to evaluate the relationship of serum activin A levels with risk factors, clinical presentation, biochemical marker levels, extent, and severity of atherosclerotic coronary artery disease (CAD). In total, 310 CAD patients [92 with ST-segment elevation myocardial infarction (STEMI), 111 with non-STEMI (NSTEMI), and 107 with unstable angina (UA)] and 207 healthy subjects (controls) were enrolled. Activin A levels in all participants were measured using ELISA. Angiographic measurements were performed in patients and not in the healthy subjects. Activin A levels were higher in all patient groups than in controls (patients vs. controls, p=0.041; NSTEMI vs. UA, p=0.744; STEMI vs. UA, p=0.172; NSTEMI vs. STEMI, p=0.104). According to the cut-off value of activin A level, patients with high and low activin A levels had a similar distribution of clinical and biochemical variables but the prevalence of severe stenosis was observed in groups with high activin A levels. Our results revealed that activin A levels did not decrease as thrombolysis in myocardial infarction (risk score increased (p=0.590). The area under the ROC curve for activin A levels in patients was 0.590±0.047 (95% CI: 0.439-0.591, p=0.193). In multiple analysis of the overall population, male gender (ß=-0.260; 95% CI: -617.39 to -110.04; p=0.005) was an independent predictor of activin A levels. This study indicated that activin A can not be a predictive marker in CAD and is not associated with extensive and severe CAD. In contrast, the increase in activin A levels in patients, especially in patients with different clinical groups of acute coronary syndromes, suggested its involvement in atherosclerosis.

  16. Fabry Disease in Families With Hypertrophic Cardiomyopathy: Clinical Manifestations in the Classic and Later-Onset Phenotypes.

    Science.gov (United States)

    Adalsteinsdottir, Berglind; Palsson, Runolfur; Desnick, Robert J; Gardarsdottir, Marianna; Teekakirikul, Polakit; Maron, Martin; Appelbaum, Evan; Neisius, Ulf; Maron, Barry J; Burke, Michael A; Chen, Brenden; Pagant, Silvere; Madsen, Christoffer V; Danielsen, Ragnar; Arngrimsson, Reynir; Feldt-Rasmussen, Ulla; Seidman, Jonathan G; Seidman, Christine E; Gunnarsson, Gunnar Th

    2017-08-01

    The screening of Icelandic patients clinically diagnosed with hypertrophic cardiomyopathy resulted in identification of 8 individuals from 2 families with X-linked Fabry disease (FD) caused by GLA (α-galactosidase A gene) mutations encoding p.D322E (family A) or p.I232T (family B). Familial screening of at-risk relatives identified mutations in 16 family A members (8 men and 8 heterozygotes) and 25 family B members (10 men and 15 heterozygotes). Clinical assessments, α-galactosidase A (α-GalA) activities, glycosphingolipid substrate levels, and in vitro mutation expression were used to categorize p.D322E as a classic FD mutation and p.I232T as a later-onset FD mutation. In vitro expression revealed that p.D322E and p.I232T had α-GalA activities of 1.4% and 14.9% of the mean wild-type activity, respectively. Family A men had markedly decreased α-GalA activity and childhood-onset classic manifestations, except for angiokeratoma and cornea verticillata. Family B men had residual α-GalA activity and developed FD manifestations in adulthood. Despite these differences, all family A and family B men >30 years of age had left ventricular hypertrophy, which was mainly asymmetrical, and had similar late gadolinium enhancement patterns. Ischemic stroke and severe white matter lesions were more frequent among family A men, but neither family A nor family B men had overt renal disease. Family A and family B heterozygotes had less severe or no clinical manifestations. Men with classic or later-onset FD caused by GLA missense mutations developed prominent and similar cardiovascular disease at similar ages, despite markedly different α-GalA activities. © 2017 American Heart Association, Inc.

  17. Clinical features and risk factors of acute hepatitis E with severe jaundice.

    Science.gov (United States)

    Xu, Bin; Yu, Hai-Bin; Hui, Wei; He, Jia-Li; Wei, Lin-Lin; Wang, Zheng; Guo, Xin-Hui

