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Sample records for willebrand disease phenotypic

  1. von Willebrand disease phenotype and von Willebrand factor marker genotype in Doberman Pinschers.

    Science.gov (United States)

    Brooks, M B; Erb, H N; Foureman, P A; Ray, K

    2001-03-01

    To define the relationship between clinical expression of a type-1 von Willebrand disease phenotype and genotype at 2 von Willebrand factor marker loci in Doberman Pinschers. 102 client-owned Doberman Pinschers. Dogs were recruited on the basis of plasma von Willebrand factor concentration, clinical history, and pedigree. Blood samples and response to a history questionnaire were obtained for each dog. Plasma von Willebrand factor concentration was measured by use of an ELISA, and genotyping was performed via polymerase chain reaction for 1 intragenic and 1 extragenic von Willebrand factor marker. Amplification product size was determined by use of polyacrylamide gel electrophoresis (intragenic marker) or automated sequence analysis (extragenic marker). Western blots were prepared from a subset of dogs with low plasma von Willebrand factor concentration to evaluate multimer distribution. Strong associations were detected between plasma von Willebrand factor concentration and von Willebrand factor marker genotype. Twenty-five dogs had substantial reduction in plasma von Willebrand factor concentration and multiple hemorrhagic events. All were homozygous for a 157-base-pair intragenic marker allele and homozygous or compound heterozygous for 1 of 4 extragenic marker alleles. These marker genotypes were exclusively detected in dogs with low plasma von Willebrand factor concentration, although some dogs with these genotypes did not have abnormal bleeding. Type-1 von Willebrand disease in Doberman Pinschers is associated with the von Willebrand factor gene locus; however, the expression pattern in this breed appears more complex than that of a simple recessive trait.

  2. von Willebrand disease and aging : an evolving phenotype

    NARCIS (Netherlands)

    Sanders, Y. V.; Giezenaar, M. A.; Laros-van Gorkom, B. A. P.; Meijer, K.; van der Bom, J. G.; Cnossen, M. H.; Nijziel, M. R.; Ypma, P. F.; Fijnvandraat, K.; Eikenboom, J.; Mauser-Bunschoten, E. P.; Leebeek, F. W. G.

    Background: Because the number of elderly von Willebrand disease (VWD) patients is increasing, the pathophysiology of aging in VWD has become increasingly relevant. Objectives: To assess age-related changes in von Willebrand factor (VWF) and factor VIII (FVIII) levels and to compare age-related

  3. Von Willebrand Disease in the Netherlands : from genetic variation to phenotypic variability

    NARCIS (Netherlands)

    Y.V. Sanders (Yvonne)

    2015-01-01

    markdownabstractAbstract Von Willebrand Disease (VWD) is the most common inherited bleeding disorder resulting in mucocutaneous bleeding, like epistaxis, oral cavity bleeding and menorrhagia. VWD is caused by reduced or dysfunctional von Willebrand Factor (VWF). VWF levels are highly variable

  4. von Willebrand Disease

    Science.gov (United States)

    ... the condition. For example, the school nurse, teacher, daycare provider, coach, or any leader of afterschool activities ... MedlinePlus) Von Willebrand Disease (MedlinePlus) Building 31 31 Center Drive Bethesda, MD 20892 Learn more about getting ...

  5. von Willebrand Disease

    Science.gov (United States)

    ... for type 1 von Willebrand disease is called desmopressin. It causes a temporary increase in the von ... injection or by being sniffed into the nose. Desmopressin may also help some people with type 2 ...

  6. Variable bleeding phenotype in an Amish pedigree with von Willebrand disease.

    Science.gov (United States)

    Gupta, Sweta; Heiman, Meadow; Duncan, Natalie; Hinckley, Jesse; Di Paola, Jorge; Shapiro, Amy D

    2016-10-01

    Through a cross-sectional study design, the bleeding phenotype in the Amish in Indiana (IN) and Wisconsin (WI) was described using two different bleeding scores. von Willebrand factor (VWF) testing was performed and bleeding questionnaires from Centers for Disease Control and Prevention (CDC) and European MCMDM-1 (Tosetto bleeding score (BS)) were administered to the IN and WI cohort respectively. Seven hundred and seventy nine subjects were recruited, 17% were diagnosed with VWD based on Ristocetin cofactor, VWF:RCo  T. The WI AF were much younger at a mean age 15 years vs 26 years in IN AF cohort. The AF subjects had a median VWF:RCo of 13IU/dl with a statistically significant higher median BS 1 versus 0 in the WI AF vs WI Unaffected (UA), 2 vs 1 in the IN AF vs IN UA, P Amish with VWD, despite a unifying mutation. Am. J. Hematol. 91:E431-E435, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  7. Living with von Willebrand Disease

    Science.gov (United States)

    ... the condition. For example, the school nurse, teacher, daycare provider, coach, or any leader of afterschool activities ... MedlinePlus) Von Willebrand Disease (MedlinePlus) Building 31 31 Center Drive Bethesda, MD 20892 Learn more about getting ...

  8. von Willebrand Disease

    Science.gov (United States)

    ... or increase the risk of bleeding. Examples include aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), clopidogrel, warfarin, or heparin. Any history of liver or kidney disease, blood or bone ...

  9. Translational medicine advances in von Willebrand disease.

    Science.gov (United States)

    Lillicrap, D

    2013-06-01

    Following the recognition of von Willebrand disease (VWD) in 1926 and the cloning of the gene for von Willebrand factor (VWF) in 1985, significant advances have been made in our fundamental knowledge of both the disease and the protein. Some of this new knowledge has also begun to impact the clinical management of VWD. First, the progressive increase in our understanding of the molecular genetic basis of VWD has resulted in rational applications of molecular testing to complement the current range of phenotypic tests for VWD. These molecular genetic strategies are most effectively directed at the prenatal diagnosis of type 3 VWD and confirmatory testing for types 2B and 2N disease. In contrast, the use of molecular testing to clarify the diagnosis of type 1 VWD is of marginal benefit, at best. In terms of VWD therapies, a new recombinant VWF concentrate has recently completed successful clinical trials and is now awaiting more widespread application. There have even been some preclinical successes with VWF gene transfer although the clinical rationale for this therapeutic strategy needs careful consideration. Much more remains to be learnt about the biology of VWF and further translational advances for the enhancement of VWD care will inevitably be realized. © 2013 International Society on Thrombosis and Haemostasis.

  10. How Is von Willebrand Disease Treated?

    Science.gov (United States)

    ... the condition. For example, the school nurse, teacher, daycare provider, coach, or any leader of afterschool activities ... MedlinePlus) Von Willebrand Disease (MedlinePlus) Building 31 31 Center Drive Bethesda, MD 20892 Learn more about getting ...

  11. How Is von Willebrand Disease Diagnosed?

    Science.gov (United States)

    ... the condition. For example, the school nurse, teacher, daycare provider, coach, or any leader of afterschool activities ... MedlinePlus) Von Willebrand Disease (MedlinePlus) Building 31 31 Center Drive Bethesda, MD 20892 Learn more about getting ...

  12. Genetics Home Reference: von Willebrand disease

    Science.gov (United States)

    ... Jun;5(6):1165-9. Citation on PubMed Kessler CM. Diagnosis and treatment of von Willebrand disease: ... consult with a qualified healthcare professional . About Selection Criteria for Links Data Files & API Site Map Customer ...

  13. Van Willebrand's disease in the Western Cape

    African Journals Online (AJOL)

    Von Willebrand's disease (VWD) is a mild-ta-moderately severe bleeding disorder characterised by mucosal bleeding such as epistaxis, gingival bleeding, gastro-intestinal bleeding and menorrhagia Haemarthroses, deep subcutaneous and intramuscular haematomas, typically seen in the severe haemophilias. are ...

  14. Joint bleeding in von Willebrand disease

    NARCIS (Netherlands)

    Galen, K.P.M. van

    2017-01-01

    Von Willebrand disease (VWD) is the most common inherited bleeding disorder occurring in approximately 1/100 people. Until now, joint bleeds did not get much attention in clinical research on VWD, since mucocutaneous bleeding is predominant. However, recurrent joint bleeds lead to arthropathy, the

  15. Response to desmopressin is influenced by the genotype and phenotype in type 1 von Willebrand disease (VWD): results from the European Study MCMDM-1VWD

    DEFF Research Database (Denmark)

    Castaman, G.; Lethagen, S.; Federici, A.B.

    2008-01-01

    We have prospectively evaluated the biologic response to desmopressin in 77 patients with type 1 von Willebrand disease (VWD) enrolled within the Molecular and Clinical Markers for the Diagnosis and Management of type 1 VWD project. Complete response to desmopressin was defined as an increase...... of subtle multimeric abnormalities did not hamper potential clinically useful responses, as in typical type 1 VWD Udgivelsesdato: 2008/4/1...

  16. Treatment of patients with von Willebrand disease

    Directory of Open Access Journals (Sweden)

    Tuohy E

    2011-04-01

    Full Text Available Emma Tuohy1, Emma Litt1, Raza Alikhan1,21Department of Haematology, University Hospital of Wales, Cardiff, UK; 2Haemophilia and Thrombosis Centre, University Hospital of Wales, Cardiff, UKAbstract: Von Willebrand disease (vWD is the most common hereditary bleeding disorder. The aim of therapy is to correct the dual hemostatic defect, due to defective platelet adhesion-aggregation and abnormal coagulation due to Factor VIII (FVIII deficiency. The choice of treatment depends on a number of factors, including the severity of the bleed, the procedure planned, the subtype and severity of the disease and the age and morbidity of the patient. Desmopressin (DDAVP is the treatment of choice for type 1 vWD as it increases endogenous release of FVIII and von Willebrand factor (vWF and is also used in some subtypes of type 2 vWD. In those patients in whom DDAVP is ineffective or contraindicated, levels can be restored by infusing vWF:FVIII concentrates. The role of antifibrinolytic treatment is an important adjunct to replacement therapy during minor or major surgery involving mucosal surfaces. The dosing and timing of vWF:FVIII concentrates is important depending on the nature of the surgical procedure. The role of secondary prophylaxis needs to be further defined.Keywords: von Willebrand disease, treatment, DDAVP 

  17. Revascularization Operation for Moyamoya Disease with Concurrent von Willebrand Disease.

    Science.gov (United States)

    Miki, Kenji; Arimura, Koichi; Nishimura, Ataru; Yoshimoto, Koji; Sayama, Tetsuro; Iihara, Koji

    2017-12-01

    Although extracranial-intracranial (EC-IC) bypass is an effective treatment strategy for symptomatic moyamoya disease, surgeons need to be cautious regarding the possibility of postoperative hemorrhagic complications in patients with a concurrent coagulation disorder. Here, we describe a case of EC-IC bypass for moyamoya disease concurrent with von Willebrand disease type 1. Following perioperative replacement of the von Willebrand factor, the patient showed an uneventful and uncomplicated clinical course. This is the first reported case of EC-IC bypass being performed for moyamoya disease in a patient with concurrent von Willebrand disease. We emphasize the importance of appropriate management with replacement of the von Willebrand factor during the perioperative period to avoid hemorrhagic complications. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Doença de von Willebrand e anestesia Enfermedad de von Willebrand y anestesia Von Willebrand's disease and anesthesia

    Directory of Open Access Journals (Sweden)

    Fabiano Timbó Barbosa

    2007-06-01

    íodo perioperatorio. CONTENIDO: Se definieron las características de la enfermedad de von Willebrand en cuanto a las fisiopatologías, la clasificación, al diagnóstico laboratorial, al tratamiento actual y a los cuidados con el manejo del paciente en el período perioperatorio. CONCLUSIONES: La enfermedad de von Willebrand es el disturbio hemorrágico hereditario más común, sin embargo ella está subdiagnosticada por la complejidad de la propia enfermedad. La correcta clasificación del paciente, el uso apropiado de la desmopresina y la transfusión del factor de von Willebrand son medidas fundamentales para la realización del procedimiento anestésico exitoso.BACKGROUND AND OBJECTIVES: von Willebrand's disease is secondary to a mutation on chromosome 12, and is characterized by a qualitative and quantitative deficiency of the von Willebrand's factor. The diversity of the mutations is responsible for several different clinical manifestations, enabling the classification of several types and subtypes. The coagulopathy is manifested basically through a platelet dysfunction associated with a reduction in the serum levels of factor VIII. The objective of this review was to present the perioperative care of patients with von Willebrand's disease. CONTENTS: The physiopathology, classification, laboratorial diagnosis, and current treatment of von Willebrand's disease, as well as the perioperative management of these patients are discussed. CONCLUSIONS: von Willebrand's disease is the most common hereditary coagulopathy, but it is underdiagnosed due to the complexity of the disease itself. The right classification, proper use of desmopressin, and transfusion of von Willebrand's factor are fundamental for a successful anesthesia.

  19. CHANGES OF VON WILLEBRAND FACTOR DURING PREGNANCY IN WOMEN WITHOUT AND WITH VON WILLEBRAND DISEASE

    Directory of Open Access Journals (Sweden)

    Giancarlo Castaman

    2013-07-01

    Full Text Available Delivery in von Willebrand disease (VWD represents a significant hemostatic challenge because of the variable pattern of changes observed during pregnancy of von Willebrand factor (VWF  and factor VIII (FVIII, the protein carried by VWF. The wide heterogeneity of phenotypes and of the underlying pathophysiological mechanisms associated with this disorder prompt a careful evaluation of pregnant women with VWD to plan the most appropriate treatment at time of parturition. VWF and FVIII increase significantly during pregnancy in normal women, already within the first trimester, reaching levels by far > 100 U/dL by the time of parturition. In women with VWD, levels at baseline of VWF and FVIII > 30 U/dL are usually associated with a high likelihood to achieve normal levels at the end of pregnancy and specific anti-hemorrhagic prophylaxis is seldom required. Women with basal level < 20 U/dL usually have a poor increase since most of these women carry mutations associated with increased VWF clearance or are compound heterozygous for different VWF mutations which prevent the achievement of satisfactory hemostatic levels. While women with mutations associated with increased clearance show a full, albeit transitory correction of their hemostatic deficiency after desmopressin administration, compound heterozygous need replacement therapy because they do not respond well to this agent. Patients with abnormal VWF:RCo/VWF:Ag ratio at baseline (e.g. < 0.6, typically associated with type 2 VWD, maintain the abnormality throughout pregnancy and VWF:RCo usually does not attain safe levels ³ 50 U/dL. These women require replacement therapy with VWF-FVIII concentrates. Delayed post-partum bleeding may occur when replacement therapy is not continued for some days. Tranexamic acid may be useful at discharge to avoid excessive lochia.

  20. VON WILLEBRAND DISEASE: DIAGNOSIS AND TREATMENT

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    Majda Benedik Dolničar

    2004-12-01

    Full Text Available Background. Von Willebrand disease (VWD is a most frequently inborn bleeding disorder caused by quantitative or qualitative defects of von Willebrand factor (VWF. VWF promotes platelet-vessel wall (adhesion and plateletplatelet interaction (aggregation. It is also the carrier for factor VIII (F VIII in plasma. A deficiency of VWF may results in impairment of both, primary and secondary haemostasis. Therefore, patients with VWD can have bleeding symptoms typical fot the defect in primary haemostasis (mucocutaneous haemorrhages. In severe deficiency of VWF there are also haemarthroses and haematomas typical for patients with coagulation defects. Several types and subtypes of VWD have been described. The diagnosis is based on measurements of VWF concentration and activity and F VIII activity in plasma. The tests identifying VWD subtypes are ristocetin induced platelet agglutination (RIPA, multimeric analysis of VWF and measurement of the binding of VWF to F VIII.Conclusions. Due to heterogeneity of VWF defects, the correct diagnosis of types and subtypes is sometimes difficult but is important for appropriate treatment. There are two main therapeutic options for patients with VWD: desmopressin and blood derived concentrates of F VIII/VWF. In certain cases antifibrinolytics and hormones can be suitable treatment. Desmopressin is the treatment of choice in patients with type 1 VWD. It raises endogenous F VIII and VWF and thereby corrects the intrinsic coagulation defect as well as the prolonged bleeding time (BT or closure time (CT-PFA100 in most type 1 VWD patients. In type 3 and in the majority of type 2 patients desmopressin is not effective and it is necessary to use concentrates containing F VIII and VWF. These are always effective in raising of F VIII activity, whereas the BT/CT may not be completely corrected, but the normalisation of the BT/CT is not always necessary.

  1. Prophylaxis escalation in severe von Willebrand disease: A prospective study from the von Willebrand Disease Prophylaxis Network

    NARCIS (Netherlands)

    T.C. Abshire (Thomas Calvin); J. Cox-Gill; C.L. Kempton; F.W.G. Leebeek (Frank); M. Carcao (M.); P. Kouides (P.); S. Donfield (S.); E. Berntorp

    2015-01-01

    textabstractBackground: Treatment of mucosal bleeding (epistaxis, gastrointestinal bleeding, and menorrhagia) and joint bleeding remains problematic in clinically severe von Willebrand disease (VWD). Patients are often unresponsive to treatment (e.g. desmopressin or antifibrinolytic therapy) and may

  2. Polymorphism in the promoter region of von Willebrand factor gene and von Willebrand disease type 1

    Directory of Open Access Journals (Sweden)

    Daniel Simon

    2003-12-01

    Full Text Available The -1185A/G polymorphism in the 5'-regulatory region of the von Willebrand factor (VWF gene was associated with VWF plasma levels in a normal population. This study was undertaken to evaluate whether there is a relationship between this polymorphism and type 1 von Willebrand disease (VWD, a disorder characterized by a quantitative deficiency of VWF. The association between this polymorphism and plasma VWF levels in normal Brazilian individuals was also analyzed. Control subjects (n = 460 and type 1 VWD patients (n = 41 were studied. Polymerase chain reaction (PCR amplification of the 864-bp VWF promoter region followed by AccII restriction-digestion was used to identify the -1185A/G genotypes. The -1185G allele frequency was 57% in normal individuals and 63% in type 1 VWD patients, this difference was not significant (p = 0.29. No significant association was observed between -1185A/G genotypes and VWF plasma levels in normal individuals, although VWF levels were in the same direction as those reported by another study, with subjects carrying the G allele having the lower levels. These results suggest that -1185A/G polymorphism is not associated with the partial deficiency of VWF in type 1 VWD patients.

  3. Idiopathic pulmonary hypertension causing acquired von Willebrand disease and menorrhagia.

    Science.gov (United States)

    Sokkary, Nancy A; Dietrich, Jennifer E; Venkateswaran, Lakshmi

    2011-10-01

    Von Willebrand disease (VWD) maybe inherited or acquired; both etiologies can be associated with heavy menstrual bleeding. Pulmonary arterial hypertension may result in acquired VWD due to the destruction of high molecular weight von Willebrand multimers. We report a case of menorrhagia due to acquired VWD in a patient with idiopathic pulmonary hypertension. An adolescent female with known idiopathic pulmonary hypertension developed acquired VWD. Her primary disease necessitates the use of platelet inhibitors and intermittent anticoagulation. At menarche she also developed menorrhagia due to acquired VWD. She is currently controlled with stimate and progesterone-only therapy. VWD in a patient with idiopathic pulmonary hypertension causing menorrhagia. Although VWD and menorrhagia are commonly linked, the treatment and disease process in a patient with idiopathic pulmonary arterial hypertension is incredibly complex. Published by Elsevier Inc.

  4. DEEP VEIN THROMBOSIS IN PATIENT WITH VON WILLEBRAND DISEASE

    Directory of Open Access Journals (Sweden)

    V. A. Elykomov

    2016-01-01

    Full Text Available Objective: to identify the possible factors of thrombogenic risk and ways of its prevention in patients with von Willebrand disease.Case description. Patient X., 42 years old, who suffers from von Willebrand disease type 3 with 5-years of age. Asked on reception to the traumatologist in the polyclinic of the Regional Hospital with pain in the left hip joint. Recommended planned operative treatment in the Altai Regional Clinical Hospital. Preoperative preparation included the infusion of concentrate of von Willebrand factor and coagulation factor VIII. Operation – cement total arthroplasty of the left hip joint. In the postoperative period analgesic treatment, elastic compression of the lower extremities, iron supplements, also conducted infusion of concentrate of von Willebrand factor and coagulation factor VIII for 20 days and thromboprophylactic with dabigatran. On the 3rd day after the operation the patient revealed deep vein thrombosis of the femoral segment (floating clot.Results. The patient was operated for emergency indications in the Department of endovascular surgery – installation of venous cava filter “Volan”. Dabigatran is cancelled, appointed clexane for 3 months. In our clinical example the patient lacked risk factors of pulmonary embolism as obesity, age, smoking, prolonged immobilization, estrogen therapy. Overdose of factor VIII were not observed – the level of factor did not exceed 135 % on transfusions. At the same time, the patient was found polymorphisms in the genes ITGA2, FGB, MTHFR, MTR – heterozygote, MTRR – mutant homozygote, which may indicate the genetic factors of thrombogenic risk. Also a significant risk factor was massive surgical intervention (total hip replacement. Despite preventive measures (elastic compression, thromboprophylactic dabigatran, early activation we cannot to avoid thrombotic complications.Conclusion. This article presents a case demonstrating a thrombotic complication in patients

  5. Screening of Von Willebrand Disease in Iranian Women With Menorrhagia

    Science.gov (United States)

    Rahbar, Nahid; Faranoush, Mohammad; Ghorbani, Raheb; Sadr Alsadat, Bahare

    2015-01-01

    Background: Menorrhagia is a common health problem in women, particularly those with bleeding disorders. Little is known about the course of menorrhagia or other bleeding symptoms in women with the most common congenital bleeding disorder, von Willebrand disease (vWD). Objectives: The aim of this study was to estimate the prevalence of vWD in women with diagnosed menorrhagia. Materials and Methods: In this cross-sectional study, a total of 460 consecutive patients, presenting menorrhagia, were analyzed. The initial screening and confirmation tests for the diagnosis of vWD included determination of prothrombin time (PT), partial thromboplastin time (PTT), bleeding time (BT), fibrinogen, factor VIII, vWF antigen, and vWF activity. A questionnaire was filled for every patient. The data were then analyzed using the SPSS software. Results: Mean age of our patients was 32.5 ± 10.6 years. The level of von Willebrand factor in 22.5% and von Willebrand activity in 19.6% of patients was abnormal. The prevalence of vWD among patients with menorrhagia was 24%. Conclusions: The high prevalence of vWD among our patients was the same as other previous reports, suggesting low awareness about this disease and under diagnosis of mild cases. PMID:25763275

  6. The effect of exercise on von Willebrand factor and ADAMTS-13 in individuals with type 1 and type 2B von Willebrand disease

    NARCIS (Netherlands)

    Stakiw, J.; Bowman, M.; Hegadorn, C.; Pruss, C.; Notley, C.; Groot, E.; Lenting, P. J.; Rapson, D.; Lillicrap, D.; James, P.

    Background: The effect of exercise on von Willebrand factor (VWF) and ADAMTS-13 levels in individuals with von Willebrand disease (VWD) has never been reported. Objectives: The aim was to quantify the effect of a standardized exercise protocol on individuals with type 1 and type 2B VWD.

  7. Nordic Haemophilia Council's practical guidelines on diagnosis and management of von Willebrand disease

    DEFF Research Database (Denmark)

    Lassila, Riitta; Holme, Pål André; Landorph, Andrea

    2011-01-01

    Von Willebrand disease (VWD) is the most common inherited bleeding disorder characterized by spontaneous or tissue injury-related, mostly mucocutaneous, bleeding events. VWD affects both males and females and is caused by quantitative or qualitative deficiency of Von Willebrand factor. The diagno...

  8. Current and Emerging Options for the Management of Inherited von Willebrand Disease

    NARCIS (Netherlands)

    Heijdra, J.M. (Jessica M.); M.H. Cnossen (Marjon); F.W.G. Leebeek (Frank)

    2017-01-01

    textabstractVon Willebrand disease (VWD) is the most common inherited bleeding disorder with an estimated prevalence of ~1% and clinically relevant bleeding symptoms in approximately 1:10,000 individuals. VWD is caused by a deficiency and/or defect of von Willebrand factor (VWF). The most common

  9. Myomectomy in a case of von Willebrand's disease in a low ...

    African Journals Online (AJOL)

    Von Willebrand's disease (vWD) is an inherited bleeding disorder with an estimated prevalence of 1% in the general population. It is caused by deficiency or dysfunction of von Willebrand's factor. Surgical procedure on patients with vWD is usually associated with increased haemorrhage. Keywords: Clotting Factors ...

  10. Acquired von Willebrand's disease and hypothyroidism: report of a case presenting with menorrhagia.

    Science.gov (United States)

    Blesing, N. E.; Hambley, H.; McDonald, G. A.

    1990-01-01

    A 17 year old woman presented with severe anaemia due to menorrhagia. On investigation, she was shown to have abnormalities of her haemostatic mechanism consistent with von Willebrand's disease Type I, although there was no family history of this disorder. In addition, she was shown to have severe primary hypothyroidism. On correction of hypothyroidism with oral thyroxine, her coagulation defects returned to normal and menorrhagia ceased. This is consistent with acquired von Willebrand's disease secondary to hypothyroidism. PMID:2217000

  11. Diagnosis and Treatment of von Willebrand Disease and Rare Bleeding Disorders

    Directory of Open Access Journals (Sweden)

    Giancarlo Castaman

    2017-04-01

    Full Text Available Along with haemophilia A and B, von Willebrand disease (VWD and rare bleeding disorders (RBDs cover all inherited bleeding disorders of coagulation. Bleeding tendency, which can range from extremely severe to mild, is the common symptom. VWD, due to a deficiency and/or abnormality of von Willebrand factor (VWF, represents the most frequent bleeding disorder, mostly inherited as an autosomal dominant trait. The diagnosis may be difficult, based on a bleeding history and different diagnostic assays, which evaluate the pleiotropic functions of VWF. Different treatment options are available for optimal management of bleeding and their prevention, and long-term outcomes are generally good. RBDs are autosomal recessive disorders caused by a deficiency of any other clotting factor, apart from factor XII, and cover roughly 5% of all bleeding disorders. The prevalence of the severe forms can range from 1 case in 500,000 up to 1 in 2–3 million, according to the defect. Diagnosis is based on bleeding history, coagulation screening tests and specific factor assays. A crucial problem in RBDs diagnosis is represented by the non-linear relationship between clinical bleeding severity and residual clotting levels; genetic diagnosis may help in understanding the phenotype. Replacement therapies are differently available for patients with RBDs, allowing the successful treatment of the vast majority of bleeding symptoms.

  12. Changes in bleeding patterns in von Willebrand disease after institution of long-term replacement therapy : results from the von Willebrand Disease Prophylaxis Network

    NARCIS (Netherlands)

    Holm, Elena; Abshire, Thomas C; Bowen, Joel; Álvarez, M Teresa; Bolton-Maggs, Paula; Carcao, Manuel; Federici, Augusto B; Gill, Joan Cox; Halimeh, Susan; Kempton, Christine; Key, Nigel S; Kouides, Peter; Lail, Alice; Landorph, Andrea; Leebeek, Frank; Makris, Michael; Mannucci, Pier; Mauser-Bunschoten, Eveline P; Nugent, Diane; Valentino, Leonard A; Winikoff, Rochelle; Berntorp, Erik

    Clinically, the leading symptom in von Willebrand disease (VWD) is bleeding, chiefly of mucosal type, for example, epistaxis, gingival, or gastrointestinal bleeding, and menorrhagia. In severe forms of VWD with secondary deficiency of factor VIII, spontaneous joint bleeding, resembling that observed

  13. Detailed von Willebrand factor multimer analysis in patients with von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease (MCMDM-1VWD)

    DEFF Research Database (Denmark)

    Budde, U.; Schneppenheim, R.; Eikenboom, J.

    2008-01-01

    BACKGROUND: Type 1 von Willebrand disease (VWD) is a congenital bleeding disorder characterized by a partial quantitative deficiency of plasma von Willebrand factor (VWF) in the absence of structural and/or functional VWF defects. Accurate assessment of the quantity and quality of plasma VWF...... is difficult but is a prerequisite for correct classification. OBJECTIVE: To evaluate the proportion of misclassification of patients historically diagnosed with type 1 VWD using detailed analysis of the VWF multimer structure. Patients and methods: Previously diagnosed type 1 VWD families and healthy controls...

  14. Towards improved diagnosis of von Willebrand disease: comparative evaluations of several automated von Willebrand factor antigen and activity assays.

    Science.gov (United States)

    Favaloro, Emmanuel J; Mohammed, Soma

    2014-12-01

    von Willebrand disease (VWD) is reportedly the most common bleeding disorder and arises from deficiency and/or defects of von Willebrand factor (VWF). Laboratory diagnosis and typing has important management implications and requires a wide range of tests, including VWF activity and antigen, and involves differential identification of qualitative vs quantitative defects. We have assessed several VWF antigen and activity assays (collagen binding [VWF:CB], ristocetin cofactor [VWF:RCo] and the new Siemens INNOVANCE assay [VWF:Ac], employing latex particles and gain of function recombinant glycoprotein Ib to facilitate VWF binding and agglutination without need for ristocetin) using different instrumentation, including the new Sysmex CS-5100, with a large sample test set (n=600). We included retrospective plus prospective study designs, and also evaluated desmopressin responsiveness plus differential sensitivity to high molecular weight VWF. VWF:Ag and VWF:RCo results from different methods were respectively largely comparable, although some notable differences were evident, including one high false normal VWF:Ag value (105 U/dL) on a type 3 VWD sample, possibly due to heterophile antibody interference in the latex-based CS-5100 methodology. VWF:Ac was largely comparable to VWF:RCo, but VWF:CB showed discrepant findings to both VWF:RCo and VWF:Ac with some patients, most notably patients with type 2M VWD. (a) VWF:Ag on different platforms are largely interchangeable, as are VWF:RCo on different platforms, except for occasional (some potentially important) differences, and manufacturer recommended methods may otherwise require some assay optimization; (b) VWF:RCo and VWF:Ac are largely interchangeable, except for occasional differences that may also relate to assay design (differing optimizations); (c) VWF:CB provides an additional activity to supplement VWF:RCo or VWF:Ac activity assays, and is not interchangeable with either. Crown Copyright © 2014. Published by

  15. Diagnostic Differentiation of von Willebrand Disease Types 1 and 2 by von Willebrand Factor Multimer Analysis and DDAVP Challenge Test.

    Science.gov (United States)

    Michiels, Jan Jacques; Smejkal, Petr; Penka, Miroslav; Batorova, Angelika; Pricangova, Tatiana; Budde, Ulrich; Vangenechten, Inge; Gadisseur, Alain

    2017-09-01

    The European Clinical Laboratory and Molecular (ECLM) classification of von Willebrand disease (vWD) is based on the splitting approach which uses sensitive and specific von Willebrand factor (vWF) assays with regard to the updated molecular data on structure and function of vWF gene and protein defects. A complete set of FVIII:C and vWF ristocetine cofactor, collagen binding, and antigen, vWF multimeric analysis in low- and medium-resolution gels, and responses to desmopressin (DDAVP) of FVIII:C and vWF parameters are mandatory. The ECLM classification distinguishes recessive types 1 and 3 vWD from recessive vWD 2C due to mutations in the D1 and D2 domains and vWD 2N due to mutations in the D'-FVIII-binding domain of vWF. The ECLM classification differentiates between mild vWD type 1 with variable penetrance of bleedings from symptomatic dominant type 1 vWD secretion defect and/or clearance defect with normal vWF multimers versus vWD 1M and 2M with normal or smeary vWF multimers in low- and medium-resolution gels. High-quality multimeric analysis of vWF in medium-resolution gels based on a DDAVP challenge test clearly delineates and distinguishes each of the dominant type 2 vWDs 1/2E, 2M, 2B, 2A, and 2D caused by vWF gene mutations in the D3 multimerization domain, loss or gain-of-function mutations in the glycoprotein Ib receptor A1 domain, gene mutations in the A2 proteolytic domain, and the C-terminal dimerization domain, respectively.

  16. Diagnosing von Willebrand disease: a short history of laboratory milestones and innovations, plus current status, challenges, and solutions.

    Science.gov (United States)

    Favaloro, Emmanuel J

    2014-07-01

    von Willebrand disease (VWD) is a disorder characterized by deficiency of, or defects in, von Willebrand factor (VWF). VWD was originally identified by Erik Adolf von Willebrand, who in early 1924 investigated a large family suffering from a bleeding disorder that seemed to differ from hemophilia. Erik von Willebrand undertook some initial laboratory investigations to conclude the involvement of a plasma factor, the lack of which prolonged the bleeding time, but failed to impair coagulation times and clot retraction. By the end of the 1960s, VWD was accepted as a combined deficiency of factor VIII (FVIII) and another plasma factor responsible for normal platelet adhesion. Just how these two functions were related to each other was less clear and the diagnostic tests available at the time were poorly reproducible, cumbersome, and unreliable; thus, VWD was poorly delineated from other coagulation and platelet disorders. The early 1970s saw a revolution in diagnostics when ristocetin was identified to induce platelet aggregation, and this formed the basis of the first consistent and reliable VWF "activity" test, permitting quantification of the platelet adhesive function missing in VWD. Concurrently, immunoprecipitating techniques specific for VWF were defined, and the application of such technologies permitted a clearer understanding of both VWF and VWD heterogeneity. Continued exploration of the structure and function of VWF contributed greatly to the understanding of platelet physiology, ligand receptor interaction and pathways of cellular interaction and activation. Recently, additional assays evaluating other functions of VWF, including collagen binding, platelet glycoprotein Ib binding, and FVIII binding, have improved the diagnosis of VWD. The purpose of this narrative review is to explore the history of phenotypic VWD diagnostics, with a focus on laboratory milestones from the past as well highlighting recent and ongoing innovations, and ongoing challenges and

  17. Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): comprehensive genetic analysis by next-generation sequencing of 480 patients.

    Science.gov (United States)

    Borràs, Nina; Batlle, Javier; Pérez-Rodríguez, Almudena; López-Fernández, María Fernanda; Rodríguez-Trillo, Ángela; Lourés, Esther; Cid, Ana Rosa; Bonanad, Santiago; Cabrera, Noelia; Moret, Andrés; Parra, Rafael; Mingot-Castellano, María Eva; Balda, Ignacia; Altisent, Carme; Pérez-Montes, Rocío; Fisac, Rosa María; Iruín, Gemma; Herrero, Sonia; Soto, Inmaculada; de Rueda, Beatriz; Jiménez-Yuste, Víctor; Alonso, Nieves; Vilariño, Dolores; Arija, Olga; Campos, Rosa; Paloma, María José; Bermejo, Nuria; Berrueco, Rubén; Mateo, José; Arribalzaga, Karmele; Marco, Pascual; Palomo, Ángeles; Sarmiento, Lizheidy; Iñigo, Belén; Nieto, María Del Mar; Vidal, Rosa; Martínez, María Paz; Aguinaco, Reyes; César, Jesús María; Ferreiro, María; García-Frade, Javier; Rodríguez-Huerta, Ana María; Cuesta, Jorge; Rodríguez-González, Ramón; García-Candel, Faustino; Cornudella, Rosa; Aguilar, Carlos; Vidal, Francisco; Corrales, Irene

    2017-12-01

    Molecular diagnosis of patients with von Willebrand disease is pending in most populations due to the complexity and high cost of conventional molecular analyses. The need for molecular and clinical characterization of von Willebrand disease in Spain prompted the creation of a multicenter project (PCM-EVW-ES) that resulted in the largest prospective cohort study of patients with all types of von Willebrand disease. Molecular analysis of relevant regions of the VWF, including intronic and promoter regions, was achieved in the 556 individuals recruited via the development of a simple, innovative, relatively low-cost protocol based on microfluidic technology and next-generation sequencing. A total of 704 variants (237 different) were identified along VWF, 155 of which had not been previously recorded in the international mutation database. The potential pathogenic effect of these variants was assessed by in silico analysis. Furthermore, four short tandem repeats were analyzed in order to evaluate the ancestral origin of recurrent mutations. The outcome of genetic analysis allowed for the reclassification of 110 patients, identification of 37 asymptomatic carriers (important for genetic counseling) and re-inclusion of 43 patients previously excluded by phenotyping results. In total, 480 patients were definitively diagnosed. Candidate mutations were identified in all patients except 13 type 1 von Willebrand disease, yielding a high genotype-phenotype correlation. Our data reinforce the capital importance and usefulness of genetics in von Willebrand disease diagnostics. The progressive implementation of molecular study as the first-line test for routine diagnosis of this condition will lead to increasingly more personalized and effective care for this patient population. Copyright© 2017 Ferrata Storti Foundation.

  18. Clinical and laboratory diagnosis of von Willebrand disease : A synopsis of the 2008 NHLBI/NIH guidelines

    NARCIS (Netherlands)

    Nichols, William L.; Rick, Margaret E.; Ortel, Thomas L.; Montgomery, Robert R.; Sadler, J. Evan; Yawn, Barbara P.; James, Andra H.; Hultin, Mae B.; Manco-Johnson, Marilyn J.; Weinstein, Mark

    Von Willebrand factor (VWF) mediates blood platelet adhesion and accumulation at sites of blood vessel injury, and also carries coagulation factor VIII (FVIII) that is important for generating procoagulant activity. Von Willebrand disease (VWD), the most common inherited bleeding disorder, affects

  19. A systematic review of the effects of hemophilia and von Willebrand disease on arterial trombosis

    NARCIS (Netherlands)

    Biere-Rafi, Sara; Zwiers, M.; Peters, Marjolein; Van Der Meer, Jan; Rosendaal, Frits R; Buller, Harry R; Kamphuisen, Pieter W

    Background: Patients with hemophilia and von Willebrand disease (VWD) may be protected against arterial thrombosis, through a hy-pocoagulable state or atherosclerosis. We performed a systematic review to assess the association between these clotting disorders, arterial thrombosis and the prevalence

  20. Health-related quality of life among adult patients with moderate and severe von Willebrand disease.

    NARCIS (Netherlands)

    Wee, E.M. de; Mauser-Bunschoten, E.P.; Bom, J.G. Van Der; Degenaar-Dujardin, M.E.; Eikenboom, H.C.; Fijnvandraat, K.; Goede-Bolder, A. de; Laros, B.A.P.; Meijer, K.; Raat, H.; Leebeek, F.W.

    2010-01-01

    SUMMARY BACKGROUND: von Willebrand Disease (VWD) is the most frequent inherited bleeding disorder. It is unknown how this disorder affects quality of life. OBJECTIVES: This nationwide multicenter cross-sectional study determined health-related quality of life (HR-QoL) in adult patients with moderate

  1. The effect of haemophilia and von Willebrand disease on arterial thrombosis : A systematic review

    NARCIS (Netherlands)

    Biere-Rafi, S.; Zwiers, M.; Peters, M.; van der Meer, J.; Rosendaal, F. R.; Buller, H. R.; Kamphuisen, P. W.

    Background: Patients with haemophilia and von Willebrand disease (VWD) may have a reduced cardiovascular mortality, due to a hypocoagulable state or decreased atherogenesis. We performed a systematic review to assess the association between haemophilia and VWD, and fatal and nonfatal arterial

  2. Gynaecological and obstetric bleeding in moderate and severe von Willebrand disease

    NARCIS (Netherlands)

    de Wee, Eva M.; Knol, H. Marieke; Mauser-Bunschoten, Eveline P.; van der Bom, Johanna G.; Eikenboom, Jeroen C. J.; Fijnvandraat, Karin; de Goede-Bolder, Arja; Laros-van Gorkom, Britta; Ypma, Paula F.; Zweegman, Sonja; Meijer, Karina; Leebeek, Frank W. G.

    2011-01-01

    A nation-wide cross-sectional study was initiated to assess gynaecological and obstetrical symptoms in an unselected cohort of women with moderate and severe von Willebrand disease (VWD) in the Netherlands. A total of 423 women aged >= 16 years were included. Bleeding severity was measured using the

  3. Gynaecological and obstetric bleeding in moderate and severe von Willebrand disease.

    NARCIS (Netherlands)

    Wee, E.M. de; Knol, H.M.; Mauser-Bunschoten, E.P.; Bom, J.G. Van Der; Eikenboom, J.C.; Fijnvandraat, K.; Goede-Bolder, A. de; Laros-van Gorkom, B.A.P.; Ypma, P.F.; Zweegman, S.; Meijer, K.; Leebeek, F.W.

    2011-01-01

    A nation-wide cross-sectional study was initiated to assess gynaecological and obstetrical symptoms in an unselected cohort of women with moderate and severe von Willebrand disease (VWD) in the Netherlands. A total of 423 women aged >/=16 years were included. Bleeding severity was measured using the

  4. Inheritance of von Willebrand's disease in a colony of Doberman Pinschers.

    Science.gov (United States)

    Riehl, J; Okura, M; Mignot, E; Nishino, S

    2000-02-01

    To determine the mode of inheritance of von Willebrand's disease (vWD) and perform linkage analysis between vWD and coat color or narcolepsy in a colony of Doberman Pinschers. 159 Doberman Pinschers. von Willebrand factor antigen (vWF:Ag) concentration was measured by use of ELISA, and results were used to classify dogs as having low ( 65%) vWF:Ag concentration, compared with results of analysis of standard pooled plasma. Buccal bleeding time was measured, and mode of inheritance of vWD was assessed by pedigree analysis. von Willebrand's disease was transmitted as a single autosomal gene defect. Results suggested that 27.04% of dogs were homozygous for vWD, 62.26% were heterozygous, and 10.69% did not have the defect. Most homozygous and some heterozygous dogs had prolonged bleeding times. Dogs with diluted coat colors (blue and fawn) were significantly overrepresented in the homozygous group, compared with black and red dogs, but a significant link between vWD and coat color was not detected. von Willebrand's disease is transmitted as an autosomal dominant trait with variable penetrance; most dogs in this colony (89.3%) were carriers of vWD. Homozygosity for vWD is not likely to be lethal. Some heterozygous dogs have prolonged bleeding times. An association between diluted coat colors and vWD may exist.

  5. Pseudo (Platelet-type von Willebrand disease in pregnancy: a case report

    Directory of Open Access Journals (Sweden)

    Grover Neetu

    2013-01-01

    Full Text Available Abstract Background Pseudo (platelet-type-von Willebrand disease is a rare autosomal dominant bleeding disorder caused by an abnormal function of the glycoprotein lb protein; the receptor for von Willebrand factor. This leads to an increased removal of VWF multimers from the circulation as well as platelets and this results in a bleeding diathesis. Worldwide, less than 50 patients are reported with platelet type von Willebrand disease (PT-VWD. Case presentation We describe the management of platelet type von Willebrand disease in pregnancy of a 26 year old Caucasian primigravida. The initial diagnosis was made earlier following a significant haemorrhage post tonsillectomy several years prior to pregnancy. The patient was managed under a multidisciplinary team which included obstetricians, haematologists, anaesthetists and neonatologists. Care plans were made for the ante- natal, intra-partum and post-partum periods in partnership with the patient. The patient’s platelet count levels dropped significantly during the antenatal period. This necessitated the active exclusion of other causes of thrombocytopenia in pregnancy. A vaginal delivery was desired and plans were made for induction of labour at 38 weeks of gestation with platelet cover in view of the progressive fall of the platelet count. The patient however went into spontaneous labour on the day of induction. She was transfused two units of platelets before delivery. She had an unassisted vaginal delivery of a healthy baby. The successful antenatal counselling has encouraged the diagnosis of the same condition in her mother and sister. We found this to be a particularly interesting case as well as challenging to manage due to its rarity. Psuedo von Willebrand disease in pregnancy can be confused with a number of other differential diagnoses, such as gestational thrombocutopenia, idiopathatic thrombocytopenia, thrombotic thrombocytopenic purpura and pre-eclampsia; all need consideration

  6. Pseudo (platelet-type) von Willebrand disease in pregnancy: a case report.

    Science.gov (United States)

    Grover, Neetu; Boama, Vincent; Chou, Munazzah Rifat

    2013-01-17

    Pseudo (platelet-type)-von Willebrand disease is a rare autosomal dominant bleeding disorder caused by an abnormal function of the glycoprotein lb protein; the receptor for von Willebrand factor. This leads to an increased removal of VWF multimers from the circulation as well as platelets and this results in a bleeding diathesis. Worldwide, less than 50 patients are reported with platelet type von Willebrand disease (PT-VWD). We describe the management of platelet type von Willebrand disease in pregnancy of a 26 year old Caucasian primigravida. The initial diagnosis was made earlier following a significant haemorrhage post tonsillectomy several years prior to pregnancy. The patient was managed under a multidisciplinary team which included obstetricians, haematologists, anaesthetists and neonatologists. Care plans were made for the ante- natal, intra-partum and post-partum periods in partnership with the patient. The patient's platelet count levels dropped significantly during the antenatal period. This necessitated the active exclusion of other causes of thrombocytopenia in pregnancy. A vaginal delivery was desired and plans were made for induction of labour at 38 weeks of gestation with platelet cover in view of the progressive fall of the platelet count. The patient however went into spontaneous labour on the day of induction. She was transfused two units of platelets before delivery. She had an unassisted vaginal delivery of a healthy baby. The successful antenatal counselling has encouraged the diagnosis of the same condition in her mother and sister. We found this to be a particularly interesting case as well as challenging to manage due to its rarity. Psuedo von Willebrand disease in pregnancy can be confused with a number of other differential diagnoses, such as gestational thrombocutopenia, idiopathatic thrombocytopenia, thrombotic thrombocytopenic purpura and pre-eclampsia; all need consideration during investigations even in a case such as this where the

  7. Management of type 2b von Willebrand disease in the neonatal period.

    Science.gov (United States)

    Proud, Lindsay; Ritchey, A Kim

    2017-01-01

    Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting one in 1,000 people. Type 2b VWD is a less common subtype caused by a gain-of-function mutation in von Willebrand factor (VWF) that leads to the formation of large, ineffective VWF-platelet multimers in circulation. This unique pathophysiology creates diagnostic and treatment dilemmas. There is limited information on the management of type 2b VWD in the neonatal period. This report describes the management of a neonate with type 2b VWD with an emphasis on the added benefit of concomitant platelet transfusion and factor replacement therapy over factor replacement therapy alone. © 2016 Wiley Periodicals, Inc.

  8. Identification and Characterization of Novel Variations in Platelet G-Protein Coupled Receptor (GPCR Genes in Patients Historically Diagnosed with Type 1 von Willebrand Disease.

    Directory of Open Access Journals (Sweden)

    Jacqueline Stockley

    Full Text Available The clinical expression of type 1 von Willebrand disease may be modified by co-inheritance of other mild bleeding diatheses. We previously showed that mutations in the platelet P2Y12 ADP receptor gene (P2RY12 could contribute to the bleeding phenotype in patients with type 1 von Willebrand disease. Here we investigated whether variations in platelet G protein-coupled receptor genes other than P2RY12 also contributed to the bleeding phenotype. Platelet G protein-coupled receptor genes P2RY1, F2R, F2RL3, TBXA2R and PTGIR were sequenced in 146 index cases with type 1 von Willebrand disease and the potential effects of identified single nucleotide variations were assessed using in silico methods and heterologous expression analysis. Seven heterozygous single nucleotide variations were identified in 8 index cases. Two single nucleotide variations were detected in F2R; a novel c.-67G>C transversion which reduced F2R transcriptional activity and a rare c.1063C>T transition predicting a p.L355F substitution which did not interfere with PAR1 expression or signalling. Two synonymous single nucleotide variations were identified in F2RL3 (c.402C>G, p.A134 =; c.1029 G>C p.V343 =, both of which introduced less commonly used codons and were predicted to be deleterious, though neither of them affected PAR4 receptor expression. A third single nucleotide variation in F2RL3 (c.65 C>A; p.T22N was co-inherited with a synonymous single nucleotide variation in TBXA2R (c.6680 C>T, p.S218 =. Expression and signalling of the p.T22N PAR4 variant was similar to wild-type, while the TBXA2R variation introduced a cryptic splice site that was predicted to cause premature termination of protein translation. The enrichment of single nucleotide variations in G protein-coupled receptor genes among type 1 von Willebrand disease patients supports the view of type 1 von Willebrand disease as a polygenic disorder.

  9. Assessing the clinical severity of type 1 von Willebrand disease patients with a microchip flow-chamber system.

    Science.gov (United States)

    Nogami, K; Ogiwara, K; Yada, K; Shida, Y; Takeyama, M; Yaoi, H; Minami, H; Furukawa, S; Hosokawa, K; Shima, M

    2016-04-01

    The clinical phenotype of von Willebrand disease (VWD) is heterogeneous, and von Willebrand factor ristocetin cofactor activity (VWF:RCo) does not always reflect clinical severity, especially in VWD type 1. We have reported the potential of a microchip flow-chamber system (Total-Thrombus Formation Analysis System [T-TAS®]) for assessing physiologic hemostasis in VWD. Aim To evaluate the relationship between T-TAS, bleeding score (BS) and laboratory test results in type 1 VWD patients. Microchips coated with collagen (platelet chip [PL-chip]) or collagen/thromboplastin (AR-chip) were used to assess platelet thrombus formation (PTF) at high shear rates or fibrin-rich PTF at low shear rates, respectively, in whole blood from 50 patients. The times needed for the flow pressure to increase by 10 kPa and 30 kPa (T10 and T30 ) from baseline were calculated from flow pressure curves. BS was determined by the use of a standardized questionnaire. PL-T10 values correlated with BS (R(2) ~ 0.45) better than VWF:RCo (R(2) ~ 0.36), irrespective of the flow rate, whereas AR-T10 showed only a weak correlation with BS (R(2) ~ 0.18). Patients with PL-T10 > 10 min or AR-T10 > 30 min had lower VWF levels and higher BS than those with PL-T10 ≤ 10 min or AR-T10 ≤ 30 min, and the greatest differences were observed with PL-T10. Clinical severity appeared to correlate best with PL-T10 > 8 min. BS was significantly higher in patients with VWF:RCo of 8 min than in those with PL-T10 ≤ 8 min. T-TAS could be a useful technique for discriminating and predicting BS in VWD type 1 patients. © 2016 International Society on Thrombosis and Haemostasis.

  10. Prevalence of von Willebrand disease in women with iron deficiency anaemia and menorrhagia in Taiwan.

    Science.gov (United States)

    Chen, Y-C; Chao, T-Y; Cheng, S-N; Hu, S-H; Liu, J-Y

    2008-07-01

    Iron deficiency anaemia (IDA) is a frequently encountered disease, which can be attributed to menorrhagia. Most female patients with von Willebrand disease (VWD) have menorrhagia. The aim of this study was to investigate the prevalence of VWD in women with both IDA and menorrhagia in Taiwan. From January to December 2005 and November 2006 to January 2007, 56 consecutive patients with both IDA and menorrhagia were enrolled in this study. Their median age was 41 years (range 18-53). IDA was diagnosed by anaemia plus either low ferritin or transferrin saturation. Menorrhagia was evaluated by patient's menses history. Both von Willebrand factor antigen (VWF:Ag) and ristocetin cofactor activity (VWF:RCo) were measured for each patient. Bleeding time (BT) and platelet function analyser (PFA)-100 assay were determined as ancillary tests. The VWD diagnosis was established if: (i) both VWF:Ag (menorrhagia might develop IDA at younger age (34.3 vs. 39.7, P = 0.09) and had more IDA recurrence (75% vs. 16%, P = 0.03) than those patients without VWD. Of the eight VWD patients with VWF multimer analyses, all were revealed to have type I VWD. Our study demonstrates that VWD was not uncommon in women with both IDA and menorrhagia in Taiwan.

  11. Evaluation of von Willebrand factor phenotypes and genotypes in Hemophilia A patients with and without identified F8 mutations.

    Science.gov (United States)

    Boylan, B; Rice, A S; De Staercke, C; Eyster, M E; Yaish, H M; Knoll, C M; Bean, C J; Miller, C H

    2015-06-01

    Hemophilia A (HA) is an X-linked bleeding disorder caused by a deficiency in factor VIII (FVIII). von Willebrand disease (VWD) is characterized by a quantitative or qualitative defect in von Willebrand factor (VWF). Patients with VWD with severely low VWF or VWD Type 2N (VWD2N), a VWD subtype distinguished by defective VWF binding to FVIII, may have reduced FVIII levels secondary to their VWD. These patients superficially resemble patients with HA and pose a potential for misdiagnosis. To investigate the unexplained cause of bleeding in HA patients without known FVIII mutations by assessing plasma VWF antigen (VWF:Ag), FVIII binding capacities and VWF genotypes. Thirty-seven of 1027 patients with HA studied as part of the Hemophilia Inhibitor Research Study lacked identifiable F8 mutations. These patients (cases) and 73 patients with identified F8 mutations (controls) were evaluated for VWF:Ag, a patient's VWF capacity to bind FVIII (VWF:FVIIIB) and VWF sequence. Four cases had VWF:Ag < 3 IU dL(-1) and VWF mutations consistent with Type 3 VWD. Six cases and one control were heterozygous for mutations previously reported to cause Type 1 VWD (VWD1) (n = five cases and one control) or predicted to be deleterious by Polyphen2 and SIFT prediction tools (n = 1 case). One control had VWF:Ag < 30 IU dL(-1) and seven patients (four cases and three controls), including two cases who were heterozygous for a known VWD2N mutation, had reduced VWF:FVIIIB. These data emphasize that some patients diagnosed with HA require VWF assessments in order to achieve a comprehensive diagnosis and an optimal treatment strategy. © 2015 International Society on Thrombosis and Haemostasis.

  12. Levonorgestrel intrauterine system as a treatment option for severe menorrhagia in adolescent with type III von Willebrand disease.

    Science.gov (United States)

    Silva, Carla Donato; Geraldes, Fernanda; Silva, Isabel Santos

    2013-04-30

    The authors describe a case of an adolescent with type III von Willebrand disease and severe menorrhagia since menarche. Antifibrinolytic, hormonal (estroprogestative pill in high doses, etonogestrel implant and gonadotropin-releasing hormone agonist goserelin) and Von Willebrand Factor/Factor VIII replacement therapies were prescribed to the patient, but symptomatic control was only obtained with high doses of VWF/FVIII twice a week. In March 2012, a levonorgestrel intrauterine system was inserted in a 14-year-old. At present, the patient is asymptomatic without regular prophylaxis (VWF/FVIII replacement therapy) and has had a remarkable improvement in her quality of life.

  13. Long-term impact of joint bleeds in von Willebrand disease: a nested case-control study

    NARCIS (Netherlands)

    Galen, K.P. van; Kleijn, P. de; Foppen, W.; Eikenboom, J.; Meijer, K.; Schutgens, R.E.; Fischer, K.; Cnossen, M.H.; Meris, J. de; Fijnvandraat, K.; Bom, J.G. Van Der; Laros-van Gorkom, B.A.P.; Leebeek, F.W.; Mauser-Bunschoten, E.P.

    2017-01-01

    Patients with severe von Willebrand disease (VWD) may develop arthropathy after joint bleeds. Information on its prevalence and severity is limited. We aimed to assess the occurrence and severity of arthropathy in VWD and its impact on daily life. VWD patients with and without verified joint bleeds

  14. Long-term impact of joint bleeds in von Willebrand disease : A nested case-control study

    NARCIS (Netherlands)

    van Galen, Karin P.M.; de Kleijn, Piet; Foppen, Wouter; Eikenboom, Jeroen H C; Meijer, Karina; Schutgens, Roger E.G.; Fischer, Kathelijn; Cnossen, Marjon H; de Meris, Joke; Fijnvandraat, Karin; van der Bom, Johanna G; Laros-van Gorkom, Britta A P; Leebeek, Frank W G; Mauser-Bunschoten, Eveline P.

    2017-01-01

    Patients with severe von Willebrand disease (VWD) may develop arthropathy after joint bleeds. Information on its prevalence and severity is limited. We aimed to assess the occurrence and severity of arthropathy in VWD and its impact on daily life. VWD patients with and without verified joint bleeds

  15. Long-term impact of joint bleeds in von Willebrand disease : A nested case-control study

    NARCIS (Netherlands)

    van Galen, Karin P. M.; de Kleijn, Piet; Foppen, Wouter; Eikenboom, Jeroen; Meijer, Karina; Schutgens, Roger E. G.; Fischer, Kathelijn; Cnossen, Marjon H.; de Meris, Joke; Fijnvandraat, Karin; van der Bom, Johanna G.; Laros-van Gorkom, Britta A. P.; Leebeek, Frank W. G.; Mauser-Bunschoten, Eveline P.

    Patients with severe von Willebrand disease (VWD) may develop arthropathy after joint bleeds. Information on its prevalence and severity is limited. We aimed to assess the occurrence and severity of arthropathy in VWD and its impact on daily life. VWD patients with and without verified joint bleeds

  16. Long-term impact of joint bleeds in von Willebrand disease: A nested case-control study

    NARCIS (Netherlands)

    K.P.M. van Galen; P. de Kleijn; W. Foppen (Wouter); J.C.J. Eikenboom (Jeroen); K. Meijer; R. Schutgens (Roger); K. Fischer (Kathelijn); M.H. Cnossen (Marjon); J. de Meris (J.); K. Fijnvandraat; J.G. van der Bom (Anske); B.A.P. Laros-Van Gorkom (Britta); F.W.G. Leebeek (Frank); E.P. Mauser-Bunschoten (Eveline)

    2017-01-01

    textabstractPatients with severe von Willebrand disease (VWD) may develop arthropathy after joint bleeds. Information on its prevalence and severity is limited. We aimed to assess the occurrence and severity of arthropathy in VWD and its impact on daily life. VWD patients with and without verified

  17. Pulmonary hypertension secondary to hyperviscosity in a patient with rheumatoid arthritis and acquired von Willebrand disease: a case report.

    Science.gov (United States)

    Hernández-Gilsoul, Thierry; Atisha-Fregoso, Yemil; Vargas-Ruíz, Angel G; Rivero-Sigarroa, Eduardo; Dominguez-Cherit, Guillermo; Namendys-Silva, Silvio A

    2013-10-02

    Acquired von Willebrand disease is initiated by autoantibodies and hyperviscosity syndrome caused by a massive polyclonal hypergammaglobulinemia. Acquired von Willebrand disease associated with autoimmune disease in addition to pulmonary hypertension during emergency room presentation is a rare condition. To the best of our knowledge, this is the second case reported in the literature treated with success; the first one was reported in 1987. A 28-year-old mestizo man with a 3-year history of inflammatory arthritis was admitted to our hospital. An overlap of rheumatoid arthritis with systemic lupus erythematosus was suspected; therefore methotrexate was initiated, and later changed to leflunomide because of liver toxicity. Prothrombin time, international normalized ratio and activated partial thromboplastin times were normal (11/10.4 seconds; 1.2; 31.1/26.9 seconds, respectively), von Willebrand factor activity was observed with low ristocetin cofactor at 33.6UI/dL, high von Willebrand factor antigen >200UI/dL, and a low von Willebrand factor: ristocetin cofactor to von Willebrand factor antigen ratio. He was admitted to the emergency room with a 24-hour evolution of progressive dyspnea, cough, thoracic pain, and palpitations, 104 beats/min, 60/40 mmHg, temperature of 38°C, pulse oximetric saturation 88% and 30 breaths/minute. Cold, pale and mottled skin was also observed. He was then transferred to the intensive care unit. The placement of a pulmonary artery catheter was made. The initial patterns showed a precapillary pulmonary hypertension; acute pulmonary embolism was the first choice for diagnosis. Pulmonary angiography was conducted, and when no clot was discovered, pulmonary artery hypertension associated with connective tissue disease was considered. Serum protein electrophoresis confirmed the presence of a massive polyclonal hypergammaglobulinemia, and no paraproteinemia or monoclonal cell population was found from the electrophoretic pattern of the

  18. Postpartum Hemorrhage in Women with Von Willebrand Disease - A Retrospective Observational Study.

    Directory of Open Access Journals (Sweden)

    Igor Govorov

    Full Text Available von Willebrand disease (VWD is a hereditary bleeding disorder, caused by a deficiency in the levels and/or function of von Willebrand factor (VWF. Women with VWD appear to be at increased risk of experiencing postpartum hemorrhage (PPH, though the levels of VWF increase during pregnancy. There is limited knowledge of how PPH is associated with the subtype of VWD, plasma levels of other coagulations factors than VWF and given hemostatic treatment.The aims were to investigate the incidence of PPH in women with VWD and to analyse the correlation between PPH and: (1 type of VWD, (2 laboratory monitoring of VWF and FVIII and (3 hemostatic drug treatment.This was a retrospective observational study. The study participants (n = 34 were recruited from the Coagulation Unit, Karolinska University hospital. Fifty-nine deliveries, which occurred in 14 different obstetrics units (years 1995-2012 were included in the study.The incidence of primary PPH was 44%, severe primary PPH 20% and secondary PPH 12%. VWD type 3 was associated with a higher risk of experiencing severe primary PPH compared to other subtypes. FVIII:C in pregnancy was inversely correlated to blood loss during delivery. There was a significantly higher incidence of secondary PPH when the VWD diagnosis was unknown at time of delivery.The women with VWD are at higher risk of PPH, especially those with type 3 VWD or when diagnosis is unknown prior to delivery. Identification of pregnant women with undiagnosed VWD may be of importance in order to prevent PPH.

  19. Genetic heterogeneity in a large cohort of Indian type 3 von Willebrand disease patients.

    Directory of Open Access Journals (Sweden)

    Priyanka Kasatkar

    Full Text Available Though von Willebrand disease (VWD is a common coagulation disorder, due to the complexity of the molecular analysis of von Willebrand factor gene (VWF, not many reports are available from this country. Large size of the gene, heterogeneous nature of mutations and presence of a highly homologous pseudogene region are the major impediments in the genetic diagnosis of VWD. The study is aimed at unravelling the molecular pathology in a large series of VWD patients from India using an effective strategy.We evaluated 85 unrelated Indian type 3 VWD families to identify the molecular defects using a combination of techniques i.e. PCR-RFLP, direct DNA sequencing and multiple ligation probe amplification (MLPA.Mutations could be characterized in 77 unrelated index cases (ICs. 59 different mutations i.e. nonsense 20 (33.9%, missense 13 (22%, splice site 4 (6.8%, gene conversions 6 (10.2%, insertions 2 (3.4%, duplication 1 (1.7%, small deletions 10 (17% and large deletions 3 (5.1% were identified, of which 34 were novel. Two common mutations i.e. p.R1779* and p.L970del were identified in our population with founder effect. Development of alloantibodies to VWF was seen in two patients, one with nonsense mutation (p.R2434* and the other had a large deletion spanning exons 16-52.The molecular pathology of a large cohort of Indian VWD patients could be identified using a combination of techniques. A wide heterogeneity was observed in the nature of mutations in Indian VWD patients.

  20. Technological advances in diagnostic testing for von Willebrand disease: new approaches and challenges.

    Science.gov (United States)

    Hayward, C P M; Moffat, K A; Graf, L

    2014-06-01

    Diagnostic tests for von Willebrand disease (VWD) are important for the assessment of VWD, which is a commonly encountered bleeding disorder worldwide. Technical innovations have been applied to improve the precision and lower limit of detection of von Willebrand factor (VWF) assays, including the ristocetin cofactor activity assay (VWF:RCo) that uses the antibiotic ristocetin to induce plasma VWF binding to glycoprotein (GP) IbIXV on target platelets. VWF-collagen-binding assays, depending on the type of collagen used, can improve the detection of forms of VWD with high molecular weight VWF multimer loss, although the best method is debatable. A number of innovations have been applied to VWF:RCo (which is commonly performed on an aggregometer), including replacing the target platelets with immobilized GPIbα, and quantification by an enzyme-linked immunosorbent assay (ELISA), immunoturbidimetric, or chemiluminescent end-point. Some common polymorphisms in the VWF gene that do not cause bleeding are associated with falsely low VWF activity by ristocetin-dependent methods. To overcome the need for ristocetin, some new VWF activity assays use gain-of-function GPIbα mutants that bind VWF without the need for ristocetin, with an improved precision and lower limit of detection than measuring VWF:RCo by aggregometry. ELISA of VWF binding to mutated GPIbα shows promise as a method to identify gain-of-function defects from type 2B VWD. The performance characteristics of many new VWF activity assays suggest that the detection of VWD, and monitoring of VWD therapy, by clinical laboratories could be improved through adopting newer generation VWF assays. © 2014 John Wiley & Sons Ltd.

  1. Characterization of recessive severe type 1 and 3 von willebrand disease (vwd), asymptomatic heterozygous carriers versus bloodgroup o-related von willebrand factor deficiency, and dominant type 1 VWD

    NARCIS (Netherlands)

    J.J. Michiels (Jan); Z. Berneman (Zwi); A. Gadisseur (Alain); M. van der Planken (Marc); W. Schroyens (Wilfried); A. van de Velde (Ann); H.H.D.M. van Vliet (Huib)

    2006-01-01

    textabstractRecessive type 3 von Willebrand disease (VWD) is caused by homozygosity or double heterozygosity for two non-sense mutations (null alleles). Type 3 VWD is easy to diagnose by the combination of a strongly prolonged bleeding time (BT), absence of ristocetine-induced platelet aggregation

  2. Heavy menstrual bleeding and health-associated quality of life in women with von Willebrand's disease.

    Science.gov (United States)

    Govorov, Igor; Ekelund, Lena; Chaireti, Roza; Elfvinge, Petra; Holmström, Margareta; Bremme, Katarina; Mints, Miriam

    2016-05-01

    Women with the inherited bleeding disorder von Willebrand's disease (VWD) face gender-specific hemostatic challenges during menstruation. Heavy menstrual bleeding (HMB) can negatively affect their overall life activities and the health-associated quality of life. The purpose of the present study was to investigate whether women with VWD experienced HMB and an impaired health-associated quality of life. The study subjects were recruited from the Coagulation Unit of Karolinska University Hospital. Information was retrieved from various self-administered forms and medical records. Of the 30 women (18-52 years) that were included in the present study, 50% suffered from HMB, although the majority received treatment for HMB. In addition, almost all the included women perceived limitations in the overall life activities due to menstruation. The health-associated quality of life for women with HMB was significantly lower (Pwomen of the general population. In conclusion, women with VWD experienced reduced health-associated quality of life as a result of HMB. Therefore, preventing limitations in overall life activities and improving their health-associated quality of life thorough counseling on menstrual bleeding is important for women with VWD.

  3. Cost-utility analysis of von Willebrand disease screening in adolescents with menorrhagia.

    Science.gov (United States)

    Sidonio, Robert Francis; Smith, Kenneth J; Ragni, Margaret V

    2010-09-01

    To construct a decision analysis model to evaluate the cost utility of von Willebrand disease (VWD) testing in adolescents with menorrhagia. A 20-year Markov decision analytic model was constructed to evaluate the cost utility of two strategies: testing or not testing for VWD. The model includes probabilities of remaining well, suffering an acute menorrhagia bleeding event, surgical complications, oral contraceptive pill complications, or dying. Probabilities, costs, and utilities were estimated from published literature. The prevalence of type 1 VWD in adolescent females with menorrhagia was estimated at 13%. The cost of testing adolescents with menorrhagia for VWD was $1790, versus $1251 for not testing for VWD. The effectiveness of not testing in quality-adjusted life-years (QALYs) gained (14.237 QALYs) was similar to the VWD testing strategy (14.246 QALYs). Compared with not testing for VWD, screening for VWD had an incremental cost-effectiveness ratio of $62,791 per QALY, a value typically considered economically reasonable. In adolescents with menorrhagia, testing for VWD before the initiation of oral contraceptives is cost-effective. Copyright (c) 2010 Mosby, Inc. All rights reserved.

  4. Long-term impact of joint bleeds in von Willebrand disease: a nested case-control study.

    Science.gov (United States)

    van Galen, Karin P M; de Kleijn, Piet; Foppen, Wouter; Eikenboom, Jeroen; Meijer, Karina; Schutgens, Roger E G; Fischer, Kathelijn; Cnossen, Marjon H; de Meris, Joke; Fijnvandraat, Karin; van der Bom, Johanna G; Laros-van Gorkom, Britta A P; Leebeek, Frank W G; Mauser-Bunschoten, Eveline P

    2017-09-01

    Patients with severe von Willebrand disease (VWD) may develop arthropathy after joint bleeds. Information on its prevalence and severity is limited. We aimed to assess the occurrence and severity of arthropathy in VWD and its impact on daily life. VWD patients with and without verified joint bleeds were matched for age, sex and Factor VIII level or von Willebrand Factor activity in a nested case-control study within the Willebrand in the Netherlands study. Assessments included the Hemophilia Joint Health Score (0-124), Pettersson score (0-13 per joint X-ray), Hemophilia Activity List score (0-100), joint pain (Visual Analog Scale 0-10), and the Impact on Participation and Autonomy questionnaire (0-20). Arthropathy was defined as a Hemophilia Joint Health Score of 10 or higher, or a Pettersson score over 3 of at least one joint. We included 48 patients with verified joint bleeds (cases) and 48 controls: 60% males, mean age 46 years (range 18-80), median von Willebrand Factor activity 5 versus 8 IU/dL and Factor VIII 24 versus 36 IU/dL. Arthropathy occurred in 40% of the cases versus 10% of the controls (PList score: 88 vs. 100, P3: 13 of 19 vs. 3 of 28, P<0.01, and median score on the participation questionnaire 6.1 vs. 0.9, P<0.01). In conclusion, arthropathy occurs in 40% of VWD patients after joint bleeds and is associated with pain, radiological abnormalities, functional limitations, and less social participation (Dutch trial register: NTR4548). Copyright© 2017 Ferrata Storti Foundation.

  5. Plasmatic ADAMTS-13 metalloprotease and von Willebrand factor in children with cyanotic congenital heart disease.

    Science.gov (United States)

    Soares, R P S; Bydlowski, S P; Nascimento, N M; Thomaz, A M; Bastos, E N M; Lopes, A A

    2013-04-01

    Changes in plasma von Willebrand factor concentration (VWF:Ag) and ADAMTS-13 activity (the metalloprotease that cleaves VWF physiologically) have been reported in several cardiovascular disorders with prognostic implications. We therefore determined the level of these proteins in the plasma of children with cyanotic congenital heart disease (CCHD) undergoing surgical treatment. Forty-eight children were enrolled (age 0.83 to 7.58 years). Measurements were performed at baseline and 48 h after surgery. ELISA, collagen-binding assays and Western blotting were used to estimate antigenic and biological activities, and proteolysis of VWF multimers. Preoperatively, VWF:Ag and ADAMTS-13 activity were decreased (65 and 71% of normal levels considered as 113 (105-129) U/dL and 91 ± 24% respectively, P membranes, followed by proteolytic cleavage. A low preoperative ADAMTS-13 activity, a longer activated partial thromboplastin time and the need for cardiopulmonary bypass correlated with postoperative bleeding (P < 0.05). Postoperatively, ADAMTS-13 activity increased but less extensively than VWF:Ag (respectively, 2.23 and 2.83 times baseline, P < 0.0001), resulting in an increased VWF:Ag/ADAMTS-13 activity ratio (1.20 to 1.54, respectively, pre- and postoperative median values, P = 0.0029). ADAMTS-13 consumption was further confirmed by decreased ADAMTS-13 antigenic concentration (0.91 ± 0.30 to 0.70 ± 0.25 µg/mL, P < 0.0001) and persistent proteolysis of VWF multimers. We conclude that, in pediatric CCHD, changes in circulating ADAMTS-13 suggest enzyme consumption, associated with abnormal structure and function of VWF.

  6. Plasmatic ADAMTS-13 metalloprotease and von Willebrand factor in children with cyanotic congenital heart disease

    Energy Technology Data Exchange (ETDEWEB)

    Soares, R.P.S. [Fundação Pró-Sangue Hemocentro de São Paulo, São Paulo, SP (Brazil); Bydlowski, S.P.; Nascimento, N.M. [Laboratório de Investigação Médica-31, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Thomaz, A.M.; Bastos, E.N.M.; Lopes, A.A. [Faculdade de Medicina, Instituto do Coração, Universidade de São Paulo, São Paulo, SP (Brazil)

    2013-04-05

    Changes in plasma von Willebrand factor concentration (VWF:Ag) and ADAMTS-13 activity (the metalloprotease that cleaves VWF physiologically) have been reported in several cardiovascular disorders with prognostic implications. We therefore determined the level of these proteins in the plasma of children with cyanotic congenital heart disease (CCHD) undergoing surgical treatment. Forty-eight children were enrolled (age 0.83 to 7.58 years). Measurements were performed at baseline and 48 h after surgery. ELISA, collagen-binding assays and Western blotting were used to estimate antigenic and biological activities, and proteolysis of VWF multimers. Preoperatively, VWF:Ag and ADAMTS-13 activity were decreased (65 and 71% of normal levels considered as 113 (105-129) U/dL and 91 ± 24% respectively, P < 0.003) and correlated (r = 0.39, P = 0.0064). High molecular weight VWF multimers were not related, suggesting an interaction of VWF with cell membranes, followed by proteolytic cleavage. A low preoperative ADAMTS-13 activity, a longer activated partial thromboplastin time and the need for cardiopulmonary bypass correlated with postoperative bleeding (P < 0.05). Postoperatively, ADAMTS-13 activity increased but less extensively than VWF:Ag (respectively, 2.23 and 2.83 times baseline, P < 0.0001), resulting in an increased VWF:Ag/ADAMTS-13 activity ratio (1.20 to 1.54, respectively, pre- and postoperative median values, P = 0.0029). ADAMTS-13 consumption was further confirmed by decreased ADAMTS-13 antigenic concentration (0.91 ± 0.30 to 0.70 ± 0.25 µg/mL, P < 0.0001) and persistent proteolysis of VWF multimers. We conclude that, in pediatric CCHD, changes in circulating ADAMTS-13 suggest enzyme consumption, associated with abnormal structure and function of VWF.

  7. Rinoplastia em paciente com doença de Von Willebrand: relato de caso Rinoplastia en paciente con enfermedad de Von Willebrand: relato de caso Rhinoplasty in a patient with Von Willebrand disease: case report

    Directory of Open Access Journals (Sweden)

    Roberto Martins Matos Junior

    2007-12-01

    minutos. En el postoperatorio fue prescrito ácido amino caproico (500 mg por vía oral a cada 8 horas, por 48 horas, con alta hospitalaria después de 24 horas, sin presentar ninguna complicación postoperatoria. CONCLUSIONES: La infusión de crioprecipitado o plasma, utilizado en la profilaxis y tratamiento de las complicaciones hemorrágicas, produce un pico de concentración máxima de factor VIII después 48 horas, y se sustenta por 72 horas; sin embargo, incluso aprobado por el FDA, ha sido una práctica utilizada solamente en circunstancias de emergencia, debido al riesgo relativo de contaminación viral. A 1-desamino, 8-D-arginina vasopresina (DDAVP-desmopresina estimula el aumento de la concentración del factor VIII, con la ventaja de eliminar la exposición a patógenos transmitidos por la sangre, además de la posibilidad de administración por vía nasal, subcutánea y venosa.BACKGROUND AND OBJECTIVES: Patients with von Willebrand disease present abnormal bleeding after being wounded or during surgeries since it affects primary and secondary hemostasia due to changes in factor VIII. The objective of this report was to elucidate the pre-, peri-, and postoperative management of patients with this disorder. CASE REPORT: A 42-year old white female, with 165 cm, 61 kg, ASA II, with a diagnosis of type 1 von Willebrand disease, underwent pre-anesthetic evaluation for rhinoplasty. She was cleared for surgery after hematological evaluation with a positive DDAVP IN26 test. On the day of the surgery, the patient received pre-anesthetic medication, was adequately monitored, oxygen was administered through a nasal cannula and intravenous desmopressin (0.4 µg.kg-1 in 100 mL of normal saline was administered 30 minutes before the surgery. Induction was accomplished with intravenous sufentanil (1 µg.kg-1, propofol (4 mg.kg-1, and rocuronium (0.6 mg.kg-1. The patient was intubated and installed on mechanical ventilation with a CO2 absorber system and maintenance consisted

  8. Pitfalls in Interventional Pain Medicine: Hyponatremia after DDAVP for a Patient with Von Willebrand Disease Undergoing an Epidural Steroid Injection

    Directory of Open Access Journals (Sweden)

    Talal W. Khan

    2017-01-01

    Full Text Available Desmopressin (DDAVP, a synthetic analog of vasopressin, has been used in patients with von Willebrand disease (VWD, mild hemophilia A, and platelet dysfunction to reduce the risk of bleeding associated with surgical and interventional procedures. We report the case of a patient with VWD presenting with a bulging disc and radicular pain that underwent transforaminal epidural steroid injections. Her course was complicated with the interval development of headaches and dizziness symptomatic of moderate hyponatremia, likely due to excessive fluid intake. This report highlights a relatively rare side effect of DDAVP when used for prophylaxis in patients with VWD and reinforces the need for vigilance in these patients.

  9. Von Willebrand factor and fibrinolytic parameters during the desmopressin test in patients with Cushing's disease

    Science.gov (United States)

    Giraldi, Francesca Pecori; Ambrogio, Alberto G; Fatti, Letizia M; Rubini, Valentina; Cozzi, Giovanna; Scacchi, Massimo; Federici, Augusto B; Cavagnini, Francesco

    2011-01-01

    AIMS Desmopressin, a vasopressin analogue, is used for various clinical purposes, including haemostasis and, in recent times, the diagnostic work-up of patients with Cushing's syndrome, a condition associated with a known prothrombotic profile. We decided to evaluate whether and to what extent a diagnostic dose of desmopressin induces significant changes in endothelial parameters in patients with Cushing's disease (CD) and obese and normal weight controls. METHODS Twelve patients with CD, 10 obese and five normal weight controls were studied. Von Willebrand antigen (VWF : Ag), tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) were measured at baseline and up to 4 h after 10 µg desmopressin i.v. RESULTS Desmopressin 10 µg transiently increased VWF : Ag and t-PA and decreased PAI-1 in all subjects. The magnitude of the VWF : Ag and t-PA increases after desmopressin was comparable in the three groups (VWF : Ag peak-to-basal ratio 1.9 ± 0.17, 1.5 ± 0.11 and 1.8 ± 0.13 and t-PA peak-to-basal ratio 1.6 ± 0.18, 1.6 ± 0.20 and 1.8 ± 0.24 for CD, obese and controls, respectively, all NS). The PAI-1 decrease observed in patients with CD was comparable with obese (0.7 ± 0.07 and 0.6 ± 0.09, NS) and controls (0.7 ± 0.07 vs. 0.4 ± 0.09, P = 0.08). CONCLUSIONS Administration of desmopressin to patients with CD for diagnostic purposes induces a transitory increase in VWF : Ag counterbalanced by a decrease in PAI-1 and increase in t-PA. The magnitude of these changes is largely comparable with that observed in obese and normal weight controls. Our data show that testing with desmopressin does not induce disease-specific changes in endothelial markers in patients with CD. PMID:21143510

  10. Utility of platelet function analyzer as a screening tool for the diagnosis of von Willebrand disease in adolescents with menorrhagia.

    Science.gov (United States)

    Naik, Swati; Teruya, Jun; Dietrich, Jennifer E; Jariwala, Purvi; Soundar, Esther; Venkateswaran, Lakshmi

    2013-07-01

    Von Willebrand disease (VWD), and in particular, VWD type 1 and low VW factor (defined as Von Willebrand Ristocetin cofactor activity (RCoF) menorrhagia and both groups benefit from similar management. Platelet function analyzer (PFA-100®) is often used as a screening test to detect VWD. We analyzed the utility of PFA-100® as a screening tool in the detection of VWD type 1 and low VW factor (VWF) in an exclusive adolescent population with menorrhagia. The study population consisted of adolescents with menorrhagia who had simultaneously drawn blood samples for VWD and PFA-100®. Abnormal PFA-100® was defined as values >183 seconds for collagen/epinephrine and/or >126 seconds for collagen/ADP. Of a total of 235 patients tested, 23 patients had RCoF menorrhagia. We conclude that in the setting of adolescent menorrhagia, PFA-100® does not have utility as an initial screening test for the diagnosis of VWD and in particular, low VWF and that clinicians need to be aware of this limitation of PFA-100® while evaluating adolescents with menorrhagia. Copyright © 2013 Wiley Periodicals, Inc.

  11. Antifibrinolytic therapy for preventing oral bleeding in patients with haemophilia or Von Willebrand disease undergoing minor oral surgery or dental extractions

    NARCIS (Netherlands)

    van Galen, Karin Pm|info:eu-repo/dai/nl/325853886; Engelen, Eveline T; Mauser-Bunschoten, Evelien P|info:eu-repo/dai/nl/074719718; van Es, Robert Jj|info:eu-repo/dai/nl/216460646; Schutgens, Roger Eg|info:eu-repo/dai/nl/258752084

    2015-01-01

    BACKGROUND: Minor oral surgery or dental extractions (oral or dental procedures) are widely performed and can be complicated by hazardous oral bleeding, especially in people with an inherited bleeding disorder such as haemophilia or Von Willebrand disease. The amount and severity of singular

  12. Dogs with hearth diseases causing turbulent high-velocity blood flow have changes in patelet function and von Willebrand factor multimer distribution

    DEFF Research Database (Denmark)

    Tarnow, Inge; Kristensen, Annemarie Thuri; Olsen, Lisbeth Høier

    2005-01-01

    The purpose of this prospective study was to investigate platelet function using in vitro tests based on both high and low shear rates and von Willebrand factor (vWf) multimeric composition in dogs with cardiac disease and turbulent high-velocity blood flow. Client-owned asymptomatic, untreated d...

  13. A 12.3-kb Duplication Within the VWF Gene in Pigs Affected by Von Willebrand Disease Type 3

    Directory of Open Access Journals (Sweden)

    Stefanie Lehner

    2018-02-01

    Full Text Available Von Willebrand Disease (VWD type 3 is a serious and sometimes fatal hereditary bleeding disorder. In pigs, the disease has been known for decades, and affected animals are used as models for the human disease. Due to the recessive mode of inheritance of VWD type 3, severe bleeding is typically seen in homozygous individuals. We sequenced the complete porcine VWF (Von Willebrand Factor complementary DNA (cDNA and detected a tandem duplication of exons 17 and 18, causing a frameshift and a premature termination codon (p.Val814LeufsTer3 in the affected pig. Subsequent next generation sequencing on genomic DNA proved the existence of a 12.3-kb tandem duplication associated with VWD. This duplication putatively originates from porcine Short Interspersed Nuclear Elements (SINEs located within VWF introns 16 and 18 with high identity. The premature termination truncates the VWF open reading frame by a large part, resulting in an almost entire loss of the mature peptide. It is therefore supposed to account for the severe VWD type 3. Our results further indicate the presence of strong, nonsense-mediated decay in VWF messenger RNA (mRNA containing the duplication, which was supported by the almost complete absence of the complete VWF protein in immunohistochemistry analysis of the VWD-affected pig. In the past, differentiation of wild-type and heterozygous pigs in this VWD colony had to rely on clinical examinations and additional laboratory methods. The present study provides the basis to distinguish both genotypes by performing a rapid and simple genetic analysis.

  14. A rapid, automated VWF ristocetin cofactor activity assay improves reliability in the diagnosis of Von Willebrand disease.

    Science.gov (United States)

    Bowyer, Annette E; Shepherd, Fiona; Kitchen, Stephen; Makris, Michael

    2011-04-01

    The effective diagnosis and monitoring of Von Willebrand Disease (VWD) requires an accurate assessment of ristocetin co-factor activity (VWF:RCo). Current methodologies include automated platelet aggregometry and manual visual agglutination both of which are laborious to perform and notoriously subject to a high degree of inter and intra assay variation. We have evaluated an automated VWF:RCo assay (BC Von Willebrand Reagent, Siemens, Marberg, Germany) for use on the Sysmex CS2100i analyser (Milton Keynes, UK) and retrospectively compared the results with an in-house manual visual agglutination assay and VWF antigen (Siemens) in normal subjects and in 53 patients with various types of VWD and 23 patients following VWF therapeutic treatment. The intra and interassay CV was improved with the automated assay (2.3% and 3.8% respectively) compared to 7% with the manual VWF:RCo assay. Good correlation was found between the two assays (r=0.91) in 53 patients with VWD. The mean manual VWF:RCo was 0.25IU/ml and mean automated VWF:RCo was 0.27IU/ml. A comparable increase in VWF:RCo following treatment, mostly with Desmopressin, was found in 13 patients with type 1 VWD (mean 3.9 fold increase with manual VWF:RCo and 3.1 fold with the automated VWF:RCo). In 13 patients with type 2 or 3 VWD following treatment mostly with concentrate , a higher increase was found with the automated VWF:RCo assay than the manual assay (mean 11.9 fold manually and mean 20.3 automated). The automated VWF:RCo assay shows enhanced precision and analysis time in this difficult and time consuming laboratory test and its introduction should greatly improve the reliability of VWF testing. Copyright © 2010. Published by Elsevier Ltd.

  15. Elevated preoperative von Willebrand factor is associated with perioperative thrombosis in infants and neonates with congenital heart disease.

    Science.gov (United States)

    Hunt, R; Hoffman, C M; Emani, S; Trenor, C C; Emani, S M; Faraoni, D; Kimchi-Sarfaty, C; Ibla, J C

    2017-12-01

    Essentials Perioperative thrombosis is a major cause of morbidity and mortality in congenital heart disease. Neonates and infants undergoing repair of congenital heart lesions were prospectively followed. Elevated von Willebrand factor (VWF) to ADAMTS-13 activity ratios typified the postoperative period. Thrombosis was associated with preoperative VWF activity and cryoprecipitate transfusion SUMMARY: Background The surgical repair of congenital heart malformations is frequently complicated by perioperative thrombosis of unclear etiology. An imbalance between von Willebrand factor (VWF) and ADAMTS-13 is an emerging variable in thrombosis. Objectives To describe perioperative changes to VWF, ADAMTS-13 and NETosis, and evaluate clinical and biochemical associations with postoperative thrombosis. Methods Neonates and infants undergoing palliation or definitive surgical repair of congenital heart malformations were recruited (n = 133). Preoperative and postoperative plasma levels of VWF, ADAMTS-13 and markers of NETosis were determined. Patients were followed for up to 30 days for the occurrence of thrombosis. Univariate and multivariate logistic regression analyses were conducted to identify variables associated with thrombosis. Results We identified significant postoperative increases in VWF activity, VWF level, DNA-histone complexes and cell-free DNA with an overall decrease in ADAMTS-13 activity. Patients experiencing postoperative thrombotic events (9%) were characterized by surgery performed at a lower intraoperative temperature, higher preoperative lactic acid levels, and higher preoperative VWF activity and level. A multivariate logistic regression model identified preoperative VWF activity (odds ratio (OR) 8.39 per IU mL-1 , 95% confidence interval [CI] 1.73-40.55) and transfusion of cryoprecipitate (OR 1.10 per mL kg-1 , 95% CI 1.03-1.17) as being associated with thrombosis. Conclusions Pediatric patients undergoing surgical repair of congenital

  16. Syringomyelia following surgery for a spontaneous spinal subdural hematoma in a 13-year-old girl with congenital von Willebrand disease: case report and literature review.

    Science.gov (United States)

    Ben Nsir, A; Boubaker, A; Jemel, H

    2016-04-01

    Spontaneous spinal subdural hematomas are rare. Their occurrence in a child with congenital von Willebrand disease and the complication of their surgery by a large secondary syringomyelia have never been previously reported. A 13-year-old girl with congenital von Willebrand disease presented to our emergency department in January 2011 for sudden onset of severe back pain centered in her thoracic spine rapidly aggravated by signs of acute myelopathy without any precipitating factor. MRI scan revealed a thoracic subdural collection anterior to the spinal cord at the T7-T9 level, hyperintense on T1- and T2-weighted sequences consistent with an acute spinal subdural hemorrhage. Evacuation of the subdural hematoma was realized immediately after hemostasis parameter correction, and post-operative course was uneventful with full functional recovery. One year later, the patient presented once again but with progressive and more severe myelopathy caused by a large syringomyelia extending from the T5 level to the conus medullaris. A syringopleural shunting was performed and the patient was unrolled under an intensive care and rehabilitation program. Her condition remarkably improved and she became able to walk independently within 2 weeks post-operatively. von Willebrand disease should be included as a possible factor of spontaneous spinal subdural hemorrhage. Surgery is advised in emergency and can be associated with remarkable recovery especially in children. Delayed syringomyelia can complicate the post-operative course and can be successfully addressed by syringopleural shunting. Long-term clinical and radiological follow-up is advocated.

  17. Cesariana em paciente com doença de von Willebrand associada à infecção pelo HIV: relato de caso Cesárea en paciente con enfermedad de von Willebrand asociada a la infección por el HIV: relato de caso Anesthesia for cesarean section in patient with von Willebrand's disease and HIV infection: case report

    Directory of Open Access Journals (Sweden)

    Vanessa Rezende Balle

    2004-12-01

    Willebrand y HIV positiva sometida a cesárea. RELATO DEL CASO: Paciente de 24 años, portadora de anemia microcítica, enfermedad de von Willebrand y HIV, llegó a la emergencia obstétrica en inicio de trabajo de alumbramiento. No realizó prenatal. Fue indicada cesárea a fin de disminuir los riesgos de transmisión vertical en paciente con carga vírica de HIV desconocida. Presentaba hematomas por el cuerpo e historia de hematoma de pared abdominal en cesárea anterior. Los tests de coagulación estaban un poco alterados. Después de infusión de concentrado de factor VIII fue realizada anestesia general. Madre y recién nacido presentaron evolución satisfactoria. CONCLUSIONES: La evaluación de manifestaciones clínicas en pacientes con coagulopatia es fundamental en la decisión del tipo de anestesia que será indicada para cada paciente. La evaluación debe ser individualizada, considerando los riesgos y beneficios de la técnica escogida. En estas pacientes, se debe siempre restringir al máximo la indicación de interrupción de la gestación por vía alta, optándose siempre por los métodos menos invasivos. La terapia con concentrado de factor VIII es actualmente la mejor opción de tratamiento, corrigiendo la deficiencia específica y dismunuyendo los riesgos de transmisión vírica.BACKGROUND AND OBJECTIVES: Von Willebrand's disease is the most common hereditary coagulation disorder in young women. The incidence of HIV infection among women has been progressively increasing, and vertical transmission may account for 25% of cases. This report aimed at describing the case of an HIV-positive patient with von Willebrand's disease scheduled for cesarean section. CASE REPORT: Female HIV-positive patient, 24 years old, with microcytic anemia and von Willebrand's disease, admitted to the emergency room in early labor. She had no pre-natal care. Cesarean section was indicated to lower vertical transmission risks since HIV viral count was unknown. Patient had hematomas

  18. Protein replacement therapy and gene transfer in canine models of hemophilia A, hemophilia B, von willebrand disease, and factor VII deficiency.

    Science.gov (United States)

    Nichols, Timothy C; Dillow, Aaron M; Franck, Helen W G; Merricks, Elizabeth P; Raymer, Robin A; Bellinger, Dwight A; Arruda, Valder R; High, Katherine A

    2009-01-01

    Dogs with hemophilia A, hemophilia B, von Willebrand disease (VWD), and factor VII deficiency faithfully recapitulate the severe bleeding phenotype that occurs in humans with these disorders. The first rational approach to diagnosing these bleeding disorders became possible with the development of reliable assays in the 1940s through research that used these dogs. For the next 60 years, treatment consisted of replacement of the associated missing or dysfunctional protein, first with plasma-derived products and subsequently with recombinant products. Research has consistently shown that replacement products that are safe and efficacious in these dogs prove to be safe and efficacious in humans. But these highly effective products require repeated administration and are limited in supply and expensive; in addition, plasma-derived products have transmitted bloodborne pathogens. Recombinant proteins have all but eliminated inadvertent transmission of bloodborne pathogens, but the other limitations persist. Thus, gene therapy is an attractive alternative strategy in these monogenic disorders and has been actively pursued since the early 1990s. To date, several modalities of gene transfer in canine hemophilia have proven to be safe, produced easily detectable levels of transgene products in plasma that have persisted for years in association with reduced bleeding, and correctly predicted the vector dose required in a human hemophilia B liver-based trial. Very recently, however, researchers have identified an immune response to adeno-associated viral gene transfer vector capsid proteins in a human liver-based trial that was not present in preclinical testing in rodents, dogs, or nonhuman primates. This article provides a review of the strengths and limitations of canine hemophilia, VWD, and factor VII deficiency models and of their historical and current role in the development of improved therapy for humans with these inherited bleeding disorders.

  19. Von Willebrand factor and aging.

    Science.gov (United States)

    Konkle, Barbara A

    2014-09-01

    von Willebrand factor (VWF) plays critical roles in initiating primary hemostasis and extending the half-life of coagulation factor VIII in circulation. VWF levels increase with age and elevated levels are associated with an increased risk of venous thromboembolism and cardiovascular disease (CVD). Patients with von Willebrand disease (VWD) due to a deficiency or dysfunction of VWF may have symptoms that ameliorate with aging or may have exacerbation of their disease. Bleeding sites of particular challenge in the aging patient include gastrointestinal bleeding and hematuria. Some medications used to treat VWD should be used with special precaution in older patients, including desmopressin and VWF-containing factor concentrates. Patients with VWD may have some protection from CVD, but in those patients who develop CVD, management is very challenging, given the role of antiplatelet therapy as the mainstay of treatment. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  20. Atypical disease phenotypes in pediatric ulcerative colitis

    DEFF Research Database (Denmark)

    Levine, Arie; de Bie, Charlotte I; Turner, Dan

    2013-01-01

    Definitive diagnosis of pediatric ulcerative colitis (UC) may be particularly challenging since isolated colitis with overlapping features is common in pediatric Crohn's disease (CD), while atypical phenotypes of UC are not uncommon. The Paris classification allows more accurate phenotyping of at...... of atypical inflammatory bowel disease (IBD) patients. Our aim was to identify the prevalence of atypical disease patterns in new-onset pediatric UC using the Paris classification.......Definitive diagnosis of pediatric ulcerative colitis (UC) may be particularly challenging since isolated colitis with overlapping features is common in pediatric Crohn's disease (CD), while atypical phenotypes of UC are not uncommon. The Paris classification allows more accurate phenotyping...

  1. Elevated levels of plasma von Willebrand factor and the risk of macro- and microvascular disease in type 2 diabetic patients with microalbuminuria

    DEFF Research Database (Denmark)

    Gaede, P; Vedel, P; Parving, H H

    2001-01-01

    according to baseline plasma von Willebrand factor levels below or above the median. The main outcome was cardiovascular disease (cardiovascular mortality, non-fatal stroke, non-fatal myocardial infarction, coronary artery bypass graft and revascularization or amputation of legs), progression to diabetic...... nephropathy or progression in diabetic retinopathy. RESULTS: At baseline the two groups were comparable for HbA(1c), fasting levels of s-total-cholesterol, s-HDL-cholesterol and s-triglycerides, systolic and diastolic blood pressure, gender, known diabetes duration, smoking habits, previous cardiovascular...

  2. Comparison of automated von Willebrand factor activity assays

    DEFF Research Database (Denmark)

    Timm, Annette; Hillarp, Andreas; Philips, Malou

    2015-01-01

    INTRODUCTION: Von Willebrand Disease (VWD) is the most common inherited bleeding disorder. Measurement of von Willebrand factor (VWF) activity in plasma is often based on platelet agglutination stimulated by the ristocetin cofactor activity. Novel assays, based on latex beads with recombinant...

  3. Haemostasis prophylaxis using single dose desmopressin acetate and extended use epsilon aminocaproic acid for adenotonsillectomy in patients with type 1 von Willebrand disease.

    Science.gov (United States)

    Santoro, C; Hsu, F; Dimichele, D M

    2012-03-01

    In patients with confirmed or suspected type 1 von Willebrand disease (VWD), adenotonsillectomy has been reported to be associated with a rate of peri-operative hemorrhage between 8 and 23%. Desmopressin acetate (DDAVP, 1-deamino 8-D arginine- vasopressin) is the treatment of choice for type 1 patients with baseline von Willebrand factor levels of 10 IU/dL or greater. DDAVP is generally well tolerated; however, severe hyponatremia and seizures have been reported in young children less than 2 years of age, limiting its use in this age group. Antifibrinolytic therapy plays an important adjunctive role in the effective treatment of mucocutaneous bleeding, particularly in the oropharynx where the salivary concentration of fibrinolytic enzymes is high. During the past 10 years, we treated 6 pediatric patients with mild/moderate type 1 VWD undergoing an adenotonsillar procedure at our institution with the same hemostatic regimen consisting of one single dose of DDAVP and an extended use of EACA. In this small case series, the above mentioned prophylactic treatment regimen was both well tolerated and efficacious in controlling hemorrhage. Furthermore, DDAVP-related complications were avoided in a pediatric population with a higher risk of developing them. © 2011 Blackwell Publishing Ltd.

  4. Anestesia para septoplastia e turbinectomia em paciente portador de doença de von Willebrand: relato de caso Anestesia para septoplastia y turbinectomia en paciente portador de enfermedad de von Willebrand: relato de caso Anesthesia for septoplasty and turbinectomy in von Willebrand disease patient: case report

    Directory of Open Access Journals (Sweden)

    Múcio Paranhos de Abreu

    2003-06-01

    Full Text Available JUSTIFICATIVA E OBJETIVOS: Embora a doença de von Willebrand seja o mais comum dos distúrbios hemorrágicos hereditários, as publicações nacionais, relacionando esta doença e a prática anestésica, são escassas. O objetivo deste relato é apresentar um caso de anestesia geral para septoplastia e turbinectomia em paciente portador de doença de von Willebrand - Tipo I, tratado profilaticamente com desmopressina (1-deamino-8-D-arginina vasopressina, DDAVP nos períodos pré e pós-operatório. RELATO DO CASO: Paciente com 19 anos, sexo feminino, 58 kg, portadora de hipotiroidismo, controlado com L-tiroxina (75 mg, e de doença de von Willebrand, que se manifestou há três anos, após extração dentária dos sisos, com sangramento persistente no período pós-operatório. Com o objetivo de se evitar novos episódios hemorrágicos nos períodos per e pós-operatório da cirurgia de septoplastia e turbinectomia a que foi submetida, a paciente foi tratada profilaticamente com desmopressina (0,3 µg.kg-1. A indução anestésica foi realizada com midazolam (2,5 mg, fentanil (150 µg, droperidol (2,5 mg, lidocaína (60 mg, atracúrio (30 mg e metoprolol (4 mg, seguida de intubação traqueal e ventilação sob pressão positiva intermitente. A manutenção da anestesia foi realizada com mistura de oxigênio e óxido nitroso a 50% e sevoflurano a 2%. Esta técnica proporcionou um bom controle da freqüência cardíaca e dos níveis pressóricos durante a cirurgia. A paciente permaneceu com tampão nasal por 24 horas e, quando este foi retirado, não houve sangramento. A paciente recebeu alta hospitalar no dia seguinte ao da cirurgia, sem intercorrências. Não houve episódio hemorrágico no período pós-operatório imediato ou tardio. CONCLUSÕES: O tratamento profilático com DDAVP associado à técnica anestésica utilizada nesse caso, mostrou-se eficaz no controle do sangramento per e pós-operatório.JUSTIFICATIVA Y OBJETIVOS: Aun cuando

  5. Phase II prospective open-label trial of recombinant interleukin-11 in women with mild von Willebrand disease and refractory menorrhagia.

    Science.gov (United States)

    Ragni, Margaret V; Jankowitz, Rachel C; Jaworski, Kristen; Merricks, Elizabeth P; Kloos, Mark T; Nichols, Timothy C

    2011-10-01

    Lack of effective treatment for menorrhagia is the greatest unmet healthcare need in women with von Willebrand disease (VWD). We conducted a single-centre phase II clinical trial to determine efficacy and safety of recombinant IL-11 (rhIL-11, Neumega®) given subcutaneously for up to seven days during six consecutive menstrual cycles each in seven women with mild VWD and menorrhagia refractory to haemostatic or hormonal agents. rhIL-11 reduced menstrual bleeding severity as measured by pictorial blood assessment chart (PBAC) ≥ 50% (to 0.05. Platelet VWF mRNA expression by quantitative PCR increased mean four-fold (1.0-13.5). rhIL-11 was well tolerated with grade 1 or less fluid retention, flushing, conjunctival erythema, and local bruising. In summary, rhIL-11 reduces menorrhagia safely and warrants further study.

  6. Phase II prospective open-label trial of recombinant interleukin-11 in women with mild von Willebrand disease and refractory menorrhagia*

    Science.gov (United States)

    Ragni, Margaret V.; Jankowitz, Rachel C.; Jaworski, Kristen; Merricks, Elizabeth P.; Kloos, Mark T.; Nichols, Timothy C.

    2014-01-01

    Summary Lack of effective treatment for menorrhagia is the greatest unmet healthcare need in women with von Willebrand disease (VWD). We conducted a single-centre phase II clinical trial to determine efficacy and safety of recombinant IL-11 (rhIL-11, Neumega®) given subcutaneously for up to seven days during six consecutive menstrual cycles each in seven women with mild VWD and menorrhagia refractory to haemostatic or hormonal agents. rhIL-11 reduced menstrual bleeding severity as measured by pictorial blood assessment chart (PBAC) ≥50% (to 0.05. Platelet VWF mRNA expression by quantitative PCR increased mean four-fold (1.0–13.5). rhIL-11 was well tolerated with grade 1 or less fluid retention, flushing, conjunctival erythema, and local bruising. In summary, rhIL-11 reduces menorrhagia safely and warrants further study. PMID:21833452

  7. von Willebrand disease type 1 in Doberman Pinscher dogs: genotyping and prevalence of the mutation in the Buenos Aires region, Argentina.

    Science.gov (United States)

    Crespi, Julian A; Barrientos, Laura S; Giovambattista, Guillermo

    2018-03-01

    von Willebrand disease (vWD) is the most common inherited coagulopathy in dogs, particularly in Doberman Pinschers. We developed a pyrosequencing-based assay to estimate the frequency of the c.7437G>A mutation associated with vWD type 1 in the Doberman Pinscher population of Buenos Aires, Argentina. We found a 0.41 frequency for the mutated allele, which varied significantly within families (family 1 = 0.43, family 2 = 0.58, unrelated animals = 0.35). The use of a popular founder male carrier of mutant allele A increased vWD incidence within a family and in the general population. The mode of inheritance was confirmed as autosomal dominant with incomplete penetrance. No differences were found between sexes and coat colors. Pyrosequencing was a good complement to clinical and coagulation tests for vWD type 1 diagnosis and a useful alternative for detecting the c.7437G>A mutation.

  8. Antifibrinolytic therapy for preventing oral bleeding in patients with haemophilia or Von Willebrand disease undergoing minor oral surgery or dental extractions.

    Science.gov (United States)

    van Galen, Karin P M; Engelen, Eveline T; Mauser-Bunschoten, Evelien P; van Es, Robert J J; Schutgens, Roger E G

    2015-12-24

    Minor oral surgery or dental extractions (oral or dental procedures) are widely performed and can be complicated by hazardous oral bleeding, especially in people with an inherited bleeding disorder such as haemophilia or Von Willebrand disease. The amount and severity of singular bleedings depend on disease-related factors, such as the severity of the haemophilia, both local and systemic patient factors (such as periodontal inflammation, vasculopathy or platelet dysfunction) and intervention-related factors (such as the type and number of teeth extracted or the dimension of the wound surface). Similar to local haemostatic measures and suturing, antifibrinolytic therapy is a cheap, safe and potentially effective treatment to prevent bleeding complications in individuals with bleeding disorders undergoing oral or dental procedures. However, a systematic review of trials reporting outcomes after oral surgery or a dental procedure in people with an inherited bleeding disorder, with or without, the use of antifibrinolytic agents has not been performed to date. The primary objective was to assess the efficacy of local or systemic use of antifibrinolytic agents to prevent bleeding complications in people with haemophilia or Von Willebrand disease undergoing oral or dental procedures. Secondary objectives were to assess if antifibrinolytic agents can replace or reduce the need for clotting factor concentrate therapy in people with haemophilia or Von Willebrand disease and to further establish the effects of these agents on bleeding in oral or dental procedures for each of these populations. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches of the Cochrane Central Register of Controlled Trials (CENTRAL), of MEDLINE and from handsearching of journals and conference abstract books. We additionally searched the reference lists of relevant articles and reviews. We searched Pub

  9. Cuidados nos pacientes com hemofilia e doença de von Willebrand na cirurgia eletiva otorrinolaringológica Otolaryngology surgery: management of elective surgery in patients with haemophilia and von Willebrand disease

    Directory of Open Access Journals (Sweden)

    Marise P. C. Marques

    2003-01-01

    Full Text Available FORMA DE ESTUDO Clínico prospectivo. MATERIAL E MÉTODO: Foi realizado um estudo prospectivo de 10 anos de 20 pacientes com hemofilias ou doença de von Willebrand (DvW com indicação de cirurgia otorrinolaringológica. Os pacientes foram submetidos a um total de 25 cirurgias otorrinolaringológicas eletivas. A idade média foi de 23,75 anos (2 a 62 anos. O grupo de estudo consistiu em 14 hemofílicos, 11 com hemofilia A grave (1 do sexo feminino, uma portadora com 30% de atividade de fator VIII (FVIII, um hemofílico B leve e uma com deficiência grave de fator X; 6 com DvW, 4 tinham o tipo 1 (3 mulheres, um o tipo 2A e um o tipo 3. Treze hemofílicos tinham síndrome de imunodeficiência adquirida. A duração média do procedimento foi de 1 hora e 37 minutos (15 minutos a 12 horas. O defeito da coagulação foi corrigido com desmopressina (DDAVP, com concentrado de FVIII de pureza intermediária 8Y, com criopreciptado ou com complexo protrombínico não ativado (PPSB, de acordo com os níveis plasmáticos do fator e da severidade da cirurgia. O ácido épsilon aminocapróico também foi usado em associação. Em 1 hemofílico A grave houve sangramento pós-operatório que se resolveu com a elevação do nível mínimo de FVIII para 80% e em 1 paciente com DvW do Tipo 3 houve sangramento pós-operatório pela dificuldade de identificação do melhor concentrado a ser reposto. Após o uso do concentrado de pureza intermediária 8Y, houve controle do sangramento. RESULTADO: Todos os outros pacientes apresentaram a hemostasia considerada normal ou excelente. CONCLUSÃO: Concluiu-se que pacientes com hemofilias ou DvW não apresentam um risco cirúrgico aumentado se for realizada uma terapia adequada.STUD DESIGN: Clinical prospective. MATERIAL AND METHOD: A 10-year prospective research was conducted in 20 patients with hemophilia or von Willebrand disease (vWD. They were submitted to a total of 25 elective otolaryngological surgical events. The

  10. Disease phenotype at diagnosis in pediatric Crohn's disease

    DEFF Research Database (Denmark)

    de Bie, Charlotte I; Paerregaard, Anders; Kolacek, Sanja

    2013-01-01

    It has been speculated that pediatric Crohn's disease (CD) is a distinct disease entity, with probably different disease subtypes. We therefore aimed to accurately phenotype newly diagnosed pediatric CD by using the pediatric modification of the Montreal classification, the Paris classification....

  11. Heritability of plasma von Willebrand factor antigen concentration in German Wirehaired pointers.

    Science.gov (United States)

    Brooks, M B; Castillo-Juarez, H; Oltenacu, P

    2001-07-01

    We applied quantitative genetic analyses to a population of German Wirehaired pointer dogs affected with type 2 von Willebrand disease. Plasma von Willebrand factor (vWF) protein concentration measured as vWF antigen (vWF:Ag), clinical history, and pedigree data were compiled for 331 dogs over a 5-year test period. Eight dogs had histories of abnormal bleeding and had markedly decreased plasma vWF:Ag concentrations (dogs were inbred, with an average inbreeding of 2.52%. The estimated heritability of plasma vWF concentration was 0.52. We found a major gene effect on vWF concentration. Using a single gene locus model and two different prediction methods, the upper threshold value for the aa genotype was less than 1% vWF:Ag, and the optimal threshold value for discrimination between the AA and Aa genotypes was between 68% and 72% vWF:Ag. Our analyses indicate that phenotype, assigned on the basis of a single vWF:Ag determination, is heritable and can be applied for selective breeding in a von Willebrand disease test programme.

  12. Weight in Parkinson's Disease: Phenotypical Significance.

    Science.gov (United States)

    Sharma, Jagdish C; Lewis, Anna

    2017-01-01

    Body weight in Parkinson's disease (PD) is a significant nonmotor feature. Weight homeostasis is a complex physiological process and gets deranged in PD patients leading to changes in weight. While both the low and high body weight have been reported as risk factors for PD, the majority of PD patients have a lower weight and a subset of patients lose weight during the course of the disease, while a small proportion gain weight. A number of clinical parameters such as older age, impaired cognition, severity of disease, and an imbalance of food intake determined by satiety and hunger hormones have been reported to be associated with but not the cause of weight change. Low body weight and weight loss have a negative impact on disease severity, dyskinesia quality of life, and mortality indicative of disease progression. An early assessment of olfactory impairment seems to identify patients at risk of weight loss, the patients with more severe olfactory loss-anosmic group, lose weight as compared to the patients with some preservation of olfaction, the hyposmic group. Higher levodopa dose per kilogram body weight increases the risk of dyskinesia, higher body weight seems to be protective against this complication. The identification of PD patients according to the nonmotor phenotype of "Park-olfaction-weight-phenotype" and the "olfaction-weight-dyskinesia" triad should help to develop strategies to prevent weight reduction and improve general health and complications of PD patients. The phenotype seems to reflect a differential prodromal pathology and influence clinical disease. Higher body weight patients would benefit from life style changes to achieve a healthy profile. Weight monitoring and weight orientated approach to management of PD patients should help to improve their outcome. Body weight change might be a surrogate to disease progression and may be used to investigate neuroprotection strategies. © 2017 Elsevier Inc. All rights reserved.

  13. The Changing Phenotype of Inflammatory Bowel Disease

    Directory of Open Access Journals (Sweden)

    Carthage Moran

    2016-01-01

    Full Text Available It is widely known that there have been improvements in patient care and an increased incidence of Inflammatory Bowel Disease (IBD worldwide in recent decades. However, less well known are the phenotypic changes that have occurred; these are discussed in this review. Namely, we discuss the emergence of obesity in patients with IBD, elderly onset disease, mortality rates, colorectal cancer risk, the burden of medications and comorbidities, and the improvement in surgical treatment with a decrease in surgical rates in recent decades.

  14. The Changing Phenotype of Inflammatory Bowel Disease

    Science.gov (United States)

    Sheehan, Donal; Shanahan, Fergus

    2016-01-01

    It is widely known that there have been improvements in patient care and an increased incidence of Inflammatory Bowel Disease (IBD) worldwide in recent decades. However, less well known are the phenotypic changes that have occurred; these are discussed in this review. Namely, we discuss the emergence of obesity in patients with IBD, elderly onset disease, mortality rates, colorectal cancer risk, the burden of medications and comorbidities, and the improvement in surgical treatment with a decrease in surgical rates in recent decades. PMID:28050166

  15. Trends in clinical management of women with von Willebrand disease: a survey of 75 women enrolled in haemophilia treatment centres in the United States.

    Science.gov (United States)

    Kirtava, A; Crudder, S; Dilley, A; Lally, C; Evatt, B

    2004-03-01

    To assess the management of women with von Willebrand disease( vWD) in an Heamophilia Treatment Center (HTC) setting. A total of 75 women with vWd who were registered in HTCs in the United States participated in this study. A telephone interview elicited information about symptoms pertaining to bleeding disorders, diagnostic issues, referral patterns, treatment modalities before and after the enrollment in the HTC, HTC services provided, and satisfaction with care in the HTC. Menorrhagia was the most commonly reported symptom (84%). The average time from the first symptom until clinician recognition was 16 years (range 0-39). In HTC, DDAVP was the most commonly used drug (31%). Of the 75 women, 71 reported a strong positive opinion and satisfaction about their care in the HTCs. Women with VWD were typically diagnosed with the condition well into adulthood, in spite of the fact that majority of them experienced several bleeding symptoms beginning in early childhood. In general an HTC setting is appropriate for management of women with bleeding disorders. Diagnosis, treatment and education provided in the HTCs were viewed positively by those surveyed.

  16. Laboratory Testing for Von Willebrand Factor Multimers.

    Science.gov (United States)

    Oliver, Susan; Lau, Kun Kan Edwin; Chapman, Kent; Favaloro, Emmanuel J

    2017-01-01

    Von Willebrand disease (VWD) is reportedly the most common inherited bleeding disorder and can also arise as an acquired syndrome (AVWS). These disorders develop due to defects and/or deficiency of the plasma protein von Willebrand factor (VWF). Laboratory testing for the VWF-related disorders requires assessment of both VWF level and VWF activity, the latter requiring multiple assays because of the many functions carried out by VWF to help prevent bleeding. As an additional step, an evaluation of VWF structural features by multimer analysis is useful in selective investigations. The current paper therefore describes a protocol for assessment of VWF multimers by gel electrophoresis, thus enabling identification of protein bands that represent differently sized multimers. The sample protocol described in this chapter is the methodology developed by Sebia.

  17. Acquired von Willebrand syndrome: A rare disorder of heterogeneous etiology

    Directory of Open Access Journals (Sweden)

    P Kasatkar

    2013-01-01

    Full Text Available Context: Acquired von Willebrand syndrome (AVWS is a rare bleeding disorder that mimics the inherited form of von Willebrand disease (VWD in terms of laboratory findings and clinical presentation. Aims: To study the etiology of acquired VWD. Settings and Design: The patients referred from various hospitals in and out of Mumbai were included in the study. Materials and Methods: Six patients with AVWS diagnosed at this center over the last 10 years were analyzed against 171 patients with inherited VWD. The differential diagnosis of AVWS was made based on reduced levels of von Willebrand antigen and von Willebrand ristocetin cofactor, decrease in ristocetin induced platelet aggregation, absence of correction in mixing studies with no prior history of bleeding problems and a negative family history for bleeding disorders. Results: In three patients, the disease was associated with systematic lupus erythematosus, out of which one was also associated with Kikuchi lymphadenitis and second with autoimmune hemolytic anemia. Fourth case was associated with hypothyroidism and fifth was a case of dermatitis and vitiligo. The last patient was a case of hemophilia A with Burkitts lymphoma, who developed autoantibodies to von Willebrand factor. Except two patients, all other patients responded to immune suppressive therapy with corticosteroids, while the patient with hypothyroidism responded to oral thyroxine. Conclusion: AVWS is a rare condition and may often be missed or diagnosed as inherited disease associated with heterogeneous disease conditions.

  18. ARHGEF9 disease: Phenotype clarification and genotype-phenotype correlation.

    Science.gov (United States)

    Alber, Michael; Kalscheuer, Vera M; Marco, Elysa; Sherr, Elliott; Lesca, Gaetan; Till, Marianne; Gradek, Gyri; Wiesener, Antje; Korenke, Christoph; Mercier, Sandra; Becker, Felicitas; Yamamoto, Toshiyuki; Scherer, Stephen W; Marshall, Christian R; Walker, Susan; Dutta, Usha R; Dalal, Ashwin B; Suckow, Vanessa; Jamali, Payman; Kahrizi, Kimia; Najmabadi, Hossein; Minassian, Berge A

    2017-06-01

    We aimed to generate a review and description of the phenotypic and genotypic spectra of ARHGEF9 mutations. Patients with mutations or chromosomal disruptions affecting ARHGEF9 were identified through our clinics and review of the literature. Detailed medical history and examination findings were obtained via a standardized questionnaire, or if this was not possible by reviewing the published phenotypic features. A total of 18 patients (including 5 females) were identified. Six had de novo, 5 had maternally inherited mutations, and 7 had chromosomal disruptions. All females had strongly skewed X-inactivation in favor of the abnormal X-chromosome. Symptoms presented in early childhood with delayed motor development alone or in combination with seizures. Intellectual disability was severe in most and moderate in patients with milder mutations. Males with severe intellectual disability had severe, often intractable, epilepsy and exhibited a particular facial dysmorphism. Patients with mutations in exon 9 affecting the protein's PH domain did not develop epilepsy. ARHGEF9 encodes a crucial neuronal synaptic protein; loss of function of which results in severe intellectual disability, epilepsy, and a particular facial dysmorphism. Loss of only the protein's PH domain function is associated with the absence of epilepsy.

  19. Mapping gene associations in human mitochondria using clinical disease phenotypes.

    Directory of Open Access Journals (Sweden)

    Curt Scharfe

    2009-04-01

    Full Text Available Nuclear genes encode most mitochondrial proteins, and their mutations cause diverse and debilitating clinical disorders. To date, 1,200 of these mitochondrial genes have been recorded, while no standardized catalog exists of the associated clinical phenotypes. Such a catalog would be useful to develop methods to analyze human phenotypic data, to determine genotype-phenotype relations among many genes and diseases, and to support the clinical diagnosis of mitochondrial disorders. Here we establish a clinical phenotype catalog of 174 mitochondrial disease genes and study associations of diseases and genes. Phenotypic features such as clinical signs and symptoms were manually annotated from full-text medical articles and classified based on the hierarchical MeSH ontology. This classification of phenotypic features of each gene allowed for the comparison of diseases between different genes. In turn, we were then able to measure the phenotypic associations of disease genes for which we calculated a quantitative value that is based on their shared phenotypic features. The results showed that genes sharing more similar phenotypes have a stronger tendency for functional interactions, proving the usefulness of phenotype similarity values in disease gene network analysis. We then constructed a functional network of mitochondrial genes and discovered a higher connectivity for non-disease than for disease genes, and a tendency of disease genes to interact with each other. Utilizing these differences, we propose 168 candidate genes that resemble the characteristic interaction patterns of mitochondrial disease genes. Through their network associations, the candidates are further prioritized for the study of specific disorders such as optic neuropathies and Parkinson disease. Most mitochondrial disease phenotypes involve several clinical categories including neurologic, metabolic, and gastrointestinal disorders, which might indicate the effects of gene defects

  20. An ELISA for the quantitation of von Willebrand Factor

    DEFF Research Database (Denmark)

    Vinholt, Pernille Just; Overgaard, Martin; Diederichsen, Axel Cosmus Pyndt

    2013-01-01

    BACKGROUND: Von Willebrand factor (VWF) is pivotal in arterial thrombosis, and osteoprotegerin (OPG) is besides being a bone protein also related to cardiovascular diseases. OPG can bind VWF, but the significance of this interaction is not known. OBJECTIVES: The aim was to develop an assay...... for measurement of von Willebrand factor-osteoprotegerin complex (VWF:OPG) in human plasma. Furthermore, the significance of VWF:OPG complex as a marker of cardiovascular disease (CVD) was evaluated. PATIENTS/METHODS: A sandwich ELISA for quantification of VWF:OPG was developed using a polyclonal rabbit anti...

  1. Diurnal variation of von Willebrand factor in plasma

    DEFF Research Database (Denmark)

    Timm, Annette; Fahrenkrug, Jan; Jørgensen, Henrik L

    2014-01-01

    BACKGROUND: Quantitation of von Willebrand factor (VWF) in plasma is a central element in assessing von Willebrand disease (VWD). VWF activity is known to vary, which has partly been ascribed to biological and preanalytical variation. However, a possible diurnal expression of VWF has not been...... of light and 9 h of darkness); the plasma concentration of melatonin was used as an internal control to confirm the normal 24-h rhythms of the individual participants. RESULTS: The data, analyzed by rhythmometric statistics, revealed a significant variation (P = 0.02) and total amplitude of 22.6% in VWF...... and VWF and (ii) VWF propeptide and VWF was determined. Taken together, the data suggest changes in release and not in clearance. CONCLUSIONS: Diurnal variation in von Willebrand antigen and activity in plasma represents an important aspect of the biological variation. Standardized time-of-day plasma...

  2. von Willebrand Disease (For Parents)

    Science.gov (United States)

    ... disorder. The most common treatment for vWD is desmopressin, a medication that causes a temporary increase in ... surgery, although they usually can be treated with desmopressin. Medication to inhibit the breakdown of blood clots ( ...

  3. Chronic obstructive pulmonary disease phenotypes: the future of COPD

    DEFF Research Database (Denmark)

    Han, MeiLan K; Agusti, Alvar; Calverley, Peter M

    2010-01-01

    Significant heterogeneity of clinical presentation and disease progression exists within chronic obstructive pulmonary disease (COPD). Although FEV(1) inadequately describes this heterogeneity, a clear alternative has not emerged. The goal of phenotyping is to identify patient groups with unique...... prognostic or therapeutic characteristics, but significant variation and confusion surrounds use of the term "phenotype" in COPD. Phenotype classically refers to any observable characteristic of an organism, and up until now, multiple disease characteristics have been termed COPD phenotypes. We, however......, propose the following variation on this definition: "a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes (symptoms, exacerbations, response to therapy, rate of disease progression, or death)." This more...

  4. Physiological phenotyping of pediatric chronic obstructive airway diseases.

    Science.gov (United States)

    Nyilas, Sylvia; Singer, Florian; Kumar, Nitin; Yammine, Sophie; Meier-Girard, Delphine; Koerner-Rettberg, Cordula; Casaulta, Carmen; Frey, Urs; Latzin, Philipp

    2016-07-01

    Inert tracer gas washout (IGW) measurements detect increased ventilation inhomogeneity (VI) in chronic lung diseases. Their suitability for different diseases, such as cystic fibrosis (CF) and primary ciliary dyskinesia (PCD), has already been shown. However, it is still unclear if physiological phenotypes based on different IGW variables can be defined independently of underlying disease. Eighty school-age children, 20 with CF, 20 with PCD, 20 former preterm children, and 20 healthy children, performed nitrogen multiple-breath washout, double-tracer gas (DTG) single-breath washout, and spirometry. Our primary outcome was the definition of physiological phenotypes based on IGW variables. We applied principal component analysis, hierarchical Ward's clustering, and enrichment analysis to compare clinical characteristics between the clusters. IGW variables used for clustering were lung clearance index (LCI) and convection-dependent [conductive ventilation heterogeneity index (Scond)] and diffusion-convection-dependent variables [acinar ventilation heterogeneity index (Sacin) and carbon dioxide and DTG phase III slopes]. Three main phenotypes were identified. Phenotype I (n = 38) showed normal values in all IGW outcome variables. Phenotype II (n = 21) was characterized by pronounced global and convection-dependent VI while diffusion-dependent VI was normal. Phenotype III (n = 21) was characterized by increased global and diffusion- and convection-dependent VI. Enrichment analysis revealed an overrepresentation of healthy children and former preterm children in phenotype I and of CF and PCD in phenotypes II and III. Patients in phenotype III showed the highest proportion and frequency of exacerbations and hospitalization in the year prior to the measurement. IGW techniques allow identification of clinically meaningful, disease-independent physiological clusters. Their predictive value of future disease outcomes remains to be determined. Copyright © 2016 the American

  5. Evolutionary history of human disease genes reveals phenotypic connections and comorbidity among genetic diseases

    Science.gov (United States)

    Park, Solip; Yang, Jae-Seong; Kim, Jinho; Shin, Young-Eun; Hwang, Jihye; Park, Juyong; Jang, Sung Key; Kim, Sanguk

    2012-10-01

    The extent to which evolutionary changes have impacted the phenotypic relationships among human diseases remains unclear. In this work, we report that phenotypically similar diseases are connected by the evolutionary constraints on human disease genes. Human disease groups can be classified into slowly or rapidly evolving classes, where the diseases in the slowly evolving class are enriched with morphological phenotypes and those in the rapidly evolving class are enriched with physiological phenotypes. Our findings establish a clear evolutionary connection between disease classes and disease phenotypes for the first time. Furthermore, the high comorbidity found between diseases connected by similar evolutionary constraints enables us to improve the predictability of the relative risk of human diseases. We find the evolutionary constraints on disease genes are a new layer of molecular connection in the network-based exploration of human diseases.