    2012-12-28

    To compares the clinical features of patients infected with hepatitis E virus (HEV) with or without severe jaundice. In addition, the risk factors for HEV infection with severe jaundice were investigated. We enrolled 235 patients with HEV into a cross-sectional study using multi-stage sampling to select the study group. Patients with possible acute hepatitis E showing elevated liver enzyme levels were screened for HEV infection using serologic and molecular tools.HEV infection was documented by HEV antibodies and by the detection of HEV-RNA in serum. We used χ(2) analysis, Fisher's exact test, and Student's t test where appropriate in this study. Significant predictors in the univariate analysis were then included in a forward, stepwise multiple logistic regression model. No significant differences in symptoms, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, or hepatitis B virus surface antigen between the two groups were observed. HEV infected patients with severe jaundice had significantly lower peak serum levels of γ-glutamyl-transpeptidase (GGT) (median: 170.31 U/L vs 237.96 U/L, P = 0.007), significantly lower ALB levels (33.84 g/L vs 36.89 g/L, P = 0.000), significantly lower acetylcholine esterase (CHE) levels (4500.93 U/L vs 5815.28 U/L, P = 0.000) and significantly higher total bile acid (TBA) levels (275.56 μmol/L vs 147.03 μmol/L, P = 0.000) than those without severe jaundice. The median of the lowest point time tended to be lower in patients with severe jaundice (81.64% vs 96.12%, P = 0.000). HEV infected patients with severe jaundice had a significantly higher viral load (median: 134 vs 112, P = 0.025) than those without severe jaundice. HEV infected patients with severe jaundice showed a trend toward longer median hospital stay (38.17 d vs 18.36 d, P = 0.073). Multivariate logistic regression indicated that there were significant differences in age, sex, viral load, GGT, albumin, TBA, CHE, prothrombin index, alcohol

  18. [Clinical effect of different sequences of debridement-antibiotic therapy in treatment of severe chronic periodontitis].

    Science.gov (United States)

    Li, Yi; Xu, Li; Lu, Rui-fang; An, Yue-bang; Wang, Xian-e; Song, Wen-li; Meng, Huan-xi

    2015-02-18

    To evaluate the feasibility of full-mouth debridement (subgingival scaling and root planning, SRP) by 2 times within 1 week and compare the clinical effects of different sequences of debridement-antibiotic usage in patients with severe chronic periodontitis (CP). A double-blinded, placebo-controlled, randomized clinical trial was conducted in 30 severe CP patients (14 males and 16 females, 40.5 ± 8.4 years old on average from 35 to 60) receiving 3 different sequences of debridement-antibiotictherapy: Group A, antibiotic usage (metronidazole, MTZ, 0.2 g, tid, 7 d; amoxicillin, AMX 0.5 g, tid, 7 d) was started together with SRP (completed by 2 times in 7 d); Group B, antibiotic usage (MTZ 0.2 g, tid, 7 d; AMX 0.5 g, tid, 7 d) was started 1 d after SRP(completed by 2 times in 7 d); Group C, SRP alone[probing depth (PD), bleeding index (BI) and tooth mobility] was examined. The average full-mouth probing depth, the average full-mouth proximal probing depth (pPD), the percentage of sites with PD>5 mm (PD>5 mm%), the percentage of sites with proximal PD>5 mm (pPD>5 mm%), the average bleeding index (BI) and the percentage of sites with bleeding on probing (BOP%) were calculated. Clinical examinations were performed at baseline and 2 months post therapy. (1) Compared with baseline conditions, all the subjects showed clinical improvements in all the parameters evaluated 2 months post therapy, Pantibiotic usage at the same time comparing with patients using antibiotics after SRP or SRP alone.

  19. REHABILITATION OF SEVERELY ATROPHIED UPPER JAW WITH INTRAOSSAL DENTAL IMPLANTS - clinical case

    Directory of Open Access Journals (Sweden)

    Ivan Chenchev

    2010-07-01

    Full Text Available Objective: The purpose of this presentation is to show the difficulty in prosthetization of a clinical case with a pronounced atrophy of the upper jaw and the various types and nature of restrictions imposed by the requirements of the patient. Methods: The clinical analysis, surgical protocol and prosthetic solution are presented in the treatment of 72 year-old woman with a pronounced atrophy of the upper jaw. OPG, standard CT of the upper jaw was used in the planning and a special surgical template was fabricated, helping us to find intraoperatively the exact locations of implants. The preliminary analysis of the number, height and diameter of intraossal implants helped us to find the exact prosthetic solution in this clinical case. The preparation of the implant bed was done by conical osteotomy in order to expand and condense the existing bone, which allowed us to use endoossal implants with a possible maximum size in a very limited maxillary volume and the reluctance of the patient to use other methods and surgical techniques. Conical threaded and self-tapping intraossal implants were used, placed according to a classic two-stage methodology with a flap and a long-term functional loading after a period of four months.Results and Conclusion: The applied surgical and prosthetic solution allowed us to achieve a good functional and aesthetic rehabilitation in this case of severe atrophy of the upper jaw, following a number of restrictions imposed on us by the reluctance of the patient to use other surgical solutions. This shows that in the case of severe atrophy of the upper jaw, a good clinical result can be achieved. For this reason, the use of CT,a well-planned surgical template, sufficient preparation ,the maximum use of available bone volume and the choice of a good prosthetic solution is very important.