  6. PCAN: phenotype consensus analysis to support disease-gene association.

    Science.gov (United States)

    Godard, Patrice; Page, Matthew

    2016-12-07

    Bridging genotype and phenotype is a fundamental biomedical challenge that underlies more effective target discovery and patient-tailored therapy. Approaches that can flexibly and intuitively, integrate known gene-phenotype associations in the context of molecular signaling networks are vital to effectively prioritize and biologically interpret genes underlying disease traits of interest. We describe Phenotype Consensus Analysis (PCAN); a method to assess the consensus semantic similarity of phenotypes in a candidate gene's signaling neighborhood. We demonstrate that significant phenotype consensus (p disease-gene associations, using a combination of high quality String interactions + Metabase pathways and use Joubert Syndrome to demonstrate the ease with which a significant result can be interrogated to highlight discriminatory traits linked to mechanistically related genes. We advocate phenotype consensus as an intuitive and versatile method to aid disease-gene association, which naturally lends itself to the mechanistic deconvolution of diverse phenotypes. We provide PCAN to the community as an R package ( http://bioconductor.org/packages/PCAN/ ) to allow flexible configuration, extension and standalone use or integration to supplement existing gene prioritization workflows.

  7. Airways Disease: Phenotyping Heterogeneity Using Measures of Airway Inflammation

    Directory of Open Access Journals (Sweden)

    Siddiqui Salman

    2007-06-01

    Full Text Available Despite asthma and chronic obstructive pulmonary disease being widely regarded as heterogeneous diseases, a consensus for an accurate system of classification has not been agreed. Recent studies have suggested that the recognition of subphenotypes of airway disease based on the pattern of airway inflammation may be particularly useful in increasing our understanding of the disease. The use of non-invasive markers of airway inflammation has suggested the presence of four distinct phenotypes: eosinophilic, neutrophilic, mixed inflammatory and paucigranulocytic asthma. Recent studies suggest that these subgroups may differ in their etiology, immunopathology and response to treatment. Importantly, novel treatment approaches targeted at specific patterns of airway inflammation are emerging, making an appreciation of subphenotypes particularly relevant. New developments in phenotyping inflammation and other facets of airway disease mean that we are entering an era where careful phenotyping will lead to targeted therapy.

  8. Angioedema Phenotypes: Disease Expression and Classification.

    Science.gov (United States)

    Wu, Maddalena Alessandra; Perego, Francesca; Zanichelli, Andrea; Cicardi, Marco

    2016-10-01

    Due to marked heterogeneity of clinical presentations, comprehensive knowledge of angioedema phenotypes is crucial for correct diagnosis and choosing the appropriate therapeutic approach. One of the ways to a meaningful clinical distinction can be made between forms of angioedema occurring "with or without wheals." Angioedema with wheals (rash) is a hallmark of urticaria, either acute or chronic, spontaneous or inducible. Angioedema without wheals may still be manifested in about 10 % of patients with urticaria, but it may also occur as a separate entity. Several classifications of angioedema as part of urticaria were published over time, while a latest one, released in 2014 (HAWK group consensus, see below), provided a classification of all forms of "angioedema without wheals" distinct from urticaria, which will be the focus of the present review. At this time, the HAWK consensus classification is the best in terms of covering the pathophysiology, mediators involved, angioedema triggers, and clinical expression. According to this classification, three types of hereditary angioedema (genetic C1-INH deficiency, normal C1-INH with factor XII mutations, and unknown origin) and four types of acquired angioedema (C1-INH deficiency, related to ACE inhibitors intake, idiopathic histaminergic, and idiopathic non-histaminergic) are presented. We will review the distinctive clinical features of each phenotype in details.

  9. Assessment of the olfactory function in Italian patients with type 3 von Willebrand disease caused by a homozygous 253 Kb deletion involving VWF and TMEM16B/ANO2.

    Directory of Open Access Journals (Sweden)

    Valentina Cenedese

    Full Text Available Type 3 Von Willebrand disease is an autosomal recessive disease caused by the virtual absence of the von Willebrand factor (VWF. A rare 253 kb gene deletion on chromosome 12, identified only in Italian and German families, involves both the VWF gene and the N-terminus of the neighbouring TMEM16B/ANO2 gene, a member of the family named transmembrane 16 (TMEM16 or anoctamin (ANO. TMEM16B is a calcium-activated chloride channel expressed in the olfactory epithelium. As a patient homozygous for the 253 kb deletion has been reported to have an olfactory impairment possibly related to the partial deletion of TMEM16B, we assessed the olfactory function in other patients using the University of Pennsylvania Smell Identification Test (UPSIT. The average UPSIT score of 4 homozygous patients was significantly lower than that of 5 healthy subjects with similar sex, age and education. However, 4 other members of the same family, 3 heterozygous for the deletion and 1 wild type, had a slightly reduced olfactory function indicating that socio-cultural or other factors were likely to be responsible for the observed difference. These results show that the ability to identify odorants of the homozygous patients for the deletion was not significantly different from that of the other members of the family, showing that the 253 kb deletion does not affect the olfactory performance. As other genes may compensate for the lack of TMEM16B, we identified some predicted functional partners from in silico studies of the protein-protein network of TMEM16B. Calculation of diversity for the corresponding genes for individuals of the 1000 Genomes Project showed that TMEM16B has the highest level of diversity among all genes of the network, indicating that TMEM16B may not be under purifying selection and suggesting that other genes in the network could compensate for its function for olfactory ability.

  10. Pharmacological Modulation of Functional Phenotypes of Microglia in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Gyun Jee Song

    2017-05-01

    Full Text Available Microglia are the resident innate immune cells of the central nervous system that mediate brain homeostasis maintenance. Microglia-mediated neuroinflammation is a hallmark shared by various neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Numerous studies have shown microglial activation phenotypes to be heterogeneous; however, these microglial phenotypes can largely be categorized as being either M1 or M2 type. Although the specific classification of M1 and M2 functionally polarized microglia remains a topic for debate, the use of functional modulators of microglial phenotypes as potential therapeutic approaches for the treatment of neurodegenerative diseases has garnered considerable attention. This review discusses M1 and M2 microglial phenotypes and their relevance in neurodegenerative disease models, as described in recent literature. The modulation of microglial polarization toward the M2 phenotype may lead to development of future therapeutic and preventive strategies for neuroinflammatory and neurodegenerative diseases. Thus, we focus on recent studies of microglial polarization modulators, with a particular emphasis on the small-molecule compounds and their intracellular target proteins.

  11. Standardized phenotyping enhances Mendelian disease gene identification

    NARCIS (Netherlands)

    Vissers, L.E.L.M.; Veltman, J.A.

    2015-01-01

    Whole-exome sequencing has revolutionized the identification of genes with dominant disease-associated variants for rare clinically and genetically heterogeneous disorders, but the identification of genes with recessive disease-associated variants has been less successful. A new study now provides a

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

    African Journals Online (AJOL)

    More children with a history of asthma had ACS. Furthermore, high steady.state white blood cell count was associated with severe disease. Conclusion: The clinical phenotypes of SCD in children from South.Western Nigeria are highly variable with the disease manifesting very early and about 10% having significant ...

  13. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes

    DEFF Research Database (Denmark)

    Cleynen, Isabelle; Boucher, Gabrielle; Jostins, Luke

    2016-01-01

    centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34,819 patients (19,713 with Crohn's disease, 14,683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype......-phenotype associations across 156,154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease...... of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time. FUNDING: International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list)....

  14. Microglia phenotypes in aging-associated diseases

    NARCIS (Netherlands)

    Yin, Zhuoran

    2017-01-01

    Due to the improvement in the public health and medical care, the life span of human beings has elongated considerably over the last decades. Consequently, the occurrence of aging-associated diseases has also increased. Inflammation of the brain increases during aging and could be an important

  15. Phenotype of asthma-chronic obstructive pulmonary disease overlap syndrome.

    Science.gov (United States)

    Rhee, Chin Kook

    2015-07-01

    Many patients with asthma or chronic obstructive pulmonary disease (COPD) have overlapping characteristics of both diseases. By spirometric definition, patients with both fixed airflow obstruction (AO) and bronchodilator reversibility or fixed AO and bronchial hyperresponsiveness can be considered to have asthma-COPD overlap syndrome (ACOS). However, patients regarded to have ACOS by spirometric criteria alone are heterogeneous and can be classified by phenotype. Eosinophilic inflammation, a history of allergic disease, and smoke exposure are important components in the classification of ACOS. Each phenotype has a different underlying pathophysiology, set of characteristics, and prognosis. Medical treatment for ACOS should be tailored according to phenotype. A narrower definition of ACOS that includes both spirometric and clinical criteria is needed.

  16. Phenotype of asthma-chronic obstructive pulmonary disease overlap syndrome

    Science.gov (United States)

    2015-01-01

    Many patients with asthma or chronic obstructive pulmonary disease (COPD) have overlapping characteristics of both diseases. By spirometric definition, patients with both fixed airflow obstruction (AO) and bronchodilator reversibility or fixed AO and bronchial hyperresponsiveness can be considered to have asthma-COPD overlap syndrome (ACOS). However, patients regarded to have ACOS by spirometric criteria alone are heterogeneous and can be classified by phenotype. Eosinophilic inflammation, a history of allergic disease, and smoke exposure are important components in the classification of ACOS. Each phenotype has a different underlying pathophysiology, set of characteristics, and prognosis. Medical treatment for ACOS should be tailored according to phenotype. A narrower definition of ACOS that includes both spirometric and clinical criteria is needed. PMID:26161009

  17. Mechanistic phenotypes: an aggregative phenotyping strategy to identify disease mechanisms using GWAS data.

    Directory of Open Access Journals (Sweden)

    Jonathan D Mosley

    Full Text Available A single mutation can alter cellular and global homeostatic mechanisms and give rise to multiple clinical diseases. We hypothesized that these disease mechanisms could be identified using low minor allele frequency (MAF<0.1 non-synonymous SNPs (nsSNPs associated with "mechanistic phenotypes", comprised of collections of related diagnoses. We studied two mechanistic phenotypes: (1 thrombosis, evaluated in a population of 1,655 African Americans; and (2 four groupings of cancer diagnoses, evaluated in 3,009 white European Americans. We tested associations between nsSNPs represented on GWAS platforms and mechanistic phenotypes ascertained from electronic medical records (EMRs, and sought enrichment in functional ontologies across the top-ranked associations. We used a two-step analytic approach whereby nsSNPs were first sorted by the strength of their association with a phenotype. We tested associations using two reverse genetic models and standard additive and recessive models. In the second step, we employed a hypothesis-free ontological enrichment analysis using the sorted nsSNPs to identify functional mechanisms underlying the diagnoses comprising the mechanistic phenotypes. The thrombosis phenotype was solely associated with ontologies related to blood coagulation (Fisher's p = 0.0001, FDR p = 0.03, driven by the F5, P2RY12 and F2RL2 genes. For the cancer phenotypes, the reverse genetics models were enriched in DNA repair functions (p = 2×10-5, FDR p = 0.03 (POLG/FANCI, SLX4/FANCP, XRCC1, BRCA1, FANCA, CHD1L while the additive model showed enrichment related to chromatid segregation (p = 4×10-6, FDR p = 0.005 (KIF25, PINX1. We were able to replicate nsSNP associations for POLG/FANCI, BRCA1, FANCA and CHD1L in independent data sets. Mechanism-oriented phenotyping using collections of EMR-derived diagnoses can elucidate fundamental disease mechanisms.

  18. Early-onset stargardt disease: phenotypic and genotypic characteristics

    NARCIS (Netherlands)

    Lambertus, S.; Huet, R.A.C. van; Bax, N.M.; Hoefsloot, L.H.; Cremers, F.P.M.; Boon, C.J.F.; Klevering, B.J.; Hoyng, C.B.

    2015-01-01

    OBJECTIVE: To describe the phenotype and genotype of patients with early-onset Stargardt disease. DESIGN: Retrospective cohort study. PARTICIPANTS: Fifty-one Stargardt patients with age at onset

  19. Von Willebrand factor for menorrhagia: a survey and literature review.

    Science.gov (United States)

    Ragni, M V; Machin, N; Malec, L M; James, A H; Kessler, C M; Konkle, B A; Kouides, P A; Neff, A T; Philipp, C S; Brambilla, D J

    2016-05-01

    von Willebrand disease (VWD) is the most common congenital bleeding disorder. In women, menorrhagia is the most common bleeding symptom, and is disabling with iron deficiency anaemia, high health cost and poor quality of life. Current hormonal and non-hormonal therapies are limited by ineffectiveness and intolerance. Few data exist regarding von Willebrand factor (VWF), typically prescribed when other treatments fail. The lack of effective therapy for menorrhagia remains the greatest unmet healthcare need in women with VWD. Better therapies are needed to treat women with menorrhagia. We conducted a survey of US haemophilia treatment centres (HTCs) and a literature review using medical subject heading (MeSH) search terms 'von Willebrand factor,' 'menorrhagia' and 'von Willebrand disease' to assess the use of VWF in menorrhagia. Analysis was by descriptive statistics. Of 83 surveys distributed to HTC MDs, 20 (24.1%) provided sufficient data for analysis. Of 1321 women with VWD seen during 2011-2014, 816 (61.8%) had menorrhagia, for which combined oral contraceptives, tranexamic acid and desmopressin were the most common first-line therapies for menorrhagia, whereas VWF was third-line therapy reported in 13 women (1.6%). Together with data from 88 women from six published studies, VWF safely reduced menorrhagia in 101 women at a dose of 33-100 IU kg(-1) on day 1-6 of menstrual cycle. This represents the largest VWD menorrhagia treatment experience to date. VWF safely and effectively reduces menorrhagia in women with VWD. A prospective clinical trial is planned to confirm these findings. © 2016 John Wiley & Sons Ltd.

  20. A comprehensive global genotype-phenotype database for rare diseases.

    Science.gov (United States)

    Trujillano, Daniel; Oprea, Gabriela-Elena; Schmitz, Yvonne; Bertoli-Avella, Aida M; Abou Jamra, Rami; Rolfs, Arndt

    2017-01-01

    The ability to discover genetic variants in a patient runs far ahead of the ability to interpret them. Databases with accurate descriptions of the causal relationship between the variants and the phenotype are valuable since these are critical tools in clinical genetic diagnostics. Here, we introduce a comprehensive and global genotype-phenotype database focusing on rare diseases. This database (CentoMD ®) is a browser-based tool that enables access to a comprehensive, independently curated system utilizing stringent high-quality criteria and a quickly growing repository of genetic and human phenotype ontology (HPO)-based clinical information. Its main goals are to aid the evaluation of genetic variants, to enhance the validity of the genetic analytical workflow, to increase the quality of genetic diagnoses, and to improve evaluation of treatment options for patients with hereditary diseases. The database software correlates clinical information from consented patients and probands of different geographical backgrounds with a large dataset of genetic variants and, when available, biomarker information. An automated follow-up tool is incorporated that informs all users whenever a variant classification has changed. These unique features fully embedded in a CLIA/CAP-accredited quality management system allow appropriate data quality and enhanced patient safety. More than 100,000 genetically screened individuals are documented in the database, resulting in more than 470 million variant detections. Approximately, 57% of the clinically relevant and uncertain variants in the database are novel. Notably, 3% of the genetic variants identified and previously reported in the literature as being associated with a particular rare disease were reclassified, based on internal evidence, as clinically irrelevant. The database offers a comprehensive summary of the clinical validity and causality of detected gene variants with their associated phenotypes, and is a valuable tool for

  1. Image-based phenotyping of plant disease symptoms

    Directory of Open Access Journals (Sweden)

    Andrew eMutka

    2015-01-01

    Full Text Available Plant diseases cause significant reductions in agricultural productivity worldwide. Disease symptoms have deleterious effects on the growth and development of crop plants, limiting yields and making agricultural products unfit for consumption. For many plant-pathogen systems, we lack knowledge of the physiological mechanisms that link pathogen infection and the production of disease symptoms in the host. A variety of quantitative high-throughput image-based methods for phenotyping plant growth and development are currently being developed. These methods range from detailed analysis of a single plant over time to broad assessment of the crop canopy for thousands of plants in a field and employ a wide variety of imaging technologies. Application of these methods to the study of plant disease offers the ability to study quantitatively how host physiology is altered by pathogen infection. These approaches have the potential to provide insight into the physiological mechanisms underlying disease symptom development. Furthermore, imaging techniques that detect the electromagnetic spectrum outside of visible light allow us to quantify disease symptoms that are not visible by eye, increasing the range of symptoms we can observe and potentially allowing for earlier and more thorough symptom detection. In this review, we summarize current progress in plant disease phenotyping and suggest future directions that will accelerate the development of resistant crop varieties.

  2. A universal mechanism ties genotype to phenotype in trinucleotide diseases.

    Directory of Open Access Journals (Sweden)

    Shai Kaplan

    2007-11-01

    Full Text Available Trinucleotide hereditary diseases such as Huntington disease and Friedreich ataxia are cureless diseases associated with inheriting an abnormally large number of DNA trinucleotide repeats in a gene. The genes associated with different diseases are unrelated and harbor a trinucleotide repeat in different functional regions; therefore, it is striking that many of these diseases have similar correlations between their genotype, namely the number of inherited repeats and age of onset and progression phenotype. These correlations remain unexplained despite more than a decade of research. Although mechanisms have been proposed for several trinucleotide diseases, none of the proposals, being disease-specific, can account for the commonalities among these diseases. Here, we propose a universal mechanism in which length-dependent somatic repeat expansion occurs during the patient's lifetime toward a pathological threshold. Our mechanism uniformly explains for the first time to our knowledge the genotype-phenotype correlations common to trinucleotide disease and is well-supported by both experimental and clinical data. In addition, mathematical analysis of the mechanism provides simple explanations to a wide range of phenomena such as the exponential decrease of the age-of-onset curve, similar onset but faster progression in patients with Huntington disease with homozygous versus heterozygous mutation, and correlation of age of onset with length of the short allele but not with the long allele in Friedreich ataxia. If our proposed universal mechanism proves to be the core component of the actual mechanisms of specific trinucleotide diseases, it would open the search for a uniform treatment for all these diseases, possibly by delaying the somatic expansion process.

  3. Hereditary kidney diseases: highlighting the importance of classical Mendelian phenotypes.

    Science.gov (United States)

    Benoit, Geneviève; Machuca, Eduardo; Heidet, Laurence; Antignac, Corinne

    2010-12-01

    A Mendelian inheritance underlies a nonnegligible proportion of hereditary kidney diseases, suggesting that the encoded proteins are essential for maintenance of the renal function. The identification of genes involved in congenital anomalies of the kidney and in familial forms of nephrotic syndrome significantly increased our understanding of the renal development and kidney filtration barrier physiology. This review will focus on the classical phenotype and clinical heterogeneity observed in the monogenic forms of these disorders. In addition, the role of susceptibility genes in kidney diseases with a complex inheritance will also be discussed. © 2010 New York Academy of Sciences.

  4. Towards building a disease-phenotype knowledge base: extracting disease-manifestation relationship from literature

    Science.gov (United States)

    Xu, Rong; Li, Li; Wang, QuanQiu

    2013-01-01

    Motivation: Systems approaches to studying phenotypic relationships among diseases are emerging as an active area of research for both novel disease gene discovery and drug repurposing. Currently, systematic study of disease phenotypic relationships on a phenome-wide scale is limited because large-scale machine-understandable disease–phenotype relationship knowledge bases are often unavailable. Here, we present an automatic approach to extract disease–manifestation (D-M) pairs (one specific type of disease–phenotype relationship) from the wide body of published biomedical literature. Data and Methods: Our method leverages external knowledge and limits the amount of human effort required. For the text corpus, we used 119 085 682 MEDLINE sentences (21 354 075 citations). First, we used D-M pairs from existing biomedical ontologies as prior knowledge to automatically discover D-M–specific syntactic patterns. We then extracted additional pairs from MEDLINE using the learned patterns. Finally, we analysed correlations between disease manifestations and disease-associated genes and drugs to demonstrate the potential of this newly created knowledge base in disease gene discovery and drug repurposing. Results: In total, we extracted 121 359 unique D-M pairs with a high precision of 0.924. Among the extracted pairs, 120 419 (99.2%) have not been captured in existing structured knowledge sources. We have shown that disease manifestations correlate positively with both disease-associated genes and drug treatments. Conclusions: The main contribution of our study is the creation of a large-scale and accurate D-M phenotype relationship knowledge base. This unique knowledge base, when combined with existing phenotypic, genetic and proteomic datasets, can have profound implications in our deeper understanding of disease etiology and in rapid drug repurposing. Availability: http://nlp.case.edu/public/data/DMPatternUMLS/ Contact: rxx@case.edu PMID:23828786

  5. CARD15 in inflammatory bowel disease and Crohn's disease phenotypes: an association study and pooled analysis.

    NARCIS (Netherlands)

    Oostenbrug, L.E.; Nolte, I.M.; Oosterom, E.; Steege, G. van der; Meerman, G.J. te; Dullemen, H.M. van; Drenth, J.P.H.; Jong, D.J. de; Linde, K. van der; Jansen, P.L.M.; Kleibeuker, J.H.

    2006-01-01

    BACKGROUND: Three major polymorphisms of the Caspase-Activation Recruitment Domain containing protein 15 gene have been described to be associated with Crohn's disease. Genotype-phenotype studies reported in literature provide conflicting data on disease localisation and behaviour. We investigated

  6. CARD15 in inflammatory bowel disease and Crohn's disease phenotypes: an association study and pooled analysis

    NARCIS (Netherlands)

    Oostenbrug, L. E.; Nolte, I. M.; Oosterom, E.; van der Steege, G.; te Meerman, G. J.; van Dullemen, H. M.; Drenth, J. P. H.; de Jong, D. J.; van der Linde, K.; Jansen, P. L. M.; Kleibeuker, J. H.

    2006-01-01

    BACKGROUND: Three major polymorphisms of the Caspase-Activation Recruitment Domain containing protein 15 gene have been described to be associated with Crohn's disease. Genotype-phenotype studies reported in literature provide conflicting data on disease localisation and behaviour. We investigated

  7. The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data

    NARCIS (Netherlands)

    Kohler, S.; Doelken, S.C.; Mungall, C.J.; Bauer, S.; Firth, H.V.; Bailleul-Forestier, I.; Black, G.C.M.; Brown, D.L.; Brudno, M.; Campbell, J.; FitzPatrick, D.R.; Eppig, J.T.; Jackson, A.P.; Freson, K.; Girdea, M.; Helbig, I.; Hurst, J.A.; Jahn, J.; Jackson, L.G.; Kelly, A.M.; Ledbetter, D.H.; Mansour, S.; Martin, C.L.; Moss, C.; Mumford, A.; Ouwehand, W.H.; Park, S.M.; Riggs, E.R.; Scott, R.H.; Sisodiya, S.; Vooren, S. van der; Wapner, R.J.; Wilkie, A.O.; Wright, C.F.; Silfhout, A.T. van; Leeuw, N. de; Vries, B. de; Washingthon, N.L.; Smith, C.L.; Westerfield, M.; Schofield, P.; Ruef, B.J.; Gkoutos, G.V.; Haendel, M.; Smedley, D.; Lewis, S.E.; Robinson, P.N.

    2014-01-01

    The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have

  8. Laboratory testing for von Willebrand's disease: an assessment of current diagnostic practice and efficacy by means of a multi-laboratory survey. RCPA Quality Assurance Program (QAP) in Haematology Haemostasis Scientific Advisory Panel.

    Science.gov (United States)

    Favaloro, E J; Smith, J; Petinos, P; Hertzberg, M; Koutts, J

    1999-10-01

    We report an evaluation of current laboratory practice for the diagnosis of von Willebrand's disease (VWD) by means of a multilaboratory survey. This assessment was undertaken with the RCPA Quality Assurance Program (QAP) in Haematology, which covers a wide geographic area encompassing Australia, New Zealand and Asia. A total of 25 laboratories actively involved in testing for VWD were selected to participate in a sample testing assessment exercise. Samples comprised 10 plasmas: (i) a normal plasma pool (in duplicate), (ii) this pool diluted to 50% (in duplicate), (iii) a normal individual (X1), (iv) severe Type 1 VWD (X1), (v) Type 2B VWD (x2 unrelated donors), (vi) Type 3 VWD (x1), (vii) Type 2A VWD (x1). Laboratories were asked to perform all tests available to them in order to establish a laboratory diagnosis of VWD, and then to comment on the possibility or otherwise of VWD. Overall findings indicated a wide variation in test practice, in the effectiveness of various test procedures in detecting VWD, and in the ability of various composite test panels to identify type 2 VWD subtypes. Firstly, while all laboratories (n = 25) performed tests for FVIII:C activity, von Willebrand factor 'antigen' (VWF:Ag) and a functional VWF assay [using the ristocetin cofactor assay (VWF:RCo; n = 23) and/or the collagen binding assay (VWF:CBA; n = 12)], only three laboratories carried out VWF:Multimer analysis. Secondly, for the three quantitative VWF assays, 10/25 (40%) laboratories performed all three, whereas 15/25 (60%) performed only two [VWF:Ag and VWF:RCo (n = 13); VWF:Ag and VWF:CBA (n = 2)]. Thirdly, a variety of assay methodologies were evident for VWF:Ag [ELISA, electro-immuno diffusion (EID), latex immuno-assay (LIA), and VIDAS assay] and VWF:RCo (platelet agglutination/'aggregometry' and a 'functional VWF:RCo-alternative' ELISA assay). Between method analysis for the quantitative VWF assays showed that the VWF:RCo yielded the greatest degree of inter

  9. Are current chronic fatigue syndrome criteria diagnosing different disease phenotypes?

    Directory of Open Access Journals (Sweden)

    Laura Maclachlan

    Full Text Available Chronic fatigue syndrome (CFS is characterised by a constellation of symptoms diagnosed with a number of different polythetic criteria. Heterogeneity across these diagnostic criteria is likely to be confounding research into the as-yet-unknown pathophysiology underlying this stigmatised and debilitating condition and may diagnose a disease spectrum with significant implications for clinical management. No studies to date have objectively investigated this possibility using a validated measure of CFS symptoms-the DePaul Symptom Questionnaire (DSQ.To examine whether current CFS diagnostic criteria are identifying different disease phenotypes using the DSQ.Case control study.Clinical Research Facility of the Royal Victoria Infirmary, Newcastle upon Tyne, UK.49 CFS subjects and ten matched, sedentary community controls, excluded for co-morbid depression.Self-reported autonomic and cognitive features were assessed with the Composite Autonomic Symptom Score (COMPASS and Cognitive Failures Questionnaire (COGFAIL respectively. Objective autonomic cardiovascular parameters were examined using the Task Force® Monitor and a battery of neuropsychological tests administered for objective cognitive assessment.Self-reported autonomic and cognitive symptoms were significantly greater in CFS subjects compared to controls. There were no statistically significant differences in objective autonomic measures between CFS and controls. There were clinically significant differences between DSQ subgroups on objective autonomic testing. Visuospatial memory, verbal memory and psychomotor speed were significantly different between DSQ subgroups.The finding of no significant differences in objective autonomic testing between CFS and control subjects may reflect the inclusion of sedentary controls or exclusion for co-morbid depression. Consistent exclusion criteria would enable better delineation of these two conditions and their presenting symptoms. Findings across CFS

  10. Active Von Willebrand Factor, thrombocytopenia and thrombosis

    NARCIS (Netherlands)

    Hulstein, J.J.J.

    2006-01-01

    Platelets and von Willebrand factor (VWF) are unable to interact in circulation. To induce an interaction, a conversion of VWF to a platelet-binding conformation is required. At higher shear stresses, the first step in thrombus formation is binding of VWF to the subendothelium. This results in

  11. Molecular mechanisms of von Willebrand Factor mechanoregulation

    NARCIS (Netherlands)

    Jakobi, A.J.|info:eu-repo/dai/nl/311489621

    2012-01-01

    Von Willebrand factor (VWF) multimers mediate primary adhesion and aggregation of platelets. The potency to recruit platelets critically depends on the size of VWF multimers, which is regulated by a feedback mechanism involving shear-induced unfolding of the A2 domain in VWF and cleavage by the

  12. Distinctive inflammatory bowel disease phenotype in primary sclerosing cholangitis.

    Science.gov (United States)

    de Vries, A Boudewijn; Janse, Marcel; Blokzijl, Hans; Weersma, Rinse K

    2015-02-14

    To review the current literature for the specific clinical characteristics of inflammatory bowel disease (IBD) associated with primary sclerosing cholangitis (PSC). A systematical review for clinical characteristics of IBD in PSC was performed by conducting a broad search for "primary sclerosing cholangitis" in Pubmed. "Clinical characteristics" were specified into five predefined subthemes: epidemiology of IBD in PSC, characteristics of IBD in PSC (i.e., location, disease behavior), risk of colorectal cancer development, IBD recurrence and de novo disease after liver transplantation for PSC, and safety and complications after proctocolectomy with ileal pouch-anal anastomosis. Papers were selected for inclusion based on their relevance to the subthemes, and were reviewed by two independent reviewers. Only full papers relevant to PSC-IBD were included. Additionally the references of recent reviews for PSC ( 75%). The highest IBD rates in PSC are found in papers reviewing both endoscopic and histological data for IBD diagnosis. Although IBD in PSC is found to be a quiescent disease, pancolitis occurs often, with rates varying from 35% to 95%. Both backwash ileitis and rectal sparing are observed infrequently. The development of dysplasia or colorectal carcinoma is increased in PSC-IBD; the cumulative 10 years risk varying between 0% and 11%. Exacerbation of IBD is common after liver transplantation for PSC and de novo disease is seen in 1.3% to 31.3% of PSC-IBD patients. The risk for development of pouchitis in PSC-IBD is found to be significant, affecting 13.8% to 90% of the patients after proctocolectomy with ileo anal-pouch anastomosis. IBD in primary sclerosing cholangitis represents a distinct phenotype that differs from UC and Crohn's disease and therefore requires specialized management.

  13. Targeting mitochondrial phenotypes for non-communicable diseases

    Directory of Open Access Journals (Sweden)

    Zhengtang Qi

    2016-06-01

    Full Text Available The concept that “Exercise is Medicine” has been challenged by the rising prevalence of non-communicable chronic diseases (NCDs. This is partly due to the fact that the underlying mechanisms of how exercise influences energy homeostasis and counteracts high-fat diets and physical inactivity is complex and remains relatively poorly understood on a molecular level. In addition to genetic polymorphisms in humans that lead to gross variations in responsiveness to exercise, adaptation in mitochondrial networks is central to physical activity, inactivity, and diet. To harness the benefits of exercise for NCDs, much work still needs to be done to improve health effectively on a societal level such as developing personalized exercise interventions aided by advances in high-throughput genomics, proteomics, and metabolomics. We propose that understanding the mitochondrial phenotype according to the molecular information of genotypes, lifestyles, and exercise responsiveness in individuals will optimize exercise effects for prevention of NCDs.

  14. Association of PRPS1 Mutations with Disease Phenotypes

    Directory of Open Access Journals (Sweden)

    Rahul Mittal

    2015-01-01

    Full Text Available Phosphoribosylpyrophosphate synthetase 1 (PRPS1 codes for PRS-I enzyme that catalyzes the first step of nucleotide synthesis. PRPS1 gene mutations have been implicated in a number of human diseases. Recently, new mutations in PRPS1 have been identified that have been associated with novel phenotypes like diabetes insipidus expanding the spectrum of PRPS1-related diseases. The purpose of this review is to evaluate current literature on PRPS1-related syndromes and summarize potential therapies. The overexpression of PRPS1 results in PRS-I superactivity resulting in purine overproduction. Patients with PRS-I superactivity demonstrate uric acid overproduction, hypotonia, ataxia, neurodevelopment abnormalities, and postlingual hearing impairment. On the other hand, decreased activity leads to X-linked nonsyndromic sensorineural deafness (DFNX-2, Charcot-Marie-Tooth disease-5 (CMTX5, and Arts syndrome depending on the residual activity of PRS-I. Mild PRS-I deficiency (DFNX-2 results in non-syndromic progressive hearing loss whereas moderate PRS-I deficiency (CMTX5 and severe PRS-I deficiency (Arts syndrome present with peripheral or optic neuropathy, prelingual progressive sensorineural hearing loss, and central nervous system impairment. Currently, purine replacement via S-adenosylmethionine (SAM supplementation in patients with Arts syndrome appears to improve their condition. This suggests that SAM supplementation can alleviate symptoms of PRPS1 deficient patients and open new avenues of therapeutic intervention.

  15. Effective diagnosis of genetic disease by computational phenotype analysis of the disease-associated genome.

    Science.gov (United States)

    Zemojtel, Tomasz; Köhler, Sebastian; Mackenroth, Luisa; Jäger, Marten; Hecht, Jochen; Krawitz, Peter; Graul-Neumann, Luitgard; Doelken, Sandra; Ehmke, Nadja; Spielmann, Malte; Oien, Nancy Christine; Schweiger, Michal R; Krüger, Ulrike; Frommer, Götz; Fischer, Björn; Kornak, Uwe; Flöttmann, Ricarda; Ardeshirdavani, Amin; Moreau, Yves; Lewis, Suzanna E; Haendel, Melissa; Smedley, Damian; Horn, Denise; Mundlos, Stefan; Robinson, Peter N

    2014-09-03

    Less than half of patients with suspected genetic disease receive a molecular diagnosis. We have therefore integrated next-generation sequencing (NGS), bioinformatics, and clinical data into an effective diagnostic workflow. We used variants in the 2741 established Mendelian disease genes [the disease-associated genome (DAG)] to develop a targeted enrichment DAG panel (7.1 Mb), which achieves a coverage of 20-fold or better for 98% of bases. Furthermore, we established a computational method [Phenotypic Interpretation of eXomes (PhenIX)] that evaluated and ranked variants based on pathogenicity and semantic similarity of patients' phenotype described by Human Phenotype Ontology (HPO) terms to those of 3991 Mendelian diseases. In computer simulations, ranking genes based on the variant score put the true gene in first place less than 5% of the time; PhenIX placed the correct gene in first place more than 86% of the time. In a retrospective test of PhenIX on 52 patients with previously identified mutations and known diagnoses, the correct gene achieved a mean rank of 2.1. In a prospective study on 40 individuals without a diagnosis, PhenIX analysis enabled a diagnosis in 11 cases (28%, at a mean rank of 2.4). Thus, the NGS of the DAG followed by phenotype-driven bioinformatic analysis allows quick and effective differential diagnostics in medical genetics. Copyright © 2014, American Association for the Advancement of Science.

  16. Serum immunoglobulin G4 levels and Graves' disease phenotype.

    Science.gov (United States)

    Martin, Carmen Sorina; Sirbu, Anca Elena; Betivoiu, Minodora Andreea; Florea, Suzana; Barbu, Carmen Gabriela; Fica, Simona Vasilica

    2017-02-01

    We investigated, at diagnosis, the relationship between serum immunoglobulin G4 levels and the main characteristics of Graves' disease: hyperthyroidism severity, goiter size, presence of active Graves' ophthalmopathy, antithyroid antibodies status, and titer. This prospective study included 80 newly diagnosed Graves' disease patients. The main parameters measured at diagnosis: thyroid-stimulating hormone, free thyroxine, free triiodothyronine, total triiodothyronine, thyroglobulin, antithyroid peroxidase antibodies, anti-thyroglobulin antibodies, thyroid-stimulating hormone receptor antibodies, immunoglobulin G4. In Graves' disease patients, serum immunoglobulin G4 levels were higher than in general population (p = 0.028) and higher in men compared to women (p = 0.002). Only one female patient with intense hypoechoic goiter, high anti-thyroglobulin antibody, and antithyroid peroxidase antibody titers had an elevated serum immunoglobulin G4 level at diagnosis. Patients with immunoglobulin G4 levels above the 75th percentile (>237.52 mg/dl, N = 20) were younger at Graves' ophthalmopathy onset (p 286.28 mg/dl, N = 8) had lower total triiodothyronine values (p = 0.001) than patients with IgG below the 90th percentile. No significant correlations were found between smoking status (p = 0.58), goiter size (p = 0.50), the presence of ophthalmopathy (p = 0.42) or thyroid-stimulating hormone receptor antibody titers (p = 0.45) and the mean value of immunoglobulin G4 levels at diagnosis. Our data suggest that Graves' disease patients with elevated immunoglobulin G4 levels at diagnosis have a phenotype characterized by higher anti-thyroglobulin antibody and antithyroid peroxidase antibody titers, less severe T3 hyperthyroidism, younger age at ophthalmopathy onset and require a shorter duration of the first methimazole treatment cycle.

  17. Chronic obstructive pulmonary disease phenotypes and balance impairment

    Directory of Open Access Journals (Sweden)

    Voica AS

    2016-04-01

    Full Text Available Alina Sorina Voica,1 Cristian Oancea,1 Emanuela Tudorache,1 Alexandru F Crisan,2 Ovidiu Fira-Mladinescu,1 Voicu Tudorache,1 Bogdan Timar3 1Department of Pulmonology, Victor Babeş University of Medicine and Pharmacy, 2Pulmonary Rehabilitation Center, Hospital of Pneumoftiziology and Infectious Diseases “Dr Victor Babeş”, 3Department of Biostatistics and Medical Informatics, Victor Babeş University of Medicine and Pharmacy, Timişoara, Romania Background/objective: Chronic obstructive pulmonary disease (COPD is a respiratory disease that results in airflow limitation and respiratory distress, also having many nonrespiratory manifestations that affect both function and mobility. Preliminary evidence suggests that balance deficits constitute an important secondary impairment in individuals with COPD. Our objective was to investigate balance performance in two groups of COPD patients with different body compositions and to observe which of these groups are more likely to experience falls in the future.Methods: We included 27 stable COPD patients and 17 healthy individuals who performed a series of balance tests. The COPD patients were divided in two groups: emphysematous and bronchitic. Patients completed the activities balance confidence scale and the COPD assessment test questionnaire and afterward performed the Berg Balance Scale, timed up and go, single leg stance and 6-minute walking distance test. We analyzed the differences in the balance tests between the studied groups.Results: Bronchitic COPD was associated with a decreased value when compared to emphysematous COPD for the following variables: single leg stance (8.7 vs 15.6; P<0.001 and activities balance confidence (53.2 vs 74.2; P=0.001. Bronchitic COPD patients had a significantly higher value of timed up and go test compared to patients with emphysematous COPD (14.7 vs 12.8; P=0.001.Conclusion: Patients with COPD have a higher balance impairment than their healthy peers

  18. Multiple phenotypes in Huntington disease mouse neural stem cells.

    Science.gov (United States)

    Ritch, James J; Valencia, Antonio; Alexander, Jonathan; Sapp, Ellen; Gatune, Leah; Sangrey, Gavin R; Sinha, Saurabh; Scherber, Cally M; Zeitlin, Scott; Sadri-Vakili, Ghazaleh; Irimia, Daniel; Difiglia, Marian; Kegel, Kimberly B

    2012-05-01

    Neural stem (NS) cells are a limitless resource, and thus superior to primary neurons for drug discovery provided they exhibit appropriate disease phenotypes. Here we established NS cells for cellular studies of Huntington's disease (HD). HD is a heritable neurodegenerative disease caused by a mutation resulting in an increased number of glutamines (Q) within a polyglutamine tract in Huntingtin (Htt). NS cells were isolated from embryonic wild-type (Htt(7Q/7Q)) and "knock-in" HD (Htt(140Q/140Q)) mice expressing full-length endogenous normal or mutant Htt. NS cells were also developed from mouse embryonic stem cells that were devoid of Htt (Htt(-/-)), or knock-in cells containing human exon1 with an N-terminal FLAG epitope tag and with 7Q or 140Q inserted into one of the mouse alleles (Htt(F7Q/7Q) and Htt(F140Q/7Q)). Compared to Htt(7Q/7Q) NS cells, HD Htt(140Q/140Q) NS cells showed significantly reduced levels of cholesterol, increased levels of reactive oxygen species (ROS), and impaired motility. The heterozygous Htt(F140Q/7Q) NS cells had increased ROS and decreased motility compared to Htt(F7Q/7Q). These phenotypes of HD NS cells replicate those seen in HD patients or in primary cell or in vivo models of HD. Huntingtin "knock-out" NS cells (Htt(-/-)) also had impaired motility, but in contrast to HD cells had increased cholesterol. In addition, Htt(140Q/140Q) NS cells had higher phospho-AKT/AKT ratios than Htt(7Q/7Q) NS cells in resting conditions and after BDNF stimulation, suggesting mutant htt affects AKT dependent growth factor signaling. Upon differentiation, the Htt(7Q/7Q) and Htt(140Q/140Q) generated numerous Beta(III)-Tubulin- and GABA-positive neurons; however, after 15 days the cellular architecture of the differentiated Htt(140Q/140Q) cultures changed compared to Htt(7Q/7Q) cultures and included a marked increase of GFAP-positive cells. Our findings suggest that NS cells expressing endogenous mutant Htt will be useful for study of mechanisms of HD

  19. Phenotypic variability of Krabbe disease across the lifespan.

    Science.gov (United States)

    Liao, Pamela; Gelinas, Jennifer; Sirrs, Sandra

    2014-01-01

    Krabbe disease (galactocerebrosidase deficiency) is an inherited leukodystrophy that results in severe neurological defects due to altered myelination. Classically, disease onset is within the first year of life. Juvenile and adult-onset cases may have less classic presentations, making diagnosis difficult and often delayed. Here, we review the literature to demonstrate the hetereogeneity of presenting symptoms across all age groups. We also discuss diagnostic approach, emphasizing variation in biochemical, functional, and genetic results among Krabbe phenotypes. Better understanding of the various Krabbe disease phenotypes is critical to facilitate timely diagnosis and appropriate treatment of this clinically heterogeneous disorder. Variabilité phénotypique dans la maladie de Krabbe au cours de la vie du patient. La maladie de Krabbe (déficit en galactocérébrosidase) est une leukodystrophie héréditaire qui donne lieu à des déficits neurologiques sévères dus à un trouble de la myélinisation. Chez les cas dont la présentation est classique, la maladie débute au cours de la première année de vie. Si la maladie commence chez un adolescent ou un adulte, le mode de présentation peut-ětre moins classique, ce qui rend le diagnostic difficile et souvent tardif. Nous analysons les articles traitant du sujet pour démontrer l'hétérogénéité des symptômes au moment de la première consultation et ceci dans tous les groupes d'âge. Nous discutons également de l'approche diagnostique en mettant l'emphase sur la variation des résultats biochimiques, fonctionnels et génétiques des différents phénotypes dans la maladie de Krabbe. Une meilleure compréhension des différents phénotypes est cruciale pour faciliter un diagnostic précoce et un traitement approprié de cette maladie dont le mode de présentation clinique est hétérogène.

  20. Phenotypic conversions of "protoplasmic" to "reactive" astrocytes in Alexander disease.

    Science.gov (United States)

    Sosunov, Alexander A; Guilfoyle, Eileen; Wu, Xiaoping; McKhann, Guy M; Goldman, James E

    2013-04-24

    Alexander Disease (AxD) is a primary disorder of astrocytes, caused by heterozygous mutations in GFAP, which encodes the major astrocyte intermediate filament protein, glial fibrillary acidic protein (GFAP). Astrocytes in AxD display hypertrophy, massive increases in GFAP, and the accumulation of Rosenthal fibers, cytoplasmic protein inclusions containing GFAP, and small heat shock proteins. To study the effects of GFAP mutations on astrocyte morphology and physiology, we have examined hippocampal astrocytes in three mouse models of AxD, a transgenic line (GFAP(Tg)) in which the normal human GFAP is expressed in several copies, a knock-in line (Gfap(+/R236H)) in which one of the Gfap genes bears an R236H mutation, and a mouse derived from the mating of these two lines (GFAP(Tg); Gfap(+/R236H)). We report changes in astrocyte phenotype in all lines, with the most severe in the GFAP(Tg);Gfap(+/R236H), resulting in the conversion of protoplasmic astrocytes to cells that have lost their bushy-like morphology because of a reduction of distal fine processes, and become multinucleated and hypertrophic. Astrocytes activate the mTOR cascade, acquire CD44, and lose GLT-1. The altered astrocytes display a microheterogeneity in phenotypes, even neighboring cells. Astrocytes also show diminished glutamate transporter current, are significantly depolarized, and not coupled to adjacent astrocytes. Thus, the accumulation of GFAP in the AxD mouse astrocytes initiates a conversion of normal, protoplasmic astrocytes to astrocytes that display severely "reactive" characteristics, many of which may be detrimental to neighboring neurons and oligodendrocytes.

  1. Alcohol consumption, Lewis phenotypes, and risk of ischemic heart disease

    Energy Technology Data Exchange (ETDEWEB)

    Hein, H.O.; Suadicani, P.; Gyntelberg, F. (Rigshospitalet State Univ. Hospital, Copenhagen (Denmark). Epidemiological Research Unit); Sorenson, H. (Rigshospitalet State Univ. Hospital, Copenhagen (Denmark). Dept. of Chemical Immunology); Hein, H.O. (Univ. of Copenhagen (Denmark). Dept. of Internal Medicine)

    1993-02-13

    The authors have previously found an increased risk of ischemic heart disease (IHD) in men with the Lewis phenotype Le(a[minus]b[minus]) and suggested that the Lewis blood group has a close genetic relation with insulin resistance. The authors have investigated whether any conventional risk factors explain the increased risk in Le(a[minus]b[minus]) men. 3,383 men aged 53-75 years were examined in 1985-86, and morbidity and mortality during the next 4 years were recorded. At baseline, the authors excluded 343 men with a history of myocardial infarction, angina pectoris, intermittent claudication, or stroke. The potential risk factors examined were alcohol consumption, physical activity, tobacco smoking, serum cotinine, serum lipids, body-mass index, blood pressure, prevalence of hypertension and non-insulin-dependent diabetes mellitus, and social class. In 280 (9.6%) men with Le(a[minus]b[minus]), alcohol was the only risk factor significantly associated with risk of IHD. There was a significant inverse dose-effect relation between alcohol consumption and risk; trend tests, with adjustment for age, were significant for fatal IHD (p=0.02), all IHD (p=0.03), and all causes of death (p=0.02). In 2649 (90.4%) men with other phenotypes, there was a limited negative association with alcohol consumption. In Le(a[minus]b[minus]) men, a group genetically at high risk of IHD, alcohol consumption seems to be especially protective. The authors suggest that alcohol consumption may modify insulin resistance in Le(a[minus]b[minus]) men.

  2. von Willebrand factor, Jedi knight of the bloodstream.

    Science.gov (United States)

    Springer, Timothy A

    2014-08-28

    When blood vessels are cut, the forces in the bloodstream increase and change character. The dark side of these forces causes hemorrhage and death. However, von Willebrand factor (VWF), with help from our circulatory system and platelets, harnesses the same forces to form a hemostatic plug. Force and VWF function are so closely intertwined that, like members of the Jedi Order in the movie Star Wars who learn to use "the Force" to do good, VWF may be considered the Jedi knight of the bloodstream. The long length of VWF enables responsiveness to flow. The shape of VWF is predicted to alter from irregularly coiled to extended thread-like in the transition from shear to elongational flow at sites of hemostasis and thrombosis. Elongational force propagated through the length of VWF in its thread-like shape exposes its monomers for multimeric binding to platelets and subendothelium and likely also increases affinity of the A1 domain for platelets. Specialized domains concatenate and compact VWF during biosynthesis. A2 domain unfolding by hydrodynamic force enables postsecretion regulation of VWF length. Mutations in VWF in von Willebrand disease contribute to and are illuminated by VWF biology. I attempt to integrate classic studies on the physiology of hemostatic plug formation into modern molecular understanding, and point out what remains to be learned. © 2014 by The American Society of Hematology.

  3. Clinical measurement of von Willebrand factor by fluorescence correlation spectroscopy.

    Science.gov (United States)

    Torres, Richard; Genzen, Jonathan R; Levene, Michael J

    2012-06-01

    Identification of von Willebrand factor (vWF) abnormalities in a variety of conditions is hampered by the limitations of currently available diagnostic tests. Although direct multimer visualization by immunoelectrophoresis is a commonly used method, it is impractical as a routine clinical test. In this study, we used a biophysical analysis tool, fluorescence correlation spectroscopy (FCS), to measure vWF distributions. The goals were to develop a method that is quicker and simpler than vWF gel electrophoresis and to evaluate the potential of FCS as a clinical diagnostic technique. We analyzed plasma from 12 patients with type 1 von Willebrand disease (vWD), 14 patients with type 2 vWD, and 10 healthy controls using a fluctuation-based immunoassay approach. FCS enabled identification and proper classification of type 1 and type 2 vWD, producing quantitative results that correspond to qualitative gel multimer patterns. FCS required minimal sample preparation and only a 5-min analysis time. This study represents the first implementation of FCS for clinical diagnostics directly on human plasma. The technique shows potential for further vWF studies and as a generally applicable laboratory test method.

  4. Identifying Multimodal Intermediate Phenotypes Between Genetic Risk Factors and Disease Status in Alzheimer's Disease.

    Science.gov (United States)

    Hao, Xiaoke; Yao, Xiaohui; Yan, Jingwen; Risacher, Shannon L; Saykin, Andrew J; Zhang, Daoqiang; Shen, Li

    2016-10-01

    Neuroimaging genetics has attracted growing attention and interest, which is thought to be a powerful strategy to examine the influence of genetic variants (i.e., single nucleotide polymorphisms (SNPs)) on structures or functions of human brain. In recent studies, univariate or multivariate regression analysis methods are typically used to capture the effective associations between genetic variants and quantitative traits (QTs) such as brain imaging phenotypes. The identified imaging QTs, although associated with certain genetic markers, may not be all disease specific. A useful, but underexplored, scenario could be to discover only those QTs associated with both genetic markers and disease status for revealing the chain from genotype to phenotype to symptom. In addition, multimodal brain imaging phenotypes are extracted from different perspectives and imaging markers consistently showing up in multimodalities may provide more insights for mechanistic understanding of diseases (i.e., Alzheimer's disease (AD)). In this work, we propose a general framework to exploit multi-modal brain imaging phenotypes as intermediate traits that bridge genetic risk factors and multi-class disease status. We applied our proposed method to explore the relation between the well-known AD risk SNP APOE rs429358 and three baseline brain imaging modalities (i.e., structural magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography (FDG-PET) and F-18 florbetapir PET scans amyloid imaging (AV45)) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The empirical results demonstrate that our proposed method not only helps improve the performances of imaging genetic associations, but also discovers robust and consistent regions of interests (ROIs) across multi-modalities to guide the disease-induced interpretation.

  5. The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data.

    Science.gov (United States)

    Köhler, Sebastian; Doelken, Sandra C; Mungall, Christopher J; Bauer, Sebastian; Firth, Helen V; Bailleul-Forestier, Isabelle; Black, Graeme C M; Brown, Danielle L; Brudno, Michael; Campbell, Jennifer; FitzPatrick, David R; Eppig, Janan T; Jackson, Andrew P; Freson, Kathleen; Girdea, Marta; Helbig, Ingo; Hurst, Jane A; Jähn, Johanna; Jackson, Laird G; Kelly, Anne M; Ledbetter, David H; Mansour, Sahar; Martin, Christa L; Moss, Celia; Mumford, Andrew; Ouwehand, Willem H; Park, Soo-Mi; Riggs, Erin Rooney; Scott, Richard H; Sisodiya, Sanjay; Van Vooren, Steven; Wapner, Ronald J; Wilkie, Andrew O M; Wright, Caroline F; Vulto-van Silfhout, Anneke T; de Leeuw, Nicole; de Vries, Bert B A; Washingthon, Nicole L; Smith, Cynthia L; Westerfield, Monte; Schofield, Paul; Ruef, Barbara J; Gkoutos, Georgios V; Haendel, Melissa; Smedley, Damian; Lewis, Suzanna E; Robinson, Peter N

    2014-01-01

    The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online.

  6. Linking human diseases to animal models using ontology-based phenotype annotation.

    Directory of Open Access Journals (Sweden)

    Nicole L Washington

    2009-11-01

    Full Text Available Scientists and clinicians who study genetic alterations and disease have traditionally described phenotypes in natural language. The considerable variation in these free-text descriptions has posed a hindrance to the important task of identifying candidate genes and models for human diseases and indicates the need for a computationally tractable method to mine data resources for mutant phenotypes. In this study, we tested the hypothesis that ontological annotation of disease phenotypes will facilitate the discovery of new genotype-phenotype relationships within and across species. To describe phenotypes using ontologies, we used an Entity-Quality (EQ methodology, wherein the affected entity (E and how it is affected (Q are recorded using terms from a variety of ontologies. Using this EQ method, we annotated the phenotypes of 11 gene-linked human diseases described in Online Mendelian Inheritance in Man (OMIM. These human annotations were loaded into our Ontology-Based Database (OBD along with other ontology-based phenotype descriptions of mutants from various model organism databases. Phenotypes recorded with this EQ method can be computationally compared based on the hierarchy of terms in the ontologies and the frequency of annotation. We utilized four similarity metrics to compare phenotypes and developed an ontology of homologous and analogous anatomical structures to compare phenotypes between species. Using these tools, we demonstrate that we can identify, through the similarity of the recorded phenotypes, other alleles of the same gene, other members of a signaling pathway, and orthologous genes and pathway members across species. We conclude that EQ-based annotation of phenotypes, in conjunction with a cross-species ontology, and a variety of similarity metrics can identify biologically meaningful similarities between genes by comparing phenotypes alone. This annotation and search method provides a novel and efficient means to identify

  7. Chronic obstructive pulmonary disease phenotypes: the future of COPD

    DEFF Research Database (Denmark)

    Han, MeiLan K; Agusti, Alvar; Calverley, Peter M

    2010-01-01

    (s) to guide the development of therapy where possible. It follows that any proposed phenotype, whether defined by symptoms, radiography, physiology, or cellular or molecular fingerprint will require an iterative validation process in which "candidate" phenotypes are identified before their relevance...

  8. Phenotyping airways disease by cluster analysis in primary care : 6 distinct clusters identified

    NARCIS (Netherlands)

    Kocks, Janwillem W.H.; Weatherall, Mark; Metting, Esther I.; Riemersma, Roland A.; Fingleton, James; Van Der Molen, Thys; Beasley, Richard

    2014-01-01

    Current obstructive airways disease classification does not sufficiently reflect disease patterns. Cluster analysis is one of the promising approaches to develop a new taxonomy. The majority of current phenotyping studies focus on severe asthma or COPD. Aim To identify phenotypes in a broad spectrum

  9. Analysis of the human diseasome using phenotype similarity between common, genetic, and infectious diseases

    Science.gov (United States)

    Hoehndorf, Robert; Schofield, Paul N.; Gkoutos, Georgios V.

    2015-06-01

    Phenotypes are the observable characteristics of an organism arising from its response to the environment. Phenotypes associated with engineered and natural genetic variation are widely recorded using phenotype ontologies in model organisms, as are signs and symptoms of human Mendelian diseases in databases such as OMIM and Orphanet. Exploiting these resources, several computational methods have been developed for integration and analysis of phenotype data to identify the genetic etiology of diseases or suggest plausible interventions. A similar resource would be highly useful not only for rare and Mendelian diseases, but also for common, complex and infectious diseases. We apply a semantic text-mining approach to identify the phenotypes (signs and symptoms) associated with over 6,000 diseases. We evaluate our text-mined phenotypes by demonstrating that they can correctly identify known disease-associated genes in mice and humans with high accuracy. Using a phenotypic similarity measure, we generate a human disease network in which diseases that have similar signs and symptoms cluster together, and we use this network to identify closely related diseases based on common etiological, anatomical as well as physiological underpinnings.

  10. Analysis of the human diseasome using phenotype similarity between common, genetic, and infectious diseases

    KAUST Repository

    Hoehndorf, Robert

    2015-06-08

    Phenotypes are the observable characteristics of an organism arising from its response to the environment. Phenotypes associated with engineered and natural genetic variation are widely recorded using phenotype ontologies in model organisms, as are signs and symptoms of human Mendelian diseases in databases such as OMIM and Orphanet. Exploiting these resources, several computational methods have been developed for integration and analysis of phenotype data to identify the genetic etiology of diseases or suggest plausible interventions. A similar resource would be highly useful not only for rare and Mendelian diseases, but also for common, complex and infectious diseases. We apply a semantic text-mining approach to identify the phenotypes (signs and symptoms) associated with over 6,000 diseases. We evaluate our text-mined phenotypes by demonstrating that they can correctly identify known disease-associated genes in mice and humans with high accuracy. Using a phenotypic similarity measure, we generate a human disease network in which diseases that have similar signs and symptoms cluster together, and we use this network to identify closely related diseases based on common etiological, anatomical as well as physiological underpinnings.

  11. Phenotypes and Pathology of Drug-Induced Liver Disease.

    Science.gov (United States)

    Goodman, Zachary D

    2017-02-01

    Drug hepatotoxicity can simulate nearly any clinical syndrome or pathologic lesion that may occur in the liver, so clinical and histopathologic diagnosis of drug-induced liver injury may be difficult. Nevertheless, most drugs that are known to idiosyncratic liver injury tend to cause patterns of injury that produce characteristic phenotypes. Recognition of these patterns or phenotypes in liver biopsy material is helpful in evaluation of clinical cases of suspected drug-induced liver injury. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Similarity-based search of model organism, disease and drug effect phenotypes

    KAUST Repository

    Hoehndorf, Robert

    2015-02-19

    Background: Semantic similarity measures over phenotype ontologies have been demonstrated to provide a powerful approach for the analysis of model organism phenotypes, the discovery of animal models of human disease, novel pathways, gene functions, druggable therapeutic targets, and determination of pathogenicity. Results: We have developed PhenomeNET 2, a system that enables similarity-based searches over a large repository of phenotypes in real-time. It can be used to identify strains of model organisms that are phenotypically similar to human patients, diseases that are phenotypically similar to model organism phenotypes, or drug effect profiles that are similar to the phenotypes observed in a patient or model organism. PhenomeNET 2 is available at http://aber-owl.net/phenomenet. Conclusions: Phenotype-similarity searches can provide a powerful tool for the discovery and investigation of molecular mechanisms underlying an observed phenotypic manifestation. PhenomeNET 2 facilitates user-defined similarity searches and allows researchers to analyze their data within a large repository of human, mouse and rat phenotypes.

  13. PhenoMiner: from text to a database of phenotypes associated with OMIM diseases.

    Science.gov (United States)

    Collier, Nigel; Groza, Tudor; Smedley, Damian; Robinson, Peter N; Oellrich, Anika; Rebholz-Schuhmann, Dietrich

    2015-01-01

    Analysis of scientific and clinical phenotypes reported in the experimental literature has been curated manually to build high-quality databases such as the Online Mendelian Inheritance in Man (OMIM). However, the identification and harmonization of phenotype descriptions struggles with the diversity of human expressivity. We introduce a novel automated extraction approach called PhenoMiner that exploits full parsing and conceptual analysis. Apriori association mining is then used to identify relationships to human diseases. We applied PhenoMiner to the BMC open access collection and identified 13,636 phenotype candidates. We identified 28,155 phenotype-disorder hypotheses covering 4898 phenotypes and 1659 Mendelian disorders. Analysis showed: (i) the semantic distribution of the extracted terms against linked ontologies; (ii) a comparison of term overlap with the Human Phenotype Ontology (HP); (iii) moderate support for phenotype-disorder pairs in both OMIM and the literature; (iv) strong associations of phenotype-disorder pairs to known disease-genes pairs using PhenoDigm. The full list of PhenoMiner phenotypes (S1), phenotype-disorder associations (S2), association-filtered linked data (S3) and user database documentation (S5) is available as supplementary data and can be downloaded at http://github.com/nhcollier/PhenoMiner under a Creative Commons Attribution 4.0 license. Database URL: phenominer.mml.cam.ac.uk. © The Author(s) 2015. Published by Oxford University Press.

  14. PhenoLines: Phenotype Comparison Visualizations for Disease Subtyping via Topic Models.

    Science.gov (United States)

    Glueck, Michael; Naeini, Mahdi Pakdaman; Doshi-Velez, Finale; Chevalier, Fanny; Khan, Azam; Wigdor, Daniel; Brudno, Michael

    2018-01-01

    PhenoLines is a visual analysis tool for the interpretation of disease subtypes, derived from the application of topic models to clinical data. Topic models enable one to mine cross-sectional patient comorbidity data (e.g., electronic health records) and construct disease subtypes-each with its own temporally evolving prevalence and co-occurrence of phenotypes-without requiring aligned longitudinal phenotype data for all patients. However, the dimensionality of topic models makes interpretation challenging, and de facto analyses provide little intuition regarding phenotype relevance or phenotype interrelationships. PhenoLines enables one to compare phenotype prevalence within and across disease subtype topics, thus supporting subtype characterization, a task that involves identifying a proposed subtype's dominant phenotypes, ages of effect, and clinical validity. We contribute a data transformation workflow that employs the Human Phenotype Ontology to hierarchically organize phenotypes and aggregate the evolving probabilities produced by topic models. We introduce a novel measure of phenotype relevance that can be used to simplify the resulting topology. The design of PhenoLines was motivated by formative interviews with machine learning and clinical experts. We describe the collaborative design process, distill high-level tasks, and report on initial evaluations with machine learning experts and a medical domain expert. These results suggest that PhenoLines demonstrates promising approaches to support the characterization and optimization of topic models.

  15. Genome sequencing reveals loci under artificial selection that underlie disease phenotypes in the laboratory rat

    NARCIS (Netherlands)

    Atanur, S.S.; Diaz, A.G.; Maratou, K.; Sarkis, A.; Rotival, M.; Game, L.; Tschannen, M.R.; Kaisaki, P.J.; Otto, G.W.; Ma, M.C.; Keane, T.M.; Hummel, O.; Saar, K.; Chen, W.; Guryev, V.; Gopalakrishnan, K.; Garrett, M.R.; Joe, B.; Citterio, L.; Bianchi, G.; McBride, M.; Dominiczak, A.; Adams, D.J.; Serikawa, T.; Flicek, P.; Cuppen, E.; Hubner, N.; Petretto, E.; Gauguier, D.; Kwitek, A.; Jacob, H.; Aitman, T.J.

    2013-01-01

    Large numbers of inbred laboratory rat strains have been developed for a range of complex disease phenotypes. To gain insights into the evolutionary pressures underlying selection for these phenotypes, we sequenced the genomes of 27 rat strains, including 11 models of hypertension, diabetes, and

  16. Genome Sequencing Reveals Loci under Artificial Selection that Underlie Disease Phenotypes in the Laboratory Rat

    NARCIS (Netherlands)

    Atanur, Santosh S.; Diaz, Ana Garcia; Maratou, Klio; Sarkis, Allison; Rotival, Maxime; Game, Laurence; Tschannen, Michael R.; Kaisaki, Pamela J.; Otto, Georg W.; Ma, Man Chun John; Keane, Thomas M.; Hummel, Oliver; Saar, Kathrin; Chen, Wei; Guryev, Victor; Gopalakrishnan, Kathirvel; Garrett, Michael R.; Joe, Bina; Citterio, Lorena; Bianchi, Giuseppe; McBride, Martin; Dominiczak, Anna; Adams, David J.; Serikawa, Tadao; Flicek, Paul; Cuppen, Edwin; Hubner, Norbert; Petretto, Enrico; Gauguier, Dominique; Kwitek, Anne; Jacob, Howard; Aitman, Timothy J.

    2013-01-01

    Large numbers of inbred laboratory rat strains have been developed for a range of complex disease phenotypes. To gain insights into the evolutionary pressures underlying selection for these phenotypes, we sequenced the genomes of 27 rat strains, including 11 models of hypertension, diabetes, and

  17. Pulmonary function parameters in high-resolution computed tomography phenotypes of chronic obstructive pulmonary disease.

    Science.gov (United States)

    Sun, Xian Wen; Gu, Shu Yi; Li, Qing Yun; Ren, Lei; Shen, Ji Min; Wan, Huan Ying; Huang, Shao Guang; Deng, Wei Wu

    2015-03-01

    Heterogeneity of clinical presentation of chronic obstructive pulmonary disease (COPD) attributes to different pathological basis. High-resolution computed tomography (HRCT) phenotypes of COPD may reflex the pathological basis of COPD indirectly by evaluating the small airway inflammation and emphysema. How the pulmonary function related with different HRCT phenotypes has not been well known. The aim was to explore the features of pulmonary function parameters in the 3 phenotypes. Sixty-three stable COPD patients were allocated in 3 groups based on HRCT findings: phenotype A (absence of emphysema, with minimal evidence of emphysema with or without bronchial wall thickening [BWT]), phenotype E (emphysema without BWT) and phenotype M (emphysema with BWT). The pulmonary function testing was also analyzed. The values of forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC%), FEV1% and maximum expiratory flows (MEF)50% were the highest in phenotype A (P 4.0 were more prevalence in phenotype A than in E and M (odds ratio = 2.214; P 40% were higher in phenotype E than in A and M (odds ratio = 3.906; P < 0.05). Receiver operating characteristic analysis showed that the cutoff value of MEF50/MEF25 ratio for identifying phenotype A was 2.5, with sensitivity 66.7% and specificity 92.9%. The cutoff value of RV/TLC% for identifying phenotype E was 57.4%, with sensitivity 75.0% and specificity 79.1%. The different features of pulmonary function parameters were found in various HRCT phenotypes; MEF50/MEF25 ratio could imply phenotype A, whereas RV/TLC% may be the indicator of phenotype E.

  18. New Discriminant Method for Identifying the Aggressive Disease Phenotype of Non-alcoholic Fatty Liver Disease.

    Science.gov (United States)

    Kawamura, Yusuke; Ikeda, Kenji; Arase, Yasuji; Fujiyama, Shunichiro; Hosaka, Tetsuya; Kobayashi, Masahiro; Saitoh, Satoshi; Sezaki, Hitomi; Akuta, Norio; Suzuki, Fumitaka; Suzuki, Yoshiyuki; Kumada, Hiromitsu

    2017-01-01

    Objective To detect the aggressive phenotype (AP) of non-alcoholic fatty liver disease (NAFLD) based on the initial laboratory data and clinical characteristics. Methods We enrolled 144 patients with histologically proven NAFLD. For the first analysis, 24 NAFLD patients underwent repeat biopsy to establish a discriminant formula for predicting the AP of NAFLD (D-APN). The AP was defined by NAFLD that had been maintained or progressed to a fibrotic stage beyond stage 2. In the second analysis, we analyzed the distribution of the AP in each stage of disease and the incidence of the PNPLA3 rs738409 GG genotype in AP in 120 other patients. Results After the analysis, the following function was found to discriminate the disease phenotype: z=0.150×body mass index (kg/m2)+0.085×age (years)+1.112×ln (AST) (IU/L)+0.127×ln (m-AST)-12.96. A positive result indicates the AP of NAFLD. The discriminant functions had a positive predictive value of 94% and a negative predictive value of 71%. The distribution of the AP and the incidence of the PNPLA3 GG genotype in the AP in each stage of the disease among the 120 patients were as follows: non-alcoholic fatty liver, 30%/33%; non-alcoholic steatohepatitis (NASH) stage 1, 53%/26%; stage 2, 71%/70%; stage 3, 92%/57%; and stage 4, 93%/64%; there was a significant increase in the incidence of the AP as the disease progressed (p<0.001). Conclusion The new discriminant formula was useful for predicting disease progression potential in NAFLD patients and the incidence of the PNPLA3 GG genotype was elevated according to the distribution of AP.

  19. Early-onset Alzheimer's Disease Phenotypes: Neuropsychology and Neural Networks

    Science.gov (United States)

    2017-05-11

    Alzheimer Disease, Early Onset; Alzheimer Disease; Alzheimer Disease, Late Onset; Dementia, Alzheimer Type; Logopenic Progressive Aphasia; Primary Progressive Aphasia; Visuospatial/Perceptual Abilities; Posterior Cortical Atrophy; Executive Dysfunction; Corticobasal Degeneration; Ideomotor Apraxia

  20. Modularity-based credible prediction of disease genes and detection of disease subtypes on the phenotype-gene heterogeneous network.

    Science.gov (United States)

    Yao, Xin; Hao, Han; Li, Yanda; Li, Shao

    2011-05-20

    Protein-protein interaction networks and phenotype similarity information have been synthesized together to discover novel disease-causing genes. Genetic or phenotypic similarities are manifested as certain modularity properties in a phenotype-gene heterogeneous network consisting of the phenotype-phenotype similarity network, protein-protein interaction network and gene-disease association network. However, the quantitative analysis of modularity in the heterogeneous network and its influence on disease-gene discovery are still unaddressed. Furthermore, the genetic correspondence of the disease subtypes can be identified by marking the genes and phenotypes in the phenotype-gene network. We present a novel network inference method to measure the network modularity, and in particular to suggest the subtypes of diseases based on the heterogeneous network. Based on a measure which is introduced to evaluate the closeness between two nodes in the phenotype-gene heterogeneous network, we developed a Hitting-Time-based method, CIPHER-HIT, for assessing the modularity of disease gene predictions and credibly prioritizing disease-causing genes, and then identifying the genetic modules corresponding to potential subtypes of the queried phenotype. The CIPHER-HIT is free to rely on any preset parameters. We found that when taking into account the modularity levels, the CIPHER-HIT method can significantly improve the performance of disease gene predictions, which demonstrates modularity is one of the key features for credible inference of disease genes on the phenotype-gene heterogeneous network. By applying the CIPHER-HIT to the subtype analysis of Breast cancer, we found that the prioritized genes can be divided into two sub-modules, one contains the members of the Fanconi anemia gene family, and the other contains a reported protein complex MRE11/RAD50/NBN. The phenotype-gene heterogeneous network contains abundant information for not only disease genes discovery but also

  1. Genetic difference in HLA-DR phenotypes between coeliac disease and transitory gluten intolerance.

    Science.gov (United States)

    Meuli, R; Pichler, W J; Gaze, H; Lentze, M J

    1995-01-01

    Genetic differences in HLA phenotypes were studied in coeliac disease to investigate why some patients do not react with mucosal damage after gluten challenge. Forty five children with coeliac disease and 16 with transitory gluten intolerance were typed; 76 subjects served as controls. HLA phenotypes in children with coeliac disease had significantly higher proportions of DR3/X and DR5/7 than controls (48.8% v 11.8% and 26.7% v 5.3%). Children with transitory gluten intolerance had lower DR3/X (43.8%) than children with coeliac disease and there were no DR5/7 phenotypes. Further analysis of similarly well defined cases might show whether genetic differences in the DR3/X and DR5/7 phenotypes can serve as a marker for the permanence of gluten intolerance.

  2. Bronchodilator responsiveness as a phenotypic characteristic of established chronic obstructive pulmonary disease

    DEFF Research Database (Denmark)

    Albert, Paul; Agusti, Alvar; Edwards, Lisa

    2012-01-01

    Bronchodilator responsiveness is a potential phenotypic characteristic of chronic obstructive pulmonary disease (COPD). We studied whether change in lung function after a bronchodilator is abnormal in COPD, whether stable responder subgroups can be identified, and whether these subgroups experience...

  3. Splice mutations preserve myophosphorylase activity that ameliorates the phenotype in McArdle disease

    DEFF Research Database (Denmark)

    Vissing, John; Duno, Morten; Schwartz, Marianne

    2009-01-01

    Over 100 mutations in the myophosphorylase gene, which cause McArdle disease, are known. All these mutations have resulted in a complete block of muscle glycogenolysis, and accordingly, no genotype-phenotype correlation has been identified in this condition. We evaluated physiologic and genetic...... with atypical McArdle disease compared to typical McArdle patients. Oxygen uptake, relative to cardiac output, was severely impaired in the 47 patients with typical McArdle disease, and partially normalized in the milder affected McArdle patients. These findings identify the first distinct genotype-phenotype...... relationship in McArdle disease, and indicate that minimal myophosphorylase activity ameliorates the typical McArdle disease phenotype by augmenting muscle oxidative capacity. The milder form of McArdle disease provides important clues to the level of functional myophosphorylase needed to support muscle...

  4. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes

    DEFF Research Database (Denmark)

    Cleynen, Isabelle; Boucher, Gabrielle; Jostins, Luke

    2016-01-01

    dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10(-78)), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10...

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

    Science.gov (United States)

    Camiciottoli, Gianna; Bigazzi, Francesca; Magni, Chiara; Bonti, Viola; Diciotti, Stefano; Bartolucci, Maurizio; Mascalchi, Mario; Pistolesi, Massimo

    2016-01-01

    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. 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. 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 significantly in predominant emphysema, and ischemic heart disease and PVD prevailed in mild COPD. All cardiovascular comorbidities prevailed significantly in predominant airway phenotype of COPD and mild COPD severity. Specific comorbidities prevail in different phenotypes of COPD; this fact may be relevant to identify patients at risk for specific, phenotype-related comorbidities. The highest prevalence of comorbidities in patients with mild disease indicates that these patients should be investigated for coexisting diseases or syndromes even in the less severe, pauci-symptomatic stages of COPD. The simple method employed to phenotype and score COPD allows these results to be

  6. Phenotypic and Genotypic Characterisation of Inflammatory Bowel Disease Presenting Before the Age of 2 years.

    Science.gov (United States)

    Kammermeier, Jochen; Dziubak, Robert; Pescarin, Matilde; Drury, Suzanne; Godwin, Heather; Reeve, Kate; Chadokufa, Sibongile; Huggett, Bonita; Sider, Sara; James, Chela; Acton, Nikki; Cernat, Elena; Gasparetto, Marco; Noble-Jamieson, Gabi; Kiparissi, Fevronia; Elawad, Mamoun; Beales, Phil L; Sebire, Neil J; Gilmour, Kimberly; Uhlig, Holm H; Bacchelli, Chiara; Shah, Neil

    2017-01-01

    Inflammatory bowel disease [IBD] presenting in early childhood is extremely rare. More recently, progress has been made to identify children with monogenic forms of IBD predominantly presenting very early in life. In this study, we describe the heterogeneous phenotypes and genotypes of patients with IBD presenting before the age of 2 years and establish phenotypic features associated with underlying monogenicity. Phenotype data of 62 children with disease onset before the age of 2 years presenting over the past 20 years were reviewed. Children without previously established genetic diagnosis were prospectively recruited for next-generation sequencing. In all, 62 patients [55% male] were identified. The median disease onset was 3 months of age (interquartile range [IQR]: 1 to 11). Conventional IBD classification only applied to 15 patients with Crohn's disease [CD]-like [24%] and three with ulcerative colitis [UC]-like [5%] phenotype; 44 patients [71%] were diagnosed with otherwise unclassifiable IBD. Patients frequently required parenteral nutrition [40%], extensive immunosuppression [31%], haematopoietic stem-cell transplantation [29%], and abdominal surgery [19%]. In 31% of patients, underlying monogenic diseases were established [EPCAM, IL10, IL10RA, IL10RB, FOXP3, LRBA, SKIV2L, TTC37, TTC7A]. Phenotypic features significantly more prevalent in monogenic IBD were: consanguinity, disease onset before the 6th month of life, stunting, extensive intestinal disease and histological evidence of epithelial abnormalities. IBD in children with disease onset before the age of 2 years is frequently unclassifiable into Crohn's disease and ulcerative colitis, particularly treatment resistant, and can be indistinguishable from monogenic diseases with IBD-like phenotype. Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  7. Prediction of disease and phenotype associations from genome-wide association studies.

    Directory of Open Access Journals (Sweden)

    Stephanie N Lewis

    Full Text Available BACKGROUND: Genome wide association studies (GWAS have proven useful as a method for identifying genetic variations associated with diseases. In this study, we analyzed GWAS data for 61 diseases and phenotypes to elucidate common associations based on single nucleotide polymorphisms (SNP. The study was an expansion on a previous study on identifying disease associations via data from a single GWAS on seven diseases. METHODOLOGY/PRINCIPAL FINDINGS: Adjustments to the originally reported study included expansion of the SNP dataset using Linkage Disequilibrium (LD and refinement of the four levels of analysis to encompass SNP, SNP block, gene, and pathway level comparisons. A pair-wise comparison between diseases and phenotypes was performed at each level and the Jaccard similarity index was used to measure the degree of association between two diseases/phenotypes. Disease relatedness networks (DRNs were used to visualize our results. We saw predominant relatedness between Multiple Sclerosis, type 1 diabetes, and rheumatoid arthritis for the first three levels of analysis. Expected relatedness was also seen between lipid- and blood-related traits. CONCLUSIONS/SIGNIFICANCE: The predominant associations between Multiple Sclerosis, type 1 diabetes, and rheumatoid arthritis can be validated by clinical studies. The diseases have been proposed to share a systemic inflammation phenotype that can result in progression of additional diseases in patients with one of these three diseases. We also noticed unexpected relationships between metabolic and neurological diseases at the pathway comparison level. The less significant relationships found between diseases require a more detailed literature review to determine validity of the predictions. The results from this study serve as a first step towards a better understanding of seemingly unrelated diseases and phenotypes with similar symptoms or modes of treatment.

  8. Haptoglobin phenotypes as a risk factor for coronary artery disease ...

    African Journals Online (AJOL)

    Objective: Diabetes has long been known to be an independent risk factor for cardiovascular disease. Recognition of diabetic individuals at greatest risk of developing coronary artery disease (CAD) would have important public health importance by allowing the distribution of limited resources to be directed on those who ...

  9. Neuromuscular Imaging and Phenotypical Variation in Pompe Disease

    NARCIS (Netherlands)

    S.C.A. Wens (Stephan)

    2016-01-01

    markdownabstractPompe disease is a progressive metabolic myopathy. It is caused by a deficiency of the enzyme acid α-glucosidase and leads to glycogen accumulation, predominantly in skeletal muscle. All Dutch patients diagnosed with Pompe disease are referred to the ‘Center of Lysosomal and

  10. Haptoglobin phenotypes as a risk factor for coronary artery disease ...

    African Journals Online (AJOL)

    Gehan Hamdy

    2014-04-22

    Apr 22, 2014 ... Abstract Objective: Diabetes has long been known to be an independent risk factor for cardiovascular disease. Recognition of diabetic individuals at greatest risk of developing coronary artery disease (CAD) would have important public health importance by allowing the distribution of limited resources to ...

  11. Genetic susceptibility and genotype-phenotype association in 588 Danish children with inflammatory bowel disease

    DEFF Research Database (Denmark)

    Jakobsen, C; Cleynen, I; Andersen, Susanne Pia

    2014-01-01

    AIM: To investigate the association between known inflammatory bowel disease (IBD)-associated genetic variants and development of paediatric IBD, and specific clinical sub-phenotypes. MATERIAL AND METHODS: In this case-control study we included IBD patients ... associated with disease localisation, medical treatment or surgery after correcting for multiple analyses. CONCLUSION: We found an association between CD and three previously published genetic variants and replicated the association with the paediatric specific ZMIZ1 gene. No Bonferroni corrected significant...... genotype-phenotype associations were found. For future studies aimed at finding predictors for disease course in (paediatric) IBD, it will be worthwhile to include a combination of genetic, clinical and serological markers....

  12. Haptoglobin Phenotype Predicts a Low Heart Rate Variability in Patients with Chronic Kidney Disease

    DEFF Research Database (Denmark)

    Svensson, My; Strandhave, Charlotte; Krarup, H.B.

    F-PO1096 Haptoglobin Phenotype Predicts a Low Heart Rate Variability in Patients with Chronic Kidney Disease My Svensson,1 Charlotte Strandhave,1 Henrik My Svensson,1 Charlotte Strandhave,1 HenrikKrarup,2 Jeppe H. Christensen.1 1Department of Nephrology, Aalborg Hospital, Aalborg, Denmark; 2...... to a phenotype-dependent antioxidant capacity where Hp 2-2 exhibits a low antioxidant ability, increasing the risk of cardiovascular disease. An attenuated heart rate variability (HRV) may be an important predictor of mortality in patients with chronic kidney disease (CKD). In the present study, we examined......Department of Clinical Biochemistry, Aalborg Hospital, Aalborg, Denmark. Introduction Three major phenotypes for the haptoglobin (Hp) gene has been identified: Hp 1-1, Hp 2-2, and the heterozygous Hp 2-1. Hp 2-2 is associated with a poor outcome in patients with cardiovascular disease. This may be due...

  13. Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis

    NARCIS (Netherlands)

    Weismueller, Tobias J.; Trivedi, Palak J; Bergquist, Annika; Imam, Mohamad; Lenzen, Henrike; Ponsioen, Cyriel Y.; Holm, Kristian; Gotthardt, Daniel; Faerkkilae, Martti A.; Marschall, Hanns-Ulrich; Thorburn, Douglas; Weersma, Rinse K.; Fevery, Johan; Mueller, Tobias; Chazouilleres, Olivier; Schulze, Kornelius; Lazaridis, Konstantinos N.; Almer, Sven; Pereira, Stephen P.; Levy, Cynthia; Mason, Andrew L.; Naess, Sigrid; Bowlus, Christopher L.; Floreani, Annarosa; Halilbasic, Emina; Yimam, Kidist K.; Milkiewicz, Piotr; Beuers, Ulrich; Huynh, Dep K.; Pares, Albert; Manser, Christine N.; Dalekos, George N.; Eksteen, Bertus; Invernizzi, Pietro; Berg, Christoph P.; Kirchner, Gabi I.; Sarrazin, Christoph; Zimmer, Vincent; Fabris, Luca; Braun, Felix; Marzioni, Marco; Juran, Brian D.; Said, Karouk; Rupp, Christian; Jokelainen, Kalle; de Valle, Maria Benito; Saffioti, Francesca; Cheung, Angela; Trauner, Michael; Schramm, Christoph; Chapman, Roger W.; Karlsen, Tom H.; Schrumpf, Erik; Strassburg, Christian P.; Manns, Michael P.; Lindor, Keith D; Hirschfield, Gideon M.; Hansen, Bettina E.; Boberg, Kirsten M.

    BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. METHODS: We

  14. Complex disease and phenotype mapping in the domestic dog

    Science.gov (United States)

    Hayward, Jessica J.; Castelhano, Marta G.; Oliveira, Kyle C.; Corey, Elizabeth; Balkman, Cheryl; Baxter, Tara L.; Casal, Margret L.; Center, Sharon A.; Fang, Meiying; Garrison, Susan J.; Kalla, Sara E.; Korniliev, Pavel; Kotlikoff, Michael I.; Moise, N. S.; Shannon, Laura M.; Simpson, Kenneth W.; Sutter, Nathan B.; Todhunter, Rory J.; Boyko, Adam R.

    2016-01-01

    The domestic dog is becoming an increasingly valuable model species in medical genetics, showing particular promise to advance our understanding of cancer and orthopaedic disease. Here we undertake the largest canine genome-wide association study to date, with a panel of over 4,200 dogs genotyped at 180,000 markers, to accelerate mapping efforts. For complex diseases, we identify loci significantly associated with hip dysplasia, elbow dysplasia, idiopathic epilepsy, lymphoma, mast cell tumour and granulomatous colitis; for morphological traits, we report three novel quantitative trait loci that influence body size and one that influences fur length and shedding. Using simulation studies, we show that modestly larger sample sizes and denser marker sets will be sufficient to identify most moderate- to large-effect complex disease loci. This proposed design will enable efficient mapping of canine complex diseases, most of which have human homologues, using far fewer samples than required in human studies. PMID:26795439

  15. Polyphosphate binds to human von Willebrand factor in vivo and modulates its interaction with glycoprotein Ib.

    Science.gov (United States)

    Montilla, M; Hernández-Ruiz, L; García-Cozar, F J; Alvarez-Laderas, I; Rodríguez-Martorell, J; Ruiz, F A

    2012-11-01

    Polyphosphate, a phosphate polymer released by activated platelets, has recently been described as a potent modulator of blood coagulation and fibrinolysis. In blood plasma, polyphosphate binds to and alters the biological functions of factor XII, fibrin(ogen), thrombin and factor VII activating protease. The aim of the present study is to investigate whether polyphosphate also binds to von Willebrand factor (VWF) and alters some of its activities. When studying patients with type 1 von Willebrand disease (VWD) and their healthy relatives, we discovered a significant correlation between von Willebrand factor (VWF) and platelet polyphosphate levels. We have also found polyphosphate in preparations of VWF isolated from normal platelets and plasma. Surface plasmon resonance and electrophoretic mobility assays indicated that polyphosphate interacts with VWF in a dose- and time-dependent manner. Treatment of normal plasma with active exopolyphosphatase decreased the VWF ristocetin cofactor (VWF:RCo) activity, a functional measure of VWF binding to platelet glycoprotein receptor Ib. VWF collagen binding and multimerization were unaltered after polyphosphate depletion. Moreover, addition of polyphosphate increased the deficient VWF:RCo activity presented by plasma from patients with type 1 VWD. Our results reveal that a new role is played by polyphosphate in hemostasis by its interaction with VWF, and suggest that this polymer may be effective in the treatment of some types of VWD. © 2012 International Society on Thrombosis and Haemostasis.

  16. Improved diagnosis of Parkinson's disease from a detailed olfactory phenotype.

    Science.gov (United States)

    Gerkin, Richard C; Adler, Charles H; Hentz, Joseph G; Shill, Holly A; Driver-Dunckley, Erika; Mehta, Shyamal H; Sabbagh, Marwan N; Caviness, John N; Dugger, Brittany N; Serrano, Geidy; Belden, Christine; Smith, Brian H; Sue, Lucia; Davis, Kathryn J; Zamrini, Edward; Beach, Thomas G

    2017-10-01

    To assess the predictive potential of the complete response pattern from the University of Pennsylvania Smell Identification Test for the diagnosis of Parkinson's disease. We analyzed a large dataset from the Arizona Study of Aging and Neurodegenerative Disorders, a longitudinal clinicopathological study of health and disease in elderly volunteers. Using the complete pattern of responses to all 40 items in each subject's test, we built predictive models of neurodegenerative disease, and we validated these models out of sample by comparing model predictions against postmortem pathological diagnosis. Consistent with anatomical considerations, we found that the specific test response pattern had additional predictive power compared with a conventional measure - total test score - in Parkinson's disease, but not Alzheimer's disease. We also identified specific test questions that carry the greatest predictive power for disease diagnosis. Olfactory ability has typically been assessed with either self-report or total score on a multiple choice test. We showed that a more accurate clinical diagnosis can be made using the pattern of responses to all the test questions, and validated this against the "gold standard" of pathological diagnosis. Information in the response pattern also suggests specific modifications to the standard test that may optimize predictive power under the typical clinical constraint of limited time. We recommend that future studies retain the individual item responses for each subject, and not just the total score, both to enable more accurate diagnosis and to enable additional future insights.

  17. How Variability in Clinical Phenotypes Should Guide Research into Disease Mechanisms in Asthma

    Science.gov (United States)

    Adcock, Ian M.

    2013-01-01

    Asthma is increasingly being considered as a collection of different phenotypes that present with intermittent wheezing. Unbiased approaches to classifying asthma have led to the identification of distinct phenotypes based on age of onset of disease, atopic state, disease severity or activity, degree of chronic airflow obstruction, and sputum eosinophilia. Linking phenotypes to known disease mechanism is likely to be more fruitful in determining the potential targets necessary for successful therapies of specific endotypes. A “Th2-high expression” signature from the epithelium of patients with asthma identifies a subset of patients with high eosinophilia and good therapeutic responsiveness to corticosteroids. Other characteristic traits of asthma include noneosinophilic asthma, corticosteroid insensitivity, obesity-associated, and exacerbation-prone. Further progress into asthma mechanisms will be driven by unbiased data integration of multiscale data sets from omics technologies with those phenotypic characteristics and by using mathematical modeling. This will lead to the discovery of new pathways and their integration into endotypes and also set up further hypothesis-driven research. Continued iteration through experimentation or modeling will be needed to refine the phenotypes that relate to outcomes and also delineate specific treatments for specific phenotypes. PMID:24313760

  18. Integrating gene set analysis and nonlinear predictive modeling of disease phenotypes using a Bayesian multitask formulation.

    Science.gov (United States)

    Gönen, Mehmet

    2016-12-13

    Identifying molecular signatures of disease phenotypes is studied using two mainstream approaches: (i) Predictive modeling methods such as linear classification and regression algorithms are used to find signatures predictive of phenotypes from genomic data, which may not be robust due to limited sample size or highly correlated nature of genomic data. (ii) Gene set analysis methods are used to find gene sets on which phenotypes are linearly dependent by bringing prior biological knowledge into the analysis, which may not capture more complex nonlinear dependencies. Thus, formulating an integrated model of gene set analysis and nonlinear predictive modeling is of great practical importance. In this study, we propose a Bayesian binary classification framework to integrate gene set analysis and nonlinear predictive modeling. We then generalize this formulation to multitask learning setting to model multiple related datasets conjointly. Our main novelty is the probabilistic nonlinear formulation that enables us to robustly capture nonlinear dependencies between genomic data and phenotype even with small sample sizes. We demonstrate the performance of our algorithms using repeated random subsampling validation experiments on two cancer and two tuberculosis datasets by predicting important disease phenotypes from genome-wide gene expression data. We are able to obtain comparable or even better predictive performance than a baseline Bayesian nonlinear algorithm and to identify sparse sets of relevant genes and gene sets on all datasets. We also show that our multitask learning formulation enables us to further improve the generalization performance and to better understand biological processes behind disease phenotypes.

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

    African Journals Online (AJOL)

    2014-07-20

    Jul 20, 2014 ... and about 48% of adult patients frequently develop multiple organ failure by the ... (dyspnea, chest pain) accompanied by new pulmonary infiltrates on chest ... Stroke (cerebro‑vascular disease): Acute neurologic symptoms/signs ..... Evaluation of clinical severity of sickle cell anemia in. Nigerian children.

  20. Macrophage phenotype modulation by CXCL4 in vascular disease

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    Christian Albert Gleissner

    2012-01-01

    Full Text Available During atherogenesis, blood monocytes transmigrate into the subendothelial space and differentiate towards macrophages and foam cells. The major driver of this differentiation process is macrophage colony-stimulation factor (M-CSF. M-CSF-induced macrophages are important promoters of atherogenesis as demonstrated in M-CSF and M-CSF receptor knock out mice. However, M-CSF is not the only relevant promoter of macrophage differentiation. The platelet chemokine CXCL4 prevents monocyte apoptosis and promotes macrophage differentiation in vitro. It is secreted from activated platelets and has effects on various cell types relevant in atherogenesis. Knocking out the Pf4 gene coding for CXCL4 in Apoe-/- mice leads to reduced atherogenesis. Thus, it seems likely that CXC4-induced macrophages may have specific pro-atherogenic capacities. We have studied CXC4-induced differentiation of human macrophages using gene chips, systems biology and functional in vitro and ex vivo experiments. Our data indicate that CXCL4-induced macrophages are distinct from both their M-CSF-induced counterparts and other known macrophage polarizations like M1 macrophages (induced by LPS and interferon-gamma or M2 macrophages (induced by interleukin-4. CXCL4-induced macrophages have distinct phenotypic and functional characteristics, e.g. the complete loss of the hemoglobin-haptoglobin (Hb-Hp scavenger receptor CD163 which is necessary for effective hemoglobin clearance after plaque hemorrhage. Lack of CD163 is accompanied by the inability to upregulate the atheroprotective enzyme heme oxygenase-1 in response to Hb-Hp complexes.This review covers the current knowledge about CXCL4-induced macrophages, which based on their unique properties we have suggested to call these macrophages M4. CXCL4 may represent an important driver of macrophage heterogeneity within atherosclerotic lesions. Further dissecting its effects on macrophage differentiation may help to identify novel

  1. Transcriptional Profiling of Egg Allergy and Relationship to Disease Phenotype.

    Directory of Open Access Journals (Sweden)

    Roman Kosoy

    Full Text Available Egg allergy is one of the most common food allergies of childhood. There is a lack of information on the immunologic basis of egg allergy beyond the role of IgE.To use transcriptional profiling as a novel approach to uncover immunologic processes associated with different phenotypes of egg allergy.Peripheral blood mononuclear cells (PBMCs were obtained from egg-allergic children who were defined as reactive (BER or tolerant (BET to baked egg, and from food allergic controls (AC who were egg non-allergic. PBMCs were stimulated with egg white protein. Gene transcription was measured by microarray after 24 h, and cytokine secretion by multiplex assay after 5 days.The transcriptional response of PBMCs to egg protein differed between BER and BET versus AC subjects. Compared to the AC group, the BER group displayed increased expression of genes associated with allergic inflammation as well as corresponding increased secretion of IL-5, IL-9 and TNF-α. A similar pattern was observed for the BET group. Further similarities in gene expression patterns between BER and BET groups, as well as some important differences, were revealed using a novel Immune Annotation resource developed for this project. This approach identified several novel processes not previously associated with egg allergy, including positive associations with TLR4-stimulated myeloid cells and activated NK cells, and negative associations with an induced Treg signature. Further pathway analysis of differentially expressed genes comparing BER to BET subjects showed significant enrichment of IFN-α and IFN-γ response genes, as well as genes associated with virally-infected DCs.Transcriptional profiling identified several novel pathways and processes that differed when comparing the response to egg allergen in BET, BER, and AC groups. We conclude that this approach is a useful hypothesis-generating mechanism to identify novel immune processes associated with allergy and tolerance to forms

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

    Directory of Open Access Journals (Sweden)

    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

  3. Von Willebrand factor in patients on mechanical circulatory support - a double-edged sword between bleeding and thrombosis.

    Science.gov (United States)

    Hudzik, Bartosz; Kaczmarski, Jacek; Pacholewicz, Jerzy; Zakliczynski, Michal; Gasior, Mariusz; Zembala, Marian

    2015-09-01

    Mechanical circulatory support (MCS) is an umbrella term describing the various technologies used in both short- and long-term management of patients with either end-stage chronic heart failure (HF) or acute HF. Most often, MCS has emerged as a bridge to transplantation, but more recently it is also used as a destination therapy. Mechanical circulatory support includes left ventricular assist device (LVAD) or bi-ventricular assist device (Bi-VAD). Currently, 2- to 3-year survival in carefully selected patients is much better than with medical therapy. However, MCS therapy is hampered by sometimes life-threatening complications including bleeding and device thrombosis. Von Willebrand factor (vWF) has two major functions in haemostasis. First, it plays a crucial role in platelet-subendothelium adhesion and platelet-platelet interactions (aggregation). Second, it is the carrier of factor VIII (FVIII) in plasma. Von Willebrand factor prolongs FVIII half-time by protecting it from proteolytic degradation. It delivers FVIII to the site of vascular injury thus enhancing haemostatic process. On one hand, high plasma levels of vWF have been associated with an increased risk of thrombosis. On the other, defects or deficiencies of vWF underlie the inherited von Willebrand disease or acquired von Willebrand syndrome. Here we review the pathophysiology of thrombosis and bleeding associated with vWF.

  4. Sporadic Alzheimer disease fibroblasts display an oxidative stress phenotype.

    Science.gov (United States)

    Ramamoorthy, Mahesh; Sykora, Peter; Scheibye-Knudsen, Morten; Dunn, Christopher; Kasmer, Cindy; Zhang, Yongqing; Becker, Kevin G; Croteau, Deborah L; Bohr, Vilhelm A

    2012-09-15

    Alzheimer disease (AD) is a major health problem in the United States, affecting one in eight Americans over the age of 65. The number of elderly suffering from AD is expected to continue to increase over the next decade, as the average age of the U.S. population increases. The risk factors for and etiology of AD are not well understood; however, recent studies suggest that exposure to oxidative stress may be a contributing factor. Here, microarray gene expression signatures were compared in AD-patient-derived fibroblasts and normal fibroblasts exposed to hydrogen peroxide or menadione (to simulate conditions of oxidative stress). Using the 23K Illumina cDNA microarray to screen expression of >14,000 human genes, we identified a total of 1017 genes that are chronically up- or downregulated in AD fibroblasts, 215 of which were also differentially expressed in normal human fibroblasts within 12h after exposure to hydrogen peroxide or menadione. Pathway analysis of these 215 genes and their associated pathways revealed cellular functions that may be critically dysregulated by oxidative stress and play a critical role in the etiology and/or pathology of AD. We then examined the AD fibroblasts for the presence of oxidative DNA damage and found increased accumulation of 8-oxo-guanine. These results indicate the possible role of oxidative stress in the gene expression profile seen in AD. Published by Elsevier Inc.

  5. Genotypes and phenotypes for apolipoprotein E and Alzheimer disease in the Honolulu-Asia aging study

    NARCIS (Netherlands)

    J.W.P.F. Kardaun (Jan); L. White (Lon); H.E. Resnick; H. Petrovitch; S.M. Marcovina; A.M. Saunders (Ann); D.J. Foley (Dan); R.J. Havlik

    2000-01-01

    textabstractBACKGROUND: The utility of apolipoprotein E (ApoE) type as an indicator of genetic susceptibility to Alzheimer disease (AD) depends on the reliability of typing. Although ApoE protein isoform phenotyping is generally assumed equivalent to genotyping from

  6. Alzheimer's Disease Phenotypes and Genotypes Associated with Mutations in Presenilin 2

    Science.gov (United States)

    Jayadev, Suman; Leverenz, James B.; Steinbart, Ellen; Stahl, Justin; Klunk, William; Yu, Cheng-En; Bird, Thomas D.

    2010-01-01

    Mutations in presenilin 2 are rare causes of early onset familial Alzheimer's disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11…

  7. Prominent scapulae mimicking an inherited myopathy expands the phenotype of CHD7-related disease

    NARCIS (Netherlands)

    O'Grady, Gina L.; Ma, Alan; Sival, Deborah; Wong, Monica T. Y.; Peduto, Tony; Menezes, Manoj P.; Young, Helen; Waddell, Leigh; Ghaoui, Roula; Needham, Merrilee; Lek, Monkol; North, Kathryn N.; MacArthur, Daniel G.; van Ravenswaaij-Arts, Conny M. A.; Clarke, Nigel F.

    CHD7 variants are a well-established cause of CHARGE syndrome, a disabling multi-system malformation disorder that is often associated with deafness, visual impairment and intellectual disability. Less severe forms of CHD7-related disease are known to exist, but the full spectrum of phenotypes

  8. Early phenotypic differences between Parkinson's disease patients with and without freezing of gait

    NARCIS (Netherlands)

    Hall, J. M.; Shine, J. M.; Walton, C. C.; Gilat, M.; Kamsma, Y. P. T.; Naismith, S. L.; Lewis, S. J. G.

    Background: Previous studies have associated freezing of gait in Parkinson's disease with the presence of specific phenotypic features such as mood disturbances, REM sleep behavior disorder and selective cognitive impairments. However, it is not clear whether these features are present in the

  9. A method for identifying genetic heterogeneity within phenotypically defined disease subgroups.

    Science.gov (United States)

    Liley, James; Todd, John A; Wallace, Chris

    2017-02-01

    Many common diseases show wide phenotypic variation. We present a statistical method for determining whether phenotypically defined subgroups of disease cases represent different genetic architectures, in which disease-associated variants have different effect sizes in two subgroups. Our method models the genome-wide distributions of genetic association statistics with mixture Gaussians. We apply a global test without requiring explicit identification of disease-associated variants, thus maximizing power in comparison to standard variant-by-variant subgroup analysis. Where evidence for genetic subgrouping is found, we present methods for post hoc identification of the contributing genetic variants. We demonstrate the method on a range of simulated and test data sets, for which expected results are already known. We investigate subgroups of individuals with type 1 diabetes (T1D) defined by autoantibody positivity, establishing evidence for differential genetic architecture with positivity for thyroid-peroxidase-specific antibody, driven generally by variants in known T1D-associated genomic regions.

  10. Lessons from model organisms: phenotypic robustness and missing heritability in complex disease.

    Directory of Open Access Journals (Sweden)

    Christine Queitsch

    Full Text Available Genetically tractable model organisms from phages to mice have taught us invaluable lessons about fundamental biological processes and disease-causing mutations. Owing to technological and computational advances, human biology and the causes of human diseases have become accessible as never before. Progress in identifying genetic determinants for human diseases has been most remarkable for Mendelian traits. In contrast, identifying genetic determinants for complex diseases such as diabetes, cancer, and cardiovascular and neurological diseases has remained challenging, despite the fact that these diseases cluster in families. Hundreds of variants associated with complex diseases have been found in genome-wide association studies (GWAS, yet most of these variants explain only a modest amount of the observed heritability, a phenomenon known as "missing heritability." The missing heritability has been attributed to many factors, mainly inadequacies in genotyping and phenotyping. We argue that lessons learned about complex traits in model organisms offer an alternative explanation for missing heritability in humans. In diverse model organisms, phenotypic robustness differs among individuals, and those with decreased robustness show increased penetrance of mutations and express previously cryptic genetic variation. We propose that phenotypic robustness also differs among humans and that individuals with lower robustness will be more responsive to genetic and environmental perturbations and hence susceptible to disease. Phenotypic robustness is a quantitative trait that can be accurately measured in model organisms, but not as yet in humans. We propose feasible approaches to measure robustness in large human populations, proof-of-principle experiments for robustness markers in model organisms, and a new GWAS design that takes differences in robustness into account.

  11. Fractal and Transgenerational Genetic Effects on Phenotypic Variation and Disease Risk

    Science.gov (United States)

    Nadeau, Joe

    To understand human biology and to manage heritable diseases, a complete picture of the genetic basis for phenotypic variation and disease risk is needed. Unexpectedly however, most of these genetic variants, even for highly heritable traits, continue to elude discovery for poorly understood reasons. The genetics community is actively exploring the usual explanations for missing heritability. But given the extraordinary work that has already been done and the exceptional magnitude of the problem, it seems likely that unconventional genetic properties are involved.

  12. Systematic analysis, comparison, and integration of disease based human genetic association data and mouse genetic phenotypic information

    Directory of Open Access Journals (Sweden)

    Wang S Alex

    2010-01-01

    Full Text Available Abstract Background The genetic contributions to human common disorders and mouse genetic models of disease are complex and often overlapping. In common human diseases, unlike classical Mendelian disorders, genetic factors generally have small effect sizes, are multifactorial, and are highly pleiotropic. Likewise, mouse genetic models of disease often have pleiotropic and overlapping phenotypes. Moreover, phenotypic descriptions in the literature in both human and mouse are often poorly characterized and difficult to compare directly. Methods In this report, human genetic association results from the literature are summarized with regard to replication, disease phenotype, and gene specific results; and organized in the context of a systematic disease ontology. Similarly summarized mouse genetic disease models are organized within the Mammalian Phenotype ontology. Human and mouse disease and phenotype based gene sets are identified. These disease gene sets are then compared individually and in large groups through dendrogram analysis and hierarchical clustering analysis. Results Human disease and mouse phenotype gene sets are shown to group into disease and phenotypically relevant groups at both a coarse and fine level based on gene sharing. Conclusion This analysis provides a systematic and global perspective on the genetics of common human disease as compared to itself and in the context of mouse genetic models of disease.

  13. 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.

  14. Defining phenotypes and disease progression in sarcomeric cardiomyopathies: contemporary role of clinical investigations.

    Science.gov (United States)

    Olivotto, Iacopo; d'Amati, Giulia; Basso, Cristina; Van Rossum, Albert; Patten, Monica; Emdin, Michele; Pinto, Yigal; Tomberli, Benedetta; Camici, Paolo G; Michels, Michelle

    2015-04-01

    Mutations in cardiac sarcomere protein genes are associated with a variety of clinical phenotypes, including hypertrophic (HCM), dilated (DCM), and restrictive (RCM) cardiomyopathy as well as left ventricular non-compaction, with the overlap of morpho-functional manifestations in individual patients and families. Over time, initial phenotypes may undergo profound changes which determine clinical course and disease progression. Although genetic defects causing HCM and DCM have opposite effects at the myofilament level, a number of downstream maladaptive mechanisms, ranging from microvascular dysfunction and ischaemia to myocardial fibrosis and from diastolic dysfunction to abnormal sympathetic activation and arrhythmogenesis, seem to recur in sarcomeric cardiomyopathies, independent of the presenting phenotype. The extent and rate at which each of these features occur and evolve may be radically different in each form of cardiomyopathy, determining a clinical heterogeneity that is not only cross-sectional, but also longitudinal, i.e. time-related. Timely and sensitive detection of these long-term modifications in the clinical setting is a key to preventing advanced disease and identifying novel therapeutic targets. The present review evaluates the contribution of contemporary technology to pre-clinical diagnosis, characterization of phenotypes, and assessment of disease progression in sarcomere cardiomyopathies, including echocardiography, positron emission tomography, magnetic resonance, pathology, and circulating biomarkers. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

  15. Genome sequencing reveals loci under artificial selection that underlie disease phenotypes in the laboratory rat.

    Science.gov (United States)

    Atanur, Santosh S; Diaz, Ana Garcia; Maratou, Klio; Sarkis, Allison; Rotival, Maxime; Game, Laurence; Tschannen, Michael R; Kaisaki, Pamela J; Otto, Georg W; Ma, Man Chun John; Keane, Thomas M; Hummel, Oliver; Saar, Kathrin; Chen, Wei; Guryev, Victor; Gopalakrishnan, Kathirvel; Garrett, Michael R; Joe, Bina; Citterio, Lorena; Bianchi, Giuseppe; McBride, Martin; Dominiczak, Anna; Adams, David J; Serikawa, Tadao; Flicek, Paul; Cuppen, Edwin; Hubner, Norbert; Petretto, Enrico; Gauguier, Dominique; Kwitek, Anne; Jacob, Howard; Aitman, Timothy J

    2013-08-01

    Large numbers of inbred laboratory rat strains have been developed for a range of complex disease phenotypes. To gain insights into the evolutionary pressures underlying selection for these phenotypes, we sequenced the genomes of 27 rat strains, including 11 models of hypertension, diabetes, and insulin resistance, along with their respective control strains. Altogether, we identified more than 13 million single-nucleotide variants, indels, and structural variants across these rat strains. Analysis of strain-specific selective sweeps and gene clusters implicated genes and pathways involved in cation transport, angiotensin production, and regulators of oxidative stress in the development of cardiovascular disease phenotypes in rats. Many of the rat loci that we identified overlap with previously mapped loci for related traits in humans, indicating the presence of shared pathways underlying these phenotypes in rats and humans. These data represent a step change in resources available for evolutionary analysis of complex traits in disease models. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Distinct prion-like strains of amyloid beta implicated in phenotypic diversity of Alzheimer's disease.

    Science.gov (United States)

    Cohen, Mark; Appleby, Brian; Safar, Jiri G

    2016-01-01

    Vast evidence on human prions demonstrates that variable disease phenotypes, rates of propagation, and targeting of distinct brain structures are determined by unique conformers (strains) of pathogenic prion protein (PrP(Sc)). Recent progress in the development of advanced biophysical tools that inventory structural characteristics of amyloid beta (Aβ) in the brain cortex of phenotypically diverse Alzheimer's disease (AD) patients, revealed unique spectrum of oligomeric particles in the cortex of rapidly progressive cases, implicating these structures in variable rates of propagation in the brain, and in distict disease manifestation. Since only ∼30% of phenotypic diversity of AD can be explained by polymorphisms in risk genes, these and transgenic bioassay data argue that structurally distinct Aβ particles play a major role in the diverse pathogenesis of AD, and may behave as distinct prion-like strains encoding diverse phenotypes. From these observations and our growing understanding of prions, there is a critical need for new strain-specific diagnostic strategies for misfolded proteins causing these elusive disorders. Since targeted drug therapy can induce mutation and evolution of prions into new strains, effective treatments of AD will require drugs that enhance clearance of pathogenic conformers, reduce the precursor protein, or inhibit the conversion of precursors into prion-like states.

  17. High throughput phenotyping to accelerate crop breeding and monitoring of diseases in the field.

    Science.gov (United States)

    Shakoor, Nadia; Lee, Scott; Mockler, Todd C

    2017-08-01

    Effective implementation of technology that facilitates accurate and high-throughput screening of thousands of field-grown lines is critical for accelerating crop improvement and breeding strategies for higher yield and disease tolerance. Progress in the development of field-based high throughput phenotyping methods has advanced considerably in the last 10 years through technological progress in sensor development and high-performance computing. Here, we review recent advances in high throughput field phenotyping technologies designed to inform the genetics of quantitative traits, including crop yield and disease tolerance. Successful application of phenotyping platforms to advance crop breeding and identify and monitor disease requires: (1) high resolution of imaging and environmental sensors; (2) quality data products that facilitate computer vision, machine learning and GIS; (3) capacity infrastructure for data management and analysis; and (4) automated environmental data collection. Accelerated breeding for agriculturally relevant crop traits is key to the development of improved varieties and is critically dependent on high-resolution, high-throughput field-scale phenotyping technologies that can efficiently discriminate better performing lines within a larger population and across multiple environments. Copyright © 2017. Published by Elsevier Ltd.

  18. Sex differences in correlates of intermediate phenotypes and prevalent cardiovascular disease in the general population

    Directory of Open Access Journals (Sweden)

    Renate B. Schnabel

    2015-04-01

    Full Text Available Background-There are marked sex differences in cardiovascular disease [CVD] manifestation. It is largely unknown how the distribution of CVD risk factors or intermediate phenotypes explain sex-specific differences.Methods and Results-In 5000 individuals of the population-based Gutenberg Health Study, mean age 55±11 years, 51% males, we examined sex-specific associations of classical CVD risk factors with intima-media thickness, ankle-brachial index, flow-mediated dilation, peripheral arterial tonometry, echocardiographic and electrocardiographic variables. Intermediate cardiovascular phenotypes were related to prevalent CVD (coronary artery disease, heart failure, stroke, myocardial infarction, lower extremity artery disease [LEAD] N=561.We observed differential distributions of CVD risk factors with a higher risk factor burden in men. Manifest coronary artery disease, stroke, myocardial infarction and LEAD were more frequent in men; the proportion of heart failure was higher in women. Intermediate phenotypes showed clear sex differences with more beneficial values in women. Fairly linear changes towards less beneficial values with age were observed in both sexes. In multivariable-adjusted regression analyses age, systolic blood pressure and body mass index were consistently associated with intermediate phenotypes in both sexes with different ranking according to random forests, maximum model R² 0.43. Risk factor-adjusted associations with prevalent CVD showed some differences by sex. No interactions by menopausal status were observed. Conclusions-In a population-based cohort we observed sex differences in risk factors and a broad range of intermediate phenotypes of noninvasive cardiovascular structure and function. Their relation to prevalent CVD differed markedly. Our results indicate the need of future investigations to understand sex differences in CVD manifestation.

  19. An Expanded Multi-Organ Disease Phenotype Associated with Mutations in YARS

    Directory of Open Access Journals (Sweden)

    Anna Tracewska-Siemiątkowska

    2017-12-01

    Full Text Available Whole exome sequence analysis was performed in a Swedish mother–father-affected proband trio with a phenotype characterized by progressive retinal degeneration with congenital nystagmus, profound congenital hearing impairment, primary amenorrhea, agenesis of the corpus callosum, and liver disease. A homozygous variant c.806T > C, p.(F269S in the tyrosyl-tRNA synthetase gene (YARS was the only identified candidate variant consistent with autosomal recessive inheritance. Mutations in YARS have previously been associated with both autosomal dominant Charcot-Marie-Tooth syndrome and a recently reported autosomal recessive multiorgan disease. Herein, we propose that mutations in YARS underlie another clinical phenotype adding a second variant of the disease, including retinitis pigmentosa and deafness, to the spectrum of YARS-associated disorders.

  20. Inflammatory Bowel Disease and Primary Sclerosing Cholangitis: A Review of the Phenotype and Associated Specific Features

    Science.gov (United States)

    Palmela, Carolina; Peerani, Farhad; Castaneda, Daniel; Torres, Joana; Itzkowitz, Steven H.

    2018-01-01

    Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic disease that is associated with inflammatory bowel disease (IBD) in approximately 70% of cases. Although the pathogenesis is still unknown for both diseases, there is increasing evidence to indicate that they share a common underlying predisposition. Herein, we review the epidemiology, diagnosis, disease pathogenesis, and specific clinical features of the PSC-IBD phenotype. Patients with PSC-IBD have a distinct IBD phenotype with an increased incidence of pancolitis, backwash ileitis, and rectal sparing. Despite often having extensive colonic involvement, these patients present with mild intestinal symptoms or are even asymptomatic, which can delay the diagnosis of IBD. Although the IBD phenotype has been well characterized in PSC patients, the natural history and disease behavior of PSC in PSC-IBD patients is less well defined. There is conflicting evidence regarding the course of IBD in PSC-IBD patients who receive liver transplantation and their risk of recurrent PSC. IBD may also be associated with an increased risk of cholangiocarcinoma in PSC patients. Overall, the PSC-IBD population has an increased risk of developing colorectal neoplasia compared to the conventional IBD population. Lifelong annual surveillance colonoscopy is currently recommended. PMID:28376583

  1. The emerging phenotype of late-onset Pompe disease: A systematic literature review.

    Science.gov (United States)

    Chan, Justin; Desai, Ankit K; Kazi, Zoheb B; Corey, Kaitlyn; Austin, Stephanie; Hobson-Webb, Lisa D; Case, Laura E; Jones, Harrison N; Kishnani, Priya S

    2017-03-01

    Pompe disease is an autosomal recessive disorder caused by deficiency of the lysosomal glycogen-hydrolyzing enzyme acid α-glucosidase (GAA). The adult-onset form, late-onset Pompe disease (LOPD), has been characterized by glycogen accumulation primarily in skeletal, cardiac, and smooth muscles, causing weakness of the proximal limb girdle and respiratory muscles. However, increased scientific study of LOPD continues to enhance understanding of an evolving phenotype. To expand our understanding of the evolving phenotype of LOPD since the approval of enzyme replacement therapy (ERT) with alglucosidase alfa (Myozyme™/Lumizyme™) in 2006. All articles were included in the review that provided data on the charactertistics of LOPD identified via the PubMed database published since the approval of ERT in 2006. All signs and symptoms of the disease that were reported in the literature were identified and included in the review. We provide a comprehensive review of the evolving phenotype of LOPD. Our findings support and extend the knowledge of the multisystemic nature of the disease. With the advent of ERT and the concurrent increase in the scientific study of LOPD, the condition once primarily conceptualized as a limb-girdle muscle disease with prominent respiratory involvement is increasingly recognized to be a condition that results in signs and symptoms across body systems and structures. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Evidence for two distinct phenotypes of chronic kidney disease in individuals with type 1 diabetes mellitus.

    Science.gov (United States)

    Penno, Giuseppe; Russo, Eleonora; Garofolo, Monia; Daniele, Giuseppe; Lucchesi, Daniela; Giusti, Laura; Sancho Bornez, Veronica; Bianchi, Cristina; Dardano, Angela; Miccoli, Roberto; Del Prato, Stefano

    2017-06-01

    In a retrospective, observational, cross-sectional, single-centre study, we assessed the prevalence and correlates of different CKD phenotypes (with and without albuminuria) in a large cohort of patients of white ethnicity with type 1 diabetes. From 2001 to 2009, 408 men and 369 women with type 1 diabetes (age 40.2 ± 11.7 years, diabetes duration 19.4 ± 12.2 years, HbA1c 7.83 ± 1.17% [62.0 ± 12.9 mmol/mol]) were recruited consecutively. Albumin-to-creatinine ratio (ACR) and eGFR (Modification of Diet in Renal Disease) were obtained for all individuals, together with CKD stage. Diabetic retinopathy and peripheral polyneuropathy were detected in 41.5% and 8.1%, respectively, and cardiovascular disease (CVD) occurred in 8.5%. Adjudications of CKD phenotype were made by blinded investigators. Normo- (ACR diabetes duration, HbA1c, HDL-cholesterol, fibrinogen and hypertension, while the CKD Alb- phenotype was associated with age and hypertension, but not with diabetes duration, HbA1c and fibrinogen. The Alb- CKD phenotype is present in a significant proportion of individuals with type 1 diabetes supporting the hypothesis of two distinct pathways (Alb+ and Alb-) of progression towards advanced kidney disease in type 1 diabetes. These are probably distinct pathways as suggested by different sets of covariates associated with the two CKD phenotypes.

  3. Differences in disease phenotype and severity in SLE across age groups.

    Science.gov (United States)

    Ambrose, N; Morgan, T A; Galloway, J; Ionnoau, Y; Beresford, M W; Isenberg, D A

    2016-12-01

    Significant differences have been reported in disease phenotype and severity of systemic lupus erythematosus (SLE) presenting in different age groups. Most indicate a more severe phenotype in juvenile-onset SLE (JSLE). There have been limited studies in older patients and no large studies looking at SLE across all age groups. We assessed the effect of age of onset of SLE on the clinical phenotype by analysing data from two large UK cohorts (the UK JSLE Cohort and the UCLH SLE cohort). A total of 924 individuals were compared (413 JSLE, 511 adult-onset SLE). A female preponderance was present, but less pronounced at either end of the age spectrum. Arthritis was more common with advancing age (93% vs 72%, p age (p < 0.001). Mortality has been declining over recent decades. However, death rates were substantially higher than the general population. The standardized mortality ratio was 18.3 in JSLE and 3.1 in adult-onset SLE. These data from the largest-ever direct comparison of JSLE with adult-onset SLE suggest an aggressive phenotype of disease with a worse outcome in patients with JSLE and emphasizes the importance of careful follow-up in this population. © The Author(s) 2016.

  4. Long-Term Risk of Atherosclerotic Cardiovascular Disease in US Adults With the Familial Hypercholesterolemia Phenotype.

    Science.gov (United States)

    Perak, Amanda M; Ning, Hongyan; de Ferranti, Sarah D; Gooding, Holly C; Wilkins, John T; Lloyd-Jones, Donald M

    2016-07-05

    Heterozygous familial hypercholesterolemia (FH) affects up to 1 in 200 individuals in the United States, but atherosclerotic cardiovascular disease (ASCVD) outcomes of FH in the general US population have not been described. We therefore sought to evaluate long-term coronary heart disease (CHD) and total ASCVD risks in US adults with an FH phenotype. Using individual pooled data from 6 large US epidemiological cohorts, we stratified participants by low-density lipoprotein cholesterol level at index ages from 20 to 79 years. For the primary analysis, low-density lipoprotein cholesterol levels ≥190 and definition. We used Cox regression models to assess covariate-adjusted associations of the FH phenotype with 30-year hazards for CHD (CHD death or nonfatal myocardial infarction) and total ASCVD (CHD or stroke). We included 68 565 baseline person-examinations; 3850 (5.6%) had the FH phenotype by the primary definition. Follow-up across index ages ranged from 78 985 to 308 378 person-years. After covariate adjustment, the FH phenotype was associated with substantially elevated 30-year CHD risk, with hazard ratios up to 5.0 (95% confidence interval, 1.1-21.7). Across index ages, CHD risk was accelerated in those with the FH phenotype by 10 to 20 years in men and 20 to 30 years in women. Similar patterns of results were found for total ASCVD risk, with hazard ratios up to 4.1 (95% confidence interval, 1.2-13.4). Alternative FH phenotype definitions incorporating family history, more stringent age-based low-density lipoprotein cholesterol thresholds, or alternative lipid fractions decreased the FH phenotype prevalence to as low as 0.2% to 0.4% without materially affecting CHD risk estimates (hazard ratios up to 8.0; 95% confidence interval, 1.0-61.6). In the general US population, the long-term ASCVD burden related to phenotypic FH, defined by low-density lipoprotein cholesterol ≥190 mg/dL, is likely substantial. Our finding of CHD risk acceleration may aid

  5. Molecular characterization of exon 28 of von Willebrand's factor ...

    African Journals Online (AJOL)

    Background: Polymorphisms in von Willebrand factor (VWF) gene are an important contributor to the expression of VWF gene and differences in ethnic distribution of these single nucleotide polymorphisms (SNPs) exists. Aims: Our objective was to molecularly characterize the exon 28 of the VWF gene in the three major ...

  6. Molecular characterization of exon 28 of von Willebrand's factor ...

    African Journals Online (AJOL)

    2016-05-12

    May 12, 2016 ... two probable cases among 95 patients with hemophilia A and 11 with hemophilia B between 1980 and 1986, but full investigation and family studies were not performed. In. Nigeria, we have been unable to find documented cases of. Molecular characterization of exon 28 of von Willebrand's factor gene in ...

  7. The Effect of Parkinson Disease Tremor Phenotype on Cepstral Peak Prominence and Transglottal Airflow in Vowels and Speech.

    Science.gov (United States)

    Burk, Brittany R; Watts, Christopher R

    2018-02-19

    The physiological manifestations of Parkinson disease are heterogeneous, as evidenced by disease subtypes. Dysphonia has been well documented as an early and progressively significant impairment associated with the disease. The purpose of this study was to investigate how acoustic and aerodynamic measures of vocal function were affected by Parkinson tremor subtype (phenotype) in an effort to better understand the heterogeneity of voice impairment severity in Parkinson disease. This is a prospective case-control study. Thirty-two speakers with Parkinson disease assigned to tremor and nontremor phenotypes and 10 healthy controls were recruited. Sustained vowels and connected speech were recorded from each speaker. Acoustic measures of cepstral peak prominence (CPP) and aerodynamic measures of transglottal airflow (TAF) were calculated from the recorded acoustic and aerodynamic waveforms. Speakers with a nontremor dominant phenotype exhibited significantly (P Parkinson tremor phenotype in mild to moderate stages of the disease. Copyright © 2018 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

  8. Genome-wide linkage analysis of von Willebrand factor plasma levels: results from the GAIT project.

    Science.gov (United States)

    Souto, Juan Carlos; Almasy, Laura; Soria, Jose Manuel; Buil, Alfonso; Stone, William; Lathrop, Mark; Blangero, John; Fontcuberta, Jordi

    2003-03-01

    High plasma levels of von Willebrand factor (vWF) have been associated with the risk of thromboembolic disease. As a complex trait, this phenotype must be influenced by genetic and environmental factors. Among the genetic factors, only the ABO gene located on chromosome 9q34 has been clearly linked to the plasma levels of vWF. This locus explains about 30-40% of the genetic variability. Therefore, the source of the majority of the genetic component remains to be identified. To search for these unknown loci, we conducted a genomewide linkage screen for genes affecting normal variation in vWF levels in 21 Spanish families as part of the GAIT (Genetic Analysis of Idiopathic Thrombophilia) Project. The results showed that the strongest linkage signal (LOD =3.46, p = 0.00003) for vWF was found on chromosome 9q34 at the DNA marker D9S290, where the ABO gene is located. Additional suggestive linkage signals were found on chromosomes 2q23.2 (LOD = 1.65, p = 0.003) and 1p36.13 (LOD =1.32, p = 0.007). After refining the linkage analysis, conditional to the ABO genotype, three additional loci on chromosomes 5, 6 and 22 showed LOD scores higher than 1, suggesting the presence of other genes linked to vWF levels. Curiously, no linkage signals were detected in other chromosome regions previously associated with vWF levels (like the structural VWF gene on 12p13.2 or Lewis blood group gene on 19q13). These results indicate that these loci are not important genetic determinants of the normal variation of vWF levels. Our results indicate that the ABO locus is the major genetic determinant of the plasma levels of the vWF in Spanish population. It is possible that there are other potential regions on chromosomes 1, 2, 5, 6 and 22 that influence this thrombosis risk factor. However, the structural vWF gene itself has a very low influence (if any) on the plasma levels of vWF.

  9. Recurrent acute liver failure due to NBAS deficiency: phenotypic spectrum, disease mechanisms, and therapeutic concepts.