  20. Clinical features and treatment of organ failure in severe acute pancreatitis

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    CUI Lijian

    2014-08-01

    Full Text Available Organ failure is an important factor causing death in patients with severe acute pancreatitis (SAP. In recent years, thanks to the further study of pathophysiology of SAP and the continuous accumulation of experience and technology, substantial progress has been made in the diagnosis and treatment of SAP complicated by organ failure. The clinical features of SAP complicated by organ failure and the measures to be strengthened in the treatment of SAP are summarized. Currently, it is thought that organ failure tends to appear once SAP occurs, so timely, standardized treatment can shorten the course of disease and significantly reduce mortality.

  1. Clinical phenotype of recurrent aphthous stomatitis and interleukin-1β genotype in a Polish cohort of patients.

    Science.gov (United States)

    Ślebioda, Zuzanna; Krawiecka, Ewa; Rozmiarek, Marta; Szponar, Elżbieta; Kowalska, Anna; Dorocka-Bobkowska, Barbara

    2017-09-01

    The aim of this study was to evaluate the relation between a clinical profile and the interleukin-1β (IL-1β) genotype in a Polish cohort of patients with RAS. One hundred and four patients with RAS were enrolled in the study and all were subject to an oral examination. The severity of RAS was assessed according to the clinical type of the disease, the number of lesions per flare-up and the length of intervals between the episodes. The genotyping of two SNPs of the IL-1β gene, IL-1β c.-511 T>C (rs16944) and IL-1β c.+3954 C>T (rs1143634), was carried out by genomic DNA isolated from blood samples and by using the PCR-RFLP approach. The results were statistically analysed with chi-square and Fisher's tests and Spearman's rank correlation, with P < 0.05 assumed to be a significance level (Statistica 10; StatSoft ® , Kraków, Poland). No statistically significant associations or correlations were found between the presence of *2 allele and minor, major or herpetiform RAS nor after the stratification using the RAS severity score and the classification based on the number of lesions per one flare-up. A weak correlation was found between the number of lesions per one flare-up and heterozygosity promoting the A type of RAS, characterized by a low number of eruptions. The presence of IL-1 β *2 allele within the c.+3954 and c.-511 SNPs was found to be neither a significant risk factor for a higher incidence of any type of RAS, nor did it influence the disease severity and mode of recurrences. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Mild Clinical Course of Severe Fever with Thrombocytopenia Syndrome Virus Infection in an Elderly Japanese Patient

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    Yuko Ohagi

    2014-01-01

    Full Text Available Severe fever with thrombocytopenia syndrome (SFTS is an emerging infectious and hemorrhagic disease recently described in China and western Japan. A 71-year-old healthy Japanese woman noticed a tick biting her after harvesting in an orchard and removed it herself. She developed diarrhea, anorexia, and chills eight days later. Because these symptoms continued, she visited a primary care physician 6 days after the onset. Laboratory data revealed thrombocytopenia, leukocytopenia, and elevated liver enzymes. She was then referred to our hospital. Although not completely fulfilling the diagnostic criteria used in a retrospective study in Japan, SFTS was suspected, and we detected SFTS virus in the patient’s blood using RT-PCR. However, she recovered without intensive treatment and severe complications 13 days after the onset. In this report, we present a mild clinical course of SFTS virus infection in Japan in detail.

  3. Clinical emergency treatment of 68 critical patients with severe organophosphorus poisoning and prognosis analysis after rescue.

    Science.gov (United States)

    Dong, Hui; Weng, Yi-Bing; Zhen, Gen-Shen; Li, Feng-Jie; Jin, Ai-Chun; Liu, Jie

    2017-06-01

    This study reports the clinical emergency treatment of 68 critical patients with severe organophosphorus poisoning, and analyzes the prognosis after rescue.The general data of 68 patients with severe organophosphorus poisoning treated in our hospital were retrospectively analyzed. These patients were divided into 2 groups: treatment group, and control group. Patients in the control group received routine emergency treatment, while patients in the treatment group additionally received hemoperfusion plus hemodialysis on the basis of routine emergency treatment. The curative effects in these 2 groups and the prognosis after rescue were compared.Compared with the control group, atropinization time, recovery time of cholinesterase activity, recovery time of consciousness, extubation time, and length of hospital stay were shorter (P poisoning rebound rate was significantly lower (P treatment group.Hemoperfusion and hemodialysis on the basis of routine emergency treatment for critical patients with organophosphorus poisoning can improve rescue outcomes and improve the prognosis of patients, which should be popularized.