    Science.gov (United States)

    Staufner, Christian; Haack, Tobias B; Köpke, Marlies G; Straub, Beate K; Kölker, Stefan; Thiel, Christian; Freisinger, Peter; Baric, Ivo; McKiernan, Patrick J; Dikow, Nicola; Harting, Inga; Beisse, Flemming; Burgard, Peter; Kotzaeridou, Urania; Lenz, Dominic; Kühr, Joachim; Himbert, Urban; Taylor, Robert W; Distelmaier, Felix; Vockley, Jerry; Ghaloul-Gonzalez, Lina; Ozolek, John A; Zschocke, Johannes; Kuster, Alice; Dick, Anke; Das, Anib M; Wieland, Thomas; Terrile, Caterina; Strom, Tim M; Meitinger, Thomas; Prokisch, Holger; Hoffmann, Georg F

    2016-01-01

    Acute liver failure (ALF) in infancy and childhood is a life-threatening emergency and in about 50% the etiology remains unknown. Recently biallelic mutations in NBAS were identified as a new molecular cause of ALF with onset in infancy, leading to recurrent acute liver failure (RALF). The phenotype and medical history of 14 individuals with NBAS deficiency was studied in detail and functional studies were performed on patients' fibroblasts. The phenotypic spectrum of NBAS deficiency ranges from isolated RALF to a multisystemic disease with short stature, skeletal dysplasia, immunological abnormalities, optic atrophy, and normal motor and cognitive development resembling SOPH syndrome. Liver crises are triggered by febrile infections; they become less frequent with age but are not restricted to childhood. Complete recovery is typical, but ALF crises can be fatal. Antipyretic therapy and induction of anabolism including glucose and parenteral lipids effectively ameliorates the course of liver crises. Patients' fibroblasts showed an increased sensitivity to high temperature at protein and functional level and a disturbed tethering of vesicles, pointing at a defect of intracellular transport between the endoplasmic reticulum and Golgi. Mutations in NBAS cause a complex disease with a wide clinical spectrum ranging from isolated RALF to a multisystemic phenotype. Thermal susceptibility of the syntaxin 18 complex is the basis of fever dependency of ALF episodes. NBAS deficiency is the first disease related to a primary defect of retrograde transport. Identification of NBAS deficiency allows optimized therapy of liver crises and even prevention of further episodes.

  10. 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.

  11. Myoclonic epilepsy in Gaucher disease: genotype-phenotype insights from a rare patient subgroup.

    Science.gov (United States)

    Park, Joseph K; Orvisky, Eduard; Tayebi, Nahid; Kaneski, Christine; Lamarca, Mary E; Stubblefield, Barbara K; Martin, Brian M; Schiffmann, Raphael; Sidransky, Ellen

    2003-03-01

    Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, presents with a wide spectrum of manifestations. Although Gaucher disease has been divided into three clinical types, patients with atypical presentations continue to be recognized. A careful phenotypic and genotypic assessment of patients with unusual symptoms may help define factors that modify phenotype in this disorder. One such example is a rare subgroup of patients with type 3 Gaucher disease who develop progressive myoclonic epilepsy. We evaluated 16 patients with myoclonic epilepsy, nine of whom were diagnosed by age 4 y with severe visceral involvement and myoclonus, and seven with a more chronic course, who were studied between ages 22 and 40. All of the patients had abnormal horizontal saccadic eye movements. Fourteen different genotypes were encountered, yet there were several shared alleles, including V394L (seen on two alleles), G377S (seen on three alleles), and L444P, N188S, and recombinant alleles (each found on four alleles). V394L, G377S, and N188S are mutations that have previously been associated with non-neuronopathic Gaucher disease. The spectrum of genotypes differed significantly from other patients with type 3 Gaucher disease, where genotypes L444P/L444P and R463C/null allele predominated. Northern blot studies revealed a normal glucocerebrosidase transcript, whereas Western studies showed that the patients studied lacked the processed 56 kD isoform of the enzyme, consistent with neuronopathic Gaucher disease. Brain autopsy samples from two patients demonstrated elevated levels of glucosylsphingosine, a toxic glycolipid, which could contribute to the development of myoclonus. Thus, although there were certain shared mutant alleles found in these patients, both the lack of a shared genotype and the variability in clinical presentations suggest that other modifiers must contribute to this rare phenotype.

  12. Components of physical capacity in patients with chronic obstructive pulmonary disease: relationship with phenotypic expression

    Directory of Open Access Journals (Sweden)

    Eduardo Márquez-Martín

    2011-01-01

    Full Text Available Eduardo Márquez-Martín1, Pilar Cejudo Ramos1, José Luis López-Campos1, María del Pilar Serrano Gotarredona2, Silvia Navarro Herrero2, Rodrigo Tallón Aguilar1, Emilia Barrot Cortes1, Francisco Ortega Ruiz11Medical-Surgical Unit of Respiratory Diseases, University Hospital Virgen del Rocío, Seville, Spain; 2Radiodiagnostic Unit, University Hospital Virgen del Rocío, Seville, SpainBackground: More accurate phenotyping of COPD is of great interest since it may have prognostic and therapeutic consequences. We attempted to explore the possible relationship between the extent of emphysema, as assessed by high-resolution computed tomography (HRCT, and COPD severity. We also included some study variables involving exercise tolerance evaluation and peripheral muscle strength (PMS measurement.Methods: Sixty-four patients with COPD (mean age 64 ± 7 years were enrolled in a prospective observational cross-sectional study. All patients underwent clinical and functional evaluations: assessment of dyspnea, body mass index (BMI, health status assessment, spirometry testing, and arterial blood gas analysis. The extent of emphysema was graded using HRCT. Functional capacity was evaluated by a cardiopulmonary maximal exercise testing (CPET, the shuttle walking test, and by estimation of PMS.Results: Half of the study patients had an emphysematous phenotype. There was a significant correlation between the score derived from analysis of HRCT images and BMI and respiratory functional parameters, as well as VO2 max (maximal oxygen uptake and chest pull 1RM (1 rep max. Compared with subjects with a nonemphysematous phenotype, those with an emphysematous phenotype showed a lower BMI, a reduced PMS, and displayed a lower power at CPET. Significant differences in lung function tests were found for diffusing capacity and hyperinflation. No significant differences in quality of life were observed between the two study groups.Conclusions: Compared with subjects with

  13. An Expanded Multi-Organ Disease Phenotype Associated with Mutations in YARS

    DEFF Research Database (Denmark)

    Tracewska-Siemiątkowska, Anna; Haer-Wigman, Lonneke; Bosch, Danielle G M

    2017-01-01

    . A homozygous variant c.806T > C, p.(F269S) in the tyrosyl-tRNA synthetase gene (YARS) was the only identified candidate variant consistent with autosomal recessive inheritance. Mutations inYARShave previously been associated with both autosomal dominant Charcot-Marie-Tooth syndrome and a recently reported...... autosomal recessive multiorgan disease. Herein, we propose that mutations inYARSunderlie another clinical phenotype adding a second variant of the disease, including retinitis pigmentosa and deafness, to the spectrum ofYARS-associated disorders....

  14. Pink1 suppresses alpha-synuclein-induced phenotypes in a Drosophila model of Parkinson's disease.

    Science.gov (United States)

    Todd, Amy M; Staveley, Brian E

    2008-12-01

    Parkinson's disease (PD) is the most prevalent human neurodegenerative movement disorder and is characterized by a selective and progressive loss of the dopaminergic neurons. Mutations in the genes parkin and PTEN-induced putative kinase 1 (PINK1) result in autosomal recessive forms of PD. It has been suggested that parkin and Pink1 function in the same pathway in Drosophila, with Pink1 acting upstream of parkin. Previous work in our laboratory has shown the ability of parkin to rescue an alpha-synuclein-induced PD-like phenotype in Drosophila. To investigate the ability of Pink1 to protect against alpha-synuclein-induced toxicity, we have performed longevity, mobility, and histological studies to determine whether Drosophila Pink1 can rescue the alpha-synuclein phenotypes. We have found that overexpression of Pink1 results in the rescue of the alpha-synuclein-induced phenotype of premature loss of climbing ability, suppression of degeneration of the ommatidial array, and the suppression of alpha-synuclein-induced developmental defects in the Drosophila eye. These results mark the first demonstration of Pink1 counteracting PD phenotypes in a protein toxicity animal model, and they show that Pink1 is able to impart protection against potentially harmful proteins such as alpha-synuclein that would otherwise result in cellular stress.

  15. Phenotypic expansion of the supernumerary derivative (22) chromosome syndrome: VACTERL and Hirschsprung's disease.

    Science.gov (United States)

    Prieto, Juan C; Garcia, Nilda M; Elder, Frederick F; Zinn, Andrew R; Baker, Linda A

    2007-11-01

    Phenotypically healthy carriers of the balanced 11;22 translocation, the most frequent non-Robertsonian constitutional translocation known in human beings, are at risk of having a progeny with supernumerary derivative (22)t(11;22) syndrome [der(22) syndrome]. We present the cases of 2 male patients with supernumerary der(22) syndrome [47,XY,+der(22)t(11;22)(q23;q11.2)mat], yielding partial trisomy for 22pter-q11 and 11q23-qter. These cases expand the phenotype of the der(22) syndrome, with the first case highlighting the phenotypic overlap of VACTERL and the second adding Hirschsprung's disease and intestinal malrotation to the list of associated anorectal anomalies. Because der(22) syndrome and cat eye syndrome (partial tetrasomy of 22q11) share a similar region of extra dosage on 22q11 and both typically manifest an anorectal phenotype, a dosage-sensitive gene for anorectal anomalies may be present in this locus.

  16. Prevalence and characteristics of three clinical phenotypes of chronic obstructive pulmonary disease (COPD).

    Science.gov (United States)

    Izquierdo-Alonso, José Luis; Rodriguez-Gonzálezmoro, Jose Miguel; de Lucas-Ramos, Pilar; Unzueta, Irune; Ribera, Xabier; Antón, Esther; Martín, Antonio

    2013-05-01

    To determine the prevalence and analyze the most relevant clinical characteristics of three clinical phenotypes of COPD: emphysema (type 1), chronic bronchitis (type 2) or COPD-asthma (type 3). Observational, multicenter study performed with 331 COPD patients recruited in pulmonology outpatient services. The stratification in three phenotypes was performed with imaging tests, pulmonary function, and a standardized clinical questionnaire. The 43.2% presented an emphysematous phenotype, 44.7% were chronic bronchitic and the other 12.1% presented a phenotype showing mixed characteristics with asthma. There were no significant differences in the smoking level, in the gasometric values or time of disease evolution. Type 1 patients showed lower FEV1 values in comparison with types 2 and 3, 46.6% (21.1), 55.2% (21.2) and 54.4% (21.8), respectively (p COPD), or in the number of hospital admittances. Type 2 patients showed a greater prevalence of cardiovascular comorbidities and of sleep apnea syndrome (4.9%, 23.6% and 12.5%, respectively, p COPD, emphysematous patients present worse pulmonary function and greater dyspnea, although there were no differences in the use of hospital health care resources. The greater comorbidity in Group 2 patients may require specific strategies in this subgroup of patients. Copyright © 2013 Elsevier Ltd. All rights reserved.

  17. Parkinsonian phenotype in Machado-Joseph disease (MJD/SCA3: a two-case report

    Directory of Open Access Journals (Sweden)

    Vasconcelos João

    2011-10-01

    Full Text Available Abstract Background Machado-Joseph disease (MJD, or spinocerebellar ataxia type 3 (SCA3, is an autosomal dominant neurodegenerative disorder of late onset, which is caused by a CAG repeat expansion in the coding region of the ATXN3 gene. This disease presents clinical heterogeneity, which cannot be completely explained by the size of the repeat tract. MJD presents extrapyramidal motor signs, namely Parkinsonism, more frequently than the other subtypes of autosomal dominant cerebellar ataxias. Although Parkinsonism seems to segregate within MJD families, only a few MJD patients develop parkinsonian features and, therefore, the clinical and genetic aspects of these rare presentations remain poorly investigated. The main goal of this work was to describe two MJD patients displaying the parkinsonian triad (tremor, bradykinesia and rigidity, namely on what concerns genetic variation in Parkinson's disease (PD associated loci (PARK2, LRRK2, PINK1, DJ-1, SNCA, MAPT, APOE, and mtDNA tRNAGln T4336C. Case presentation Patient 1 is a 40 year-old female (onset at 30 years of age, initially with a pure parkinsonian phenotype (similar to the phenotype previously reported for her mother. Patient 2 is a 38 year-old male (onset at 33 years of age, presenting an ataxic phenotype with parkinsonian features (not seen either in other affected siblings or in his father. Both patients presented an expanded ATXN3 allele with 72 CAG repeats. No PD mutations were found in the analyzed loci. However, allelic variants previously associated with PD were observed in DJ-1 and APOE genes, for both patients. Conclusions The present report adds clinical and genetic information on this particular and rare MJD presentation, and raises the hypothesis that DJ-1 and APOE polymorphisms may confer susceptibility to the parkinsonian phenotype in MJD.

  18. High phenotypic variability in Gerstmann-Sträussler-Scheinker disease

    Directory of Open Access Journals (Sweden)

    Jerusa Smid

    Full Text Available ABSTRACT Gerstmann-Sträussler-Scheinker is a genetic prion disease and the most common mutation is p.Pro102Leu. We report clinical, molecular and neuropathological data of seven individuals, belonging to two unrelated Brazilian kindreds, carrying the p.Pro102Leu. Marked differences among patients were observed regarding age at onset, disease duration and clinical presentation. In the first kindred, two patients had rapidly progressive dementia and three exhibited predominantly ataxic phenotypes with variable ages of onset and disease duration. In this family, age at disease onset in the mother and daughter differed by 39 years. In the second kindred, different phenotypes were also reported and earlier ages of onset were associated with 129 heterozygosis. No differences were associated with apoE genotype. In these kindreds, the codon 129 polymorphism could not explain the clinical variability and 129 heterozygosis was associated with earlier disease onset. Neuropathological examination in two patients confirmed the presence of typical plaques and PrPsc immunopositivity.

  19. Carboxypeptidase N-deficient mice present with polymorphic disease phenotypes on induction of experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Hu, Xianzhen; Wetsel, Rick A; Ramos, Theresa N; Mueller-Ortiz, Stacey L; Schoeb, Trenton R; Barnum, Scott R

    2014-02-01

    Carboxypeptidase N (CPN) is a member of the carboxypeptidase family of enzymes that cleave carboxy-terminal lysine and arginine residues from a large number of biologically active peptides and proteins. These enzymes are best known for their roles in modulating the activity of kinins, complement anaphylatoxins and coagulation proteins. Although CPN makes important contributions to acute inflammatory events, little is known about its role in autoimmune disease. In this study we used CPN(-/-) mice in experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. Unexpectedly, we observed several EAE disease phenotypes in CPN(-/-) mice compared to wild type mice. The majority of CPN(-/-) mice died within five to seven days after disease induction, before displaying clinical signs of disease. The remaining mice presented with either mild EAE or did not develop EAE. In addition, CPN(-/-) mice injected with complete or incomplete Freund's adjuvant died within the same time frame and in similar numbers as those induced for EAE. Overall, the course of EAE in CPN(-/-) mice was significantly delayed and attenuated compared to wild type mice. Spinal cord histopathology in CPN(-/-) mice revealed meningeal, but not parenchymal leukocyte infiltration, and minimal demyelination. Our results indicate that CPN plays an important role in EAE development and progression and suggests that multiple CPN ligands contribute to the disease phenotypes we observed. Copyright © 2013 Elsevier GmbH. All rights reserved.

  20. rs657075 (CSF2 Is Associated with the Disease Phenotype (BAS-G of Ankylosing Spondylitis

    Directory of Open Access Journals (Sweden)

    Wei-Chiao Chen

    2017-01-01

    Full Text Available Ankylosing spondylitis (AS is a systemic autoimmune disease mainly affecting the lumbar spine and sacroiliac joints, and exhibits peripheral inflammatory arthropathy. More than 25 loci have been identified as associated with AS. Because both AS and rheumatoid arthritis (RA are autoimmune diseases that may share some common genetic factors, we therefore examined if the newly identified RA genetic polymorphisms were associated with AS in a Taiwanese population. In this study, we enrolled 475 AS patients and 11,301 healthy subjects from a Taiwanese biobank as controls. Although none of single-nucleotide polymorphisms (SNPs were associated with the susceptibility to AS, the AS disease index Bath AS Global (BAS-G clinical phenotype was observed as significantly correlated to the AA genotype of rs657075 (CSF2. The significance remains after gender/age/disease duration adjustment and after group categorization by human leukocyte antigen-B 27 (HLA-B27 genotype. We further investigated the possible functions of rs657075 through bioinformatics approaches. Results revealed that polymorphism of rs657075 is able to influence the expression of acyl-CoA synthetase long-chain family member 6 (ACSL6. In conclusion, our study indicated that rs657075 (CSF2 is strongly associated with the AS disease index Bath AS Global (BAS-G clinical phenotype.

  1. Interstitial lung disease in children – genetic background and associated phenotypes

    Directory of Open Access Journals (Sweden)

    Griese Matthias

    2005-04-01

    Full Text Available Abstract Interstitial lung disease in children represents a group of rare chronic respiratory disorders. There is growing evidence that mutations in the surfactant protein C gene play a role in the pathogenesis of certain forms of pediatric interstitial lung disease. Recently, mutations in the ABCA3 transporter were found as an underlying cause of fatal respiratory failure in neonates without surfactant protein B deficiency. Especially in familiar cases or in children of consanguineous parents, genetic diagnosis provides an useful tool to identify the underlying etiology of interstitial lung disease. The aim of this review is to summarize and to describe in detail the clinical features of hereditary interstitial lung disease in children. The knowledge of gene variants and associated phenotypes is crucial to identify relevant patients in clinical practice.

  2. Supporting the annotation of chronic obstructive pulmonary disease (COPD) phenotypes with text mining workflows.

    Science.gov (United States)

    Fu, Xiao; Batista-Navarro, Riza; Rak, Rafal; Ananiadou, Sophia

    2015-01-01

    Chronic obstructive pulmonary disease (COPD) is a life-threatening lung disorder whose recent prevalence has led to an increasing burden on public healthcare. Phenotypic information in electronic clinical records is essential in providing suitable personalised treatment to patients with COPD. However, as phenotypes are often "hidden" within free text in clinical records, clinicians could benefit from text mining systems that facilitate their prompt recognition. This paper reports on a semi-automatic methodology for producing a corpus that can ultimately support the development of text mining tools that, in turn, will expedite the process of identifying groups of COPD patients. A corpus of 30 full-text papers was formed based on selection criteria informed by the expertise of COPD specialists. We developed an annotation scheme that is aimed at producing fine-grained, expressive and computable COPD annotations without burdening our curators with a highly complicated task. This was implemented in the Argo platform by means of a semi-automatic annotation workflow that integrates several text mining tools, including a graphical user interface for marking up documents. When evaluated using gold standard (i.e., manually validated) annotations, the semi-automatic workflow was shown to obtain a micro-averaged F-score of 45.70% (with relaxed matching). Utilising the gold standard data to train new concept recognisers, we demonstrated that our corpus, although still a work in progress, can foster the development of significantly better performing COPD phenotype extractors. We describe in this work the means by which we aim to eventually support the process of COPD phenotype curation, i.e., by the application of various text mining tools integrated into an annotation workflow. Although the corpus being described is still under development, our results thus far are encouraging and show great potential in stimulating the development of further automatic COPD phenotype extractors.

  3. Hypertrophic cardiomyopathy in pompe disease is not limited to the classic infantile-onset phenotype.

    Science.gov (United States)

    Lee, Dong-Hwan; Qiu, Wen-Juan; Lee, Jeongho; Chien, Yin-Hsiu; Hwu, Wuh-Liang

    2014-01-01

    Pompe disease is a genetic disorder caused by a deficiency of acid α-glucosidase (GAA). Patients with classic infantile-onset Pompe disease usually present with hypertrophic cardiomyopathy and die before 1 year of age, if not treated with enzyme replacement therapy (ERT). In comparison, patients with late-onset Pompe disease typically do not have hypertrophic cardiomyopathy. However, here we describe five patients who presented with hypertrophic cardiomyopathy but did not fit the criteria of classic infantile-onset Pompe disease. Their ages at diagnosis of cardiomyopathy were 1 month in two patients following detection of an audible cardiac murmur and 2-3 years in the three remaining patients. All patients survived for 5-8 years without ERT. Three patients died before the advent of ERT from causes other than congestive heart failure. One patient had a good response to ERT starting at 5 years of age. The sibling of one patient, who did not receive ERT and died at age seven, was diagnosed prenatally. At 3 months of age, the sibling had hypertrophic cardiomyopathy, and a muscle biopsy at that time revealed glycogen accumulation.This case series demonstrates that Pompe disease is a continuum of disease, and the development of cardiomyopathy is not limited to classic infantile-onset Pompe disease. These patients do not fit into the discrete phenotypes of infantile- or late-onset Pompe disease, which may suggest reconsidering the nomenclature of Pompe disease.

  4. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study

    Science.gov (United States)

    Cleynen, Isabelle; Boucher, Gabrielle; Jostins, Luke; Schumm, L Philip; Zeissig, Sebastian; Ahmad, Tariq; Andersen, Vibeke; Andrews, Jane M; Annese, Vito; Brand, Stephan; Brant, Steven R; Cho, Judy H; Daly, Mark J; Dubinsky, Marla; Duerr, Richard H; Ferguson, Lynnette R; Franke, Andre; Gearry, Richard B; Goyette, Philippe; Hakonarson, Hakon; Halfvarson, Jonas; Hov, Johannes R; Huang, Hailang; Kennedy, Nicholas A; Kupcinskas, Limas; Lawrance, Ian C; Lee, James C; Satsangi, Jack; Schreiber, Stephan; Théâtre, Emilie; van der Meulen-de Jong, Andrea E; Weersma, Rinse K; Wilson, David C; Parkes, Miles; Vermeire, Severine; Rioux, John D; Mansfield, John; Silverberg, Mark S; Radford-Smith, Graham; McGovern, Dermot P B; Barrett, Jeffrey C; Lees, Charlie W

    2016-01-01

    Summary Background Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. Methods This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34 819 patients (19 713 with Crohn's disease, 14 683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype–phenotype associations across 156 154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. Findings After quality control, the primary analysis included 29 838 patients (16 902 with Crohn's disease, 12 597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for

  5. Unusual presentations and intrafamilial phenotypic variability in infantile onset Alexander disease.

    Science.gov (United States)

    Tonduti, Davide; Ardissone, Anna; Ceccherini, Isabella; Giaccone, Giorgio; Farina, Laura; Moroni, Isabella

    2016-06-01

    Alexander disease is an hereditary leukodystrophy related to mutations of GFAP. Classically AxD was divided in infantile, juvenile, and adult subgroups. Recent data suggested considering only two subtypes: type I (infantile onset with lesions extending to the cerebral hemispheres); type II (adult onset with primary involvement of subtentorial structures). We report two related and one unrelated patients presenting with a peculiar association of clinical and neuroradiological features. GFAP analysis disclosed the presence of one novel and two previously reported mutations. Our patients underline the importance of considering AxD in patients with bulbar symptoms and autonomic dysfunction even if MRI shows only posterior fossa abnormalities, supporting the hypothesis of a third type of AxD sharing features of both type I and type II. The evidence of an intrafamilial phenotypic variability suggests the possible role of still unknown factors influencing the effect of GFAP mutation and determining the phenotype.

  6. Behavioral Phenotyping and Pathological Indicators of Parkinson's Disease in C. elegans Models

    Science.gov (United States)

    Maulik, Malabika; Mitra, Swarup; Bult-Ito, Abel; Taylor, Barbara E.; Vayndorf, Elena M.

    2017-01-01

    Parkinson's disease (PD) is a neurodegenerative disorder with symptoms that progressively worsen with age. Pathologically, PD is characterized by the aggregation of α-synuclein in cells of the substantia nigra in the brain and loss of dopaminergic neurons. This pathology is associated with impaired movement and reduced cognitive function. The etiology of PD can be attributed to a combination of environmental and genetic factors. A popular animal model, the nematode roundworm Caenorhabditis elegans, has been frequently used to study the role of genetic and environmental factors in the molecular pathology and behavioral phenotypes associated with PD. The current review summarizes cellular markers and behavioral phenotypes in transgenic and toxin-induced PD models of C. elegans. PMID:28659967

  7. High-Throughput Automated Phenotyping of Two Genetic Mouse Models of Huntington's Disease.

    Science.gov (United States)

    Balci, Fuat; Oakeshott, Stephen; Shamy, Jul Lea; El-Khodor, Bassem F; Filippov, Igor; Mushlin, Richard; Port, Russell; Connor, David; Paintdakhi, Ahmad; Menalled, Liliana; Ramboz, Sylvie; Howland, David; Kwak, Seung; Brunner, Dani

    2013-07-11

    Phenotyping with traditional behavioral assays constitutes a major bottleneck in the primary screening, characterization, and validation of genetic mouse models of disease, leading to downstream delays in drug discovery efforts. We present a novel and comprehensive one-stop approach to phenotyping, the PhenoCube™. This system simultaneously captures the cognitive performance, motor activity, and circadian patterns of group-housed mice by use of home-cage operant conditioning modules (IntelliCage) and custom-built computer vision software. We evaluated two different mouse models of Huntington's Disease (HD), the R6/2 and the BACHD in the PhenoCube™ system. Our results demonstrated that this system can efficiently capture and track alterations in both cognitive performance and locomotor activity patterns associated with these disease models. This work extends our prior demonstration that PhenoCube™ can characterize circadian dysfunction in BACHD mice and shows that this system, with the experimental protocols used, is a sensitive and efficient tool for a first pass high-throughput screening of mouse disease models in general and mouse models of neurodegeneration in particular.

  8. Molecular characterization of exon 28 of von Willebrand's factor gene in Nigerian population.

    Science.gov (United States)

    Ezigbo, E D; Ukaejiofo, E O; Nwagha, T U

    2017-02-01

    Polymorphisms in von Willebrand factor (VWF) gene are an important contributor to the expression of VWF gene and differences in ethnic distribution of these single nucleotide polymorphisms (SNPs) exists. Our objective was to molecularly characterize the exon 28 of the VWF gene in the three major ethnic groups of Nigeria. We recruited 90 subjects, 45 had a history of bleeding. Questions included those used in the Zimmerman Program for the Molecular and Clinical Biology of von Willebrand disease (VWD), and the bleeding scores were calculated using the Molecular and Clinical Markers for the Diagnosis and Management of type 1 VWD scoring system. Full blood count, coagulation profile, VWF:antigen level and VWF:collagen-binding activities were carried out. Data were analyzed using GraphPad Prism (5.03). GraphPad Software, Inc USA. The BigDye terminator chemistry was used to determine the nucleotide sequences of VWF gene (exon 28). Eight SNPs were identified, rs 216310 (T1547), rs 1800385 (V1565L), rs1800384 (A1515), rs1800383 (D1472H), rs 1800386 (Y1584C), rs 216311 (T1381A), rs 216312 (intronic) and rs 1800381 (P1337). The SNPs rs 216311, rs 1800383 and rs 1800386 associated significantly with bleeding in study subjects. rs1800386 occurred in all with bleeding history, no ethnic variations were noted.

  9. Characterization of Zebrafish von Willebrand Factor Reveals Conservation of Domain Structure, Multimerization, and Intracellular Storage

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    Arunima Ghosh

    2012-01-01

    Full Text Available von Willebrand disease (VWD is the most common inherited human bleeding disorder and is caused by quantitative or qualitative defects in von Willebrand factor (VWF. VWF is a secreted glycoprotein that circulates as large multimers. While reduced VWF is associated with bleeding, elevations in overall level or multimer size are implicated in thrombosis. The zebrafish is a powerful genetic model in which the hemostatic system is well conserved with mammals. The ability of this organism to generate thousands of offspring and its optical transparency make it unique and complementary to mammalian models of hemostasis. Previously, partial clones of zebrafish vwf have been identified, and some functional conservation has been demonstrated. In this paper we clone the complete zebrafish vwf cDNA and show that there is conservation of domain structure. Recombinant zebrafish Vwf forms large multimers and pseudo-Weibel-Palade bodies (WPBs in cell culture. Larval expression is in the pharyngeal arches, yolk sac, and intestinal epithelium. These results provide a foundation for continued study of zebrafish Vwf that may further our understanding of the mechanisms of VWD.

  10. 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...

  11. Atrazine induced epigenetic transgenerational inheritance of disease, lean phenotype and sperm epimutation pathology biomarkers.

    Science.gov (United States)

    McBirney, Margaux; King, Stephanie E; Pappalardo, Michelle; Houser, Elizabeth; Unkefer, Margaret; Nilsson, Eric; Sadler-Riggleman, Ingrid; Beck, Daniel; Winchester, Paul; Skinner, Michael K

    2017-01-01

    Ancestral environmental exposures to a variety of environmental toxicants and other factors have been shown to promote the epigenetic transgenerational inheritance of adult onset disease. The current study examined the potential transgenerational actions of the herbicide atrazine. Atrazine is one of the most commonly used herbicides in the agricultural industry, in particular with corn and soy crops. Outbred gestating female rats were transiently exposed to a vehicle control or atrazine. The F1 generation offspring were bred to generate the F2 generation and then the F2 generation bred to generate the F3 generation. The F1, F2 and F3 generation control and atrazine lineage rats were aged and various pathologies investigated. The male sperm were collected to investigate DNA methylation differences between the control and atrazine lineage sperm. The F1 generation offspring (directly exposed as a fetus) did not develop disease, but weighed less compared to controls. The F2 generation (grand-offspring) was found to have increased frequency of testis disease and mammary tumors in males and females, early onset puberty in males, and decreased body weight in females compared to controls. The transgenerational F3 generation rats were found to have increased frequency of testis disease, early onset puberty in females, behavioral alterations (motor hyperactivity) and a lean phenotype in males and females. The frequency of multiple diseases was significantly higher in the transgenerational F3 generation atrazine lineage males and females. The transgenerational transmission of disease requires germline (egg or sperm) epigenetic alterations. The sperm differential DNA methylation regions (DMRs), termed epimutations, induced by atrazine were identified in the F1, F2 and F3 generations. Gene associations with the DMRs were identified. For the transgenerational F3 generation sperm, unique sets of DMRs (epimutations) were found to be associated with the lean phenotype or testis

  12. Phenotype variability of infantile-onset multisystem neurologic, endocrine, and pancreatic disease IMNEPD.

    Science.gov (United States)

    Picker-Minh, Sylvie; Mignot, Cyril; Doummar, Diane; Hashem, Mais; Faqeih, Eissa; Josset, Patrice; Dubern, Béatrice; Alkuraya, Fowzan S; Kraemer, Nadine; Kaindl, Angela M

    2016-04-29

    Infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD) has been recently linked to biallelic mutation of the peptidyl-tRNA hydrolase 2 gene PTRH2. Two index patients with IMNEPD in the original report had multiple neurological symptoms such as postnatal microcephaly, intellectual disability, developmental delay, sensorineural deafness, cerebellar atrophy, ataxia, and peripheral neuropathy. In addition, distal muscle weakness and abnormalities of thyroid, pancreas, and liver were found. Here, we report five further IMNEPD patients with a different homozygous PTRH2 mutation, broaden the phenotypic spectrum of the disease and differentiate common symptoms and interindividual variability in IMNEPD associated with a unique mutation. We thereby hope to better define IMNEPD and promote recognition and diagnosis of this novel disease entity.

  13. Genetics of kidney disease and related cardiometabolic phenotypes in Zuni Indians: The Zuni Kidney Project

    Directory of Open Access Journals (Sweden)

    Sandra L Laston

    2015-01-01

    Full Text Available The objective of this study is to identify genetic factors associated with chronic kidney disease (CKD and related cardiometabolic phenotypes among participants of the Genetics of Kidney Disease in Zuni Indians study. The study was conducted as a community-based participatory research project in the Zuni Indians, a small endogamous tribe in rural New Mexico. We recruited 998 members from 28 extended multigenerational families, ascertained through probands with CKD who had at least one sibling with CKD. We used the Illumina Infinium Human1M-Duo v3.0 BeadChips to type 1.1 million single nucleotide polymorphisms (SNPs. Prevalence estimates for CKD, hyperuricemia, diabetes and hypertension were 24%, 30%, 17% and 34%, respectively. We found a significant (p<1.58 × 10-7 association for a SNP in a novel gene for serum creatinine (PTPLAD2. We replicated significant associations for genes with serum uric acid (SLC2A9, triglyceride levels (APOA1, BUD13, ZNF259, and total cholesterol (PVRL2. We found novel suggestive associations (p<1.58 × 10-6 for SNPs in genes with systolic (OLFML2B, and diastolic blood pressure (NFIA. We identified a series of genes associated with CKD and related cardiometabolic phenotypes among Zuni Indians, a population with a high prevalence of kidney disease. Illuminating genetic variations that modulate the risk for these disorders may ultimately provide a basis for novel preventive strategies and therapeutic interventions.

  14. Phenotypic charactheristics of fluorescent pseudomonss, biological control agent of lincat disease of temanggung tobacco

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    NINING NURUL AZIZAH

    2007-04-01

    Full Text Available Fluorescent pseudomonass isolated from local plants-rishosphere in temanggung controlled lincat disease of tobacco. This report describe phenotypic charactheristics of the bacteria in order to be used as a base for the development of the bacteria as a biological control agent of lincat disease. Phenotypic charactheristics of six isolates of fluorescent Pseudomonass which controlled lincat disease in the field were determined in the laboratory of Plant Bacteriology, Faculty of Agriculture, Gadjah Mada University. Plant pathogenicity tests were conducted by hypersensitive reaction into tobacco leaf and inoculation to tobacco plants. Antagonism test between fluorescent Pseudomonass and other candidate of biological control agents were also conducted. The results indicated that the bacteria were rod shape, Gram negative, positive reaction in catalase and oxidase tests. Nitrate reduce to nitrite, arginine was hydrolysed, fluorescent pigment were produced on King’s B medium, levan formation positive and all bacteria denitrifiy. The bacteria used urea, tween 80 and amylum were not hydrolised, poly--hydroxybutyrate was not accumulated in the cells. Negative reactions were observed for lysine decarboxylation, indol production, VP/MR reaction, and gelatn liquefation. Some compounds could be used as solely carbon sources. All isolates grew on the medium containing 2% NaCl. The best pH for growth was 6-7 and all isolates grew at 20-41C. Negative result were obtained for hypersensitive reaction and pathogenicity tests.

  15. Physical Activity across Frailty Phenotypes in Females with Parkinson’s Disease

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    Kaitlyn P. Roland

    2012-01-01

    Full Text Available Females with Parkinson’s disease (PD are vulnerable to frailty. PD eventually leads to decreased physical activity, an indicator of frailty. We speculate PD results in frailty through reduced physical activity. Objective. Determine the contribution of physical activity on frailty in PD (n=15, 65 ± 9 years and non-PD (n=15, 73 ± 14 years females. Methods. Frailty phenotype (nonfrail/prefrail/frail was categorized and 8 hours of physical activity was measured using accelerometer, global positioning system, and self-report. Two-way ANCOVA (age as covariate was used to compare physical activity between disease and frailty phenotypes. Spearman correlation assessed relationships, and linear regression determined associations with frailty. Results. Nonfrail recorded more physical activity (intensity, counts, self-report compared with frail. Self-reported physical activity was greater in PD than non-PD. In non-PD, step counts, light physical activity time, sedentary time, and self-reported physical activity were related to frailty (R=0.91. In PD, only carbidopa-levodopa dose was related to frailty (r=0.61. Conclusion. Physical activity influences frailty in females without PD. In PD females, disease management may be a better indicator of frailty than physical activity. Further investigation into how PD associated factors contribute to frailty is warranted.

  16. A massively parallel pipeline to clone DNA variants and examine molecular phenotypes of human disease mutations.

    Directory of Open Access Journals (Sweden)

    Xiaomu Wei

    2014-12-01

    Full Text Available Understanding the functional relevance of DNA variants is essential for all exome and genome sequencing projects. However, current mutagenesis cloning protocols require Sanger sequencing, and thus are prohibitively costly and labor-intensive. We describe a massively-parallel site-directed mutagenesis approach, "Clone-seq", leveraging next-generation sequencing to rapidly and cost-effectively generate a large number of mutant alleles. Using Clone-seq, we further develop a comparative interactome-scanning pipeline integrating high-throughput GFP, yeast two-hybrid (Y2H, and mass spectrometry assays to systematically evaluate the functional impact of mutations on protein stability and interactions. We use this pipeline to show that disease mutations on protein-protein interaction interfaces are significantly more likely than those away from interfaces to disrupt corresponding interactions. We also find that mutation pairs with similar molecular phenotypes in terms of both protein stability and interactions are significantly more likely to cause the same disease than those with different molecular phenotypes, validating the in vivo biological relevance of our high-throughput GFP and Y2H assays, and indicating that both assays can be used to determine candidate disease mutations in the future. The general scheme of our experimental pipeline can be readily expanded to other types of interactome-mapping methods to comprehensively evaluate the functional relevance of all DNA variants, including those in non-coding regions.

  17. Mutant Huntingtin Does Not Affect the Intrinsic Phenotype of Human Huntington's Disease T Lymphocytes.

    Science.gov (United States)

    Miller, James R C; Träger, Ulrike; Andre, Ralph; Tabrizi, Sarah J

    2015-01-01

    Huntington's disease is a fatal neurodegenerative condition caused by a CAG repeat expansion in the huntingtin gene. The peripheral innate immune system is dysregulated in Huntington's disease and may contribute to its pathogenesis. However, it is not clear whether or to what extent the adaptive immune system is also involved. Here, we carry out the first comprehensive investigation of human ex vivo T lymphocytes in Huntington's disease, focusing on the frequency of a range of T lymphocyte subsets, as well as analysis of proliferation, cytokine production and gene transcription. In contrast to the innate immune system, the intrinsic phenotype of T lymphocytes does not appear to be affected by the presence of mutant huntingtin, with Huntington's disease T lymphocytes exhibiting no significant functional differences compared to control cells. The transcriptional profile of T lymphocytes also does not appear to be significantly affected, suggesting that peripheral immune dysfunction in Huntington's disease is likely to be mediated primarily by the innate rather than the adaptive immune system. This study increases our understanding of the effects of Huntington's disease on peripheral tissues, while further demonstrating the differential effects of the mutant protein on different but related cell types. Finally, this study suggests that the potential use of novel therapeutics aimed at modulating the Huntington's disease innate immune system should not be extended to include the adaptive immune system.

  18. A mixed phenotype of airway wall thickening and emphysema is associated with dyspnea and hospitalization for chronic obstructive pulmonary disease.

    Science.gov (United States)

    Van Tho, Nguyen; Ogawa, Emiko; Trang, Le Thi Huyen; Ryujin, Yasushi; Kanda, Rie; Nakagawa, Hiroaki; Goto, Kenichi; Fukunaga, Kentaro; Higami, Yuichi; Seto, Ruriko; Wada, Hiroshi; Yamaguchi, Masafumi; Nagao, Taishi; Lan, Le Thi Tuyet; Nakano, Yasutaka

    2015-07-01

    Quantitative computed tomography (CT) has been used to phenotype patients with chronic obstructive pulmonary disease (COPD). A mixed phenotype is defined as the presence of both airway wall thickening and emphysema on quantitative CT. Little is known about patients with COPD with the mixed phenotype. To propose a method of phenotyping COPD based on quantitative CT and to compare clinically relevant outcomes between patients with COPD with the mixed phenotype and those with other CT-based phenotypes. Each of 427 male smokers (187 without COPD, 240 with COPD) underwent a complete medical interview, pulmonary function testing, and whole-lung CT on the same day. The percentage of low-attenuation volume at the threshold of -950 Hounsfield units (%LAV) and the square root of wall area of a hypothetical airway with an internal perimeter of 10 mm (Pi10) were measured. Patients with COPD were classified into four distinct phenotypes based on the upper limits of normal for %LAV and Pi10, which were derived from the data of smokers without COPD by using quantile regression. Of 240 patients with COPD, 52 (21.7%) were classified as CT-normal phenotype, 39 (16.3%) as airway-dominant phenotype, 103 (42.9%) as emphysema-dominant phenotype, and 46 (19.2%) as mixed phenotype. Patients with COPD with the mixed phenotype were associated with more severe dyspnea than those with each of the remaining CT-based phenotypes (P < 0.01 for all comparisons). The number of hospitalizations for COPD exacerbations during the preceding year was 2.0 to 3.6 times higher in patients with the mixed phenotype than in those with each of the remaining CT-based phenotypes (P < 0.05 for all comparisons). Findings persisted after adjustment for age, pack-years of smoking, smoking status, body mass index, and FEV1. Patients with COPD with the mixed phenotype are associated with more severe dyspnea and more frequent hospitalizations than those with each of the remaining CT-based phenotypes. Thus

  19. Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype

    OpenAIRE

    Yin, Hao; Xue, Wen; Chen, Sidi; Bogorad, Roman L; Benedetti, Eric; Grompe, Markus; Koteliansky, Victor; Sharp, Phillip A.; Jacks, Tyler; Anderson, Daniel G.

    2014-01-01

    We demonstrate CRISPR-Cas9–mediated correction of a Fah mutation in hepatocytes in a mouse model of the human disease hereditary tyrosinemia. Delivery of components of the CRISPR-Cas9 system by hydrodynamic injection resulted in initial expression of the wild-type Fah protein in ~1/250 liver cells. Expansion of Fah-positive hepatocytes rescued the body weight loss phenotype. Our study indicates that CRISPR-Cas9–mediated genome editing is possible in adult animals and has potential for correct...

  20. Delirium prior to dementia as a clinical phenotype of Lewy body disease: an autopsied case report.

    Science.gov (United States)

    Fujishiro, Hiroshige; Kawakami, Ito; Oshima, Kenichi; Niizato, Kazuhiro; Iritani, Shuji

    2017-04-01

    Although delirium shares clinical characteristics with dementia with Lewy bodies (DLB), there is limited information regarding the relationship between delirium and Lewy body pathology. Here, we report an 89-year-old Japanese woman with an episode of delirium who was pathologically confirmed to have limbic-type Lewy body disease (LBD). Although she exhibited transient visual hallucinations during the delirium, she had no overt dementia. She developed no core clinical features of DLB and died of pneumonia at the age of 90 years. This autopsied case suggests that delirium may be one of the clinical phenotypes of LBD prior to the onset of dementia.

  1. Cortical excitability changes distinguish the motor neuron disease phenotypes from hereditary spastic paraplegia.

    Science.gov (United States)

    Geevasinga, N; Menon, P; Sue, C M; Kumar, K R; Ng, K; Yiannikas, C; Kiernan, M C; Vucic, S

    2015-05-01

    Cortical hyperexcitability has been identified as an important pathogenic mechanism in motor neuron disease (MND). The issue as to whether cortical hyperexcitability is a common process across the MND phenotypes, including amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS), remains unresolved. Separately, the clinical distinction between PLS and 'mimic disorders' such as hereditary spastic paraparesis (HSP) may be difficult, potentially delaying diagnosis. Consequently, the aim of the present study was to determine the nature and spectrum of cortical excitability changes across the MND phenotypes, and to determine whether the presence of cortical dysfunction distinguishes PLS from HSP. Cortical excitability studies were undertaken on a cohort of 14 PLS, 82 ALS and 13 HSP patients with mutations in the spastin gene. Cortical hyperexcitability, as heralded by reduction of short interval intracortical inhibition (PLS 0.26%, -3.8% to 1.4%; ALS -0.15%, -3.6% to 7.0%; P < 0.01) and cortical silent period duration (CSPPLS 172.2 ± 5.4 ms; CSPALS 178.1 ± 5.1 ms; P < 0.001), along with an increase in intracortical facilitation was evident in ALS and PLS phenotypes, although appeared more frequently in ALS. Inexcitability of the motor cortex was more frequent in PLS (PLS 71%, ALS 24%, P < 0.0001). Cortical excitability was preserved in HSP. Cortical dysfunction appears to be an intrinsic process across the MND phenotypes, with cortical inexcitability predominating in PLS and cortical hyperexcitability predominating in ALS. Importantly, cortical excitability was preserved in HSP, thereby suggesting that the presence of cortical dysfunction could help differentiate PLS from HSP in a clinical setting. © 2015 EAN.

  2. Mathematical modeling of atopic dermatitis reveals "double-switch" mechanisms underlying 4 common disease phenotypes.

    Science.gov (United States)

    Domínguez-Hüttinger, Elisa; Christodoulides, Panayiotis; Miyauchi, Kosuke; Irvine, Alan D; Okada-Hatakeyama, Mariko; Kubo, Masato; Tanaka, Reiko J

    2017-06-01

    The skin barrier acts as the first line of defense against constant exposure to biological, microbial, physical, and chemical environmental stressors. Dynamic interplay between defects in the skin barrier, dysfunctional immune responses, and environmental stressors are major factors in the development of atopic dermatitis (AD). A systems biology modeling approach can yield significant insights into these complex and dynamic processes through integration of prior biological data. We sought to develop a multiscale mathematical model of AD pathogenesis that describes the dynamic interplay between the skin barrier, environmental stress, and immune dysregulation and use it to achieve a coherent mechanistic understanding of the onset, progression, and prevention of AD. We mathematically investigated synergistic effects of known genetic and environmental risk factors on the dynamic onset and progression of the AD phenotype, from a mostly asymptomatic mild phenotype to a severe treatment-resistant form. Our model analysis identified a "double switch," with 2 concatenated bistable switches, as a key network motif that dictates AD pathogenesis: the first switch is responsible for the reversible onset of inflammation, and the second switch is triggered by long-lasting or frequent activation of the first switch, causing irreversible onset of systemic T H 2 sensitization and worsening of AD symptoms. Our mathematical analysis of the bistable switch predicts that genetic risk factors decrease the threshold of environmental stressors to trigger systemic T H 2 sensitization. This analysis predicts and explains 4 common clinical AD phenotypes from a mild and reversible phenotype through to severe and recalcitrant disease and provides a mechanistic explanation for clinically demonstrated preventive effects of emollient treatments against development of AD. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Acquired von Willebrand syndrome in children with aortic and pulmonary stenosis.

    Science.gov (United States)

    Binnetoğlu, Fatih Köksal; Babaoğlu, Kadir; Filiz, Şayegan Güven; Zengin, Emine; Altun, Gürkan; Kılıç, Suar Çakı; Sarper, Nazan

    This prospective study was planned to investigate the frequency and relationship of acquired von Willebrand syndrome (AVWS) with aortic and pulmonary stenosis in patients. A total of 84 children, ranging from two to 18 years of age, were enrolled in this study. Of these, 28 had isolated aortic stenosis, 32 had isolated pulmonary stenosis and 24 were healthy. Children with aortic and pulmonary stenosis associated with other congenital heart diseases were excluded. Children with hypothyroidism, renal or liver disease, malignancy or autoimmune disease were also excluded. Wholeblood count, blood group, factor VIII level, prothrombin time (PT), activated partial thromboplastin time (aPTT), von Willebrand factor antigen (VWF:Ag), ristocetin co-factor (VWF:RCo), and bleeding time using a platelet-function analyser (PFA-100) were performed in all patients. All of the children in the study underwent a detailed physical examination and echocardiographic evaluation. A history of bleeding was positive in 18% of the aortic stenosis group, 9% of the pulmonary stenosis group, and 4% of the control group. Seven of 60 (12%) patients had laboratory findings that implied a diagnosis of AVWS, and two of these (28%) had a history of bleeding. The frequency of AVWS was 14% in patients with aortic stenosis and 9% in those with pulmonary stenosis. AVWS is not rare in stenotic obstructive cardiac diseases. A detailed history of bleeding should be taken from patients with valvular disease. Even if the history is negative, whole blood count, PT and aPTT should be performed. If necessary, PFA-100 closure time and further tests should be planned for the diagnosis of AVWS.

  4. Exhaled volatile organic compounds for phenotyping chronic obstructive pulmonary disease: a cross-sectional study

    Directory of Open Access Journals (Sweden)

    Basanta Maria

    2012-08-01

    Full Text Available Abstract Background Non-invasive phenotyping of chronic respiratory diseases would be highly beneficial in the personalised medicine of the future. Volatile organic compounds can be measured in the exhaled breath and may be produced or altered by disease processes. We investigated whether distinct patterns of these compounds were present in chronic obstructive pulmonary disease (COPD and clinically relevant disease phenotypes. Methods Breath samples from 39 COPD subjects and 32 healthy controls were collected and analysed using gas chromatography time-of-flight mass spectrometry. Subjects with COPD also underwent sputum induction. Discriminatory compounds were identified by univariate logistic regression followed by multivariate analysis: 1. principal component analysis; 2. multivariate logistic regression; 3. receiver operating characteristic (ROC analysis. Results Comparing COPD versus healthy controls, principal component analysis clustered the 20 best-discriminating compounds into four components explaining 71% of the variance. Multivariate logistic regression constructed an optimised model using two components with an accuracy of 69%. The model had 85% sensitivity, 50% specificity and ROC area under the curve of 0.74. Analysis of COPD subgroups showed the method could classify COPD subjects with far greater accuracy. Models were constructed which classified subjects with ≥2% sputum eosinophilia with ROC area under the curve of 0.94 and those having frequent exacerbations 0.95. Potential biomarkers correlated to clinical variables were identified in each subgroup. Conclusion The exhaled breath volatile organic compound profile discriminated between COPD and healthy controls and identified clinically relevant COPD subgroups. If these findings are validated in prospective cohorts, they may have diagnostic and management value in this disease.

  5. Hirschsprung disease as a yet undescribed phenotype in a patient with ARID1B mutation.

    Science.gov (United States)

    Takenouchi, Toshiki; Yoshihashi, Hiroshi; Sakaguchi, Yuri; Uehara, Tomoko; Honda, Masataka; Takahashi, Takao; Kosaki, Kenjiro; Miyama, Sahoko

    2016-12-01

    Mutations in the BAF complex (mammalian SWI/SNF complex) are responsible for Coffin-Siris syndrome, which is characterized by developmental delay, distinctive facial features, hirsutism, and hypoplasia/aplasia of the fifth finger/fingernails. Hirschsprung disease is characterized by defective stem cells in the enteric neural system, and the involvement of multiple signaling cascades has been implicated. So far, the roles of the BAF complex in the genesis of Hirschsprung disease have remained unknown. Here, we document a patient with coarse facial features, postnatal growth failure, developmental delay, epilepsy, and hypoplasia of the corpus callosum and cerebellum but without a hypoplastic fifth finger/fingernail. In addition, he had Hirschsprung disease. Exome sequencing with a gene set representing a total of 4,813 genes with known relationships to human diseases revealed a heterozygous frameshift mutation in ARID1B (c.5789delC p.Pro1930Leufs*44). The presence of a congenital cataract and Hirschsprung disease in the presently reported patient further expands the phenotypic spectrum of patients with ARID1B mutations and may suggest the potential role of the BAF complex in the pathogenesis of the enteric neural system. The present observation is in agreement with a recent study of Drosophila neuroblasts showing that the dysregulated BAF complex leads to an abnormal lineage progression of neural stem cell lineages and that Hirschsprung disease is caused by abnormal stem cell lineages in the peripheral neural tissues. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  6. Regulation of plasma von Willebrand factor [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Karl C Desch

    2018-01-01

    Full Text Available Von Willebrand factor (VWF is a multimeric plasma glycoprotein that plays a central role in the initiation of blood coagulation. Through interactions between its specific functional domains, the vascular wall, coagulation factor VIII, and platelet receptors, VWF maintains hemostasis by binding to platelets and delivering factor VIII to the sites of vascular injury. In the healthy human population, plasma VWF levels vary widely. The important role of VWF is illustrated by individuals at the extremes of the normal distribution of plasma VWF concentrations where individuals with low VWF levels are more likely to present with mucocutaneous bleeding. Conversely, people with high VWF levels are at higher risk for venous thromboembolic disease, stroke, and coronary artery disease. This report will summarize recent advances in our understanding of environmental influences and the genetic control of VWF plasma variation in healthy and symptomatic populations and will also highlight the unanswered questions that are currently driving this field of study.

  7. Sinusoidal endothelial cell and hepatic stellate cell phenotype correlates with stage of fibrosis in chronic liver disease in dogs.

    Science.gov (United States)

    Vince, Andrew R; Hayes, M Anthony; Jefferson, Barbara J; Stalker, Margaret J

    2016-09-01

    We evaluated the extent of hepatic fibrosis in chronic liver disease of dogs using a modification of Ishak's staging criteria for human chronic liver disease, and examined the association of stage of fibrosis with immunophenotypic markers of transdifferentiation of hepatic sinusoidal endothelial cells and hepatic stellate cells. Formalin-fixed, paraffin-embedded, hematoxylin and eosin-stained liver biopsy specimens from 45 case dogs with chronic liver disease and 55 healthy control dogs were scored for the presence and extent of fibrosis. This stage score for fibrosis strongly correlated with upregulated von Willebrand factor (vWF) expression in lobular sinusoidal endothelial cells (Spearman correlation coefficient [SCC] = 0.57, p < 0.05). Immunoreactivity for vWF factor was identified in 68.9% of case biopsies, varying in distribution from periportal to diffuse, whereas vWF immunoreactivity was identified in only 14.5% of control specimens, and was restricted to the immediate periportal sinusoids. The majority of both case and control biopsies exhibited similar prominent lobular perisinusoidal expression of alpha-smooth muscle actin (α-SMA). A minority of specimens (17.8% of case biopsies, 1.8% of control biopsies) exhibited low perisinoidal α-SMA expression, and there was a weak negative correlation between α-SMA expression and stage of fibrosis (SCC = -0.29, p = 0.0037). These results document a method for staging the severity of fibrosis in canine liver biopsies, and show a strong association between fibrosis and increased expression of vWF in hepatic sinusoidal endothelial cells. © 2016 The Author(s).

  8. A Systematic Review of the Huntington Disease-Like 2 Phenotype.

    Science.gov (United States)

    Anderson, David G; Walker, Ruth H; Connor, Myles; Carr, Jonathan; Margolis, Russell L; Krause, Amanda

    2017-01-01

    Huntington Disease-like 2 (HDL2) is a neurodegenerative disorder similar to Huntington Disease (HD) in its clinical phenotype, genetic characteristics, neuropathology and longitudinal progression. Proposed specific differences include an exclusive African ancestry, lack of eye movement abnormalities, increased Parkinsonism, and acanthocytes in HDL2. The objective was to determine the similarities and differences between HD and HDL2 by establishing the clinical phenotype of HDL2 with the published cases. A literature review of all clinically described cases of HDL2 until the end of 2016 was performed and a descriptive analysis was carried out. Sixty-nine new cases were described between 2001 and 2016. All cases had likely African ancestry, and most were found in South Africa and the USA. Many features were found to be similar to HD, including a strong negative correlation between repeat length and age of onset. Chorea was noted in 48/57 cases (84%). Dementia was reported in 74% patients, and Parkinsonism in 37%. Psychiatric features were reported in 44 out of 47 cases. Patients with chorea had lower expanded repeat lengths compared to patients without chorea. Eye movements were described in 19 cases, 8 were abnormal. Acanthocytes were detected in 4 of the 13 patients tested. Nineteen out of 20 MRIs were reported as abnormal with findings similar to HD. This review clarifies some aspects of the HDL2 phenotype and highlights others which require further investigation. Features that are unique to HDL2 have been documented in a minority of subjects and require prospective validation.

  9. A "dose" effect of mutations in the GBA gene on Parkinson's disease phenotype.

    Science.gov (United States)

    Thaler, Avner; Gurevich, Tanya; Bar Shira, Anat; Gana Weisz, Mali; Ash, Elissa; Shiner, Tamara; Orr-Urtreger, Avi; Giladi, Nir; Mirelman, Anat

    2017-03-01

    Mutations in the GBA gene are associated with Parkinson's disease (PD). A definite description of the clinical characteristics of PD patients who are compound heterozygotes or homozygotes for mutations in the GBA gene (GD-PD) requires further elucidation. We assessed motor, cognitive, olfactory and autonomic functions as well as demographic data and medical history in a cohort of Ashkenazi Jewish PD patients who were screened for seven common mutations in the GBA gene. We then compared three groups of patients (matched for age and disease duration) who were distinguished by their GBA mutation status, idiopathic PD (iPD), GBA heterozygote PD (GBA-PD) and GD-PD. Out of a total of 1050 AJ PD patients screened, 12 were found to be either homozygotes or compound heterozygotes for mutations in the GBA gene. These patients had an earlier age of onset, more severe motor impairment, poorer cognition and lower olfactory scores. They also had a higher prevalence of REM sleep behavior disorder and higher frequencies of hallucinations compared to both GBA-PD and iPD. The severity of PD phenotype is related to the burden of GBA mutations with GD-PD patients manifesting a more severe phenotype. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Dynamic phenotypes of degenerative myxomatous mitral valve disease: quantitative 3-dimensional echocardiographic study.

    Science.gov (United States)

    Clavel, Marie-Annick; Mantovani, Francesca; Malouf, Joseph; Michelena, Hector I; Vatury, Ori; Jain, Mothilal Sonia; Mankad, Sunil V; Suri, Rakesh M; Enriquez-Sarano, Maurice

    2015-05-01

    Fibro-elastic deficiency (FED) and diffuse myxomatous degeneration (DMD) are phenotypes of degenerative mitral valve disease defined morphologically. Whether physiological differences in annular and valvular dynamics exist between these phenotypes remains unknown. We performed triple quantitation of cardiac remodeling and of mitral regurgitation severity and of annular and valvular dimensions by real-time 3-dimensional-transesophageal-echocardiography. Forty-nine patients with degenerative mitral valve disease classified as FED (n=31) and DMD (n=18) by surgical observation showed no difference in age (65±10 versus 59±13; P=0.5), body surface area (2.0±0.2 versus 2.0±0.2 m(2); P=0.5), left ventricular and atrial dimensions (all P>0.55), and mitral regurgitation regurgitant orifice (P=0.62). On average, annular dimensions were larger in DMD versus FED, but height was similar resulting in lower saddle shape. Dynamically, annular DMD versus FED display poorer contraction and saddle-shape accentuation in early systole and abnormal enlargement, particularly intercommissural, in late-systole (all Pmitral regurgitation, despite larger prolapse and valve redundancy, underscoring potential compensatory role of tissue redundancy of DMD (or aggravating role of tissue paucity of FED) on mitral regurgitation severity. © 2015 American Heart Association, Inc.

  11. Cerebral Small Vessel Disease Clinical, Neuropsychological, and Radiological Phenotypes, Histopathological Correlates, and Described Genotypes: A Review

    Directory of Open Access Journals (Sweden)

    Thomas Gregor Issac

    2015-01-01

    Full Text Available Introduction. Vascular cognitive impairment is a common yet preventable cause for dementia. It needs high degree of suspicion and appropriate designing of investigatory tools to confirm diagnosis, identify comorbidities, and ascertain the areas of impairment. Commonly DSM-IV criterion is applied for diagnosis and detailed clinical and neuropsychological examination for identifying the specific phenotype is used. Early diagnosis using the mandatory criteria will help in early initiation of disease modifying treatment strategies which can result in partial reversal of vascular changes and arrest of progression. Patients with young onset disease might require genetic characterization for designing more aggressive treatment. Discussion and Conclusion. Dementias as such carry poor course and prognosis resulting in severe Disability Adjusted Life Years (DALYs for patients and caregivers. Therefore, it is mandatory to identify treatable and preventable causes so that man power loss can be reduced.

  12. Phenotypic and Genetic Characterization of a Cohort of Pediatric Wilson Disease Patients

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    Elnaghy Suzan

    2011-06-01

    Full Text Available Abstract Background In Egypt, Wilson disease seems to be under diagnosed and clinical data on large cohorts are limited. The aim of this study is to highlight the clinical, laboratory and genetic characteristics of this disease in our pediatric population as well as to report our experience with both treatment options and outcome. Methods The study included 77 patients from 50 unrelated families (62 were followed up for a mean period of 58.9 ± 6.4 months and 27 were asymptomatic siblings. Data were collected retrospectively by record analysis and patient interviews. Diagnosis was confirmed by sequencing of the ATP7B gene in 64 patients Results Our patients had unique characteristics compared to other populations. They had a younger age of onset (median: 10 years, higher prevalence of Kayser-Fleischer rings (97.6% in the symptomatic patients, low ceruloplasmin (93.5%, high rate of parental consanguinity (78.9% as well as a more severe course. 71.42% of those on long term D-penicillamine improved or were stable during the follow up with severe side effects occurring in only 11.5%. Preemptive treatment with zinc monotherapy was an effective non-toxic alternative to D-penicillamine. Homozygous mutations were found in 85.7%, yet limited by the large number of mutations detected, it was difficult to find genotype-phenotype correlations. Missense mutations were the most common while protein-truncating mutations resulted in a more severe course with higher incidence of acute liver failure and neurological symptoms. Conclusions Egyptian children with Wilson disease present with early Kayser-Fleischer rings and early onset of liver and neurological disease. The mutational spectrum identified differs from that observed in other countries. The high rate of homozygous mutations (reflecting the high rate of consanguinity may potentially offer further insights on genotype-phenotype correlation

  13. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series.