  4. Community-acquired pneumonia: economics of inpatient medical care vis-à-vis clinical severity,

    Directory of Open Access Journals (Sweden)

    Vojislav Cupurdija

    2015-02-01

    Full Text Available Objective: To assess the direct and indirect costs of diagnosing and treating community-acquired pneumonia (CAP, correlating those costs with CAP severity at diagnosis and identifying the major cost drivers. Methods: This was a prospective cost analysis study using bottom-up costing. Clinical severity and mortality risk were assessed with the pneumonia severity index (PSI and the mental Confusion-Urea-Respiratory rate-Blood pressure-age ≥ 65 years (CURB-65 scale, respectively. The sample comprised 95 inpatients hospitalized for newly diagnosed CAP. The analysis was run from a societal perspective with a time horizon of one year. Results: Expressed as mean ± standard deviation, in Euros, the direct and indirect medical costs per CAP patient were 696 ± 531 and 410 ± 283, respectively, the total per-patient cost therefore being 1,106 ± 657. The combined budget impact of our patient cohort, in Euros, was 105,087 (66,109 and 38,979 in direct and indirect costs, respectively. The major cost drivers, in descending order, were the opportunity cost (lost productivity; diagnosis and treatment of comorbidities; and administration of medications, oxygen, and blood derivatives. The CURB-65 and PSI scores both correlated with the indirect costs of CAP treatment. The PSI score correlated positively with the overall frequency of use of health care services. Neither score showed any clear relationship with the direct costs of CAP treatment. Conclusions: Clinical severity at admission appears to be unrelated to the costs of CAP treatment. This is mostly attributable to unwarranted hospital admission (or unnecessarily long hospital stays in cases of mild pneumonia, as well as to over-prescription of antibiotics. Authorities should strive to improve adherence to guidelines and promote cost-effective prescribing practices among physicians in southeastern Europe.

  5. [The clinical study of IgA nephropathy with severe chronic periodontitis and aggressive periodontitis].

    Science.gov (United States)

    Cao, Y L; Qiao, M; Xu, Z H; Zou, G M; Ma, L L; Li, W G; Xu, B H

    2016-01-05

    To explore the clinical characteristics of IgA nephropathy (IgAN) with severe chronic periodontitis and aggressive periodontitis. A total of 436 hospitalized patients who underwent renal needle biopsy in the department of nephrology of China-Japan Friendship Hospital from November 2013 to December 2014 were recruited in the study and blindly had periodontal examination. The patients were divided into IgAN group and non-IgAN group according to the renal pathology. The patients with IgAN were further categorized as non-periodontitis, chronic periodontitis and aggressive peridontitis group by Haas classification. The chronic periodontitis group was continually divided into mild, moderate and severe periodontitis group. The levels of interleukin (IL)-1β and IL-6 in gingival crevicular fluid were analyzed by enzyme-linked immunosorbent assays. The prevalence of periodontitis in the study was 88.3% (385/436). The prevalence of chronic periodontitis and aggressive periodontitis were higher in patients with IgAN than those with non-IgAN (Pchronic periodontitis was correlated with pathologic grading of IgAN (r=0.48, Pperiodontitis, those with severe chronic and aggressive periodontitis had more severe pathology, more frequent recurrent gross hematuria, higher levels of 24 h proteinuria, serum triglyceride and uric acid, higher periodontal probing depth and clinical attatchment level, as well as higer levels of IL-1β and IL-6, but had lower creatinine clearance rate (all Pchronic and aggressive periodontitis was higher in patients with IgAN. Chronic periodontitis is correlated with the onset and development of IgAN. Patients with IgAN have worse condition with the aggravation of periodontitis.

  6. Trace elements in ALS patients and their relationships with clinical severity.

    Science.gov (United States)

    Oggiano, Riccardo; Solinas, Giuliana; Forte, Giovanni; Bocca, Beatrice; Farace, Cristiano; Pisano, Andrea; Sotgiu, Maria Alessandra; Clemente, Simonetta; Malaguarnera, Michele; Fois, Alessandro Giuseppe; Pirina, Pietro; Montella, Andrea; Madeddu, Roberto

    2018-04-01

    An exploratory study of trace elements in ALS and their relationships with clinical severity was detected. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that causes irreversible damage in humans, with the consequent loss of function of motoneurons (MNs), with a prognosis up to 5 years after diagnosis. Except to genetic rare cases it is not known the etiology of the disorder. Aim of our research is to investigate the possible role of heavy metals in the severity of the disease. In this study, by the use of plasma mass (ICP-MS), we have analyzed the content of essential and heavy metals such: Pb, Cd, Al, Hg, Mn, Fe, Cu, Zn, Se, Mg, and Ca, in blood, urine and hair of ALS patients and controls; moreover we divided the patients in two groups for disease severity and analyzed the difference among the groups, in order to study a possible involvement of metals in the severity of the damage. Our results suggest a protective role of Selenium, involved in protective antioxidant mechanisms, and a risk factor in the case of presence of Lead in blood. The levels of the other metals are not easy to interpret, because these may be due to life style and for essential metals a consequence of the disease condition, not a cause. Copyright © 2018 Elsevier Ltd. All rights reserved.

  7. Somatic involvement assessed through a cumulative score of clinical severity in patients with eating disorders.

    Science.gov (United States)

    Scanelli, Giovanni; Gualandi, Malvina; Simoni, Marzia; Manzato, Emilia

    2014-03-01

    To evaluate the overall somatic involvement in patients with eating disorders (EDs). The medical records of 206 patients (age 15-56 years, 96.1% females) with diagnosis of anorexia nervosa (AN, n = 63, 30.6%), bulimia nervosa (BN, n = 78, 37.9%), or eating disorder not otherwise specified (EDNOS, n = 65, 31.6 %) were analyzed. A cumulative score of clinical severity (SCS) was computed according to the presence of physical, instrumental, and laboratory abnormalities, as well as to their prognostic impact. Based on the tertile distribution of SCS, three levels of severity were defined: low, medium, and high. A medium/high level of severity was found in 63% of the whole sample, 89% of AN, 49% of BN, and 55% of EDNOS. In the whole sample, the risk of medium/high SCS was significantly and inversely related to the body mass index (BMI) and to the lifetime minimum BMI. The severity level was significantly and positively associated with diagnosis of AN, duration of amenorrhea C1 year, and presence of ED-related symptoms. EDNOS patients showed a higher risk for increased SCS than BN patients, although not significantly. The non-negligible frequency of a relevant somatic involvement in patients with EDNOS suggests that a transdiagnostic scoring system might be helpful to identify ED cases at risk of medical complications.

  8. Prevalence and clinical characteristics of metabolically healthy obese individuals and other obese/non-obese metabolic phenotypes in a working population: results from the Icaria study

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    Albert Goday

    2016-04-01

    Full Text Available Abstract Background Metabolically healthy obese (MHO phenotype may present with distinct characteristics compared with those with a metabolically unhealthy obese phenotype. Epidemiologic data on the distribution of these conditions in the working population are lacking. We aimed to evaluate the prevalence and clinical characteristics of MHO and other obese/non-obese metabolic phenotypes in a working population. Methods Cross-sectional analysis of all subjects who had undergone a medical examination with Ibermutuamur Prevention Society from May 2004 to December 2007. Participants were classified into 5 categories according to their body mass index (BMI; within each of these categories, participants were further classified as metabolically healthy (MH or metabolically unhealthy (MUH according to the modified NCEP-ATPIII criteria. A logistic regression analysis was performed to evaluate some clinically relevant factors associated with a MH status. Results In the overall population, the prevalence of the MHO phenotype was 8.6 %. The proportions of MH individuals in the overweight and obese categories were: 87.1 % (overweight and 55.5 % (obese I-III [58.8, 40.0, and 38.7 % of the obese I, II, and III categories, respectively]. When the overweight and obese categories were considered, compared with individuals who were MUH, those who were MH tended to be younger and more likely to be female or participate in physical exercise; they were also less likely to smoke, or to be a heavy drinker. In the underweight and normal weight categories, compared with individuals who were MH, those who were MUH were more likely to be older, male, manual (blue collar workers, smokers and heavy drinkers. Among participants in the MUH, normal weight group, the proportion of individuals with a sedentary lifestyle was higher relative to those in the MH, normal weight group. The factors more strongly associated with the MUH phenotype were BMI and age, followed by the