    Science.gov (United States)

    Ryan, Natalie S; Nicholas, Jennifer M; Weston, Philip S J; Liang, Yuying; Lashley, Tammaryn; Guerreiro, Rita; Adamson, Gary; Kenny, Janna; Beck, Jon; Chavez-Gutierrez, Lucia; de Strooper, Bart; Revesz, Tamas; Holton, Janice; Mead, Simon; Rossor, Martin N; Fox, Nick C

    2016-12-01

    The causes of phenotypic heterogeneity in familial Alzheimer's disease with autosomal dominant inheritance are not well understood. We aimed to characterise clinical phenotypes and genetic associations with APP and PSEN1 mutations in symptomatic autosomal dominant familial Alzheimer's disease (ADAD). We retrospectively analysed genotypic and phenotypic data (age at symptom onset, initial cognitive or behavioural symptoms, and presence of myoclonus, seizures, pyramidal signs, extrapyramidal signs, and cerebellar signs) from all individuals with ADAD due to APP or PSEN1 mutations seen at the Dementia Research Centre in London, UK. We examined the frequency of presenting symptoms and additional neurological features, investigated associations with age at symptom onset, APOE genotype, and mutation position, and explored phenotypic differences between APP and PSEN1 mutation carriers. The proportion of individuals presenting with various symptoms was analysed with descriptive statistics, stratified by mutation type. Between July 1, 1987, and Oct 31, 2015, age at onset was recorded for 213 patients (168 with PSEN1 mutations and 45 with APP mutations), with detailed history and neurological examination findings available for 121 (85 with PSEN1 mutations and 36 with APP mutations). We identified 38 different PSEN1 mutations (four novel) and six APP mutations (one novel). Age at onset differed by mutation, with a younger onset for individuals with PSEN1 mutations than for those with APP mutations (mean age 43·6 years [SD 7·2] vs 50·4 years [SD 5·2], respectively, ponset variance was explained by the specific mutation. A cluster of five mutations with particularly early onset (mean age at onset onset and clinical features being influenced by mutation position as well as causative gene. This highlights the importance of considering genetic testing in young patients with dementia and additional neurological features in order to appropriately diagnose and treat their

  14. Unusual phenotype of hemoglobin EE with hemoglobin H disease: a pitfall in clinical diagnosis and genetic counseling.

    Science.gov (United States)

    Viprakasit, Vip; Tanphaichitr, Voravarn S

    2004-03-01

    Two unrelated individuals previously diagnosed as hemoglobin (Hb) EE were found to be, in fact, Hb EE with Hb H disease. This globin genotype normally results as Hb EF Bart disease. This unusual genotype-phenotype interaction highlights the need for molecular analysis in affected individuals with Hb E disorders before appropriate genetic counseling and genetic risk estimation in offspring can be given.

  15. Human glia can both induce and rescue aspects of disease phenotype in Huntington disease

    DEFF Research Database (Denmark)

    Benraiss, Abdellatif; Wang, Su; Herrlinger, Stephanie

    2016-01-01

    The causal contribution of glial pathology to Huntington disease (HD) has not been heavily explored. To define the contribution of glia to HD, we established human HD glial chimeras by neonatally engrafting immunodeficient mice with mutant huntingtin (mHTT)-expressing human glial progenitor cells...

  16. Geographic associations between lactase phenotype, multiple sclerosis, and inflammatory bowel diseases; Does obesity trump geography?

    Science.gov (United States)

    Szilagyi, Andew; Xue, Xiaoqing

    2016-11-01

    Geographic patterns with diminishing rates from north to south toward the equator have been described for a number of diseases, putatively related largely to "western" lifestyle. Among these the inflammatory bowel diseases; Crohn's (CD) and Ulcerative colitis (UC) have been prominent in sharing distributions with a number of autoimmune diseases. One of the interesting associations is the epidemiologic similarity with multiple sclerosis (MS). However, in addition, at least some of these diseases also correlated inversely with lactase non persistent population (LNP) distributions. It is hypothesized that MS should also have an inverse relationship with LNP. We provide support for this by comparing published MS, CD, UC and LNP national rates to the beginning of the new millennium. Possible links among these diseases may be an evolutionary signature of new genes which may have accompanied emergence of lactase persistence millennia ago. The emergent phenotypic dichotomy also forced different assimilation responses to lactose digestion. While intestinal retention of lactase results in direct host enzymatic digestion, in LNP persons intestinal bacterial metabolism of lactose impacts on the host micro-flora. These microbial changes may play some role in altering rates of diseases including IBD and MS. However, since the late 20th century previously observed patterns are changing. Although industrialization is considered to play an important modifying role, the rising rates of obesity with an emphasis on diet, and microfloral pathogenesis, but with an independent geographic pattern may also facilitate altering rates and geographic distributions of both of these and other diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. The calcineurin inhibitor Sarah (Nebula exacerbates Aβ42 phenotypes in a Drosophila model of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Soojin Lee

    2016-03-01

    Full Text Available Expression of the Down syndrome critical region 1 (DSCR1 protein, an inhibitor of the Ca2+-dependent phosphatase calcineurin, is elevated in the brains of individuals with Down syndrome (DS or Alzheimer's disease (AD. Although increased levels of DSCR1 were often observed to be deleterious to neuronal health, its beneficial effects against AD neuropathology have also been reported, and the roles of DSCR1 on the pathogenesis of AD remain controversial. Here, we investigated the role of sarah (sra; also known as nebula, a Drosophila DSCR1 ortholog, in amyloid-β42 (Aβ42-induced neurological phenotypes in Drosophila. We detected sra expression in the mushroom bodies of the fly brain, which are a center for learning and memory in flies. Moreover, similar to humans with AD, Aβ42-expressing flies showed increased Sra levels in the brain, demonstrating that the expression pattern of DSCR1 with regard to AD pathogenesis is conserved in Drosophila. Interestingly, overexpression of sra using the UAS-GAL4 system exacerbated the rough-eye phenotype, decreased survival rates and increased neuronal cell death in Aβ42-expressing flies, without modulating Aβ42 expression. Moreover, neuronal overexpression of sra in combination with Aβ42 dramatically reduced both locomotor activity and the adult lifespan of flies, whereas flies with overexpression of sra alone showed normal climbing ability, albeit with a slightly reduced lifespan. Similarly, treatment with chemical inhibitors of calcineurin, such as FK506 and cyclosporin A, or knockdown of calcineurin expression by RNA interference (RNAi, exacerbated the Aβ42-induced rough-eye phenotype. Furthermore, sra-overexpressing flies displayed significantly decreased mitochondrial DNA and ATP levels, as well as increased susceptibility to oxidative stress compared to that of control flies. Taken together, our results demonstrating that sra overexpression augments Aβ42 cytotoxicity in Drosophila suggest that DSCR1

  18. The calcineurin inhibitor Sarah (Nebula) exacerbates Aβ42 phenotypes in a Drosophila model of Alzheimer's disease.

    Science.gov (United States)

    Lee, Soojin; Bang, Se Min; Hong, Yoon Ki; Lee, Jang Ho; Jeong, Haemin; Park, Seung Hwan; Liu, Quan Feng; Lee, Im-Soon; Cho, Kyoung Sang

    2016-03-01

    Expression of the Down syndrome critical region 1 (DSCR1) protein, an inhibitor of the Ca(2+)-dependent phosphatase calcineurin, is elevated in the brains of individuals with Down syndrome (DS) or Alzheimer's disease (AD). Although increased levels of DSCR1 were often observed to be deleterious to neuronal health, its beneficial effects against AD neuropathology have also been reported, and the roles of DSCR1 on the pathogenesis of AD remain controversial. Here, we investigated the role of sarah (sra; also known as nebula), a Drosophila DSCR1 ortholog, in amyloid-β42 (Aβ42)-induced neurological phenotypes in Drosophila. We detected sra expression in the mushroom bodies of the fly brain, which are a center for learning and memory in flies. Moreover, similar to humans with AD, Aβ42-expressing flies showed increased Sra levels in the brain, demonstrating that the expression pattern of DSCR1 with regard to AD pathogenesis is conserved in Drosophila. Interestingly, overexpression of sra using the UAS-GAL4 system exacerbated the rough-eye phenotype, decreased survival rates and increased neuronal cell death in Aβ42-expressing flies, without modulating Aβ42 expression. Moreover, neuronal overexpression of sra in combination with Aβ42 dramatically reduced both locomotor activity and the adult lifespan of flies, whereas flies with overexpression of sra alone showed normal climbing ability, albeit with a slightly reduced lifespan. Similarly, treatment with chemical inhibitors of calcineurin, such as FK506 and cyclosporin A, or knockdown of calcineurin expression by RNA interference (RNAi), exacerbated the Aβ42-induced rough-eye phenotype. Furthermore, sra-overexpressing flies displayed significantly decreased mitochondrial DNA and ATP levels, as well as increased susceptibility to oxidative stress compared to that of control flies. Taken together, our results demonstrating that sra overexpression augments Aβ42 cytotoxicity in Drosophila suggest that DSCR1

  19. Frameshift mutations in dentin phosphoprotein and dependence of dentin disease phenotype on mutation location.

    Science.gov (United States)

    Nieminen, Pekka; Papagiannoulis-Lascarides, Lisa; Waltimo-Siren, Janna; Ollila, Päivi; Karjalainen, Sara; Arte, Sirpa; Veerkamp, Jaap; Tallon Walton, Victoria; Chimenos Küstner, Eduard; Siltanen, Tarja; Holappa, Heidi; Lukinmaa, Pirjo-Liisa; Alaluusua, Satu

    2011-04-01

    We describe results from a mutational analysis of the region of the dentin sialophosphoprotein (DSPP) gene encoding dentin phosphoprotein (DPP) in 12 families with dominantly inherited dentin diseases. In eight families (five mutations in the N-terminal third of DPP), the clinical and radiologic features were uniform and compatible with dentin dysplasia type II (DD-II) with major clinical signs in the deciduous dentition. In the other families (four mutations in the more C-terminal part), the permanent teeth also were affected, and the diseases could be classified as variants of dentinogenesis imperfecta. Attrition was not prominent, but periapical infections were common. Discoloring with varying intensity was evident, and pulps and root canals were obliterated in the permanent dentition. All mutations caused a frameshift that replaced the Ser-Ser-Asx repeat by a code for a hydrophobic downstream sequence of approximately original length. We conclude that frameshift mutations in DSPP explain a significant part of dentin diseases. Furthermore, we propose that the location of the mutation is reflected in the phenotypic features as a gradient from DD-II to more severe disease that does not conform to the classic definitions of DI-II. Copyright © 2011 American Society for Bone and Mineral Research.

  20. Prognostic significance of weight changes in Parkinson's disease: the Park-weight phenotype.

    Science.gov (United States)

    Sharma, Jagdish C; Vassallo, Michael

    2014-01-01

    Neurodegenerative Parkinson's disease (PD) is associated with a changing profile of weight as the disease advances. Whilst some patients gain weight, a significant proportion of patients lose weight. PD patients have a lower body weight as compared with non-PD controls. Weight loss is not a benign phenomenon. Patients with lower initial body weight and weight losers have a higher risk of developing dyskinesia. There is a relationship between body weight and levodopa dose, patients with higher levodopa dose per kilogram are at a higher risk of dyskinesia, the risk escalates above 6 mg per kilogram. Lower weight patients have risk of undernutrition and the associated disease pathology due to frailty. Weight losers are at risk of higher mortality and poor quality of life. PD patients should be assessed for body weight and the dose of levodopa be adjusted according to periodic weight changes, supplemented by other dopaminergic medications. Patients at risk of weight loss may be identified by their severe loss of olfaction since there seems to exist the olfaction-weight-dyskinesia phenotype. Measures should be taken to prevent weight loss in at-risk patients to prevent low-weight-related adverse outcomes in PD patients. These measures may protect PD patients from motor and non-motor adverse effects as the disease advances.

  1. Is Chronic Obstructive Pulmonary Disease Caused by Wood Smoke a Different Phenotype or a Different Entity?

    Science.gov (United States)

    Torres-Duque, Carlos A; García-Rodriguez, María Carmen; González-García, Mauricio

    2016-08-01

    Around 40% of the world's population continue using solid fuel, including wood, for cooking or heating their homes. Chronic exposure to wood smoke is a risk factor for developing chronic obstructive pulmonary disease (COPD). In some regions of the world, this can be a more important cause of COPD than exposure to tobacco smoke from cigarettes. Significant differences between COPD associated with wood smoke (W-COPD) and that caused by smoking (S-COPD) have led some authors to suggest that W-COPD should be considered a new COPD phenotype. We present a review of the differences between W-COPD and S-COPD. On the premise that wood smoke and tobacco smoke are not the same and the physiopathological mechanisms they induce may differ, we have analyzed whether W-COPD can be considered as another COPD phenotype or a distinct nosological entity. Copyright © 2016 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.

  2. Brain ischemia with Alzheimer phenotype dysregulates Alzheimer's disease-related proteins.

    Science.gov (United States)

    Ułamek-Kozioł, Marzena; Pluta, Ryszard; Bogucka-Kocka, Anna; Januszewski, Sławomir; Kocki, Janusz; Czuczwar, Stanisław J

    2016-06-01

    There are evidences for the influence of Alzheimer's proteins on postischemic brain injury. We present here an overview of the published evidence underpinning the relationships between β-amyloid peptide, hyperphosphorylated tau protein, presenilins, apolipoproteins, secretases and neuronal survival/death decisions after ischemia and development of postischemic dementia. The interactions of above molecules and their influence and contribution to final ischemic brain degeneration resulting in dementia of Alzheimer phenotype are reviewed. Generation and deposition of β-amyloid peptide and tau protein pathology are essential factors involved in Alzheimer's disease development as well as in postischemic brain dementia. Postischemic injuries demonstrate that ischemia may stimulate pathological amyloid precursor protein processing by upregulation of β- and γ-secretases and therefore are capable of establishing a vicious cycle. Functional postischemic brain recovery is always delayed and incomplete by an injury-related increase in the amount of the neurotoxic C-terminal of amyloid precursor protein and β-amyloid peptide. Finally, we present here the concept that Alzheimer's proteins can contribute to and/or precipitate postischemic brain neurodegeneration including dementia with Alzheimer's phenotype. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  3. Characterization of cellular phenotypes and cytokine expression in balt from children with congenital heart diseases.

    Science.gov (United States)

    Moussallem, T M; Guedes, F; Fernandes, E R; Pagliari, C; Andrade, H F; Duarte, M I S; Lancellotti, C L P

    2003-01-01

    The present study was performed to target and call attention to the bronchial associated lymphoid tissue (BALT), part of our immune system, from which, we believe, several forms of prophylactic and therapeutic approaches can be developed. The characterization of its immune components, cells, and cytokines, in absence of antigenic stimuli, is pioneer in literature. Eighteen cases of necropsies were chosen and selected the paraffin-embedded lungs. The ages of 11 females and 7 males varied from 5 to 31 months. Cause of death: congenital heart diseases. lung infection at necropsy and/or arterial hypertrophy greater than Heath-Edwards' 1st degree. Immunohistochemical technique was applied to identify the cell phenotypes and the cytokines in situ. BALT was identified in all cases in this study. The main cellular phenotypes in BALT were T helper (TH) and B lymphocytes surrounded by T cytotoxic lymphocytes, natural killer cells, and dendritic cells in less quantities. Interleukin 10 and Tumor Necrosis Factor alpha were the predominant cytokines in BALT without antigenic stimuli. BALT is an important structure of the lung immune system in infants, with a tendency to maintain an environment favorable to the Th2 arm of immune response. It needs more exploration to define its behavior in front of infections, especially those with pulmonary tropism.

  4. Advances in huntington disease drug discovery: novel approaches to model disease phenotypes.

    Science.gov (United States)

    Bard, Jonathan; Wall, Michael D; Lazari, Ovadia; Arjomand, Jamshid; Munoz-Sanjuan, Ignacio

    2014-02-01

    Huntington disease is a monogenic, autosomal dominant, progressive neurodegenerative disorder caused by a trinucleotide CAG repeat expansion in exon 1 of the huntingtin (HTT) gene; age of onset of clinical symptoms inversely correlates with expanded CAG repeat length. HD leads to extensive degeneration of the basal ganglia, hypothalamic nuclei, and selected cortical areas, and a wide range of molecular mechanisms have been implicated in disease pathology in animal or cellular models expressing mutated HTT (mHTT) proteins, either full-length or amino-terminal fragments. However, HD cellular models that recapitulate the slow progression of the disease have not been available due to the toxicity of overexpressed exogenous mHTT or to limitations with using primary cells for long-term studies. Most investigations of the effects of mHTT relied on cytotoxicity or aggregation end points in heterologous systems or in primary embryonic neuroglial cultures derived from HD mouse models. More innovative approaches are currently under active investigation, including screening using electrophysiological endpoints, as well as the recent use of primary blood mononuclear cells and of human embryonic stem cells derived from a variety of HD research participants. Here we describe how these cellular systems are being used to investigate HD biology as well as to identify mechanisms with therapeutic potential.

  5. Novel antiplatelet agents: ALX-0081, a Nanobody directed towards von Willebrand factor.

    Science.gov (United States)

    Bartunek, Jozef; Barbato, Emanuele; Heyndrickx, Guy; Vanderheyden, Marc; Wijns, William; Holz, Josefin-Beate

    2013-06-01

    This manuscript reviews the studies performed with ALX-0081 (INN: caplacizumab), a Nanobody targeting von Willebrand factor, in the context of current antithrombotic therapy in coronary artery disease. ALX-0081 specifically inhibits platelet adhesion to the vessel wall, and may control platelet aggregation and subsequent clot formation without increasing bleeding risk. A substantial number of antithrombotics are aimed at this cascade; however, their generally indiscriminative mode of action can result in a narrow therapeutic window, defined by the risk for bleeding complications, and thrombotic events. Nonclinically, ALX-0081 compared favorably to several antithrombotics. In Phase I studies in healthy subjects and stable angina patients undergoing percutaneous coronary intervention (PCI), ALX-0081 was well tolerated, and effectively inhibited pharmacodynamic markers. Following these results, a phase II study was initiated in high-risk acute coronary syndrome patients undergoing PCI. Based on its mechanism of action, ALX-0081 is also being developed for acquired thrombotic thrombocytopenic purpura.

  6. Nucleation of protein aggregation kinetics as a basis for genotype-phenotype correlations in polyglutamine diseases

    Directory of Open Access Journals (Sweden)

    Matsubara Shiro

    2009-07-01

    Full Text Available Abstract Recent studies of inherited neurodegenerative disorders have suggested a linkage between the propensity toward aggregation of mutant protein and disease onset. This is particularly apparent for polyglutamine (polyQ diseases caused by expansion of CAG-trinucleotide repeats. However, a quantitative framework for relating aggregation kinetics with molecular mechanisms of neurodegeneration initiation is lacking. Here, using the repeat-length-dependent age-of-onset in polyQ diseases, we derived a mathematical model based on nucleation of aggregation kinetics to describe genotype-phenotype correlations, and validated the model using both in vitro data and clinical data. Instead of describing polyQ aggregation kinetics with a derivative equation, our model divided age-of-onset (equivalent to the time required for aggregation into two processes: nucleation lag time (a first-order exponential function of CAG-repeat length and elongation time. With the exception of spinocerebellar ataxia (SCA 3, the relation between CAG-repeat length and age-of-onset in all examined polyQ diseases, including Huntington's disease, dentatorubral-pallidoluysian atrophy and SCA1, -2, -6 and -7, could be well explained by three parameters derived from linear regression analysis based on the nucleated growth polymerization model. These parameters composed of probability of nucleation at an individual repeat, a protein concentration associated factor, and elongation time predict the overall features of neurodegeneration initiation, including constant risk for cell death, toxic polyQ species, main pathological subcellular site and the contribution of cellular factors. Our model also presents an alternative therapeutic strategy according to the distinct subcellular loci by the finding that nuclear localization of soluble mutant protein monomers itself has great impact on disease onset.

  7. Public support for neonatal screening for Pompe disease, a broad-phenotype condition

    Directory of Open Access Journals (Sweden)

    Weinreich Stephanie

    2012-03-01

    screening for Pompe disease, not only among those who have personal experience of the disease but also among the general public in the Netherlands. Optional screening on the basis of informed parental consent is probably unrealistic, underlining the need for new guidelines to help policymakers in their consideration of newborn screening for broad phenotype conditions.

  8. Public support for neonatal screening for Pompe disease, a broad-phenotype condition.

    Science.gov (United States)

    Weinreich, Stephanie Shifra; Rigter, Tessel; van El, Carla Geertruida; Dondorp, Wybo Jan; Kostense, Pieter Johannes; van der Ploeg, Ans T; Reuser, Arnold J J; Cornel, Martina Cornelia; Hagemans, Marloes Louise Catharina

    2012-03-14

    Neonatal screening for Pompe disease has been introduced in Taiwan and a few U.S. states, while other jurisdictions including some European countries are piloting or considering this screening. First-tier screening flags both classic infantile and late-onset Pompe disease, which challenges current screening criteria. Previously, advocacy groups have sometimes supported expanded neonatal screening more than professional experts, while neutral citizens' views were unknown. This study aimed to measure support for neonatal screening for Pompe disease in the general public and to compare it to support among (parents of) patients with this condition. The study was done in the Netherlands, where newborns are not currently screened for Pompe disease. Newborn screening is not mandatory in the Netherlands but current uptake is almost universal. A consumer panel (neutral group) and (parents of) patients with Pompe disease (Pompe group) were sent information and a questionnaire. Responses were analyzed of 555 neutral and 58 Pompe-experienced informants who had demonstrated sufficient understanding. 87% of the neutral group and 88% of the Pompe group supported the introduction of screening (95% CI of difference -10 to 7%). The groups were similar in their moral reasoning about screening and acceptance of false positives, but the Pompe-experienced group expected greater benefit from neonatal detection of late-onset disease. Multivariate regression analysis controlling for demographics confirmed that approval of the introduction of screening was independent of having (a child with) Pompe disease. Furthermore, respondents with university education, regardless of whether they have (a child with) Pompe disease, were more likely to be reluctant about the introduction of screening than those with less education, OR for approval 0.29 (95% CI 0.18 to 0.49, p Pompe disease, not only among those who have personal experience of the disease but also among the general public in the

  9. Blepharophimosis, short humeri, developmental delay and hirschsprung disease: expanding the phenotypic spectrum of MED12 mutations.

    Science.gov (United States)

    Isidor, Bertrand; Lefebvre, Tiphaine; Le Vaillant, Claudine; Caillaud, Gaëlle; Faivre, Laurence; Jossic, Frédéric; Joubert, Madeleine; Winer, Norbert; Le Caignec, Cédric; Borck, Guntram; Pelet, Anna; Amiel, Jeanne; Toutain, Annick; Ronce, Nathalie; Raynaud, Martine; Verloes, Alain; David, Albert

    2014-07-01

    We report on two male sibs, a fetus and a newborn, with short humeri and dysmorphic facial features including blepharophimosis. The newborn also had Hirschsprung disease. Goldberg-Shprintzen syndrome and the Say-Barber-Biesecker-Young-Simpson type of Ohdo syndrome were suspected but direct sequencing of KBP and KAT6B failed to identify a mutation. Finally, direct sequencing of MED12, the gene mutated in Opitz-Kaveggia syndrome, Lujan-Fryns syndrome and X-linked Ohdo syndrome identified in the two sibs the missense mutation c.3443G>A (p.Arg1148His) inherited from the mother. This report further expands the phenotypic spectrum of MED12 mutations. © 2014 Wiley Periodicals, Inc.

  10. Similarity of molecular phenotype between known epilepsy gene LGI1 and disease candidate gene LGI2

    Directory of Open Access Journals (Sweden)

    Eisenhaber Frank

    2010-09-01

    Full Text Available Abstract Background The LGI2 (leucine-rich, glioma inactivated 2 gene, a prime candidate for partial epilepsy with pericentral spikes, belongs to a family encoding secreted, beta-propeller domain proteins with EPTP/EAR epilepsy-associated repeats. In another family member, LGI1 (leucine-rich, glioma inactivated 1 mutations are responsible for autosomal dominant lateral temporal epilepsy (ADLTE. Because a few LGI1 disease mutations described in the literature cause secretion failure, we experimentally analyzed the secretion efficiency and subcellular localization of several LGI1 and LGI2 mutant proteins corresponding to observed non-synonymous single nucleotide polymorphisms (nsSNPs affecting the signal peptide, the leucine-rich repeats and the EAR propeller. Results Mapping of disease-causing mutations in the EAR domain region onto a 3D-structure model shows that many of these mutations co-localize at an evolutionary conserved surface region of the propeller. We find that wild-type LGI2 is secreted to the extracellular medium in glycosylated form similarly to LGI1, whereas several mutant proteins tested in this study are secretion-deficient and accumulate in the endoplasmic reticulum. Interestingly, mutations at structurally homologous positions in the EAR domain have the same effect on secretion in LGI1 and LGI2. Conclusions This similarity of experimental mislocalization phenotypes for mutations at homologous positions of LGI2 and the established epilepsy gene LGI1 suggests that both genes share a potentially common molecular pathogenesis mechanism that might be the reason for genotypically distinct but phenotypically related forms of epilepsy.

  11. Phenotypic characterization of canine intestinal intraepithelial lymphocytes in dogs with inflammatory bowel disease.

    Science.gov (United States)

    Haas, E; Rütgen, B C; Gerner, W; Richter, B; Tichy, A; Galler, A; Bilek, A; Thalhammer, J G; Saalmüller, A; Luckschander-Zeller, N

    2014-01-01

    Many dogs suffering from inflammatory bowel disease (IBD) are presented to veterinary clinics. These patients are diagnosed based on a history of chronic gastrointestinal signs and biopsy-confirmed histopathologic intestinal inflammation. Intestinal intraepithelial lymphocytes (IEL) are part of the first line of defense in the gastrointestinal immune system. Alterations in IEL subsets may play a role in the pathogenesis of IBD. The aim of this study was to characterize the phenotypes of IEL in dogs with IBD compared with healthy control dogs. Intestinal intraepithelial lymphocytes subpopulations of control dogs (n = 5) obtained from endoscopic biopsies (EB) were compared to those obtained from full thickness biopsies (FTB) on the same day. In addition, the phenotypes of IEL from FTB of control dogs (n = 10) were compared with EB of IBD dogs (n = 10). Each participant was scored clinically using the canine inflammatory bowel disease activity index (CIBDAI), and all samples were graded histopathologically. Three-color flow cytometry of isolated IEL was performed using monoclonal antibodies against T- and B-lymphocyte subpopulations. No significant differences in the composition of IEL subpopulations were found in control dogs based on method of biopsy. The IBD dogs had significantly higher CIBDAI and histopathologic scores compared with control dogs and their IEL contained a significantly higher frequency TCRγδ T-cells. Endoscopic biopsies provide suitable samples for 3-color flow cytometry when studying canine intestinal IEL and IBD patients show significant changes of major T-cell subsets compared to healthy control dogs. Copyright © 2014 by the American College of Veterinary Internal Medicine.

  12. Chronic obstructive pulmonary disease phenotype desaturator with hypoxic vascular remodelling and pulmonary hypertension obtained by cluster analysis

    Directory of Open Access Journals (Sweden)

    Toraldo Domenico

    2012-11-01

    Full Text Available Abstract Significant heterogeneity of clinical presentation and disease progression exists within chronic obstructive pulmonary disease (COPD. This article discusses and refines the concept of desaturator phenotypes in COPD with pulmonary hypertension (PH obtained by cluster analysis and presents a pattern of phenotypic markers that could be used as a framework for future diagnosis and research. Nocturnal oxygen desaturation results in sleep disturbances which predispose to nocturnal cardiac dysrhythmias, PH and possibly nocturnal death, particularly during acute exacerbations. We assume that in patients with COPD at least two factors play a role in PH: the severity of pulmonary impairment, and the severity of systemic nocturnal hypoxaemia due to reduced pulmonary functions. Establishing a common language for future research will facilitate our understanding and management of such a disease. This knowledge could lead to different pharmacological treatments and other interventions directed at specific phenotypic groups.

  13. Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis.

    Science.gov (United States)

    Weismüller, Tobias J; Trivedi, Palak J; Bergquist, Annika; Imam, Mohamad; Lenzen, Henrike; Ponsioen, Cyriel Y; Holm, Kristian; Gotthardt, Daniel; Färkkilä, Martti A; Marschall, Hanns-Ulrich; Thorburn, Douglas; Weersma, Rinse K; Fevery, Johan; Mueller, Tobias; Chazouillères, Olivier; Schulze, Kornelius; Lazaridis, Konstantinos N; Almer, Sven; Pereira, Stephen P; Levy, Cynthia; Mason, Andrew; Naess, Sigrid; Bowlus, Christopher L; Floreani, Annarosa; Halilbasic, Emina; Yimam, Kidist K; Milkiewicz, Piotr; Beuers, Ulrich; Huynh, Dep K; Pares, Albert; Manser, Christine N; Dalekos, George N; Eksteen, Bertus; Invernizzi, Pietro; Berg, Christoph P; Kirchner, Gabi I; Sarrazin, Christoph; Zimmer, Vincent; Fabris, Luca; Braun, Felix; Marzioni, Marco; Juran, Brian D; Said, Karouk; Rupp, Christian; Jokelainen, Kalle; Benito de Valle, Maria; Saffioti, Francesca; Cheung, Angela; Trauner, Michael; Schramm, Christoph; Chapman, Roger W; Karlsen, Tom H; Schrumpf, Erik; Strassburg, Christian P; Manns, Michael P; Lindor, Keith D; Hirschfield, Gideon M; Hansen, Bettina E; Boberg, Kirsten M

    2017-06-01

    Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates. Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 41-50 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P primary endpoint, small-duct PSC

  14. Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease.

    Science.gov (United States)

    Van Limbergen, Johan; Russell, Richard K; Drummond, Hazel E; Aldhous, Marian C; Round, Nicola K; Nimmo, Elaine R; Smith, Linda; Gillett, Peter M; McGrogan, Paraic; Weaver, Lawrence T; Bisset, W Michael; Mahdi, Gamal; Arnott, Ian D; Satsangi, Jack; Wilson, David C

    2008-10-01

    Childhood-onset inflammatory bowel disease (IBD) might be etiologically different from adult-onset IBD. We analyzed disease phenotypes and progression of childhood-onset disease and compared them with characteristics of adult-onset disease in patients in Scotland. Anatomic locations and behaviors were assessed in 416 patients with childhood-onset (276 Crohn's disease [CD], 99 ulcerative colitis [UC], 41 IBD type unclassified [IBDU] diagnosed before seventeenth birthday) and 1297 patients with adult-onset (596 CD, 701 UC) IBD using the Montreal classification. At the time of diagnosis in children, CD involved small bowel and colon (L3) in 51% (138/273), colon (L2) in 36%, and ileum (L1) in 6%; the upper gastrointestinal (GI) tract (L4) was also affected in 51%. In 39%, the anatomic extent increased within 2 years. Behavioral characteristics progressed; 24% of children developed stricturing or penetrating complications within 4 years (vs 9% at diagnosis; P L1; 2% vs 31%; P L2; 15% vs 36%; P < .0001; OR, 0.31; 95% CI, 0.21-0.46). UC was extensive in 82% of the children at diagnosis, versus 48% of adults (P < .0001; OR, 5.08; 95% CI, 2.73-9.45); 46% of the children progressed to develop extensive colitis during follow-up. Forty-six percent of children with CD and 35% with UC required immunomodulatory therapy within 12 months of diagnosis. The median time to first surgery was longer in childhood-onset than adult-onset patients with CD (13.7 vs 7.8 years; P < .001); the reverse was true for UC. Childhood-onset IBD is characterized by extensive intestinal involvement and rapid early progression.

  15. Lyme Disease Diagnosed by Alternative Methods: A Phenotype Similar to That of Chronic Fatigue Syndrome.

    Science.gov (United States)

    Patrick, David M; Miller, Ruth R; Gardy, Jennifer L; Parker, Shoshana M; Morshed, Muhammad G; Steiner, Theodore S; Singer, Joel; Shojania, Kam; Tang, Patrick

    2015-10-01

    A subset of patients reporting a diagnosis of Lyme disease can be described as having alternatively diagnosed chronic Lyme syndrome (ADCLS), in which diagnosis is based on laboratory results from a nonreference Lyme specialty laboratory using in-house criteria. Patients with ADCLS report symptoms similar to those reported by patients with chronic fatigue syndrome (CFS). We performed a case-control study comparing patients with ADCLS and CFS to each other and to both healthy controls and controls with systemic lupus erythematosus (SLE). Subjects completed a history, physical exam, screening laboratory tests, 7 functional scales, reference serology for Lyme disease using Centers for Disease Control and Prevention criteria, reference serology for other tick-associated pathogens, and cytokine expression studies. The study enrolled 13 patients with ADCLS (12 of whom were diagnosed by 1 alternative US laboratory), 25 patients with CFS, 25 matched healthy controls, and 11 SLE controls. Baseline clinical data and functional scales indicate significant disability among ADCLS and CFS patients and many important differences between these groups and controls, but no significant differences between each other. No ADCLS patient was confirmed as having positive Lyme serology by reference laboratory testing, and there was no difference in distribution of positive serology for other tick-transmitted pathogens or cytokine expression across the groups. In British Columbia, a setting with low Lyme disease incidence, ADCLS patients have a similar phenotype to that of CFS patients. Disagreement between alternative and reference laboratory Lyme testing results in this setting is most likely explained by false-positive results from the alternative laboratory. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  16. Familial Prion Disease with Alzheimer Disease-Like Tau Pathology and Clinical Phenotype

    Science.gov (United States)

    Jayadev, Suman; Nochlin, David; Poorkaj, Parvoneh; Steinbart, Ellen J.; Mastrianni, James A.; Montine, Thomas J.; Ghetti, Bernardino; Schellenberg, Gerard D.; Bird, Thomas D.; Leverenz, James B.

    2011-01-01

    Objective To describe the Alzheimer disease (AD)-like clinical and pathological features, including marked neurofibrillary tangle (NFT) pathology, of a familial prion disease due to a rare nonsense mutation of the prion gene (PRNP). Methods Longitudinal clinical assessments were available for the proband and her mother. After death, both underwent neuropathological evaluation. PRNP was sequenced after failure to find immunopositive Aβ deposits in the proband and the documentation of prion protein (PrP) immunopositive pathology. Results The proband presented at age 42 years with a 3-year history of progressive short-term memory impairment and depression. Neuropsychological testing found impaired memory performance, with relatively preserved attention and construction. She was diagnosed with AD and died at age 47 years. Neuropathologic evaluation revealed extensive limbic and neocortical NFT formation and neuritic plaques consistent with a Braak stage of VI. The NFTs were immunopositive, with multiple tau antibodies, and electron microscopy revealed paired helical filaments. However, the neuritic plaques were immunonegative for Aβ, whereas immunostaining for PrP was positive. The mother of the proband had a similar presentation, including depression, and had been diagnosed clinically and pathologically as AD. Reevaluation of her brain tissue confirmed similar tau and PrP immunostaining findings. Genetic analysis revealed that both the proband and her mother had a rare PRNP mutation (Q160X) that resulted in the production of truncated PrP. Interpretation We suggest that PRNP mutations that result in a truncation of PrP lead to a prolonged clinical course consistent with a clinical diagnosis of AD and severe AD-like NFTs. PMID:21416485

  17. Human Retrotransposon Insertion Polymorphisms Are Associated with Health and Disease via Gene Regulatory Phenotypes

    Directory of Open Access Journals (Sweden)

    Lu Wang

    2017-08-01

    Full Text Available The human genome hosts several active families of transposable elements (TEs, including the Alu, LINE-1, and SVA retrotransposons that are mobilized via reverse transcription of RNA intermediates. We evaluated how insertion polymorphisms generated by human retrotransposon activity may be related to common health and disease phenotypes that have been previously interrogated through genome-wide association studies (GWAS. To address this question, we performed a genome-wide screen for retrotransposon polymorphism disease associations that are linked to TE induced gene regulatory changes. Our screen first identified polymorphic retrotransposon insertions found in linkage disequilibrium (LD with single nucleotide polymorphisms that were previously associated with common complex diseases by GWAS. We further narrowed this set of candidate disease associated retrotransposon polymorphisms by identifying insertions that are located within tissue-specific enhancer elements. We then performed expression quantitative trait loci analysis on the remaining set of candidates in order to identify polymorphic retrotransposon insertions that are associated with gene expression changes in B-cells of the human immune system. This progressive and stringent screen yielded a list of six retrotransposon insertions as the strongest candidates for TE polymorphisms that lead to disease via enhancer-mediated changes in gene regulation. For example, we found an SVA insertion within a cell-type specific enhancer located in the second intron of the B4GALT1 gene. B4GALT1 encodes a glycosyltransferase that functions in the glycosylation of the Immunoglobulin G (IgG antibody in such a way as to convert its activity from pro- to anti-inflammatory. The disruption of the B4GALT1 enhancer by the SVA insertion is associated with down-regulation of the gene in B-cells, which would serve to keep the IgG molecule in a pro-inflammatory state. Consistent with this idea, the B4GALT1 enhancer

  18. Microglial phenotypes and toll-like receptor 2 in the substantia nigra and hippocampus of incidental Lewy body disease cases and Parkinson's disease patients

    NARCIS (Netherlands)

    Doorn, K.J.; Moors, T.; Drukarch, B; van de Berg, W.D.J.; Lucassen, P.J.; van Dam, A-M.

    2014-01-01

    Next to α-synuclein deposition, microglial activation is a prominent pathological feature in the substantia nigra (SN) of Parkinson’s disease (PD) patients. Little is known, however, about the different phenotypes of microglia and how they change during disease progression, in the SN or in another

  19. A comparative evaluation of a new automated assay for von Willebrand factor activity.

    Science.gov (United States)

    Lawrie, A S; Stufano, F; Canciani, M T; Mackie, I J; Machin, S J; Peyvandi, F

    2013-03-01

    The ristocetin cofactor assay (VWF:RCo) is the reference method for assessing von Willebrand factor (VWF) activity in the diagnosis of von Willebrand's Disease (VWD). However, the assay suffers from poor reproducibility and sensitivity at low levels of VWF and is labour intensive. We have undertaken an evaluation of a new immunoturbidimetric VWF activity (VWF:Ac) assay (INNOVANCE(®) VWF Ac. Siemens Healthcare Diagnostics, Marburg, Germany) relative to an established platelet-based VWF:RCo method. Samples from 50 healthy normal subjects, 80 patients with VWD and 50 samples that exhibited 'HIL' (i.e. Haemolysis, Icterus or Lipaemia) were studied. VWF:Ac, VWF:RCo and VWF:Ag were performed on a CS-analyser (Sysmex UK Ltd, Milton Keynes, UK), all reagents were from Siemens Healthcare Diagnostics. The VWF:Ac assay, gave low intra- and inter-assay imprecision (over a 31-day period, n = 200 replicate readings) using commercial normal (Mean 96.2 IU dL(-1), CV < 3.0%) and pathological (Mean 36.1 IU dL(-1), CV < 3.5%) control plasmas. The normal and clinical samples exhibited good correlation between VWF:RCo (range 3-753 IU dL(-1)) and VWF:Ac (rs = 0.97, P < 0.0001), with a mean bias of 5.6 IU dL(-1). Ratios of VWF:Ac and VWF:RCo to VWF:Ag in the VWD samples were comparable, although VWF:Ac had a superior lower level of detection to that of VWF:RCo (3% and 5% respectively). A subset (n = 97) of VWD and HIL samples were analysed for VWF:Ac at two different dilutions to assess the effect on relative potency, no significant difference was observed (P = 0.111). The INNOVANCE(®) VWF Ac assay was shown to be reliable and precise. © 2012 Blackwell Publishing Ltd.

  20. Neuropsychology, neuroimaging or motor phenotype in diagnosis of Parkinson's disease-dementia: which matters most?

    Science.gov (United States)

    Di Biasio, Francesca; Vanacore, Nicola; Fasano, Alfonso; Modugno, Nicola; Gandolfi, Barbara; Lena, Francesco; Grillea, Giovanni; Pietracupa, Sara; Caranci, Giovanni; Ruggieri, Stefano

    2012-05-01

    Parkinson's disease (PD) is a neurodegenerative disorder affecting not only the motor system but also the cognitive and behavioral domains. Although there are many studies addressing the issue of cognition, a universally recognized method to diagnose patients with dementia is still lacking. The aim of this study was to determine which neuropsychological test is the most reliable in the diagnosis of dementia in PD and to establish if mini mental state examination (MMSE) is enough to detect this condition. We studied 200 consecutive PD patients through an extensive neuropsychological battery, clinical evaluation and brain magnetic resonance imaging over a period of 4 years. A logistic regression model was used to evaluate the interplay between possible risk factors and the accuracy of different neuropsychological tests. PD patients with dementia performed significantly worse in all the tests as compared to patients with PD alone: phonological verbal fluency, attentional matrices, Rey auditory verbal learning test and digit span were the most useful tools. Age and disease duration were correlated with cognitive impairment. No relevant differences were detected in phenotype, affected body side at onset, levodopa equivalent daily dose or neuroimaging findings (except for the occurrence of atrophy). Despite reasonable accuracy of MMSE (90%), its positive predictive value is only 74%. Using at least 3 neuropsychological tests, among those more significant detected with logistic regression analysis, the positive predictive value rises to 91%. In conclusion, the use of an extensive neuropsychological battery is still recommended in the diagnosis of dementia in PD. © Springer-Verlag 2011

  1. Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype

    Science.gov (United States)

    Rutherford, Nicola J.; Heckman, Michael G.; DeJesus-Hernandez, Mariely; Baker, Matt C.; Soto-Ortolaza, Alexandra I.; Rayaprolu, Sruti; Stewart, Heather; Finger, Elizabeth; Volkening, Kathryn; Seeley, William W.; Hatanpaa, Kimmo J.; Lomen-Hoerth, Catherine; Kertesz, Andrew; Bigio, Eileen H.; Lippa, Carol; Knopman, David S.; Kretzschmar, Hans A.; Neumann, Manuela; Caselli, Richard J.; White, Charles L.; Mackenzie, Ian R.; Petersen, Ronald C.; Strong, Michael J.; Miller, Bruce L.; Boeve, Bradley F.; Uitti, Ryan J.; Boylan, Kevin; Wszolek, Zbigniew K.; Graff-Radford, Neill R.; Dickson, Dennis W.; Ross, Owen A.; Rademakers, Rosa

    2012-01-01

    Expansions of the non-coding GGGGCC hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene were recently identified as the long sought-after cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) on chromosome 9p. In this study we aimed to determine whether the length of the normal - unexpanded - allele of the GGGGCC repeat in C9ORF72 plays a role in the presentation of disease or affects age at onset in C9ORF72 mutation carriers. We also studied whether the GGGGCC repeat length confers risk or affects age at onset in FTD and ALS patients without C9ORF72 repeat expansions. C9ORF72 genotyping was performed in 580 FTD, 995 ALS and 160 FTD-ALS patients and 1444 controls, leading to the identification of 211 patients with pathogenic C9ORF72 repeat expansions and an accurate quantification of the length of the normal alleles in all patients and controls. No meaningful association between the repeat length of the normal alleles of the GGGGCC repeat in C9ORF72 and disease phenotype or age at onset was observed in C9ORF72 mutation carriers or non-mutation carriers. PMID:22840558

  2. A case of variant biochemical phenotype of Niemann-Pick disease type C accompanying savant syndrome.

    Science.gov (United States)

    Hamatani, Mio; Jingami, Naoto; Uemura, Kengo; Nakasone, Naoe; Kinoshita, Hisanori; Yamakado, Hodaka; Ninomiya, Haruaki; Takahashi, Ryosuke

    2016-06-22

    A 40-year-old man was referred to our hospital because of vertical supranuclear gaze palsy, frequent sudden loss of muscle tonus and ataxia for several years. He had a history of prolonged neonatal jaundice. He was given a diagnosis of autism in his childhood, followed by a diagnosis of schizophrenia in his teenage. He also developed a savant skill of calendar calculating. (123)I-IMP-SPECT showed decreased cerebral blood flow in the left frontotemporal lobe as often seen in savant syndrome. Although genetic analysis of NPC1 and NPC2 revealed no pathogenic mutation, filipin staining of cultured fibroblasts from his biopsied skin revealed a certain amount of intracellular cholesterol storage pattern, indicating a variant biochemical phenotype of Niemann-Pick disease type C (NPC). The diagnosis of adulthood onset NPC is difficult and challenging, especially for neurologists, because the symptoms and signs are not as clear as those in the classical childhood onset NPC and this subtype is not yet widely known. However, the diagnosis can be made by a combination of filipin staining of fibroblast and/or gene analysis. As a disease-specific therapy for NPC has been approved in Japan, the diagnosis of NPC is of significance.

  3. Sleep Physiology Alterations Precede Plethoric Phenotypic Changes in R6/1 Huntington's Disease Mice.

    Directory of Open Access Journals (Sweden)

    Fanny Lebreton

    Full Text Available In hereditary neurodegenerative Huntington's disease (HD, there exists a growing consideration that sleep and circadian dysregulations may be important symptoms. It is not known, however, whether sleep abnormalities contribute to other behavioral deficits in HD patients and mouse models. To determine the precise chronology for sleep physiology alterations and other sensory, motor, psychiatric and cognitive symptoms of HD, the same R6/1 HD transgenics and their wild-type littermates were recorded monthly for sleep electroencephalogram (EEG together with a wide range of behavioral tests according to a longitudinal plan. We found an early and progressive deterioration of both sleep architecture and EEG brain rhythms in R6/1 mice, which are correlated timely with their spatial working memory impairments. Sleep fragmentation and memory impairments were accompanied by the loss of delta (1-4 Hz power in the transgenic mice, the magnitude of which increased with age and disease progression. These precocious sleep and cognitive impairments were followed by deficits in social behavior, sensory and motor abilities. Our data confirm the existence and importance of sleep physiology alterations in the widely used R6/1 mouse line and highlight their precedence over other plethoric phenotypic changes. The brainwave abnormalities, may represent a novel biomarker and point to innovative therapeutic interventions against HD.

  4. Patient with von Willebrand Disease for Gynaecologic Surgery - Perianaesthetic Concerns

    Directory of Open Access Journals (Sweden)

    Rakesh Garg

    2008-01-01

    Patients with vWD do not carry an increased operative risk during elective procedures if appropriate prophylac-tic and corrective therapy is administered. Although the administration of cryoprecipitate and other blood products has traditionally been the cornerstone of treatment for vWD, the recent development of desmopressin(DDAVP for clinical use may provide an effective alternative to replacement therapy with blood products. Further laparaoscopic procedures, taking care during ryle′s tube and foley′s catheter insertion, in such patients are the safer alternative for all kind of gynecologic surgeries.

  5. Von Willebrand's disease: case report and review of literature ...

    African Journals Online (AJOL)

    His birth histories, his familie's social history and developmental milestones were unremarkable. He was born at full term with no antenatal or perinatal complications. Prior to the symptoms, the child was on a normal diet and was thriving appropriately. The child presented one days before his admission trauma to the inner ...

  6. Phenotypic Diversity of Sickle Cell Disease in Patients with a Double Heterozygosity for Hb S and Hb D-Punjab.

    Science.gov (United States)

    Torres, Lidiane S; Okumura, Jéssika V; Belini-Júnior, Édis; Oliveira, Renan G; Nascimento, Patrícia P; Silva, Danilo G H; Lobo, Clarisse L C; Oliani, Sonia M; Bonini-Domingos, Claudia R

    2016-09-01

    Phenotypic heterogeneity for sickle cell disease is associated to several genetic factors such as genotype for sickle cell disease, β-globin gene cluster haplotypes and Hb F levels. The coinheritance of Hb S (HBB: c.20A > T) and Hb D-Punjab (HBB: c.364G > C) results in a double heterozygosity, which constitutes one of the genotypic causes of sickle cell disease. This study aimed to assess the phenotypic diversity of sickle cell disease presented by carriers of the Hb S/Hb D-Punjab genotype and the Bantu [- + - - - -] haplotype. We evaluated medical records from 12 patients with sickle cell disease whose Hb S/Hb D-Punjab genotype and Bantu haplotype were confirmed by molecular analysis. Hb S and Hb D-Punjab levels were quantified by chromatographic analysis. Mean concentrations of Hb S and Hb D-Punjab were 44.8 ± 2.3% and 43.3 ± 1.8%, respectively. Painful crises were present in eight (66.7%) patients evaluated, representing the most common clinical event. Acute chest syndrome (ACS) was the second most prevalent manifestation, occurring in two individuals (16.7%). Three patients were asymptomatic, while another two exhibited greater diversity of severe clinical manifestations. Medical records here analyzed reported a significant clinical diversity in sickle cell disease ranging from the absence of symptoms to wide phenotypic variety. The sickle cell disease genotype, Bantu haplotype and hemoglobin (Hb) levels did not influence the clinical diversity. Thus, we concluded that the phenotypic variation in sickle cell disease was present within a specific genotype for disease regardless of the β-globin gene cluster haplotypes.

  7. Development of an Inflammatory Bowel Disease Research Registry Derived from Observational Electronic Health Record Data for Comprehensive Clinical Phenotyping.

    Science.gov (United States)

    Anderson, Alyce J M; Click, Benjamin; Ramos-Rivers, Claudia; Babichenko, Dmitriy; Koutroubakis, Ioannis E; Hartman, Douglas J; Hashash, Jana G; Schwartz, Marc; Swoger, Jason; Barrie, Arthur M; Dunn, Michael A; Regueiro, Miguel; Binion, David G

    2016-11-01

    Inflammatory bowel disease (IBD) is a heterogeneous collection of chronic inflammatory disorders of the digestive tract. Clinical, genetic, and pathological heterogeneity makes it increasingly difficult to translate efficacy studies into real-world practice. Our objective was to develop a comprehensive natural history registry derived from multi-year observational data to facilitate effectiveness and clinical phenotypic research in IBD. A longitudinal, consented registry with prospectively collected data was developed at UPMC. All adult IBD patients receiving care at the tertiary care center of UPMC are eligible for enrollment. Detailed data in the electronic health record are accessible for registry research purposes. Data are exported directly from the electronic health record and temporally organized for research. To date, there are over 2565 patients participating in the IBD research registry. All patients have demographic data, clinical disease characteristics, and disease course data including healthcare utilization, laboratory values, health-related questionnaires quantifying disease activity and quality of life, and analytical information on treatment, temporally organized for 6 years (2009-2015). The data have resulted in a detailed definition of clinical phenotypes suitable for association studies with parameters of disease outcomes and treatment response. We have established the infrastructure required to examine the effectiveness of treatment and disease course in the real-world setting of IBD. The IBD research registry offers a unique opportunity to investigate clinical research questions regarding the natural course of the disease, phenotype association studies, effectiveness of treatment, and quality of care research.

  8. Wilson Disease: Epigenetic effects of choline supplementation on phenotype and clinical course in a mouse model.

    Science.gov (United States)

    Medici, Valentina; Kieffer, Dorothy A; Shibata, Noreene M; Chima, Harpreet; Kim, Kyoungmi; Canovas, Angela; Medrano, Juan F; Islas-Trejo, Alma D; Kharbanda, Kusum K; Olson, Kristin; Su, Ruijun J; Islam, Mohammad S; Syed, Raisa; Keen, Carl L; Miller, Amy Y; Rutledge, John C; Halsted, Charles H; LaSalle, Janine M

    2016-11-01

    Wilson disease (WD), a genetic disorder affecting copper transport, is characterized by hepatic and neurological manifestations with variable and often unpredictable presentation. Global DNA methylation in liver was previously modified by dietary choline in tx-j mice, a spontaneous mutant model of WD. We therefore hypothesized that the WD phenotype and hepatic gene expression of tx-j offspring could be modified by maternal methyl supplementation during pregnancy. In an initial experiment, female tx-j mice or wild type mice were fed control or choline-supplemented diets 2 weeks prior to mating through embryonic day 17. Transcriptomic analysis (RNA-seq) on embryonic livers revealed tx-j-specific differences in genes related to oxidative phosphorylation, mitochondrial dysfunction, and the neurological disorders Huntington's disease and Alzheimer disease. Maternal choline supplementation restored the transcript levels of a subset of genes to wild type levels. In a separate experiment, a group of tx-j offspring continued to receive choline-supplemented or control diets, with or without the copper chelator penicillamine (PCA) for 12 weeks until 24 weeks of age. Combined choline supplementation and PCA treatment of 24-week-old tx-j mice was associated with increased liver transcript levels of methionine metabolism and oxidative phosphorylation-related genes. Sex differences in gene expression within each treatment group were also observed. These results demonstrate that the transcriptional changes in oxidative phosphorylation and methionine metabolism genes in WD that originate during fetal life are, in part, prevented by prenatal maternal choline supplementation, a finding with potential relevance to preventive treatments of WD.

  9. The impact of phenotypic and genetic heterogeneity on results of genome wide association studies of complex diseases.

    Science.gov (United States)

    Manchia, Mirko; Cullis, Jeffrey; Turecki, Gustavo; Rouleau, Guy A; Uher, Rudolf; Alda, Martin

    2013-01-01

    Phenotypic misclassification (between cases) has been shown to reduce the power to detect association in genetic studies. However, it is conceivable that complex traits are heterogeneous with respect to individual genetic susceptibility and disease pathophysiology, and that the effect of heterogeneity has a larger magnitude than the effect of phenotyping errors. Although an intuitively clear concept, the effect of heterogeneity on genetic studies of common diseases has received little attention. Here we investigate the impact of phenotypic and genetic heterogeneity on the statistical power of genome wide association studies (GWAS). We first performed a study of simulated genotypic and phenotypic data. Next, we analyzed the Wellcome Trust Case-Control Consortium (WTCCC) data for diabetes mellitus (DM) type 1 (T1D) and type 2 (T2D), using varying proportions of each type of diabetes in order to examine the impact of heterogeneity on the strength and statistical significance of association previously found in the WTCCC data. In both simulated and real data, heterogeneity (presence of "non-cases") reduced the statistical power to detect genetic association and greatly decreased the estimates of risk attributed to genetic variation. This finding was also supported by the analysis of loci validated in subsequent large-scale meta-analyses. For example, heterogeneity of 50% increases the required sample size by approximately three times. These results suggest that accurate phenotype delineation may be more important for detecting true genetic associations than increase in sample size.

  10. The impact of phenotypic and genetic heterogeneity on results of genome wide association studies of complex diseases.

    Directory of Open Access Journals (Sweden)

    Mirko Manchia

    Full Text Available Phenotypic misclassification (between cases has been shown to reduce the power to detect association in genetic studies. However, it is conceivable that complex traits are heterogeneous with respect to individual genetic susceptibility and disease pathophysiology, and that the effect of heterogeneity has a larger magnitude than the effect of phenotyping errors. Although an intuitively clear concept, the effect of heterogeneity on genetic studies of common diseases has received little attention. Here we investigate the impact of phenotypic and genetic heterogeneity on the statistical power of genome wide association studies (GWAS. We first performed a study of simulated genotypic and phenotypic data. Next, we analyzed the Wellcome Trust Case-Control Consortium (WTCCC data for diabetes mellitus (DM type 1 (T1D and type 2 (T2D, using varying proportions of each type of diabetes in order to examine the impact of heterogeneity on the strength and statistical significance of association previously found in the WTCCC data. In both simulated and real data, heterogeneity (presence of "non-cases" reduced the statistical power to detect genetic association and greatly decreased the estimates of risk attributed to genetic variation. This finding was also supported by the analysis of loci validated in subsequent large-scale meta-analyses. For example, heterogeneity of 50% increases the required sample size by approximately three times. These results suggest that accurate phenotype delineation may be more important for detecting true genetic associations than increase in sample size.

  11. Is the activated partial thromboplastin time suitable to screen for von Willebrand factor deficiencies?

    Science.gov (United States)

    Lippi, Giuseppe; Franchini, Massimo; Poli, Giovanni; Salvagno, Gian Luca; Montagnana, Martina; Guidi, Gian Cesare

    2007-06-01

    The diagnostic approach to von Willebrand factor deficiencies is challenging and requires discretionary use of laboratory resources. Although extensive preoperative testing is not recommended, the activated partial thromboplastin time may be useful, especially in selected categories of patients. To establish the diagnostic sensitivity of this test to identify isolate von Willebrand factor deficiencies, 204 consecutive patients underwent a routine preoperative screening consisting of activated partial thromboplastin time, von Willebrand factor antigen, intrinsic pathway clotting factors activity, lupus anticoagulants and thrombin time. Thirty-seven patients were diagnosed with haemostasis disturbances other than von Willebrand factor deficiencies and were excluded from the evaluation. Isolated von Willebrand factor deficiency was diagnosed in 11 of the remaining 167 patients. A significant correlation was observed between von Willebrand factor antigen and activated partial thromboplastin time. Receiver operating characteristic curve analysis showed an area under the curve of 0.982 (95% confidence interval: 0.972-0.992; P thromboplastin time, sensitivity and specificity were 100 and 85%, respectively, with negative and positive predictive values of 100 and 31%, respectively. These results demonstrate that activated partial thromboplastin time has an excellent diagnostic sensitivity and a satisfactory specificity for identifying isolated von Willebrand factor deficiencies.

  12. [Structure and function of the factor VIII/von Willebrand factor complex].

    Science.gov (United States)

    Müller, G

    1990-03-01

    In the blood plasma factor VIII is bound to the von Willebrand factor. The primary structure of the two proteins were clarified by gene clonation. Factor VIII descends from a precursor protein with 2,351 amino acids by splitting of 19 amino acid residues and is activated by partial proteolysis. In the blood coagulation factor VIII acts as co-factor for the activation of factor X by factor IX in the presence of phospholipids and Ca++ within the intrinsic coagulation system. The formation of the von Willebrand factor takes place by splitting of 22 and 741 amino acid residues, respectively, from pre-pro-von Willebrand factor via pro-von Willebrand factor. The subunits of the von Willebrand factor consist od 2,050 amino acid residues. In the blood plasma the von Willebrand factor is existing as a mixture of multimeres. Receptors of the von Willebrand factor on the thrombocytic membrane are the glycoproteins GPIb and GPIIb/GPIIIa, by means of which the adhesion of thrombocytes at the subendoethelium of the vascular wall and the aggregation of thrombocytes are mediated.

  13. Comparative analysis of von Willebrand factor profiles after implantation of left ventricular assist device and total artificial heart.

    Science.gov (United States)

    Reich, H J; Morgan, J; Arabia, F; Czer, L; Moriguchi, J; Ramzy, D; Esmailian, F; Lam, L; Dunhill, J; Volod, O

    2017-08-01

    Essentials Bleeding is a major source of morbidity during mechanical circulatory support. von Willebrand factor (VWF) multimer loss may contribute to bleeding. Different patterns of VWF multimer loss were seen with the two device types. This is the first report of total artificial heart associated VWF multimer loss. Background Bleeding remains a challenge during mechanical circulatory support and underlying mechanisms are incompletely understood. Functional von Willebrand factor (VWF) impairment because of loss of high-molecular-weight multimers (MWMs) produces acquired von Willebrand disease (VWD) after left ventricular assist device (LVAD). Little is known about VWF multimers with total artificial hearts (TAHs). Here, VWF profiles with LVADs and TAHs are compared using a VWD panel. Methods VWD evaluations for patients with LVAD or TAH (2013-14) were retrospectively analyzed and included: VWF activity (ristocetin cofactor, VWF:RCo), VWF antigen (VWF:Ag), ratio of VWF:RCo to VWF:Ag, and quantitative VWF multimeric analysis. Results Twelve patients with LVADs and 12 with TAHs underwent VWD evaluation. All had either normal (47.8%) or elevated (52.2%) VWF:RCo, normal (26.1%) or elevated (73.9%) VWF:Ag and 50.0% were disproportional (ratio ≤ 0.7). Multimeric analysis showed abnormal patterns in all patients with LVADs: seven with high MWM loss; five with highest MWM loss. With TAH, 10/12 patients had abnormal patterns: all with highest MWM loss. High MWM loss correlated with presence of LVAD and highest MWM loss with TAH. Increased low MWMs were detected in 22/24. Conclusion Using VWF multimeric analysis, abnormalities after LVAD or TAH were detected that would be missed with measurements of VWF level alone: loss of high MWM predominantly in LVAD, loss of highest MWM in TAH, and elevated levels of low MWM in both. This is the first study to describe TAH-associated highest MWM loss, which may contribute to bleeding. © 2017 International Society on Thrombosis and

  14. Biomarker-driven phenotyping in Parkinson's 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

    2017-03-01

    Past clinical trials of putative neuroprotective therapies have targeted PD as a single pathogenic disease entity. From an Oslerian clinicopathological 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 pathological 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. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

  15. Loci identified by genome-wide association studies influence different disease-related phenotypes in chronic obstructive pulmonary disease.

    Science.gov (United States)

    Pillai, Sreekumar G; Kong, Xiangyang; Edwards, Lisa D; Cho, Michael H; Anderson, Wayne H; Coxson, Harvey O; Lomas, David A; Silverman, Edwin K

    2010-12-15

    Genome-wide association studies have shown significant associations between variants near hedgehog interacting protein HHIP, FAM13A, and cholinergic nicotinic acetylcholine receptor CHRNA3/5 with increased risk of chronic obstructive pulmonary disease (COPD) in smokers; however, the disease mechanisms behind these associations are not well understood. To identify the association between replicated loci and COPD-related phenotypes in well-characterized patient populations. The relationship between these three loci and COPD-related phenotypes was assessed in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-point (ECLIPSE) cohort. The results were validated in the family-based International COPD Genetics Network (ICGN). The CHRNA3/5 locus was significantly associated with pack-years of smoking (P = 0.002 and 3 × 10⁻⁴), emphysema assessed by a radiologist using high-resolution computed tomography (P = 2 × 10⁻⁴ and 4.8 × 10⁻⁵), and airflow obstruction (P = 0.004 and 1.8 × 10⁻⁵) in the ECLIPSE and ICGN populations, respectively. However, variants in the IREB2 gene were only significantly associated with FEV₁. The HHIP locus was not associated with smoking intensity but was associated with FEV₁/FVC (P = 1.9 × 10⁻⁴ and 0.004 in the ECLIPSE and ICGN populations). The HHIP locus was also associated with fat-free body mass (P = 0.007) and with both retrospectively (P = 0.015) and prospectively (P = 0.024) collected COPD exacerbations in the ECLIPSE cohort. Single-nucleotide polymorphisms in the FAM13A locus were associated with lung function. The CHRNA3/5 locus was associated with increased smoking intensity and emphysema in individuals with COPD, whereas the HHIP and FAM13A loci were not associated with smoking intensity. The HHIP locus was associated with the systemic components of COPD and with the frequency of COPD exacerbations. FAM13A locus was associated with lung function.