  9. The cranial MRI in severe cerebral palsy; A comparative study with clinical data

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    Yamada, Kazutaka; Itoh, Masahiro; Fueki, Noboru; Hirasawa, Kyoko; Suzuki, Noriko; Kurata, Kiyoko (Metropolitan Medical Center of the Severely Handicapped, Tokyo (Japan)); Sato, Junichi; Morimatsu, Yoshio; Yagishita, Akira

    1993-09-01

    The magnetic resonance examination was performed in 38 patients with severe cerebral palsy (CP; 15 males and 23 females) who had both motor delay (unable to move anywhere) and mental retardation (I.Q. or D.Q. below 30). Neuroimaging findings were compared with the CP type, etiology, and grade of understanding of language. Cranial magnetic resonance imagings (MRI) in CP were divided into five types. In type 1, nine predominantly showed cyst-liked ventricles and periventricular hyperintensity on T[sub 2]-weighted imaging (PVH) and only scarred basal ganglia and thalamus were visible. All suffered from neonatal asphyxia and the clinical type was rigospastic tetraplegia (RST). In type 2, eleven predominantly showed PVH and hyperintensity on T[sub 2]-weighted (HT2) in basal ganglia and thalamus. All suffered from neonatal asphyxia and the clinical type was RST or rigospastic diplegia. In type 3, five showed PVH and three had cortical atrophy. All suffered from neonatal asphyxia and the clinical type was spastic diplegia. In type 4, four predominantly showed HT2 in putamen and thalamus. Three had cortical atrophy. All suffered from neonatal asphyxia. The clinical type was athetotic CP (ATH). In type 5, nine predominantly showed HT2 in globus pallidus. Four had cortical atrophy and two had hippocampal atrophy. All suffered from neonatal jaundice and the clinical type was ATH. All patients who suffered from neonatal asphyxia and spastic CP had MRI in PVH. All patients who suffered from neonatal asphyxia and ATH showed HT2 in putamen and thalamus. Almost patients who suffered from neonatal jaundice and ATH showed HT2 in globus pallidus. With athetotic CP, cases with atrophy of the cerebral cortex and/or hippocampus were lower grade of understanding of language than no atrophy of both. The results of studies of MRI are in agreement with neuropathological findings. (author).

  10. [A comparative study between the Vitek YBC and Microscan Walk Away RYID automated systems with conventional phenotypic methods for the identification of yeasts of clinical interest].

    Science.gov (United States)

    Ferrara, Giuseppe; Mercedes Panizol, Maria; Mazzone, Marja; Delia Pequeneze, Maria; Reviakina, Vera

    2014-12-01

    The aim of this study was to compare the identification of clin- ically relevant yeasts by the Vitek YBC and Microscan Walk Away RYID automated methods with conventional phenotypic methods. One hundred and ninety three yeast strains isolated from clinical samples and five controls strains were used. All the yeasts were identified by the automated methods previously mentioned and conventional phenotypic methods such as carbohydrate assimilation, visualization of microscopic morphology on corn meal agar and the use of chromogenic agar. Variables were assessed by 2 x 2 contingency tables, McNemar's Chi square, the Kappa index, and concordance values were calculated, as well as major and minor errors for the automated methods. Yeasts were divided into two groups: (1) frequent isolation and (2) rare isolation. The Vitek YBC and Microscan Walk Away RYID systems were concordant in 88.4 and 85.9% respectively, when compared to conventional phenotypic methods. Although both automated systems can be used for yeasts identification, the presence of major and minor errors indicates the possibility of misidentifications; therefore, the operator of this equipment must use in parallel, phenotypic tests such as visualization of microscopic morphology on corn meal agar and chromogenic agar, especially against infrequently isolated yeasts. Automated systems are a valuable tool; however, the expertise and judgment of the microbiologist are an important strength to ensure the quality of the results.

  11. Mining skeletal phenotype descriptions from scientific literature.

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    Tudor Groza

    Full Text Available Phenotype descriptions are important for our understanding of genetics, as they enable the computation and analysis of a varied range of issues related to the genetic and developmental bases of correlated characters. The literature contains a wealth of such phenotype descriptions, usually reported as free-text entries, similar to typical clinical summaries. In this paper, we focus on creating and making available an annotated corpus of skeletal phenotype descriptions. In addition, we present and evaluate a hybrid Machine Learning approach for mining phenotype descriptions from free text. Our hybrid approach uses an ensemble of four classifiers and experiments with several aggregation techniques. The best scoring technique achieves an F