  16. The Use of Kosher Phenotyping for Mapping QTL Affecting Susceptibility to Bovine Respiratory Disease.

    Directory of Open Access Journals (Sweden)

    Ehud Lipkin

    Full Text Available Bovine respiratory disease (BRD is the leading cause of morbidity and mortality in feedlot cattle, caused by multiple pathogens that become more virulent in response to stress. As clinical signs often go undetected and various preventive strategies failed, identification of genes affecting BRD is essential for selection for resistance. Selective DNA pooling (SDP was applied in a genome wide association study (GWAS to map BRD QTLs in Israeli Holstein male calves. Kosher scoring of lung adhesions was used to allocate 122 and 62 animals to High (Glatt Kosher and Low (Non-Kosher resistant groups, respectively. Genotyping was performed using the Illumina BovineHD BeadChip according to the Infinium protocol. Moving average of -logP was used to map QTLs and Log drop was used to define their boundaries (QTLRs. The combined procedure was efficient for high resolution mapping. Nineteen QTLRs distributed over 13 autosomes were found, some overlapping previous studies. The QTLRs contain polymorphic functional and expression candidate genes to affect kosher status, with putative immunological and wound healing activities. Kosher phenotyping was shown to be a reliable means to map QTLs affecting BRD morbidity.

  17. The Use of Kosher Phenotyping for Mapping QTL Affecting Susceptibility to Bovine Respiratory Disease.

    Science.gov (United States)

    Lipkin, Ehud; Strillacci, Maria Giuseppina; Eitam, Harel; Yishay, Moran; Schiavini, Fausta; Soller, Morris; Bagnato, Alessandro; Shabtay, Ariel

    2016-01-01

    Bovine respiratory disease (BRD) is the leading cause of morbidity and mortality in feedlot cattle, caused by multiple pathogens that become more virulent in response to stress. As clinical signs often go undetected and various preventive strategies failed, identification of genes affecting BRD is essential for selection for resistance. Selective DNA pooling (SDP) was applied in a genome wide association study (GWAS) to map BRD QTLs in Israeli Holstein male calves. Kosher scoring of lung adhesions was used to allocate 122 and 62 animals to High (Glatt Kosher) and Low (Non-Kosher) resistant groups, respectively. Genotyping was performed using the Illumina BovineHD BeadChip according to the Infinium protocol. Moving average of -logP was used to map QTLs and Log drop was used to define their boundaries (QTLRs). The combined procedure was efficient for high resolution mapping. Nineteen QTLRs distributed over 13 autosomes were found, some overlapping previous studies. The QTLRs contain polymorphic functional and expression candidate genes to affect kosher status, with putative immunological and wound healing activities. Kosher phenotyping was shown to be a reliable means to map QTLs affecting BRD morbidity.

  18. Value of Von Willebrand Factor as a Predictor for Osteoporosis Development in Women with Hypothyroidism

    Directory of Open Access Journals (Sweden)

    I.V. Pankiv

    2015-08-01

    Full Text Available The paper presents the study of the value of von Willebrand factor as a marker of endothelial dysfunction for osteoporosis development and for prediction of risk of its formation in women with hypothyroidism. Postmenopausal women with hypothyroidism have significant increase of von Willebrand factor at lumbar osteopenia. High concentrations of von Willebrand factor in women with hypothyroidism follows to consider it as a predictor for osteoporosis development. Increased level of С-reactive protein belongs to the unfavorable prognostic signs in relation to the decline of bone mineral density for patients with primary hypothyroidism.

  19. Distribution of von Willebrand factor levels in young women with and without bleeding symptoms: influence of ABO blood group and promoter haplotypes

    DEFF Research Database (Denmark)

    Lethagen, S.; Hillarp, A.; Ekholm, C.

    2008-01-01

    The normal distribution of von Willebrand factor (VWF) levels is wide. Low levels are associated with bleeding symptoms and von Willebrand disease (VWD). We have recently described a high prevalence of bleeding symptoms in a whole age group of young females (n = 1,019) from Malmo, Sweden....... It was the objective of the present study to evaluate the distribution of VWF levels in young females with or without bleeding symptoms in this population, and the influence of ABO blood group and promoter haplotypes on VWF levels and to identify a possible increased prevalence of VWD in females with bleeding symptoms....... A random selection of the female age group (n = 246), into a study group (n = 176) with, and a control group (n = 70) without bleeding symptoms, was evaluated. Eighteen girls had VWF:RCo below the reference range, of which 17 belonged to the study group (17/176, 9.7%), and one to the control group (1/70, 1...

  20. Disruption of the gaa Gene in Zebrafish Fails to Generate the Phenotype of Classical Pompe Disease.

    Science.gov (United States)

    Wu, Jing; Yang, Yi; Sun, Chengjun; Sun, Shaoyang; Li, Qiang; Yao, Yuxiao; Fei, Fei; Lu, Lingeng; Chang, Zhuo; Zhang, Wenting; Wang, Xu; Luo, Feihong

    2017-01-01

    The underlying pathogenic lesions of glycogen storage disease type II (GSD II) and the diversity of this disease among different species are still under exploration. Thus, we created an acid alpha-glucosidase (gaa) gene-mutated zebrafish model of GSD II and examined the sequential pathogenic changes. gaa mRNA and protein expression, enzymatic activity, and lysosomal glycogen accumulation were assessed, and the phenotypic changes were compared between wild-type (WT) and gaa-mutated zebrafish. The presence of a Δ13 frameshift mutation in the gaa gene was confirmed at both the DNA and transcribed mRNA levels by Sanger sequencing. The relative amount of gaa mRNA was decreased before 2 days postfertilization (dpf), after which it unexpectedly increased in the mutant compared with the WT zebrafish. Consistent with the mRNA expression, the Gaa enzymatic activity in the mutant was downregulated before 3 dpf, while the Gaa protein level was slightly decreased at 4 dpf and was maintained at a consistent level in the adult gaa mutant muscle tissue. However, more than half of the adult mutant zebrafish exhibited excessive glycogen accumulation in the liver and muscles, along with the presence of autophagosomes, as determined by transmission electron microscopy. Thus, we have successfully generated a frameshift mutation in the gaa gene in zebrafish. The unique gaa gene expression changes and mild GSD II features during the adult stage strongly indicate the existence of species-specific differences, as well as an underlying compensatory network, which may warrant further examination.

  1. Phenotypic Screening Identifies Modulators of Amyloid Precursor Protein Processing in Human Stem Cell Models of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Philip W. Brownjohn

    2017-04-01

    Full Text Available Human stem cell models have the potential to provide platforms for phenotypic screens to identify candidate treatments and cellular pathways involved in the pathogenesis of neurodegenerative disorders. Amyloid precursor protein (APP processing and the accumulation of APP-derived amyloid β (Aβ peptides are key processes in Alzheimer's disease (AD. We designed a phenotypic small-molecule screen to identify modulators of APP processing in trisomy 21/Down syndrome neurons, a complex genetic model of AD. We identified the avermectins, commonly used as anthelmintics, as compounds that increase the relative production of short Aβ peptides at the expense of longer, potentially more toxic peptides. Further studies demonstrated that this effect is not due to an interaction with the core γ-secretase responsible for Aβ production. This study demonstrates the feasibility of phenotypic drug screening in human stem cell models of Alzheimer-type dementia, and points to possibilities for indirectly modulating APP processing, independently of γ-secretase modulation.

  2. Genetic spectrum of Saudi Arabian patients with antenatal cystic kidney disease and ciliopathy phenotypes using a targeted renal gene panel.

    Science.gov (United States)

    Al-Hamed, Mohamed H; Kurdi, Wesam; Alsahan, Nada; Alabdullah, Zainab; Abudraz, Rania; Tulbah, Maha; Alnemer, Maha; Khan, Rubina; Al-Jurayb, Haya; Alahmed, Ahmed; Tahir, Asma I; Khalil, Dania; Edwards, Noel; Al Abdulaziz, Basma; Binhumaid, Faisal S; Majid, Salma; Faquih, Tariq; El-Kalioby, Mohamed; Abouelhoda, Mohamed; Altassan, Nada; Monies, Dorota; Meyer, Brian; Sayer, John A; Albaqumi, Mamdouh

    2016-05-01

    Inherited cystic kidney disorders are a common cause of end-stage renal disease. Over 50 ciliopathy genes, which encode proteins that influence the structure and function of the primary cilia, are implicated in cystic kidney disease. To define the phenotype and genotype of cystic kidney disease in fetuses and neonates, we correlated antenatal ultrasound examination and postnatal renal ultrasound examination with targeted exon sequencing, using a renal gene panel. A cohort of 44 families in whom antenatal renal ultrasound scanning findings in affected cases included bilateral cystic kidney disease, echogenic kidneys or enlarged kidneys was investigated. In this cohort, disease phenotypes were severe with 36 cases of stillbirth or perinatal death. Extra renal malformations, including encephalocele, polydactyly and heart malformations, consistent with ciliopathy phenotypes, were frequently detected. Renal gene panel testing identified causative mutations in 21 out of 34 families (62%), where patient and parental DNA was available. In the remaining 10 families, where only parental DNA was available, 7 inferred causative mutations were found. Together, mutations were found in 12 different genes with a total of 13 novel pathogenic variants, including an inferred novel variant in NEK8. Mutations in CC2D2A were the most common cause of an antenatal cystic kidney disease and a suspected ciliopathy in our cohort. In families with ciliopathy phenotypes, mutational analysis using a targeted renal gene panel allows a rapid molecular diagnosis and provides important information for patients, parents and their physicians. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  3. Different prion disease phenotypes result from inoculation of cattle with two temporally separated sources of sheep scrapie from Great Britain

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    Hawkins Steve AC

    2006-10-01

    Full Text Available Abstract Background Given the theoretical proposal that bovine spongiform encephalopathy (BSE could have originated from sheep scrapie, this study investigated the pathogenicity for cattle, by intracerebral (i.c. inoculation, of two pools of scrapie agents sourced in Great Britain before and during the BSE epidemic. Two groups of ten cattle were each inoculated with pools of brain material from sheep scrapie cases collected prior to 1975 and after 1990. Control groups comprised five cattle inoculated with sheep brain free from scrapie, five cattle inoculated with saline, and for comparison with BSE, naturally infected cattle and cattle i.c. inoculated with BSE brainstem homogenate from a parallel study. Phenotypic characterisation of the disease forms transmitted to cattle was conducted by morphological, immunohistochemical, biochemical and biological methods. Results Disease occurred in 16 cattle, nine inoculated with the pre-1975 inoculum and seven inoculated with the post-1990 inoculum, with four cattle still alive at 83 months post challenge (as at June 2006. The different inocula produced predominantly two different disease phenotypes as determined by histopathological, immunohistochemical and Western immunoblotting methods and biological characterisation on transmission to mice, neither of which was identical to BSE. Whilst the disease presentation was uniform in all scrapie-affected cattle of the pre-1975 group, the post-1990 inoculum produced a more variable disease, with two animals sharing immunohistochemical and molecular profile characteristics with animals in the pre-1975 group. Conclusion The study has demonstrated that cattle inoculated with different pooled scrapie sources can develop different prion disease phenotypes, which were not consistent with the phenotype of BSE of cattle and whose isolates did not have the strain typing characteristics of the BSE agent on transmission to mice.

  4. SNAP23 Regulates Endothelial Exocytosis of von Willebrand Factor.

    Science.gov (United States)

    Zhu, Qiuyu Martin; Zhu, Qiuyu; Yamakuchi, Munekazu; Lowenstein, Charles J

    2015-01-01

    Endothelial exocytosis regulates vascular thrombosis and inflammation. The trafficking and release of endothelial vesicles is mediated by SNARE (Soluble NSF Attachment protein REceptors) molecules, but the exact identity of endothelial SNAREs has been unclear. Three SNARE molecules form a ternary complex, including isoforms of the syntaxin (STX), vesicle-associated membrane protein (VAMP), and synaptosomal-associated protein (SNAP) families. We now identify SNAP23 as the predominant endothelial SNAP isoform that mediates endothelial exocytosis of von Willebrand Factor (VWF). SNAP23 was localized to the plasma membrane. Knockdown of SNAP23 decreased endothelial exocytosis, suggesting it is important for endothelial exocytosis. SNAP23 interacted with the endothelial exocytic machinery, and formed complexes with other known endothelial SNARE molecules. Taken together, these data suggest that SNAP23 is a key component of the endothelial SNARE machinery that mediates endothelial exocytosis.

  5. Genotypic Diversity of Clinical Actinomyces Species: Phenotype, Source, and Disease Correlation among Genospecies

    Science.gov (United States)

    Clarridge III, Jill E.; Zhang, Qing

    2002-01-01

    novel genospecies. One novel group with three strains, Actinomyces houstonensis sp. nov., was phenotypically similar to A. meyeri and A. turicensis but was genotypically closest to Actinomyces neuii. A. houstonensis sp. nov. was associated with abscesses. Our data documented consistent site and disease associations for 21 genogroups of Actinomyces spp. that provide greater insights into appropriate treatments. However, we also demonstrated a complexity within the Actinomyces genus that compromises the biochemical identification of Actinomyces that can be performed in most clinical laboratories. It is our hope that this large group of well-defined strains will be used to find a simple and accurate biochemical test for differentiation of the species in routine laboratories. PMID:12202591

  6. Novel mutations in the PRX and the MTMR2 genes are responsible for unusual Charcot-Marie-Tooth disease phenotypes.

    Science.gov (United States)

    Nouioua, Sonia; Hamadouche, Tarik; Funalot, Benoit; Bernard, Rafaëlle; Bellatache, Nora; Bouderba, Radia; Grid, Djamel; Assami, Salima; Benhassine, Traki; Levy, Nicolas; Vallat, Jean-Michel; Tazir, Meriem

    2011-08-01

    Autosomal recessive Charcot-Marie-Tooth diseases, relatively common in Algeria due to high prevalence of consanguineous marriages, are clinically and genetically heterogeneous. We report on two consanguineous families with demyelinating autosomal recessive Charcot-Marie-Tooth disease (CMT4) associated with novel homozygous mutations in the MTMR2 gene, c.331dupA (p.Arg111LysfsX24) and PRX gene, c.1090C>T (p.Arg364X) respectively, and peculiar clinical phenotypes. The three patients with MTMR2 mutations (CMT4B1 family) had a typical phenotype of severe early onset motor and sensory neuropathy with typical focally folded myelin on nerve biopsy. Associated clinical features included vocal cord paresis, prominent chest deformities and claw hands. Contrasting with the classical presentation of CMT4F (early-onset Dejerine-Sottas phenotype), the four patients with PRX mutations (CMT4F family) had essentially a late age of onset and a protracted and relatively benign evolution, although they presented marked spine deformities. These observations broaden the spectrum of clinical phenotypes associated with these two CMT4 forms. Copyright © 2011 Elsevier B.V. All rights reserved.

  7. Distinct phenotypes of speech and voice disorders in Parkinson's disease after subthalamic nucleus deep brain stimulation.

    Science.gov (United States)

    Tsuboi, Takashi; Watanabe, Hirohisa; Tanaka, Yasuhiro; Ohdake, Reiko; Yoneyama, Noritaka; Hara, Kazuhiro; Nakamura, Ryoichi; Watanabe, Hazuki; Senda, Jo; Atsuta, Naoki; Ito, Mizuki; Hirayama, Masaaki; Yamamoto, Masahiko; Fujimoto, Yasushi; Kajita, Yasukazu; Wakabayashi, Toshihiko; Sobue, Gen

    2015-08-01

    To elucidate the phenotypes and pathophysiology of speech and voice disorders in Parkinson's disease (PD) with subthalamic nucleus deep brain stimulation (STN-DBS). We conducted a cross-sectional study on 76 PD patients treated with bilateral STN-DBS (PD-DBS) and 33 medically treated PD patients (PD-Med). Speech and voice functions, electrode positions, motor function and cognitive function were comprehensively assessed. Moreover, speech and voice functions were compared between the on-stimulation and off-stimulation conditions in 42 PD-DBS patients. Speech and voice disorders in PD-DBS patients were significantly worse than those in PD-Med patients. Factor analysis and subsequent cluster analysis classified PD-DBS patients into five clusters: relatively good speech and voice function type, 25%; stuttering type, 24%; breathy voice type, 16%; strained voice type, 18%; and spastic dysarthria type, 17%. STN-DBS ameliorated voice tremor or low volume; however, it deteriorated the overall speech intelligibility in most patients. Breathy voice did not show significant changes and stuttering exhibited slight improvement after stopping stimulation. In contrast, patients with strained voice type or spastic dysarthria type showed a greater improvement after stopping stimulation. Spastic dysarthria type patients showed speech disorders similar to spastic dysarthria, which is associated with bilateral upper motor neuron involvement. Strained voice type and spastic dysarthria type appeared to be related to current diffusion to the corticobulbar fibres. Stuttering and breathy voice can be aggravated by STN-DBS, but are mainly due to aging or PD itself. Strained voice and spastic dysarthria are considered corticobulbar side effects. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  8. Obesity phenotype and coronary heart disease risk as estimated by the Framingham risk score.

    Science.gov (United States)

    Park, Yong Soon; Kim, Jun-Su

    2012-03-01

    There are conflicting data as to whether general or abdominal obesity is a better predictor of cardiovascular risk. This cross-sectional study involved 4,573 subjects aged 30 to 74 yr who participated in the Fourth Korea National Health and Nutrition Examination Survey conducted in 2008. Obesity phenotype was classified by means of body mass index (BMI) and waist circumference (WC), and participants were categorized into 4 groups. Individuals' 10-yr risk of coronary heart diseases (CHD) was determined from the Framingham risk score. Subjects with obese WC had a higher proportion of high risk for CHD compared to the normal WC group, irrespective of BMI level. Relative to subjects with normal BMI/normal WC, the adjusted odds ratios (ORs) of normal BMI/obese WC group (OR 2.93 [1.70, 5.04] and OR 3.10 [1.49, 6.46]) for CHD risk in male were higher than obese BMI/obese WC group (OR 1.91 [1.40, 2.61] and OR 1.70 [1.16, 2.47]), whereas the adjusted ORs of obese BMI/obese WC group (OR 1.94 [1.24, 3.04] and OR 3.92 [1.75, 8.78]) were higher than the others in female. Subjects with obese BMI/normal WC were not significantly associated with 10-yr CHD risk in men (P = 0.449 and P = 0.067) and women (P = 0.702 and P = 0.658). WC is associated with increased CHD risk regardless of the level of BMI. Men with normal BMI and obese WC tend to be associated with CHD risk than those with obese BMI and obese WC.

  9. Maternal transmission of Alzheimer's disease: Prodromal metabolic phenotype and the search for genes

    Directory of Open Access Journals (Sweden)

    Mosconi Lisa

    2010-02-01

    Full Text Available Abstract After advanced age, having a parent affected with Alzheimer's disease (AD is the most significant risk factor for developing AD among cognitively normal (NL individuals. Although rare genetic mutations have been identified among the early-onset forms of familial AD (EOFAD, the genetics of the more common forms of late-onset AD (LOAD remain elusive. While some LOAD cases appear to be sporadic in nature, genetically mediated risk is evident from the familial aggregation of many LOAD cases. The patterns of transmission and biological mechanisms through which a family history of LOAD confers risk to the offspring are not known. Brain imaging studies using 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET have shown that NL individuals with a maternal history of LOAD, but not with a paternal family history, express a phenotype characterised by a pattern of progressive reductions of brain glucose metabolism, similar to that in AD patients. As maternally inherited AD may be associated with as many as 20 per cent of the total LOAD population, understanding the causes and mechanisms of expression of this form of AD is of great relevance. This paper reviews known genetic mutations implicated in EOFAD and their effects on brain chemistry, structure and function; epidemiology and clinical research findings in LOAD, including in vivo imaging findings showing selective patterns of hypometabolism in maternally inherited AD; possible genetic mechanisms involved in maternal transmission of AD, including chromosome X mutations, mitochondrial DNA and imprinting; and genetic mechanisms involved in other neurological disorders with known or suspected maternal inheritance. The review concludes with a discussion of the potential role of brain imaging for identifying endophenotypes in NL individuals at risk for AD, and for directing investigation of potential susceptibility genes for AD.

  10. Depletion of the IKBKAP ortholog in zebrafish leads to hirschsprung disease-like phenotype.

    Science.gov (United States)

    Cheng, William Wai-Chun; Tang, Clara Sze-Man; Gui, Hong-Sheng; So, Man-Ting; Lui, Vincent Chi-Hang; Tam, Paul Kwong-Hang; Garcia-Barcelo, Maria-Mercè

    2015-02-21

    To investigate the role of IKBKAP (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein) in the development of enteric nervous system (ENS) and Hirschsprung disease (HSCR). In this study, we injected a morpholino that blocked the translation of ikbkap protein to 1-cell stage zebrafish embryos. The phenotype in the ENS was analysed by antibody staining of the pan-neuronal marker HuC/D followed by enteric neuron counting. The mean numbers of enteric neurons were compared between the morphant and the control. We also studied the expressions of ret and phox2bb, which are involved in ENS development, in the ikbkap morpholino injected embryos by quantitative reverse transcriptase polymerase chain reaction and compared them with the control. We observed aganglionosis (χ2, P<0.01) and a reduced number of enteric neurons (38.8±9.9 vs 50.2±17.3, P<0.05) in the zebrafish embryos injected with ikbkap translation-blocking morpholino (morphant) when compared with the control embryos. Specificity of the morpholino was confirmed by similar results obtained using a second non-overlapping morpholino that blocked the translation of ikbkap. We further studied the morphant by analysing the expression levels of genes involved in ENS development such as ret, phox2bb and sox10, and found that phox2bb, the ortholog of human PHOX2B, was significantly down-regulated (0.51±0.15 vs 1.00±0, P<0.05). Although we also observed a reduction in the expression of ret, the difference was not significant. Loss of IKBKAP contributed to HSCR as demonstrated by functional analysis in zebrafish embryos.

  11. Differential localization of P-selectin and von Willebrand factor during megakaryocyte maturation

    DEFF Research Database (Denmark)

    Zingariello, M; Fabucci, M E; Bosco, D

    2010-01-01

    Willebrand factor are two proteins present in the alpha-granules that recognize P-selectin glycoprotein ligand on neutrophils and collagen in the subendothelial matrix. These proteins may play an important role in determining the differential release of the alpha-granule contents in response to external....... These observations support the hypothesis that P-selectin and von Willebrand factor may ensure differential release of the alpha-granule content in response to external stimuli....

  12. Structural specializations of A2, a force-sensing domain in the ultralarge vascular protein von Willebrand factor

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Qing; Zhou, Yan-Feng; Zhang, Cheng-Zhong; Zhang, Xiaohui; Lu, Chafen; Springer, Timothy A.; Harvard-Med

    2009-06-30

    The lengths of von Willebrand factor (VWF) concatamers correlate with hemostatic potency. After secretion in plasma, length is regulated by hydrodynamic shear force-dependent unfolding of the A2 domain, which is then cleaved by a specific protease. The 1.9-{angstrom} crystal structure of the A2 domain demonstrates evolutionary adaptations to this shear sensor function. Unique among VWF A (VWA) domains, A2 contains a loop in place of the {alpha}4 helix, and a cis-proline. The central {beta}4-strand is poorly packed, with multiple side-chain rotamers. The Tyr-Met cleavage site is buried in the {beta}4-strand in the central hydrophobic core, and the Tyr structurally links to the C-terminal {alpha}6-helix. The {alpha}6-helix ends in 2 Cys residues that are linked by an unusual vicinal disulfide bond that is buried in a hydrophobic pocket. These features may narrow the force range over which unfolding occurs and may also slow refolding. Von Willebrand disease mutations, which presumably lower the force at which A2 unfolds, are illuminated by the structure.

  13. Innate and adaptive cellular phenotypes contributing to pulmonary disease in mice after respiratory syncytial virus immunization and infection.

    Science.gov (United States)

    Lee, Young-Tae; Kim, Ki-Hye; Hwang, Hye Suk; Lee, Youri; Kwon, Young-Man; Ko, Eun-Ju; Jung, Yu-Jin; Lee, Yu-Na; Kim, Min-Chul; Kang, Sang-Moo

    2015-11-01

    Respiratory syncytial virus (RSV) is the major leading cause of infantile viral bronchiolitis. However, cellular phenotypes contributing to the RSV protection and vaccine-enhanced disease remain largely unknown. Upon RSV challenge, we analyzed phenotypes and cellularity in the lung of mice that were naïve, immunized with formalin inactivated RSV (FI-RSV), or re-infected with RSV. In comparison with naïve and live RSV re-infected mice, the high levels of eosinophils, neutrophils, plasmacytoid and CD11b(+) dendritic cells, and IL-4(+) CD4(+) T cells were found to be contributing to pulmonary inflammation in FI-RSV immune mice despite lung viral clearance. Alveolar macrophages appeared to play differential roles in protection and inflammation upon RSV infection of different RSV immune mice. These results suggest that multiple innate and adaptive immune components differentially contribute to RSV disease and inflammation. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Flow-induced elongation of von Willebrand factor precedes tension-dependent activation.

    Science.gov (United States)

    Fu, Hongxia; Jiang, Yan; Yang, Darren; Scheiflinger, Friedrich; Wong, Wesley P; Springer, Timothy A

    2017-08-23

    Von Willebrand factor, an ultralarge concatemeric blood protein, must bind to platelet GPIbα during bleeding to mediate hemostasis, but not in the normal circulation to avoid thrombosis. Von Willebrand factor is proposed to be mechanically activated by flow, but the mechanism remains unclear. Using microfluidics with single-molecule imaging, we simultaneously monitored reversible Von Willebrand factor extension and binding to GPIbα under flow. We show that Von Willebrand factor is activated through a two-step conformational transition: first, elongation from compact to linear form, and subsequently, a tension-dependent local transition to a state with high affinity for GPIbα. High-affinity sites develop only in upstream regions of VWF where tension exceeds ~21 pN and depend upon electrostatic interactions. Re-compaction of Von Willebrand factor is accelerated by intramolecular interactions and increases GPIbα dissociation rate. This mechanism enables VWF to be locally activated by hydrodynamic force in hemorrhage and rapidly deactivated downstream, providing a paradigm for hierarchical mechano-regulation of receptor-ligand binding.Von Willebrand factor (VWF) is a blood protein involved in clotting and is proposed to be activated by flow, but the mechanism is unknown. Here the authors show that VWF is first converted from a compact to linear form by flow, and is subsequently activated to bind GPIbα in a tension-dependent manner.

  15. 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.

  16. Controlling the Regional Identity of hPSC-Derived Neurons to Uncover Neuronal Subtype Specificity of Neurological Disease Phenotypes

    Directory of Open Access Journals (Sweden)

    Kent Imaizumi

    2015-12-01

    Full Text Available The CNS contains many diverse neuronal subtypes, and most neurological diseases target specific subtypes. However, the mechanism of neuronal subtype specificity of disease phenotypes remains elusive. Although in vitro disease models employing human pluripotent stem cells (PSCs have great potential to clarify the association of neuronal subtypes with disease, it is currently difficult to compare various PSC-derived subtypes. This is due to the limited number of subtypes whose induction is established, and different cultivation protocols for each subtype. Here, we report a culture system to control the regional identity of PSC-derived neurons along the anteroposterior (A-P and dorsoventral (D-V axes. This system was successfully used to obtain various neuronal subtypes based on the same protocol. Furthermore, we reproduced subtype-specific phenotypes of amyotrophic lateral sclerosis (ALS and Alzheimer’s disease (AD by comparing the obtained subtypes. Therefore, our culture system provides new opportunities for modeling neurological diseases with PSCs.

  17. Relationship of disease-associated gene expression to cardiac phenotype is buffered by genetic diversity and chromatin regulation.

    Science.gov (United States)

    Karbassi, Elaheh; Monte, Emma; Chapski, Douglas J; Lopez, Rachel; Rosa Garrido, Manuel; Kim, Joseph; Wisniewski, Nicholas; Rau, Christoph D; Wang, Jessica J; Weiss, James N; Wang, Yibin; Lusis, Aldons J; Vondriska, Thomas M

    2016-08-01

    Expression of a cohort of disease-associated genes, some of which are active in fetal myocardium, is considered a hallmark of transcriptional change in cardiac hypertrophy models. How this transcriptome remodeling is affected by the common genetic variation present in populations is unknown. We examined the role of genetics, as well as contributions of chromatin proteins, to regulate cardiac gene expression and heart failure susceptibility. We examined gene expression in 84 genetically distinct inbred strains of control and isoproterenol-treated mice, which exhibited varying degrees of disease. Unexpectedly, fetal gene expression was not correlated with hypertrophic phenotypes. Unbiased modeling identified 74 predictors of heart mass after isoproterenol-induced stress, but these predictors did not enrich for any cardiac pathways. However, expanded analysis of fetal genes and chromatin remodelers as groups correlated significantly with individual systemic phenotypes. Yet, cardiac transcription factors and genes shown by gain-/loss-of-function studies to contribute to hypertrophic signaling did not correlate with cardiac mass or function in disease. Because the relationship between gene expression and phenotype was strain specific, we examined genetic contribution to expression. Strikingly, strains with similar transcriptomes in the basal heart did not cluster together in the isoproterenol state, providing comprehensive evidence that there are different genetic contributors to physiological and pathological gene expression. Furthermore, the divergence in transcriptome similarity versus genetic similarity between strains is organ specific and genome-wide, suggesting chromatin is a critical buffer between genetics and gene expression. Copyright © 2016 the American Physiological Society.

  18. von Willebrand Factor and Oxidative Stress Parameters in Acute Coronary Syndromes

    Directory of Open Access Journals (Sweden)

    Zoran Koprivica

    2011-01-01

    Full Text Available Considering the role of von Willebrand factor (vWf in hemostasis, and the role of oxidative stress in the development of endothelial dysfunction and atherosclerotic disease, the aim of our study was to investigate the relationship between vWf, parameters of oxidative stress and different types of acute coronary syndromes (ACS. Levels of vWf activity (vWfAct, vWf antigen (vWfAg, nitric oxide (estimated through nitrites–NO2 −, superoxide anion radical (O2 −, hydrogen peroxide (H2O2, index of lipid peroxidation (estimated through thiobarbituric acid reactive substances–TBARS, superoxide dismutase (SOD and catalase (CAT activity of 115 patients were compared with those of 40 healthy controls. ACS patients had significantly higher vWfAct and vWfAg levels, as well as TBARS levels, while their levels of NO2 −, H2O2, SOD and CAT activities were lower than controls'. vWfAg showed high specificity and sensitivity as a test to reveal healthy or diseased subjects. Multivariant logistic regression marked only vWfAg and TBARS as parameters that were under independent effect of ACS type. The results of our study support the implementation of vWf in clinical rutine and into therapeutic targets, and suggest that ACS patients are in need of antioxidant supplementation to improve their impaired antioxidant defence.

  19. Distinct disease phenotypes linked to different combinations of GAA mutations in a large late-onset GSDII sibship.

    Science.gov (United States)

    Sampaolo, Simone; Esposito, Teresa; Farina, Olimpia; Formicola, Daniela; Diodato, Daria; Gianfrancesco, Fernando; Cipullo, Federica; Cremone, Gaetana; Cirillo, Mario; Del Viscovo, Luca; Toscano, Antonio; Angelini, Corrado; Di Iorio, Giuseppe

    2013-10-10

    Glycogenosis type II (GSDII or Pompe disease) is an autosomal recessive disease, often characterized by a progressive accumulation of glycogen within lysosomes caused by a deficiency of α-1,4-glucosidase (GAA; acid maltase), a key enzyme of the glycogen degradation pathway. To date, more than 326 different mutations in the GAA gene have been identified in patients with GSDII but the course of the disease is difficult to be predicted on the basis of molecular genetic changes. Studies on large informative families are advisable to better define how genetics and non genetics factors like exercise and diet may influence the clinical phenotype. In this study, we report on clinical, instrumental, and pathological features as well as on molecular analysis of a family with 10 out of 13 siblings affected by late-onset Pompe disease. Three mutations segregated in the family, two of which are novel mutations. Siblings showing a more severe phenotype were compound heterozygous for c.118C > T [p.R40X] and c.2647-7G > A [p.N882fs] on GAA, whereas, two patients showing a mild phenotype were compound heterozygous c.2647-7G > A [p.N882fs] and c.2276G > C [p.G759A] mutations. Quantitative expression analysis showed, in the patients carrying p.R40X/ p.N882fs, a significant (p 0.01) correlation between the levels of expression of the mutated allele and the age at onset of the disease. As far as we know, this is the largest informative family with late-onset Pompe disease described in the literature showing a peculiar complex set of mutations of GAA gene that may partially elucidate the clinical heterogeneity of this family.

  20. Very mild disease phenotype of congenic CftrTgH(neoimHgu cystic fibrosis mice

    Directory of Open Access Journals (Sweden)

    Leonhard-Marek Sabine

    2008-04-01

    Full Text Available Abstract Background A major boost to cystic fibrosis disease research was given by the generation of various mouse models using gene targeting in embryonal stem cells. Moreover, the introduction of the same mutation on different inbred strains generating congenic strains facilitated the search for modifier genes. From the original CftrTgH(neoimHgu mouse model with a divergent genetic background (129/Sv, C57BL/6, HsdOla:MF1 two inbred mutant mouse strains CF/1-CftrTgH(neoimHgu and CF/3-CftrTgH(neoimHgu had been generated using strict brother × sister mating. CF/1-CftrTgH(neoimHgu and CF/3-CftrTgH(neoimHgu mice were fertile and showed normal growth and lifespan. In this work the CftrTgH(neoimHgu insertional mutation was backcrossed from CF/3-CftrTgH(neoimHgu onto the inbred backgrounds C57BL/6J and DBA/2J generating congenic animals in order to clarify the differential impact of the Cftr mutation and the genetic background on the disease phenotype of the cystic fibrosis mutant mice. Clinical and electrophysiological features of the two congenic strains were compared with those of CF/1-CftrTgH(neoimHgu and CF/3-CftrTgH(neoimHgu and wild type controls. Results Under the standardized housing conditions of the animal facility, the four mouse strains CF/1-CftrTgH(neoimHgu, CF/3-CftrTgH(neoimHgu, D2.129P2(CF/3-CftrTgH(neoimHgu and B6.129P2(CF/3-CftrTgH(neoimHgu exhibited normal life expectancy. Growth of congenic cystic fibrosis mice was comparable with that of wild type controls. All mice but D2.129P2(CF/3-CftrTgH(neoimHgu females were fertile. Short circuit current measurements revealed characteristic response profiles of the HsdOla:MF1, DBA/2J and C57BL/6J backgrounds in nose, ileum and colon. All cystic fibrosis mouse lines showed the disease-typical hyperresponsiveness to amiloride in the respiratory epithelium. The mean chloride secretory responses to carbachol or forskolin were 15–100% of those of the cognate wild type control animals

  1. Chronic Mild Stress Assay Leading to Early Onset and Propagation of Alzheimer's Disease Phenotype in Mouse Models.

    Science.gov (United States)

    Cuadrado-Tejedor, Mar; García-Osta, Ana

    2016-01-01

    A comprehensive chronic mild stress (CMS) procedure is presented, which consists in the application of unpredictable mild stressors to animal models in a random order for several weeks. This assay can be applied to Alzheimer's disease (AD) mouse models, leading to accelerated onset and increased severity of AD phenotypes and signs, including memory deficits and the accumulation of amyloid-β and phospho-tau. These assays open the way towards advanced studies on the influence of sustained mild stress, stress responses and pathways on the onset and propagation of Alzheimer's disease.

  2. 24-HOUR ARTERIAL STIFFNESS VALUES IN MEN WITH DIFFERENT PHENOTYPES OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE CONCURRENT WITH HYPERTENSION

    Directory of Open Access Journals (Sweden)

    N. A. Karoli

    2015-01-01

    Full Text Available Objective: to study the specific features of the daily arterial stiffness (AS profile in men with different phenotypes of chronic obstructive pulmonary disease (COPD concurrent with hypertension. Subjects and methods. The investigation enrolled 78 male patients with COPD and hypertension. The patients were divided according to COPD phenotypes into 2 groups: 1 COPD patients with emphysema; 2 those with bronchitis. The exclusion criteria were less than 40 years and more than 80 years of age; diabetes mellitus; coronary heart disease; vascular diseases; an exacerbation of chronic diseases; bronchial and pulmonary diseases of another etiology. The patients underwent 24-hour blood pressure and AS monitoring, external respiratory function testing: spirography with a short-acting β2-agonist test, a six-minute walk test at baseline and after a hemoglobin oxygen saturation test, and a CAT test. Results. The patients of both groups were observed to have a statistically significant increase in (dP/dtmax as compared to those of the control group (p < 0.05; p < 0.01 in both the daytime and nighttime. In these periods, the COPD patients with emphysema had a higher AIx than those with bronchitis (p < 0.001. There was a statistically significantly (p < 0.001 higher AIx in the nighttime than in the daytime in Groups 1 and 2 patients. Conclusion. The patients with different COPD phenotypes were noted to have impaired arterial elastic properties, circadian AS changes with predominantly nocturnal impaired vascular stiffness. Relationships were found between 24-hour AS values and clinicoanamnestic findings. 

  3. Apo(a) phenotyping and long-term prognosis for coronary artery disease. : Apo(a) phenotype and coronary artery disease.

    OpenAIRE

    Baños-González, M. A.; Peña-Duque, M. A.; Anglés-Cano, Eduardo; Martinez-Rios, M. A.; Bahena, A.; Valente-Acosta, B.; Cardoso-Saldaña, G.; Angulo-Ortíz, J.; De La Peña-Díaz, A.

    2010-01-01

    International audience; Objectives Identify whether the plasma concentration of Lp(a), apo(a) size or a greater affinity for fibrin predict the likelihood of cardiac death, non-fatal myocardial infarction, unstable angina, the need for additional revascularization, and stroke (MACCE). Design and methods We analyzed the clinical prognosis of 68 patients with coronary artery disease included in a case-controlled study which evaluated Lp(a) concentration, apo(a) size, and Lp(a) fibrin-binding. C...

  4. Genome-wide association study of N370S homozygous Gaucher disease reveals the candidacy of CLN8 gene as a genetic modifier contributing to extreme phenotypic variation

    NARCIS (Netherlands)

    Zhang, Clarence K.; Stein, Philip B.; Liu, Jun; Wang, Zuoheng; Yang, Ruhua; Cho, Judy H.; Gregersen, Peter K.; Aerts, Johannes M. F. G.; Zhao, Hongyu; Pastores, Gregory M.; Mistry, Pramod K.

    2012-01-01

    Mutations in GBA1 gene result in defective acid beta-glucosidase and the complex phenotype of Gaucher disease (GD) related to the accumulation of glucosylceramide-laden macrophages. The phenotype is highly variable even among patients harboring identical GBA1 mutations. We hypothesize that modifier

  5. The influence of radiographic phenotype and smoking status on peripheral blood biomarker patterns in chronic obstructive pulmonary disease.

    Directory of Open Access Journals (Sweden)

    Jessica M Bon

    2009-08-01

    Full Text Available Chronic obstructive pulmonary disease (COPD is characterized by both airway remodeling and parenchymal destruction. The identification of unique biomarker patterns associated with airway dominant versus parenchymal dominant patterns would support the existence of unique phenotypes representing independent biologic processes. A cross-sectional study was performed to examine the association of serum biomarkers with radiographic airway and parenchymal phenotypes of COPD.Serum from 234 subjects enrolled in a CT screening cohort was analyzed for 33 cytokines and growth factors using a multiplex protein array. The association of serum markers with forced expiratory volume in one second percent predicted (FEV1% and quantitative CT measurements of airway thickening and emphysema was assessed with and without stratification for current smoking status. Significant associations were found with several serum inflammatory proteins and measurements of FEV1%, airway thickening, and parenchymal emphysema independent of smoking status. The association of select analytes with airway thickening and emphysema was independent of FEV1%. Furthermore, the relationship between other inflammatory markers and measurements of physiologic obstruction or airway thickening was dependent on current smoking status.Airway and parenchymal phenotypes of COPD are associated with unique systemic serum biomarker profiles. Serum biomarker patterns may provide a more precise classification of the COPD syndrome, provide insights into disease pathogenesis and identify targets for novel patient-specific biological therapies.

  6. Cigarette Smoke Modulates Vascular Smooth Muscle Phenotype: Implications for Carotid and Cerebrovascular Disease

    Science.gov (United States)

    Jabbour, Pascal M.; Tjoumakaris, Stavropoula I.; Gonzalez, Fernando; Hasan, David M.; Rosenwasser, Robert H.; Owens, Gary K.; Koch, Walter J.; Dumont, Aaron S.

    2013-01-01

    Background The role of smooth muscle cell (SMC) phenotypic modulation in the cerebral circulation and pathogenesis of stroke has not been determined. Cigarette smoke is a major risk factor for atherosclerosis, but potential mechanisms are unclear, and its role in SMC phenotypic modulation has not been established. Methods and Results In cultured cerebral vascular SMCs, exposure to cigarette smoke extract (CSE) resulted in decreased promoter activity and mRNA expression of key SMC contractile genes (SM-α-actin, SM-22α, SM-MHC) and the transcription factor myocardin in a dose-dependent manner. CSE also induced pro-inflammatory/matrix remodeling genes (MCP-1, MMPs, TNF-α, IL-1β, NF-κB). CSE increased expression of KLF4, a known regulator of SMC differentiation, and siKLF4 inhibited CSE induced suppression of SMC contractile genes and myocardin and activation of inflammatory genes. These mechanisms were confirmed in vivo following exposure of rat carotid arteries to CSE. Chromatin immune-precipitation assays in vivo and in vitro demonstrated that CSE promotes epigenetic changes with binding of KLF4 to the promoter regions of myocardin and SMC marker genes and alterations in promoter acetylation and methylation. Conclusion CSE exposure results in phenotypic modulation of cerebral SMC through myocardin and KLF4 dependent mechanisms. These results provides a mechanism by which cigarette smoke induces a pro-inflammatory/matrix remodeling phenotype in SMC and an important pathway for cigarette smoke to contribute to atherosclerosis and stroke. PMID:23967268

  7. Phenotype-genotype correlation in Wilson disease in a large Lebanese family: association of c.2299insC with hepatic and of p. Ala1003Thr with neurologic phenotype.

    Directory of Open Access Journals (Sweden)

    Julnar Usta

    Full Text Available Genotype phenotype correlations in Wilson disease (WD are best established in homozygous patients or in compound heterozygous patients carrying the same set of mutations. We determined the clinical phenotype of patients with WD carrying the c.2298_2299insC in Exon 8 (c.2299insC or the p. Ala1003Thr missense substitution in Exon 13 mutations in the homozygous or compound heterozygous state. We investigated 76 members of a single large Lebanese family. Their genotypes were determined, and clinical assessments were carried out for affected subjects. We also performed a literature search retrieving the phenotypes of patients carrying the same mutations of our patients in the homozygous or compound heterozygous state. There were 7 consanguineous marriages in this family and the prevalence of WD was 8.9% and of carriers of ATP7B mutation 44.7%. WD was confirmed in 9 out of 76 subjects. All 9 had the c.2299insC mutation, 5 homozygous and 4-compound heterozygous with p. Ala1003Thr. Six of our patients had hepatic, 2 had neurologic and 1 had asymptomatic phenotype. Based on our data and a literature review, clear phenotypes were reported for 38 patients worldwide carrying the c.2299insC mutation. About 53% of those have hepatic and 29% have neurologic phenotype. Furthermore, there were 10 compound heterozygous patients carrying the p. Ala1003Thr mutation. Among those, 80% having c.2299insC as the second mutation had hepatic phenotype, and all others had neurologic phenotype. We hereby report an association between the c.2299insC mutation and hepatic phenotype and between the p. Ala1003Thr mutation and neurologic phenotype.

  8. Phenotype-genotype correlation in Wilson disease in a large Lebanese family: association of c.2299insC with hepatic and of p. Ala1003Thr with neurologic phenotype.

    Science.gov (United States)

    Usta, Julnar; Wehbeh, Antonios; Rida, Khaled; El-Rifai, Omar; Estiphan, Theresa Alicia; Majarian, Tamar; Barada, Kassem

    2014-01-01

    Genotype phenotype correlations in Wilson disease (WD) are best established in homozygous patients or in compound heterozygous patients carrying the same set of mutations. We determined the clinical phenotype of patients with WD carrying the c.2298_2299insC in Exon 8 (c.2299insC) or the p. Ala1003Thr missense substitution in Exon 13 mutations in the homozygous or compound heterozygous state. We investigated 76 members of a single large Lebanese family. Their genotypes were determined, and clinical assessments were carried out for affected subjects. We also performed a literature search retrieving the phenotypes of patients carrying the same mutations of our patients in the homozygous or compound heterozygous state. There were 7 consanguineous marriages in this family and the prevalence of WD was 8.9% and of carriers of ATP7B mutation 44.7%. WD was confirmed in 9 out of 76 subjects. All 9 had the c.2299insC mutation, 5 homozygous and 4-compound heterozygous with p. Ala1003Thr. Six of our patients had hepatic, 2 had neurologic and 1 had asymptomatic phenotype. Based on our data and a literature review, clear phenotypes were reported for 38 patients worldwide carrying the c.2299insC mutation. About 53% of those have hepatic and 29% have neurologic phenotype. Furthermore, there were 10 compound heterozygous patients carrying the p. Ala1003Thr mutation. Among those, 80% having c.2299insC as the second mutation had hepatic phenotype, and all others had neurologic phenotype. We hereby report an association between the c.2299insC mutation and hepatic phenotype and between the p. Ala1003Thr mutation and neurologic phenotype.

  9. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes : a genetic association study

    NARCIS (Netherlands)

    Cleynen, Isabelle; Boucher, Gabrielle; Jostins, Luke; Schumm, L. Philip; Zeissig, Sebastian; Ahmad, Tariq; Andersen, Vibeke; Andrews, Jane M.; Annese, Vito; Brand, Stephan; Brant, Steven R.; Cho, Judy H.; Daly, Mark J.; Dubinsky, Marla; Duerr, Richard H.; Ferguson, Lynnette R.; Franke, Andre; Gearry, Richard B.; Goyette, Philippe; Hakonarson, Hakon; Halfvarson, Jonas; Hov, Johannes R.; Huang, Hailang; Kennedy, Nicholas A.; Kupcinskas, Limas; Lawrance, Ian C.; Lee, James C.; Satsangi, Jack; Schreiber, Stephan; Theatre, Emilie; van der Meulen-de Jong, Andrea E.; Weersma, Rinse K.; Wilson, David C.; Parkes, Miles; Vermeire, Severine; Rioux, John D.; Mansfield, John; Silverberg, Mark S.; Radford-Smith, Graham; McGovern, Dermot P. B.; Barrett, Jeffrey C.; Lees, Charlie W.

    2015-01-01

    Background Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between

  10. Modeling Shear Induced Von Willebrand Factor Binding to Collagen

    Science.gov (United States)

    Dong, Chuqiao; Wei, Wei; Morabito, Michael; Webb, Edmund; Oztekin, Alparslan; Zhang, Xiaohui; Cheng, Xuanhong

    2017-11-01

    Von Willebrand factor (vWF) is a blood glycoprotein that binds with platelets and collagen on injured vessel surfaces to form clots. VWF bioactivity is shear flow induced: at low shear, binding between VWF and other biological entities is suppressed; for high shear rate conditions - as are found near arterial injury sites - VWF elongates, activating its binding with platelets and collagen. Based on parameters derived from single molecule force spectroscopy experiments, we developed a coarse-grain molecular model to simulate bond formation probability as a function of shear rate. By introducing a binding criterion that depends on the conformation of a sub-monomer molecular feature of our model, the model predicts shear-induced binding, even for conditions where binding is highly energetically favorable. We further investigate the influence of various model parameters on the ability to predict shear-induced binding (vWF length, collagen site density and distribution, binding energy landscape, and slip/catch bond length) and demonstrate parameter ranges where the model provides good agreement with existing experimental data. Our results may be important for understanding vWF activity and also for achieving targeted drug therapy via biomimetic synthetic molecules. National Science Foundation (NSF),Division of Mathematical Sciences (DMS).

  11. Cooperation within von Willebrand factors enhances adsorption mechanism.

    Science.gov (United States)

    Heidari, Maziar; Mehrbod, Mehrdad; Ejtehadi, Mohammad Reza; Mofrad, Mohammad R K

    2015-08-06

    von Willebrand factor (VWF) is a naturally collapsed protein that participates in primary haemostasis and coagulation events. The clotting process is triggered by the adsorption and conformational changes of the plasma VWFs localized to the collagen fibres found near the site of injury. We develop coarse-grained models to simulate the adsorption dynamics of VWF flowing near the adhesive collagen fibres at different shear rates and investigate the effect of factors such as interaction and cooperativity of VWFs on the success of adsorption events. The adsorption probability of a flowing VWF confined to the receptor field is enhanced when it encounters an adhered VWF in proximity to the collagen receptors. This enhancement is observed within a wide range of shear rates and is mostly controlled by the attractive van der Waals interactions rather than the hydrodynamic interactions among VWF monomers. The cooperativity between the VWFs acts as an effective mechanism for enhancing VWF adsorption to the collagen fibres. Additionally, this implies that the adsorption of such molecules is nonlinearly dependent on the density of flowing VWFs. These findings are important for studies of primary haemostasis as well as general adsorption dynamics processes in polymer physics. © 2015 The Author(s).

  12. Cellular copper levels determine the phenotype of the Arg875 variant of ATP7B/Wilson disease protein

    Science.gov (United States)

    Gupta, Arnab; Bhattacharjee, Ashima; Dmitriev, Oleg Y.; Nokhrin, Sergiy; Braiterman, Lelita; Hubbard, Ann L.; Lutsenko, Svetlana

    2011-01-01

    In human disorders, the genotype-phenotype relationships are often complex and influenced by genetic and/or environmental factors. Wilson disease (WD) is a monogenic disorder caused by mutations in the copper-transporting P-type ATPase ATP7B. WD shows significant phenotypic diversity even in patients carrying identical mutations; the basis for such diverse manifestations is unknown. We demonstrate that the 2623A/G polymorphism (producing the Gly875→Arg substitution in the A-domain of ATP7B) drastically alters the intracellular properties of ATP7B, whereas copper reverses the effects. Under basal conditions, the common Gly875 variant of ATP7B is targeted to the trans-Golgi network (TGN) and transports copper into the TGN lumen. In contrast, the Arg875 variant is located in the endoplasmic reticulum (ER) and does not deliver copper to the TGN. Elevated copper corrects the ATP7B-Arg875 phenotype. Addition of only 0.5–5 μM copper triggers the exit of ATP7B-Arg875 from the ER and restores copper delivery to the TGN. Analysis of the recombinant A-domains by NMR suggests that the ER retention of ATP7B-Arg875 is attributable to increased unfolding of the Arg875-containing A-domain. Copper is not required for the folding of ATP7B-Arg875 during biosynthesis, but it stabilizes protein and stimulates its activity. A chemotherapeutical drug, cisplatin, that mimics a copper-bound state of ATP7B also corrects the “disease-like” phenotype of ATP7B-Arg875 and promotes its TGN targeting and transport function. We conclude that in populations harboring the Arg875 polymorphism, the levels of bioavailable copper may play a vital role in the manifestations of WD. PMID:21406592

  13. Maternal genetic mutations as gestational and early life influences in producing psychiatric disease-like phenotypes in mice

    Directory of Open Access Journals (Sweden)

    Georgia eGleason

    2011-05-01

    Full Text Available Risk factors for psychiatric disorders have traditionally been classified as genetic or environmental. Risk (candidate genes, although typically possessing small effects, represent a clear starting point to elucidate downstream cellular/molecular pathways of disease. Environmental effects, especially during development, can also lead to altered behavior and increased risk for disease. An important environmental factor is the mother, demonstrated by the negative effects elicited by maternal gestational stress and altered maternal care. These maternal effects can also have a genetic basis (e.g. maternal genetic variability and mutations. The focus of this review is maternal genotype effects that influence the emotional development of the offspring resulting in life-long psychiatric disease-like phenotypes. We have recently found that genetic inactivation of the serotonin1A receptor (5-HT1AR and the fmr-1 gene (encoding the fragile X mental retardation protein in mouse dams results in psychiatric disease-like phenotypes in their genetically unaffected offspring. 5-HT1AR deficiency in dams results in anxiety and increased stress responsiveness in their offspring. Mice with 5-HT1AR deficient dams display altered development of the hippocampus, which could be linked to their anxiety-like phenotype. Maternal inactivation of fmr-1, like its inactivation in the offspring, results in a hyperactivity-like condition and is associated with receptor alterations in the striatum. These data indicate a high sensitivity of the offspring to maternal mutations and suggest that maternal genotype effects can increase the impact of genetic risk factors in a population by increasing the risk of the genetically normal offspring as well as by enhancing the effects of offspring mutations.

  14. Junctophilin 3 (JPH3) expansion mutations causing Huntington disease like 2 (HDL2) are common in South African patients with African ancestry and a Huntington disease phenotype.

    Science.gov (United States)

    Krause, Amanda; Mitchell, Claire; Essop, Fahmida; Tager, Susan; Temlett, James; Stevanin, Giovanni; Ross, Christopher; Rudnicki, Dobrila; Margolis, Russell

    2015-10-01

    Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder, characterized by abnormal movements, cognitive decline, and psychiatric symptoms, caused by a CAG repeat expansion in the huntingtin (HTT) gene on chromosome 4p. A CAG/CTG repeat expansion in the junctophilin-3 (JPH3) gene on chromosome 16q24.2 causes a Huntington disease-like phenotype (HDL2). All patients to date with HDL2 have some African ancestry. The present study aimed to characterize the genetic basis of the Huntington disease phenotype in South Africans and to investigate the possible origin of the JPH3 mutation. In a sample of unrelated South African individuals referred for diagnostic HD testing, 62% (106/171) of white patients compared to only 36% (47/130) of black patients had an expansion in HTT. However, 15% (20/130) of black South African patients and no white patients (0/171) had an expansion in JPH3, confirming the diagnosis of Huntington disease like 2 (HDL2). Individuals with HDL2 share many clinical features with individuals with HD and are clinically indistinguishable in many cases, although the average age of onset and diagnosis in HDL2 is 5 years later than HD and individual clinical features may be more prominent. HDL2 mutations contribute significantly to the HD phenotype in South Africans with African ancestry. JPH3 haplotype studies in 31 families, mainly from South Africa and North America, provide evidence for a founder mutation and support a common African origin for all HDL2 patients. Molecular testing in individuals with an HD phenotype and African ancestry should include testing routinely for JPH3 mutations. © 2015 Wiley Periodicals, Inc.

  15. LORD: a phenotype-genotype semantically integrated biomedical data tool to support rare disease diagnosis coding in health information systems.

    Science.gov (United States)

    Choquet, Remy; Maaroufi, Meriem; Fonjallaz, Yannick; de Carrara, Albane; Vandenbussche, Pierre-Yves; Dhombres, Ferdinand; Landais, Paul

    Characterizing a rare disease diagnosis for a given patient is often made through expert's networks. It is a complex task that could evolve over time depending on the natural history of the disease and the evolution of the scientific knowledge. Most rare diseases have genetic causes and recent improvements of sequencing techniques contribute to the discovery of many new diseases every year. Diagnosis coding in the rare disease field requires data from multiple knowledge bases to be aggregated in order to offer the clinician a global information space from possible diagnosis to clinical signs (phenotypes) and known genetic mutations (genotype). Nowadays, the major barrier to the coding activity is the lack of consolidation of such information scattered in different thesaurus such as Orphanet, OMIM or HPO. The Linking Open data for Rare Diseases (LORD) web portal we developed stands as the first attempt to fill this gap by offering an integrated view of 8,400 rare diseases linked to more than 14,500 signs and 3,270 genes. The application provides a browsing feature to navigate through the relationships between diseases, signs and genes, and some Application Programming Interfaces to help its integration in health information systems in routine.

  16. The vascular phenotype in pseudoxanthoma elasticum and related disorders: Contribution of a genetic disease to the understanding of vascular calcification.

    Directory of Open Access Journals (Sweden)

    Georges eLeftheriotis

    2013-02-01

    Full Text Available Vascular calcification is a complex and dynamic process occurring in various physiological conditions such as aging and exercise or in acquired metabolic disorders like diabetes or chronic renal insufficiency. Arterial calcifications are also observed in several genetic diseases revealing the important role of unbalanced or defective anti- or pro-calcifying factors. Pseudoxanthoma elasticum (PXE is an inherited disease (OMIM 264800 characterized by elastic fiber fragmentation and calcification in various soft conjunctive tissues including the skin, eyes and arterial media. The PXE disease results from mutations in the ABCC6 gene, encoding an ATP-binding cassette transporter primarily expressed in the liver, kidneys suggesting that it is a prototypic metabolic soft-tissue calcifying disease of genetic origin. The clinical expression of the PXE arterial disease is characterized by an increased risk for coronary (myocardial infarction, cerebral (aneurysm and stroke and lower limb peripheral artery disease. However, the structural and functional changes in the arterial wall induced by PXE are still unexplained. The use of a recombinant mouse model inactivated for the Abcc6 gene is an important tool for the understanding of the PXE pathophysiology although the vascular impact in this model remains limited to date. Overlapping of the PXE phenotype with other inherited calcifying diseases could bring important informations to our comprehension of the PXE disease.

  17. Cleft palate, retrognathia and congenital heart disease in velo-cardio-facial syndrome: a phenotype correlation study.

    Science.gov (United States)

    Friedman, Marcia A; Miletta, Nathanial; Roe, Cheryl; Wang, Dongliang; Morrow, Bernice E; Kates, Wendy R; Higgins, Anne Marie; Shprintzen, Robert J

    2011-09-01

    Velo-cardio-facial syndrome (VCFS) is caused by a microdeletion of approximately 40 genes from one copy of chromosome 22. Expression of the syndrome is a variable combination of over 190 phenotypic characteristics. As of yet, little is known about how these phenotypes correlate with one another or whether there are predictable patterns of expression. Two of the most common phenotypic categories, congenital heart disease and cleft palate, have been proposed to have a common genetic relationship to the deleted T-box 1 gene (TBX1). The purpose of this study is to determine if congenital heart disease and cleft palate are correlated in a large cohort of human subjects with VCFS. This study is a retrospective chart review including 316 Caucasian non-Hispanic subjects with FISH or CGH microarray confirmed chromosome 22q11.2 deletions. All subjects were evaluated by the interdisciplinary team at the Velo-Cardio-Facial Syndrome International Center at Upstate Medical University, Syracuse, NY. Each combination of congenital heart disease, cleft palates, and retrognathia was analyzed by Chi square or Fisher exact test. For all categories of congenital heart disease and cleft palate or retrognathia no significant associations were found, with the exception of submucous cleft palate and retrognathia (nominal p=0.0325) and occult submucous cleft palate and retrognathia (nominal p=0.000013). Congenital heart disease and cleft palate do not appear to be correlated in human subjects with VCFS despite earlier suggestions from animal models. Possible explanations include modification of the effect of TBX1 by genes outside of the 22q11.2 region that may further influence the formation of the palate or heart, or the presence of epigenetic factors that may effect genes within the deleted region, modifying genes elsewhere, or polymorphisms on the normal copy of chromosome 22. Lastly, it is possible that TBX1 plays a role in palate formation in some species, but not in humans. In VCFS

  18. GeneYenta: a phenotype-based rare disease case matching tool based on online dating algorithms for the acceleration of exome interpretation.

    Science.gov (United States)

    Gottlieb, Michael M; Arenillas, David J; Maithripala, Savanie; Maurer, Zachary D; Tarailo Graovac, Maja; Armstrong, Linlea; Patel, Millan; van Karnebeek, Clara; Wasserman, Wyeth W

    2015-04-01

    Advances in next-generation sequencing (NGS) technologies have helped reveal causal variants for genetic diseases. In order to establish causality, it is often necessary to compare genomes of unrelated individuals with similar disease phenotypes to identify common disrupted genes. When working with cases of rare genetic disorders, finding similar individuals can be extremely difficult. We introduce a web tool, GeneYenta, which facilitates the matchmaking process, allowing clinicians to coordinate detailed comparisons for phenotypically similar cases. Importantly, the system is focused on phenotype annotation, with explicit limitations on highly confidential data that create barriers to participation. The procedure for matching of patient phenotypes, inspired by online dating services, uses an ontology-based semantic case matching algorithm with attribute weighting. We evaluate the capacity of the system using a curated reference data set and 19 clinician entered cases comparing four matching algorithms. We find that the inclusion of clinician weights can augment phenotype matching. © 2015 WILEY PERIODICALS, INC.

  19. [NOD2 gene mutation in Moroccan patients with Crohn's disease: prevalence, genotypic study and correlation of NOD2 gene mutation with the phenotype of Crohn's disease].

    Science.gov (United States)

    Tamzaourte, Mouna; Errabih, Ikram; Krami, Hayat; Maha, Fadlouallah; Maria, Lahmiri; Benzzoubeir, Nadia; Ouazzani, Laaziza; Sefiani, Ahmed; Ouazzani, Houria

    2017-01-01

    The aim of this study was to determine the prevalence of NOD2/CARD15 gene mutations in a group of Moroccan patients with Crohn's disease and to study its correlation with genotype-phenotypic expression. We conducted a cross-sectional case-control study over a period of 16 months. 101 patients with Crohn's disease were enrolled between January 2012 and April 2013 as well as a control group of 107 patients. We performed a genetic analysis to identify 3 NOD2 gene variants: p.Arg702Trp, p.Gly908Arg and p.Leu1007fsins. Then we conducted a study of the correlation between genotype and phenotypic expression. The genetic analysis of patients with Crohn's disease highlighted the presence of NOD2 mutation in 14 patients (13.77%) versus 7 patients (6.53%) in the control group. The study of the frequency of different alleles showed p.Gly908Arg mutation in 6.43%, p.Leu1007fsins in 0.99% and p.Arg702Trp in 0.49% versus 2.80%, 0% and 0.46% in the control group respectively. The study of the correlation between genotype and phenotypic expression showed that CARD15 mutation is associated with ileocecal Crohn's disease, with fistulizing and stenosing behavior in Crohn's disease as well as with severe evolution and frequent recourse to surgery and immunosuppressants. The prevalence of NOD2/ CARD15 mutation in our case series is low. This mutation is correlated with severe Crohn's disease.

  20. The Role of Alcohol Consumption in the Aetiology of Different Cardiovascular Disease Phenotypes: a CALIBER Study

    Science.gov (United States)

    2013-05-28

    Chronic Stable Angina; Unstable Angina; Coronary Heart Disease Not Otherwise Specified; Acute Myocardial Infarction; Heart Failure; Ventricular Arrhythmias; Cardiac Arrest; Abdominal Aortic Aneurysm; Peripheral Arterial Disease; Ischaemic Stroke; Subarachnoid Haemorrhagic Stroke; Intracerebral Haemorrhagic Stroke; Stroke Not Otherwise Specified; Sudden Cardiac Death; Unheralded Coronary Death; Mortality; Coronary Heart Disease (CHD); Cardiovascular Disease (CVD); Fatal Cardiovascular Disease (Fatal CVD); ST Elevation Myocardial Infarction (STEMI); Non-ST Elevation Myocardial Infarction (nSTEMI); Myocardial Infarction Not Otherwise Specified (MI NOS)

  1. Chronic granulomatous disease, the McLeod phenotype and the contiguous gene deletion syndrome-a review

    Directory of Open Access Journals (Sweden)

    Watkins Casey E

    2011-11-01

    Full Text Available Abstract Chronic Granulomatous Disease (CGD, a disorder of the NADPH oxidase system, results in phagocyte functional defects and subsequent infections with bacterial and fungal pathogens (such as Aspergillus species and Candida albicans. Deletions and missense, frameshift, or nonsense mutations in the gp91phox gene (also termed CYBB, located in the Xp21.1 region of the X chromosome, are associated with the most common form of CGD. When larger X-chromosomal deletions occur, including the XK gene deletion, a so-called "Contiguous Gene Deletion Syndrome" may result. The contiguous gene deletion syndrome is known to associate the Kell phenotype/McLeod syndrome with diseases such as X-linked chronic granulomatous disease, Duchenne muscular dystrophy, and X-linked retinitis pigmentosa. These patients are often complicated and management requires special attention to the various facets of the syndrome.

  2. Epistatic Networks Jointly Influence Phenotypes Related to Metabolic Disease and Gene Expression in Diversity Outbred Mice.

    Science.gov (United States)

    Tyler, Anna L; Ji, Bo; Gatti, Daniel M; Munger, Steven C; Churchill, Gary A; Svenson, Karen L; Carter, Gregory W

    2017-06-01

    Genetic studies of multidimensional phenotypes can potentially link genetic variation, gene expression, and physiological data to create multi-scale models of complex traits. The challenge of reducing these data to specific hypotheses has become increasingly acute with the advent of genome-scale data resources. Multi-parent populations derived from model organisms provide a resource for developing methods to understand this complexity. In this study, we simultaneously modeled body composition, serum biomarkers, and liver transcript abundances from 474 Diversity Outbred mice. This population contained both sexes and two dietary cohorts. Transcript data were reduced to functional gene modules with weighted gene coexpression network analysis (WGCNA), which were used as summary phenotypes representing enriched biological processes. These module phenotypes were jointly analyzed with body composition and serum biomarkers in a combined analysis of pleiotropy and epistasis (CAPE), which inferred networks of epistatic interactions between quantitative trait loci that affect one or more traits. This network frequently mapped interactions between alleles of different ancestries, providing evidence of both genetic synergy and redundancy between haplotypes. Furthermore, a number of loci interacted with sex and diet to yield sex-specific genetic effects and alleles that potentially protect individuals from the effects of a high-fat diet. Although the epistatic interactions explained small amounts of trait variance, the combination of directional interactions, allelic specificity, and high genomic resolution provided context to generate hypotheses for the roles of specific genes in complex traits. Our approach moves beyond the cataloging of single loci to infer genetic networks that map genetic etiology by simultaneously modeling all phenotypes. Copyright © 2017 by the Genetics Society of America.

  3. Distinct inflammatory phenotypes of microglia and monocyte-derived macrophages in Alzheimer's disease models: effects of aging and amyloid pathology.

    Science.gov (United States)

    Martin, Elodie; Boucher, Céline; Fontaine, Bertrand; Delarasse, Cécile

    2017-02-01

    Alzheimer's disease (AD) is a neurodegenerative disease characterized by formation of amyloid-β (Aβ) plaques, activated microglia, and neuronal cell death leading to progressive dementia. Recent data indicate that microglia and monocyte-derived macrophages (MDM) are key players in the initiation and progression of AD, yet their respective roles remain to be clarified. As AD occurs mostly in the elderly and aging impairs myeloid functions, we addressed the inflammatory profile of microglia and MDM during aging in TgAPP/PS1 and TgAPP/PS1dE9, two transgenic AD mouse models, compared to WT littermates. We only found MDM infiltration in very aged mice. We determined that MDM highly expressed activation markers at basal state. In contrast, microglia exhibited an activated phenotype only with normal aging and Aβ pathology. Our study showed that CD14 and CD36, two receptors involved in phagocytosis, were upregulated during Aβ pathogenesis. Moreover, we observed, at the protein levels in AD models, higher production of pro-inflammatory mediators: IL-1β, p40, iNOS, CCL-3, CCL-4, and CXCL-1. Taken together, our data indicate that microglia and MDM display distinct phenotypes in AD models and highlight the specific effects of normal aging vs Aβ peptides on inflammatory processes that occur during the disease progression. These precise phenotypes of different subpopulations of myeloid cells in normal and pathologic conditions may allow the design of pertinent therapeutic strategy for AD. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  4. Characterization of a novel mutation in the von Willebrand factor propeptide in a distinct subtype of recessive von Willebrand disease

    DEFF Research Database (Denmark)

    Lanke, Elsa; Kristoffersson, Ann-Charlotte; Philips, Malou

    2008-01-01

    mutation in the VWFpp abolishes multimerization of VWF. The mutation probably disrupts the normal configuration of the VWFpp, which is essential for correct orientation of the protomers and ultimately multimerization. The mutant amino acid is located in a region that is highly conserved across several...

  5. Low-dose ionizing radiation alleviates Aβ42-induced defective phenotypes in Drosophila Alzheimer's disease models

    Energy Technology Data Exchange (ETDEWEB)

    Hwang, SooJin; Jeong, Hae Min; Nam, Seon Young [Low-dose Radiation Research Team, Radiation Health Institute, Korea Hydro & Nuclear Power Co. Ltd., Daejeon (Korea, Republic of)

    2017-04-15

    Alzheimer's disease (AD) is the most common neurodegenerative disease that is characterized by amyloid plaques, progressive neuronal loss, and gradual deterioration of memory. Amyloid imaging using positron emission tomography (PET) radiotracers have been developed and approved for clinical use in the evaluation of suspected neurodegenerative disease, including AD. Particularly, previous studies involving low-dose ionizing radiation on Aβ 42-treated mouse hippocampal neurons have suggested a potential role for low-dose ionizing radiation in the treatment of AD. However, associated in vivo studies involving the therapy effects of low-dose ionizing radiation on AD are still insufficient. As a powerful cell biological system, Drosophila AD models have been generated and established a useful model organism for study on the etiology of human AD. In this study, we investigated the hormesis effects of low-dose ionizing radiation on Drosophila AD models. Our results suggest that low-dose ionizing radiation have the beneficial effects on not only the Aβ42-induced developmental defective phenotypes but also motor defects in Drosophila AD models. These results might be due to a regulation of apoptosis, and provide insight into the hormesis effects of low-dose ionizing radiation. Our results suggest that low-dose ionizing radiation have the beneficial effects on not only the Aβ42-induced developmental defective phenotypes but also motor defects in Drosophila AD models. These results might be due to a regulation of apoptosis, and provide insight into the hormesis effects of low-dose ionizing radiation.

  6. LAMA/LABA vs ICS/LABA in the treatment of COPD in Japan based on the disease phenotypes

    Directory of Open Access Journals (Sweden)

    Hizawa N

    2015-06-01

    Full Text Available Nobuyuki Hizawa Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan Abstract: In the combined use of bronchodilators of different classes, ie, long-acting β2-agonists (LABAs and long-acting muscarinic antagonists (LAMAs, bronchodilation is obtained both directly, through LABA-mediated stimulation of β2-adrenergic receptors, and indirectly, through LAMA-mediated inhibition of acetylcholine action at muscarinic receptors. The clinical trial data for LABAs/LAMAs in the treatment of chronic obstructive pulmonary disease (COPD continue to be promising, and these combinations will provide the convenience of delivering the two major bronchodilator classes, recommended as first-line maintenance options in COPD treatment guidelines. COPD is a complex condition that has pulmonary and extrapulmonary manifestations. These clinical manifestations are highly variable, and several are associated with different responses to currently available therapies. The concept of a COPD phenotype is rapidly evolving from one focusing on the clinical characteristics to one linking the underlying biology to the phenotype of the disease. Identification of the peculiarities of the different COPD phenotypes will permit us to implement a more personalized treatment in which the patient’s characteristics, together with his or her genotype, will be key to choosing the best treatment option. At present in Japan, fixed combinations of inhaled corticosteroids (ICSs and LABAs are frequently prescribed in the earlier stages of COPD. However, ICSs increase the risk of pneumonia. Notably, 10%–30% of patients with COPD with or without a history of asthma have persistent circulating and airway eosinophilia associated with an increased risk of exacerbations and sensitivity to steroids. Thus, sputum or blood eosinophil counts might identify a subpopulation in which ICSs could have potentially deleterious effects as well as a subpopulation that

  7. Genotype to phenotype

    National Research Council Canada - National Science Library

    Malcolm, Sue; Goodship, Timothy H. J

    2001-01-01

    ... Disorders Molecular Genetics of Hypertension Human Gene EvolutionAnalysis of Multifactorial Disease Transcription Factors Molecular Genetics of Cancer, Second edition Genotype to Phenotype, second e...

  8. Phenotypic transition of microglia into astrocyte-like cells associated with disease onset in a model of inherited ALS

    Directory of Open Access Journals (Sweden)

    Emiliano eTrias

    2013-12-01

    Full Text Available Microglia and reactive astrocytes accumulate in the spinal cord of rats expressing the ALS-linked SOD1G93A mutation. We previously reported that the rapid progression of paralysis in ALS rats is associated with the appearance of proliferative astrocyte-like cells thatsurroundmotor neurons. These cells, designated as Aberrant Astrocytes (AbA cells because of their atypical astrocytic phenotype, exhibit high toxicity to motor neurons. However, the cellular origin of AbA cells remains unknown. Because AbA cells are labeled with the proliferation marker Ki67, we analyzed the phenotypic makers of proliferating glial cells that surround motor neurons by immunohistochemistry. The number of Ki67+AbA cells sharply increased in symptomatic rats, displaying large cell bodies with processes embracing motor neurons. Most were co-labeled with astrocytic marker GFAP concurrently with the microglial markers Iba1 and CD163. Cultures of spinal cord prepared from symptomatic SOD1G93A rats yielded large numbers of microglia expressing Iba1, CD11b and CD68. Cells sortedfor CD11b expression by flow cytometry transformed into AbA cells within two weeks. During these two weeks, the expression of microglial markers largely disappeared, while GFAP and S100β expression increased. The phenotypic transition to AbA cells was stimulated by forskolin. These findings provide evidence for a subpopulation of proliferating microglial cells in SOD1G93A rats that undergo a phenotypic transition into AbA cells after onset of paralysis that may promote the fulminant disease progression. These cells could be a therapeutic target for slowing paralysis progression in ALS.

  9. Phenotype-driven strategies for exome prioritization of human Mendelian disease genes

    OpenAIRE

    Smedley, Damian; Robinson, Peter N.

    2015-01-01

    Whole exome sequencing has altered the way in which rare diseases are diagnosed and disease genes identified. Hundreds of novel disease-associated genes have been characterized by whole exome sequencing in the past five years, yet the identification of disease-causing mutations is often challenging because of the large number of rare variants that are being revealed. Gene prioritization aims to rank the most probable candidate genes towards the top of a list of potentially pathogenic variants...

  10. Molecular and phenotypic characterisation of novel Phaeoacremonium species isolated from esca diseased grapevines

    NARCIS (Netherlands)

    Essakhi, S.; Mugnai, L.; Crous, P.W.; Groenewald, J.Z.; Surico, G.

    2008-01-01

    Petri disease and esca are very destructive grapevine decline diseases that occur in most countries where grapevine (Vitis vinifera) is cultivated. Phaeoacremonium species are among the principal hyphomycetes associated with symptoms of the two diseases, producing a range of enzymes and phytotoxic

  11. Von Willebrand Factor Gene Variants Associate with Herpes simplex Encephalitis.

    Directory of Open Access Journals (Sweden)

    Nada Abdelmagid

    Full Text Available Herpes simplex encephalitis (HSE is a rare complication of Herpes simplex virus type-1 infection. It results in severe parenchymal damage in the brain. Although viral latency in neurons is very common in the population, it remains unclear why certain individuals develop HSE. Here we explore potential host genetic variants predisposing to HSE. In order to investigate this we used a rat HSE model comparing the HSE susceptible SHR (Spontaneously Hypertensive Rats with the asymptomatic infection of BN (Brown Norway. Notably, both strains have HSV-1 spread to the CNS at four days after infection. A genome wide linkage analysis of 29 infected HXB/BXH RILs (recombinant inbred lines-generated from the prior two strains, displayed variable susceptibility to HSE enabling the definition of a significant QTL (quantitative trait locus named Hse6 towards the end of chromosome 4 (160.89-174Mb containing the Vwf (von Willebrand factor gene. This was the only gene in the QTL with both cis-regulation in the brain and included several non-synonymous SNPs (single nucleotide polymorphism. Intriguingly, in human chromosome 12 several SNPs within the intronic region between exon 43 and 44 of the VWF gene were associated with human HSE pathogenesis. In particular, rs917859 is nominally associated with an odds ratio of 1.5 (95% CI 1.11-2.02; p-value = 0.008 after genotyping in 115 HSE cases and 428 controls. Although there are possibly several genetic and environmental factors involved in development of HSE, our study identifies variants of the VWF gene as candidates for susceptibility in experimental and human HSE.

  12. Organization of von Willebrand factor on surface-activated platelets.

    Science.gov (United States)

    Escolar, G; White, J G

    1993-12-01

    The distribution and organization of von Willebrand factor (vWF) multimers on platelets after surface activation have not been fully characterized. In the present study, washed human platelets were allowed to interact with Formvar-coated, electron microscope grids for 20 minutes at 37 degrees C and then fixed. After fixation, cells were washed and then incubated with buffer alone, human plasma, human plasma preincubated with ristocetin (1.2 mg/mL), purified human vWF plus ristocetin, or bovine plasma. Macromolecular complexes were revealed by ultrastructural immunocytochemistry employing a polyclonal antibody against vWF and protein A-gold (PAG) as the electron-dense probe. vWF multimers were not present in discoid platelets but appeared on the central zone of dendritic cells and over larger central areas of fully spread platelets. Exposure to human plasma alone did not affect the distribution of electron-dense probes for vWF in central regions of surface-activated cells. Incubation of spread platelets with ristocetin-activated human plasma or bovine plasma resulted in the appearance of randomly dispersed, mottled areas of increased density covering the surface from edge to edge. Exposure to vWF antibody and PAG resulted in specific labeling of the dense areas in a serpentine, linear array. The gold-probe distribution suggested that the vWF multimers were not superimposed and were distributed in a random, irregular manner from edge to edge with label-free, clear areas between them. The results extend previous observations demonstrating that glycoprotein Ib-IX receptors are not spontaneously cleared from the plasma membranes of surface-activated platelets by showing that the receptor function of glycoprotein Ib-IX complex remains unchanged.

  13. Super-Resolution of Plant Disease Images for the Acceleration of Image-based Phenotyping and Vigor Diagnosis in Agriculture.

    Science.gov (United States)

    Yamamoto, Kyosuke; Togami, Takashi; Yamaguchi, Norio

    2017-11-06

    Unmanned aerial vehicles (UAVs or drones) are a very promising branch of technology, and they have been utilized in agriculture-in cooperation with image processing technologies-for phenotyping and vigor diagnosis. One of the problems in the utilization of UAVs for agricultural purposes is the limitation in flight time. It is necessary to fly at a high altitude to capture the maximum number of plants in the limited time available, but this reduces the spatial resolution of the captured images. In this study, we applied a super-resolution method to the low-resolution images of tomato diseases to recover detailed appearances, such as lesions on plant organs. We also conducted disease classification using high-resolution, low-resolution, and super-resolution images to evaluate the effectiveness of super-resolution methods in disease classification. Our results indicated that the super-resolution method outperformed conventional image scaling methods in spatial resolution enhancement of tomato disease images. The results of disease classification showed that the accuracy attained was also better by a large margin with super-resolution images than with low-resolution images. These results indicated that our approach not only recovered the information lost in low-resolution images, but also exerted a beneficial influence on further image analysis. The proposed approach will accelerate image-based phenotyping and vigor diagnosis in the field, because it not only saves time to capture images of a crop in a cultivation field but also secures the accuracy of these images for further analysis.

  14. Oxidative stress is increased in C. elegans models of Huntington's disease but does not contribute to polyglutamine toxicity phenotypes.

    Science.gov (United States)

    Machiela, Emily; Dues, Dylan J; Senchuk, Megan M; Van Raamsdonk, Jeremy M

    2016-12-01

    Huntington's disease (HD) is an adult onset neurodegenerative disorder for which there is currently no cure. While HD patients and animal models of the disease exhibit increased oxidative damage, it is currently uncertain to what extent oxidative stress contributes to disease pathogenesis. In this work, we use a genetic approach to define the role of oxidative stress in HD. We find that a C. elegans model of HD expressing a disease-length polyglutamine tract in the body wall muscle is hypersensitive to oxidative stress and shows an upregulation of antioxidant defense genes, indicating that the HD worm model has increased levels of oxidative stress. To determine whether this increase in oxidative stress contributes to the development of polyglutamine-toxicity phenotypes in this HD model, we examined the effect of deleting individual superoxide dismutase (sod) genes in the HD worm model. As predicted, we found that deletion of sod genes in the HD worm model resulted in a clear increase in sensitivity to oxidative stress. However, we found that increasing oxidative stress in the HD worm model did not exacerbate deficits caused by polyglutamine toxicity. We confirmed these observations in two worm models expressing disease-length polyglutamine tracts in neurons. Furthermore, we found that treatment with antioxidants failed to rescue movement deficits or decrease aggregation in HD worm models. Combined, this suggests that the increase in oxidative stress in worm models of HD does not contribute to the phenotypic deficits observed in these worms, and provides a possible explanation for the failure of antioxidants in HD clinical trials. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Super-Resolution of Plant Disease Images for the Acceleration of Image-based Phenotyping and Vigor Diagnosis in Agriculture

    Directory of Open Access Journals (Sweden)

    Kyosuke Yamamoto

    2017-11-01

    Full Text Available Unmanned aerial vehicles (UAVs or drones are a very promising branch of technology, and they have been utilized in agriculture—in cooperation with image processing technologies—for phenotyping and vigor diagnosis. One of the problems in the utilization of UAVs for agricultural purposes is the limitation in flight time. It is necessary to fly at a high altitude to capture the maximum number of plants in the limited time available, but this reduces the spatial resolution of the captured images. In this study, we applied a super-resolution method to the low-resolution images of tomato diseases to recover detailed appearances, such as lesions on plant organs. We also conducted disease classification using high-resolution, low-resolution, and super-resolution images to evaluate the effectiveness of super-resolution methods in disease classification. Our results indicated that the super-resolution method outperformed conventional image scaling methods in spatial resolution enhancement of tomato disease images. The results of disease classification showed that the accuracy attained was also better by a large margin with super-resolution images than with low-resolution images. These results indicated that our approach not only recovered the information lost in low-resolution images, but also exerted a beneficial influence on further image analysis. The proposed approach will accelerate image-based phenotyping and vigor diagnosis in the field, because it not only saves time to capture images of a crop in a cultivation field but also secures the accuracy of these images for further analysis.

  16. Atypical sporadic CJD-MM phenotype with white matter kuru plaques associated with intranuclear inclusion body and argyrophilic grain disease.

    Science.gov (United States)

    Berghoff, Anna S; Trummert, Anita; Unterberger, Ursula; Ströbel, Thomas; Hortobágyi, Tibor; Kovacs, Gabor G

    2015-08-01

    We describe an atypical neuropathological phenotype of sporadic Creutzfeldt-Jakob disease in a 76-year-old man. The clinical symptoms were characterized by progressive dementia, gait ataxia, rigidity and urinary incontinence. The disease duration was 6 weeks. MRI did not show prominent atrophy or hyperintensities in cortical areas, striatum or thalamus. Biomarker examination of the cerebrospinal fluid deviated from that seen in pure Alzheimer's disease. Triphasic waves in the EEG were detected only later in the disease course, while 14-3-3 assay was positive. PRNP genotyping revealed methionine homozygosity (MM) at codon 129. Neuropathology showed classical CJD changes corresponding to the MM type 1 cases. However, a striking feature was the presence of abundant kuru-type plaques in the white matter. This rare morphology was associated with neuropathological signs of intranuclear inclusion body disease and advanced stage of argyrophilic grain disease. These alterations did not show correlation with each other, thus seemed to develop independently. This case further highlights the complexity of neuropathological alterations in the ageing brain. © 2015 Japanese Society of Neuropathology.

  17. Searching for Genotype-Phenotype Structure: Using Hierarchical Log-Linear Models in Crohn Disease

    Science.gov (United States)

    Chapman, Juliet M.; Onnie, Clive M.; Prescott, Natalie J.; Fisher, Sheila A.; Mansfield, John C.; Mathew, Christopher G.; Lewis, Cathryn M.; Verzilli, Claudio J.; Whittaker, John C.

    2009-01-01

    There has been considerable recent success in the detection of gene-disease associations. We consider here the development of tools that facilitate the more detailed characterization of the effect of a genetic variant on disease. We replace the simplistic classification of individuals according to a single binary disease indicator with classification according to a number of subphenotypes. This more accurately reflects the underlying biological complexity of the disease process, but it poses additional analytical difficulties. Notably, the subphenotypes that make up a particular disease are typically highly associated, and it becomes difficult to distinguish which genes might be causing which subphenotypes. Such problems arise in many complex diseases. Here, we concentrate on an application to Crohn disease (CD). We consider this problem as one of model selection based upon log-linear models, fitted in a Bayesian framework via reversible-jump Metropolis-Hastings approach. We evaluate the performance of our suggested approach with a simple simulation study and then apply the method to a real data example in CD, revealing a sparse disease structure. Most notably, the associated NOD2.908G→R mutation appears to be directly related to more severe disease behaviors, whereas the other two associated NOD2 variants, 1007L→FS and 702R→W, are more generally related to disease in the small bowel (ileum and jejenum). The ATG16L1.300T→A variant appears to be directly associated with only disease of the small bowel. PMID:19185283

  18. [Study of the clinical phenotype of symptomatic chronic airways disease by hierarchical cluster analysis and two-step cluster analyses].

    Science.gov (United States)

    Ning, P; Guo, Y F; Sun, T Y; Zhang, H S; Chai, D; Li, X M

    2016-09-01

    To study the distinct clinical phenotype of chronic airway diseases by hierarchical cluster analysis and two-step cluster analysis. A population sample of adult patients in Donghuamen community, Dongcheng district and Qinghe community, Haidian district, Beijing from April 2012 to January 2015, who had wheeze within the last 12 months, underwent detailed investigation, including a clinical questionnaire, pulmonary function tests, total serum IgE levels, blood eosinophil level and a peak flow diary. Nine variables were chosen as evaluating parameters, including pre-salbutamol forced expired volume in one second(FEV1)/forced vital capacity(FVC) ratio, pre-salbutamol FEV1, percentage of post-salbutamol change in FEV1, residual capacity, diffusing capacity of the lung for carbon monoxide/alveolar volume adjusted for haemoglobin level, peak expiratory flow(PEF) variability, serum IgE level, cumulative tobacco cigarette consumption (pack-years) and respiratory symptoms (cough and expectoration). Subjects' different clinical phenotype by hierarchical cluster analysis and two-step cluster analysis was identified. (1) Four clusters were identified by hierarchical cluster analysis. Cluster 1 was chronic bronchitis in smokers with normal pulmonary function. Cluster 2 was chronic bronchitis or mild chronic obstructive pulmonary disease (COPD) patients with mild airflow limitation. Cluster 3 included COPD patients with heavy smoking, poor quality of life and severe airflow limitation. Cluster 4 recognized atopic patients with mild airflow limitation, elevated serum IgE and clinical features of asthma. Significant differences were revealed regarding pre-salbutamol FEV1/FVC%, pre-salbutamol FEV1% pred, post-salbutamol change in FEV1%, maximal mid-expiratory flow curve(MMEF)% pred, carbon monoxide diffusing capacity per liter of alveolar(DLCO)/(VA)% pred, residual volume(RV)% pred, total serum IgE level, smoking history (pack-years), St.George's respiratory questionnaire

  19. Elevated TIMP-1 expression is associated with a prometastatic phenotype, disease relapse, and poor survival in neuroblastoma.

    Science.gov (United States)

    Paul, Pritha; Rellinger, Eric J; Qiao, Jingbo; Lee, Sora; Volny, Natasha; Padmanabhan, Chandrasekhar; Romain, Carmelle V; Mobley, Bret; Correa, Hernan; Chung, Dai H

    2017-10-10

    Approximately two-thirds of patients with neuroblastoma are found to have metastatic disease at time of diagnosis with frequent skeletal, lymph node, central nervous system, and liver involvement. Using a serial in vivo splenic injection model, we have isolated an aggressive subclone (BE(2)-C/LM2) from MYCN-amplified neuroblastomas that demonstrate an enhanced propensity to develop metastatic liver lesions. BE(2)-C/LM2 subclone cells demonstrate increased adherent, soft agar colony and tumorsphere growth in vitro. Components of the tumor microenvironment regulate cancer progression, via networks of cytokines and growth factors. Cytokine array analysis identified increased TIMP-1 in the plasma of mice injected with BE(2)-C/LM2 subclone cells, leading us to hypothesize that TIMP-1 may play a role in our observed prometastatic phenotype. Immunoblotting and ELISA demonstrated enhanced endogenous TIMP-1 expression in our isolated neuroblastoma subclone. Silencing endogenous TIMP-1 successfully blocked in vitro proliferation, soft agar colony formation and tumorsphere formation by BE(2)-C/LM2 cells. Stable RNA interference of endogenous TIMP-1 failed to reverse the prometastatic phenotype of our BE(2)-C/LM2 subclone in our liver metastasis model, suggesting that endogenous TIMP-1 levels may not be an essential component of this in vivo behavior. Notably, tissue microarray analysis and Kaplan-Meier by gene expression demonstrates that elevated TIMP-1 expression is correlated with increased disease relapse and mortality in patients with neuroblastoma. Taken together, our study identifies TIMP-1 as a novel soluble factor that is associated with a prometastatic phenotype in our in vivo model and adverse outcomes in patients with neuroblastoma.

  20. Whole-Genome Sequencing and Concordance Between Antimicrobial Susceptibility Genotypes and Phenotypes of Bacterial Isolates Associated with Bovine Respiratory Disease

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    Joseph R. Owen

    2017-09-01

    Full Text Available Extended laboratory culture and antimicrobial susceptibility testing timelines hinder rapid species identification and susceptibility profiling of bacterial pathogens associated with bovine respiratory disease, the most prevalent cause of cattle mortality in the United States. Whole-genome sequencing offers a culture-independent alternative to current bacterial identification methods, but requires a library of bacterial reference genomes for comparison. To contribute new bacterial genome assemblies and evaluate genetic diversity and variation in antimicrobial resistance genotypes, whole-genome sequencing was performed on bovine respiratory disease–associated bacterial isolates (Histophilus somni, Mycoplasma bovis, Mannheimia haemolytica, and Pasteurella multocida from dairy and beef cattle. One hundred genomically distinct assemblies were added to the NCBI database, doubling the available genomic sequences for these four species. Computer-based methods identified 11 predicted antimicrobial resistance genes in three species, with none being detected in M. bovis. While computer-based analysis can identify antibiotic resistance genes within whole-genome sequences (genotype, it may not predict the actual antimicrobial resistance observed in a living organism (phenotype. Antimicrobial susceptibility testing on 64 H. somni, M. haemolytica, and P. multocida isolates had an overall concordance rate between genotype and phenotypic resistance to the associated class of antimicrobials of 72.7% (P < 0.001, showing substantial discordance. Concordance rates varied greatly among different antimicrobial, antibiotic resistance gene, and bacterial species combinations. This suggests that antimicrobial susceptibility phenotypes are needed to complement genomically predicted antibiotic resistance gene genotypes to better understand how the presence of antibiotic resistance genes within a given bacterial species could potentially impact optimal bovine respiratory

  1. 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.

  2. In silico analysis of a disease-causing mutation in PCDH15 gene in a consanguineous Pakistani family with Usher phenotype.

    Science.gov (United States)

    Saleha, Shamim; Ajmal, Muhammad; Jamil, Muhammad; Nasir, Muhammad; Hameed, Abdul

    2016-01-01

    To map Usher phenotype in a consanguineous Pakistani family and identify disease-associated mutation in a causative gene to establish phenotype-genotype correlation. A consanguineous Pakistani family in which Usher phenotype was segregating as an autosomal recessive trait was ascertained. On the basis of results of clinical investigations of affected members of this family disease was diagnosed as Usher syndrome (USH). To identify the locus responsible for the Usher phenotype in this family, genomic DNA from blood sample of each individual was genotyped using microsatellite Short Tandem Repeat (STR) markers for the known Usher syndrome loci. Then direct sequencing was performed to find out disease associated mutations in the candidate gene. By genetic linkage analysis, the USH phenotype of this family was mapped to PCDH15 locus on chromosome 10q21.1. Three different point mutations in exon 11 of PCDH15 were identified and one of them, c.1304A>C was found to be segregating with the disease phenotype in Pakistani family with Usher phenotype. This, c.1304A>C transversion mutation predicts an amino-acid substitution of aspartic acid with an alanine at residue number 435 (p.D435A) of its protein product. Moreover, in silico analysis revealed conservation of aspartic acid at position 435 and predicated this change as pathogenic. The identification of c.1304A>C pathogenic mutation in PCDH15 gene and its association with Usher syndrome in a consanguineous Pakistani family is the first example of a missense mutation of PCDH15 causing USH1 phenotype. In previous reports, it was hypothesized that severe mutations such as truncated protein of PCDH15 led to the Usher I phenotype and that missense variants are mainly responsible for non-syndromic hearing impairment.

  3. In silico analysis of a disease-causing mutation in PCDH15 gene in a consanguineous Pakistani family with Usher phenotype

    Directory of Open Access Journals (Sweden)

    Shamim Saleha

    2016-05-01

    Full Text Available AIM: To map Usher phenotype in a consanguineous Pakistani family and identify disease-associated mutation in a causative gene to establish phenotype-genotype correlation. METHODS: A consanguineous Pakistani family in which Usher phenotype was segregating as an autosomal recessive trait was ascertained. On the basis of results of clinical investigations of affected members of this family disease was diagnosed as Usher syndrome (USH. To identify the locus responsible for the Usher phenotype in this family, genomic DNA from blood sample of each individual was genotyped using microsatellite Short Tandem Repeat (STR markers for the known Usher syndrome loci. Then direct sequencing was performed to find out disease associated mutations in the candidate gene. RESULTS: By genetic linkage analysis, the USH phenotype of this family was mapped to PCDH15 locus on chromosome 10q21.1. Three different point mutations in exon 11 of PCDH15 were identified and one of them, c.1304A>C was found to be segregating with the disease phenotype in Pakistani family with Usher phenotype. This, c.1304A>C transversion mutation predicts an amino-acid substitution of aspartic acid with an alanine at residue number 435 (p.D435A of its protein product. Moreover, in silico analysis revealed conservation of aspartic acid at position 435 and predicated this change as pathogenic. CONCLUSION: The identification of c.1304A>C pathogenic mutation in PCDH15 gene and its association with Usher syndrome in a consanguineous Pakistani family is the first example of a missense mutation of PCDH15 causing USH1 phenotype. In previous reports, it was hypothesized that severe mutations such as truncated protein of PCDH15 led to the Usher I phenotype and that missense variants are mainly responsible for non-syndromic hearing impairment.

  4. Impact of senescence-associated secretory phenotype and its potential as a therapeutic target for senescence-associated diseases.

    Science.gov (United States)

    Watanabe, Sugiko; Kawamoto, Shimpei; Ohtani, Naoko; Hara, Eiji

    2017-04-01

    "Cellular senescence" is a state in which cells undergo irreversible cell cycle arrest in response to a variety of cellular stresses. Once cells senesce, they are strongly resistant to any mitogens, including oncogenic stimuli. Therefore, cellular senescence has been assumed to be a potent anticancer mechanism. Although irreversible cell-cycle arrest is traditionally considered the major characteristic of senescent cells, recent studies have revealed some additional functions. Most noteworthy is the increased secretion of various secretory proteins, such as inflammatory cytokines, chemokines, growth factors, and MMPs, into the surrounding extracellular fluid. These newly recognized senescent phenotypes, termed senescence-associated secretory phenotypes (SASPs), reportedly contribute to tumor suppression, wound healing, embryonic development, and even tumorigenesis promotion. Thus, SASPs appear to be beneficial or deleterious, depending on the biological context. As senescent cells are known to accumulate during the aging process in vivo, it is quite possible that their accumulation in aged tissues promotes age-associated functional decline and various diseases, including cancers, at least to some extent. Here, we focus on and discuss the functional and regulatory network of SASPs toward opening up new possibilities for controlling aging and aging-associated diseases. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  5. Non-Invasive Spectral Phenotyping Methods can Improve and Accelerate Cercospora Disease Scoring in Sugar Beet Breeding

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    Marcus Jansen

    2014-05-01

    Full Text Available Breeding for Cercospora resistant sugar beet cultivars requires field experiments for testing resistance levels of candidate genotypes in conditions that are close to agricultural cultivation. Non-invasive spectral phenotyping methods can support and accelerate resistance rating and thereby speed up breeding process. In a case study, experimental field plots with strongly infected beet genotypes of different resistance levels were measured with two different spectrometers. Vegetation indices were calculated from measured wavelength signature to determine leaf physiological status, e.g., greenness with the Normalized Differenced Vegetation Index (NDVI, leaf water content with the Leaf Water Index (LWI and Cercospora disease severity with the Cercospora Leaf Spot Index (CLSI. Indices values correlated significantly with visually scored disease severity, thus connecting the classical breeders’ scoring approach with advanced non-invasive technology.

  6. Public support for neonatal screening for Pompe disease, a broad-phenotype condition

    NARCIS (Netherlands)

    S.S. Weinreich (Stephanie ); T. Rigter (Tessel); C.G. El (Carla); W.J. Dondorp (Wybo Jan); P.J. Kostense (Piet); A.T. van der Ploeg (Ans); A.J.J. Reuser (Arnold); M.C. Cornel (Martina); M.L.C. Hagemans (Marloes)

    2012-01-01

    textabstractBackground: Neonatal screening for Pompe disease has been introduced in Taiwan and a few U.S. states, while other jurisdictions including some European countries are piloting or considering this screening. First-tier screening flags both classic infantile and late-onset Pompe disease,

  7. Public support for neonatal screening for Pompe disease, a broad-phenotype condition

    NARCIS (Netherlands)

    Weinreich, S.S.; Rigter, T.; van El, C.G.; Dondorp, W.J.; Kostense, P.J.; van der Ploeg, A.T.; Reuser, A.J.; Cornel, M.C.; Hagemans, M.L.

    2012-01-01

    Background: Neonatal screening for Pompe disease has been introduced in Taiwan and a few U.S. states, while other jurisdictions including some European countries are piloting or considering this screening. First-tier screening flags both classic infantile and late-onset Pompe disease, which

  8. The Bcl-2 homologue Buffy rescues α-synuclein-induced Parkinson disease-like phenotypes in Drosophila.

    Science.gov (United States)

    M'Angale, P Githure; Staveley, Brian E

    2016-05-18

    In contrast to the complexity found in mammals, only two Bcl-2 family genes have been found in Drosophila melanogaster including the pro-cell survival, human Bok-related orthologue, Buffy. The directed expression of α-synuclein, the first gene identified to contribute to inherited forms of Parkinson disease (PD), in the dopaminergic neurons (DA) of flies has provided a robust and well-studied Drosophila model of PD complete with the loss of neurons and accompanying motor defects. To more fully understand the biological basis of Bcl-2 genes in PD, we altered the expression of Buffy in the dopamine producing neurons with and without the expression of α-synuclein, and in the developing neuron-rich eye. To alter the expression of Buffy in the dopaminergic neurons of Drosophila, the Ddc-Gal4 transgene was used. The directed expression of Buffy in the dopamine producing neurons resulted in flies with increased climbing ability and enhanced survival, while the inhibition of Buffy in the dopaminergic neurons reduced climbing ability over time prematurely, similar to the phenotype observed in the α-synuclein-induced Drosophila model of PD. Subsequently, the expression of Buffy was altered in the α-synuclein-induced Drosophila model of PD. Analysis revealed that Buffy acted to rescue the associated loss of locomotor ability observed in the α-synuclein-induced model of PD, while Buffy RNA interference resulted in an enhanced α-synuclein-induced loss of climbing ability. In complementary experiments the overexpression of Buffy in the developing eye suppressed the mild rough eye phenotype that results from Gal4 expression and from α-synuclein expression. When Buffy is inhibited the roughened eye phenotype is enhanced. The inhibition of Buffy in DA neurons produces a novel model of PD in Drosophila. The directed expression of Buffy in DA neurons provide protection and counteracts the α-synuclein-induced Parkinson disease-like phenotypes. Taken all together this

  9. Phenotype-Genotype Correlation in Wilson Disease in a Large Lebanese Family: Association of c.2299insC with Hepatic and of p. Ala1003Thr with Neurologic Phenotype

    OpenAIRE

    Usta, Julnar; Wehbeh, Antonios; Rida, Khaled; El-Rifai, Omar; Estiphan, Theresa Alicia; Majarian, Tamar; Barada, Kassem

    2014-01-01

    Genotype phenotype correlations in Wilson disease (WD) are best established in homozygous patients or in compound heterozygous patients carrying the same set of mutations. We determined the clinical phenotype of patients with WD carrying the c.2298_2299insC in Exon 8 (c.2299insC) or the p. Ala1003Thr missense substitution in Exon 13 mutations in the homozygous or compound heterozygous state. We investigated 76 members of a single large Lebanese family. Their genotypes were determined, and cli...

  10. Late-onset Pompe disease with phenotype of the limb-girdle muscular dystrophy

    Directory of Open Access Journals (Sweden)

    S. A. Kurbatov

    2015-01-01

    Full Text Available Pompe disease, also known as type II glycogenosis, is a rare autosomal recessive disease. Two main types include early-onset Pompe disease – severe, rapidly progressive multisystem deficency, manifestating on the first year of life, and late-onset Pompe disease (LOPD, with the age of onset ranging from the first year till late adulthood. Both types are caused by the deficiency of lysosomal acid-α-glucosidase due to the mutations in GAA gene, leading to an excessive storage of glycogen in body cells. LOPD is a slowly progressive disease with a primary lesion of a skeletal, respiratory and cardiac muscles, affected in different grade, and moderately elevated сreatine kinase. It is often difficult to perform differential diagnosis with a large group of hereditary and non-hereditary myopathies. We present a case report of LOPD with signs of limb-girdle muscular dystrophy.

  11. Platelet function analyser (PFA-100) results and von Willebrand factor deficiency: a 16-year 'real-world' experience.

    Science.gov (United States)

    Ardillon, L; Ternisien, C; Fouassier, M; Sigaud, M; Lefrançois, A; Pacault, M; Ribeyrol, O; Fressinaud, E; Boisseau, P; Trossaërt, M

    2015-09-01

    The platelet function analyser (PFA-100) is a biological tool designed to explore primary haemostasis. This system has thus been widely demonstrated as reliable in detecting von Willebrand factor (VWF) deficiency. However, most studies were based on patients benefitting from regular medical care and accurate diagnosis, and it would seem probable that the results were somewhat optimistic, and do not reflect its performances in 'real-world' situations. We have chosen to study the reliability of PFA-100 for screening VWF ristocetin cofactor (VWF:RCo) deficiency. We retrospectively analysed the results (n = 6431) of 4027 patients referred to our centre between October 1997 and June 2013 and in whom PFA-Epi, PFA-ADP, and VWF:RCo activity had been evaluated. We studied the influence of blood group on the results and the performances of each method in a subgroup of 213 patients with genetically confirmed von Willebrand disease. We have shown that the PFA-100 system, in our experience, constitutes an excellent screening test for detecting VWF:RCo deficiency, whatever the clinical situation, in 'real-world' conditions. The negative predictive value (NPV), the positive predictive value, the sensitivity and the specificity were respectively: 0.98, 0.51, 0.98 and 0.40. When values adjusted for blood group are used, NPV and sensitivity are inferior to those using normal values which have not been adjusted for blood group. We have shown the PFA-100 method to be more efficient in screening for VWF deficiency than the VWF:RCo technique. © 2015 John Wiley & Sons Ltd.

  12. Genetic knock-down of HDAC3 does not modify disease-related phenotypes in a mouse model of Huntington's disease.

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    Lara Moumné

    Full Text Available Huntington's disease (HD is an autosomal dominant progressive neurodegenerative disorder caused by an expansion of a CAG/polyglutamine repeat for which there are no disease modifying treatments. In recent years, transcriptional dysregulation has emerged as a pathogenic process that appears early in disease progression and has been recapitulated across multiple HD models. Altered histone acetylation has been proposed to underlie this transcriptional dysregulation and histone deacetylase (HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA, have been shown to improve polyglutamine-dependent phenotypes in numerous HD models. However potent pan-HDAC inhibitors such as SAHA display toxic side-effects. To better understand the mechanism underlying this potential therapeutic benefit and to dissociate the beneficial and toxic effects of SAHA, we set out to identify the specific HDAC(s involved in this process. For this purpose, we are exploring the effect of the genetic reduction of specific HDACs on HD-related phenotypes in the R6/2 mouse model of HD. The study presented here focuses on HDAC3, which, as a class I HDAC, is one of the preferred targets of SAHA and is directly involved in histone deacetylation. To evaluate a potential benefit of Hdac3 genetic reduction in R6/2, we generated a mouse carrying a critical deletion in the Hdac3 gene. We confirmed that the complete knock-out of Hdac3 is embryonic lethal. To test the effects of HDAC3 inhibition, we used Hdac3(+/- heterozygotes to reduce nuclear HDAC3 levels in R6/2 mice. We found that Hdac3 knock-down does not ameliorate physiological or behavioural phenotypes and has no effect on molecular changes including dysregulated transcripts. We conclude that HDAC3 should not be considered as the major mediator of the beneficial effect induced by SAHA and other HDAC inhibitors in HD.

  13. Genetic or pharmacological activation of the Drosophila PGC-1α ortholog spargel rescues the disease phenotypes of genetic models of Parkinson's disease.

    Science.gov (United States)

    Ng, Chee-Hoe; Basil, Adeline H; Hang, Liting; Tan, Royston; Goh, Kian-Leong; O'Neill, Sharon; Zhang, Xiaodong; Yu, Fengwei; Lim, Kah-Leong

    2017-07-01

    Despite intensive research, the etiology of Parkinson's disease (PD) remains poorly understood and the disease remains incurable. However, compelling evidence gathered over decades of research strongly support a role for mitochondrial dysfunction in PD pathogenesis. Related to this, PGC-1α, a key regulator of mitochondrial biogenesis, has recently been proposed to be an attractive target for intervention in PD. Here, we showed that silencing of expression of the Drosophila PGC-1α ortholog spargel results in PD-related phenotypes in flies and also seem to negate the effects of AMPK activation, which we have previously demonstrated to be neuroprotective, that is, AMPK-mediated neuroprotection appears to require PGC-1α. Importantly, we further showed that genetic or pharmacological activation of the Drosophila PGC-1α ortholog spargel is sufficient to rescue the disease phenotypes of Parkin and LRRK2 genetic fly models of PD, thus supporting the proposed use of PGC-1α-related strategies for neuroprotection in PD. Copyright © 2017 National Neuroscience Institute. Published by Elsevier Inc. All rights reserved.

  14. 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.

  15. New rat model that phenotypically resembles autosomal recessive polycystic kidney disease

    NARCIS (Netherlands)

    J. Nauta (Jeroen); M.A. Goedbloed (Miriam); H.V. Herck; D.A. Hesselink (Dennis); P. Visser (Pim); R. Willemsen (Rob); R.P.E. van Dokkum (Richard); C.J. Wright; L.M. Guay-Woodford

    2000-01-01

    textabstractNumerous murine models of polycystic kidney disease (PKD) have been described. While mouse models are particularly well suited for investigating the molecular pathogenesis of PKD, rats are well established as an experimental model of renal physiologic

  16. Familial frontotemporal lobar degeneration : Phenotypical characterization of presymptomatic and clinical disease stages

    NARCIS (Netherlands)

    E.G.P. Dopper (Elise)

    2015-01-01

    markdownabstractAbstract Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia, and is characterized by neurodegeneration of the frontal and temporal lobes. The disease typically presents with behavioral disturbances and language difficulties that occur

  17. Direct Lineage Reprogramming Reveals Disease-Specific Phenotypes of Motor Neurons from Human ALS Patients

    Directory of Open Access Journals (Sweden)

    Meng-Lu Liu

    2016-01-01

    Full Text Available Subtype-specific neurons obtained from adult humans will be critical to modeling neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS. Here, we show that adult human skin fibroblasts can be directly and efficiently converted into highly pure motor neurons without passing through an induced pluripotent stem cell stage. These adult human induced motor neurons (hiMNs exhibit the cytological and electrophysiological features of spinal motor neurons and form functional neuromuscular junctions (NMJs with skeletal muscles. Importantly, hiMNs converted from ALS patient fibroblasts show disease-specific degeneration manifested through poor survival, soma shrinkage, hypoactivity, and an inability to form NMJs. A chemical screen revealed that the degenerative features of ALS hiMNs can be remarkably rescued by the small molecule kenpaullone. Taken together, our results define a direct and efficient strategy to obtain disease-relevant neuronal subtypes from adult human patients and reveal their promising value in disease modeling and drug identification.

  18. Elevated plasma glucosylsphingosine in Gaucher disease: relation to phenotype, storage cell markers, and therapeutic response

    NARCIS (Netherlands)

    Dekker, Nick; van Dussen, Laura; Hollak, Carla E. M.; Overkleeft, Herman; Scheij, Saskia; Ghauharali, Karen; van Breemen, Mariëlle J.; Ferraz, Maria J.; Groener, Johanna E. M.; Maas, Mario; Wijburg, Frits A.; Speijer, Dave; Tylki-Szymanska, Anna; Mistry, Pramod K.; Boot, Rolf G.; Aerts, Johannes M.

    2011-01-01

    Gaucher disease, caused by a deficiency of the lysosomal enzyme glucocerebrosidase, leads to prominent glucosylceramide accumulation in lysosomes of tissue macrophages (Gaucher cells). Here we show glucosylsphingosine, the deacylated form of glucosylceramide, to be markedly increased in plasma of

  19. Gene-Environment Interactions in the Development of Complex Disease Phenotypes

    Directory of Open Access Journals (Sweden)

    Kenneth Olden

    2008-03-01

    Full Text Available The lack of knowledge about the earliest events in disease development is due to the multi-factorial nature of disease risk. This information gap is the consequence of the lack of appreciation for the fact that most diseases arise from the complex interactions between genes and the environment as a function of the age or stage of development of the individual. Whether an environmental exposure causes illness or not is dependent on the efficiency of the so-called “environmental response machinery” (i.e., the complex of metabolic pathways that can modulate response to environmental perturbations that one has inherited. Thus, elucidating the causes of most chronic diseases will require an understanding of both the genetic and environmental contribution to their etiology. Unfortunately, the exploration of the relationship between genes and the environment has been hampered in the past by the limited knowledge of the human genome, and by the inclination of scientists to study disease development using experimental models that consider exposure to a single environmental agent. Rarely in the past were interactions between multiple genes or between genes and environmental agents considered in studies of human disease etiology. The most critical issue is how to relate exposure-disease association studies to pathways and mechanisms. To understand how genes and environmental factors interact to perturb biological pathways to cause injury or disease, scientists will need tools with the capacity to monitor the global expression of thousands of genes, proteins and metabolites simultaneously. The generation of such data in multiple species can be used to identify conserved and functionally significant genes and pathways involved in geneenvironment interactions. Ultimately, it is this knowledge that will be used to guide agencies such as the U.S. Department of Health and Human Services in decisions regarding biomedical research funding

  20. GenIO: a phenotype-genotype analysis web server for clinical genomics of rare diseases.

    Science.gov (United States)

    Koile, Daniel; Cordoba, Marta; de Sousa Serro, Maximiliano; Kauffman, Marcelo Andres; Yankilevich, Patricio

    2018-01-27

    GenIO is a novel web-server, designed to assist clinical genomics researchers and medical doctors in the diagnostic process of rare genetic diseases. The tool identifies the most probable variants causing a rare disease, using the genomic and clinical information provided by a medical practitioner. Variants identified in a whole-genome, whole-exome or target sequencing studies are annotated, classified and filtered by clinical significance. Candidate genes associated with the patient's symptoms, suspected disease and complementary findings are identified to obtain a small manageable number of the most probable recessive and dominant candidate gene variants associated with the rare disease case. Additionally, following the American College of Medical Genetics and Genomics and the Association of Molecular Pathology (ACMG-AMP) guidelines and recommendations, all potentially pathogenic variants that might be contributing to disease and secondary findings are identified. A retrospective study was performed on 40 patients with a diagnostic rate of 40%. All the known genes that were previously considered as disease causing were correctly identified in the final inherit model output lists. In previously undiagnosed cases, we had no additional yield. This unique, intuitive and user-friendly tool to assists medical doctors in the clinical genomics diagnostic process is openly available at https://bioinformatics.ibioba-mpsp-conicet.gov.ar/GenIO/ .

  1. Inflammatory bowel diseases phenotype, C. difficile and NOD2 genotype are associated with shifts in human ileum associated microbial composition.

    Directory of Open Access Journals (Sweden)

    Ellen Li

    Full Text Available We tested the hypothesis that Crohn's disease (CD-related genetic polymorphisms involved in host innate immunity are associated with shifts in human ileum-associated microbial composition in a cross-sectional analysis of human ileal samples. Sanger sequencing of the bacterial 16S ribosomal RNA (rRNA gene and 454 sequencing of 16S rRNA gene hypervariable regions (V1-V3 and V3-V5, were conducted on macroscopically disease-unaffected ileal biopsies collected from 52 ileal CD, 58 ulcerative colitis and 60 control patients without inflammatory bowel diseases (IBD undergoing initial surgical resection. These subjects also were genotyped for the three major NOD2 risk alleles (Leu1007fs, R708W, G908R and the ATG16L1 risk allele (T300A. The samples were linked to clinical metadata, including body mass index, smoking status and Clostridia difficile infection. The sequences were classified into seven phyla/subphyla categories using the Naïve Bayesian Classifier of the Ribosome Database Project. Centered log ratio transformation of six predominant categories was included as the dependent variable in the permutation based MANCOVA for the overall composition with stepwise variable selection. Polymerase chain reaction (PCR assays were conducted to measure the relative frequencies of the Clostridium coccoides - Eubacterium rectales group and the Faecalibacterium prausnitzii spp. Empiric logit transformations of the relative frequencies of these two microbial groups were included in permutation-based ANCOVA. Regardless of sequencing method, IBD phenotype, Clostridia difficile and NOD2 genotype were selected as associated (FDR ≤ 0.05 with shifts in overall microbial composition. IBD phenotype and NOD2 genotype were also selected as associated with shifts in the relative frequency of the C. coccoides--E. rectales group. IBD phenotype, smoking and IBD medications were selected as associated with shifts in the relative frequency of F. prausnitzii spp. These

  2. Inflammatory Bowel Diseases Phenotype, C. difficile and NOD2 Genotype Are Associated with Shifts in Human Ileum Associated Microbial Composition

    Science.gov (United States)

    Li, Ellen; Hamm, Christina M.; Gulati, Ajay S.; Sartor, R. Balfour; Chen, Hongyan; Wu, Xiao; Zhang, Tianyi; Rohlf, F. James; Zhu, Wei; Gu, Chi; Robertson, Charles E.; Pace, Norman R.; Boedeker, Edgar C.; Harpaz, Noam; Yuan, Jeffrey; Weinstock, George M.; Sodergren, Erica; Frank, Daniel N.

    2012-01-01

    We tested the hypothesis that Crohn’s disease (CD)-related genetic polymorphisms involved in host innate immunity are associated with shifts in human ileum–associated microbial composition in a cross-sectional analysis of human ileal samples. Sanger sequencing of the bacterial 16S ribosomal RNA (rRNA) gene and 454 sequencing of 16S rRNA gene hypervariable regions (V1–V3 and V3–V5), were conducted on macroscopically disease-unaffected ileal biopsies collected from 52 ileal CD, 58 ulcerative colitis and 60 control patients without inflammatory bowel diseases (IBD) undergoing initial surgical resection. These subjects also were genotyped for the three major NOD2 risk alleles (Leu1007fs, R708W, G908R) and the ATG16L1 risk allele (T300A). The samples were linked to clinical metadata, including body mass index, smoking status and Clostridia difficile infection. The sequences were classified into seven phyla/subphyla categories using the Naïve Bayesian Classifier of the Ribosome Database Project. Centered log ratio transformation of six predominant categories was included as the dependent variable in the permutation based MANCOVA for the overall composition with stepwise variable selection. Polymerase chain reaction (PCR) assays were conducted to measure the relative frequencies of the Clostridium coccoides – Eubacterium rectales group and the Faecalibacterium prausnitzii spp. Empiric logit transformations of the relative frequencies of these two microbial groups were included in permutation-based ANCOVA. Regardless of sequencing method, IBD phenotype, Clostridia difficile and NOD2 genotype were selected as associated (FDR ≤0.05) with shifts in overall microbial composition. IBD phenotype and NOD2 genotype were also selected as associated with shifts in the relative frequency of the C. coccoides – E. rectales group. IBD phenotype, smoking and IBD medications were selected as associated with shifts in the relative frequency of F. prausnitzii spp. These

  3. Glucosylsphingosine accumulation in tissues from patients with Gaucher disease: correlation with phenotype and genotype.

    Science.gov (United States)

    Orvisky, Eduard; Park, Joseph K; LaMarca, Mary E; Ginns, Edward I; Martin, Brian M; Tayebi, Nahid; Sidransky, Ellen

    2002-08-01

    Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, presents with a wide spectrum of clinical manifestations including neuronopathic and non-neuronopathic forms. While the lipid glucosylceramide is stored in both patients with Gaucher disease and in a null allele mouse model of Gaucher disease, elevated levels of a second potentially toxic substrate, glucosylsphingosine, are also found. Using high performance liquid chromatography, glucosylsphingosine levels were measured in tissues from patients with type 1, 2, and 3 Gaucher disease. Glucosylsphingosine was measured in 16 spleen samples (8 type 1; 4 type 2; and 4, type 3) and levels ranged from 54 to 728 ng/mg protein in the patients with type 1 disease, 133 to 1200 ng/mg protein in the patients with type 2, and 109 to 1298 ng/mg protein in the type 3 samples. The levels of splenic glucosylsphingosine bore no relation to the type of Gaucher disease, the age of the patient, the genotype, nor the clinical course. In the same patients, hepatic glucosylsphingosine levels were lower than in spleen. Glucosylsphingosine was also measured in brains from 13 patients (1 type 1; 8 type 2; and 4 type 3). While the glucosylsphingosine level in the brain from the type 1 patient, 1.0 ng/mg protein, was in the normal range, the levels in the type 3 samples ranged from 14 to 32 ng/mg protein, and in the type 2 samples from 24 to 437 ng/mg protein, with the highest values detected in two fetuses with hydrops fetalis. The elevated levels found in brains from patients with neuronopathic Gaucher disease support the hypothesis that glucosylsphingosine may contribute to the nervous system involvement in these patients.

  4. Small GTP-binding protein Ral modulates regulated exocytosis of von Willebrand factor by endothelial cells

    NARCIS (Netherlands)

    de Leeuw, H. P.; Fernandez-Borja, M.; Reits, E. A.; Romani de Wit, T.; Wijers-Koster, P. M.; Hordijk, P. L.; Neefjes, J.; van Mourik, J. A.; Voorberg, J.

    2001-01-01

    Weibel-Palade bodies are endothelial cell-specific organelles, which contain von Willebrand factor (vWF), P-selectin, and several other proteins. Recently, we found that the small GTP-binding protein Ral is present in a subcellular fraction containing Weibel-Palade bodies. In the present study, we

  5. Efficiency of von Willebrand factor-mediated targeting of interleukin-8 into Weibel-Palade bodies

    NARCIS (Netherlands)

    Bierings, R.; van den Biggelaar, M.; Kragt, A.; Mertens, K.; Voorberg, J.; van Mourik, J. A.

    2007-01-01

    Background: After de novo synthesis in endothelial cells, the chemokine interleukin-8 (IL-8) is targeted to endothelial cell-specific storage vesicles, the Weibel-Palade bodies (WPBs), where it colocalizes with von Willebrand factor (VWF). Objective: In this study we investigated a putative

  6. Binding of von Willebrand factor and plasma proteins to the eggshell of Schistosoma mansoni

    NARCIS (Netherlands)

    Dewalick, Saskia; Hensbergen, Paul J; Bexkens, Michiel L; Grosserichter-Wagener, Christina; Hokke, Cornelis H; Deelder, André M; de Groot, Philip G; Tielens, Aloysius G M; van Hellemond, Jaap J

    Schistosoma mansoni eggs have to cross the endothelium and intestinal wall to leave the host and continue the life cycle. Mechanisms involved in this essential step are largely unknown. Here we describe direct binding to the S. mansoni eggshell of von Willebrand factor and other plasma proteins

  7. von Willebrand Factor and Prekallikrein in Plasma Are Associated With Thrombus Volume in Abdominal Aortic Aneurysms

    DEFF Research Database (Denmark)

    Ghulam, Qasam M; Bredahl, Kim; Gram, Jørgen Brodersen

    2016-01-01

    was consecutively obtained from 38 patients with asymptomatic infrarenal abdominal aortic aneurysm. von Willebrand factor activity, thrombin generation time, factor XII, and prekallikrein concentration were measured in plasma on automated and in-house platforms. In total, 8 patients were excluded due to ongoing...

  8. Altered glycosylation of platelet-derived von Willebrand factor confers resistance to ADAMTS13 proteolysis

    NARCIS (Netherlands)

    McGrath, Rachel T.; van den Biggelaar, Maartje; Byrne, Barry; O'Sullivan, Jamie M.; Rawley, Orla; O'Kennedy, Richard; Voorberg, Jan; Preston, Roger J. S.; O'Donnell, James S.

    2013-01-01

    Platelet-von Willebrand factor (VWF) is stored within α-granules and accounts for ∼20% of total VWF in platelet-rich plasma. This platelet-VWF pool is distinct from plasma-VWF and is enriched in high molecular weight multimers (HMWM). Previous studies have described significant functional

  9. ADAMTS-13 and von Willebrand factor predict venous thromboembolism in patients with cancer

    NARCIS (Netherlands)

    Pepin, M.; Kleinjan, A.; Hajage, D.; Buller, H. R.; Di Nisio, M.; Kamphuisen, P. W.; Salomon, L.; Veyradier, A.; Stepanian, A.; Mahe, I.

    Essentials Cancer patients are at high risk of venous thromboembolism (VTE). In this study, cases and controls were cancer patients who did or did not develop VTE. von Willebrand factor (VWF) levels were higher if compared with controls and correlated with cancer stage. VWF and ADAMTS-13 are

  10. Isolated Ro52 Antibodies as Immunological Marker of a Mild Phenotype of Undifferentiated Connective Tissue Diseases

    Directory of Open Access Journals (Sweden)

    Ana Alonso-Larruga

    2017-01-01

    Full Text Available The term undifferentiated connective tissue disease (UCTD is used to describe undiagnosed patients that do not fulfill classification criteria for definite connective tissue disease (Systemic Lupus, Systemic Sclerosis, Sjögren Syndrome, and Dermatomyositis/Polymyositis. It is important to find serological markers as predictors of the evolution or severity of these diseases. The objective of this retrospective study was to investigate if there was a milder subgroup of UCTD with a special clinical profile consisting only in the presence of anti-Ro52 autoantibodies. Immunological and clinical records of 62 patients attending the hospital during 30 months were studied. Results showed a target population formed by mostly women, aged between 40 and 80 years at the moment of the study, with a registered age of onset between 40 and 60 years. Speckled pattern was the most frequent pattern found by indirect immunofluorescence. Given the obtained results and keeping in mind possible limitations because of sample size, isolated positive anti-Ro52 autoantibodies seem to lead to a benign effect in terms of evolution of the disease. As a future objective, the follow-up of these patients should be necessary to investigate new clinical symptoms, serological markers, or development of a definite connective tissue disease over time.

  11. Intermittent fasting alleviates the neuropathic phenotype in a mouse model of Charcot-Marie-Tooth disease

    Science.gov (United States)

    Madorsky, Irina; Opalach, Katherine; Waber, Amanda; Verrier, Jonathan D.; Solmo, Chelsea; Foster, Thomas; Dunn, William A; Notterpek, Lucia

    2009-01-01

    Charcot-Marie-Tooth type 1A (CMT1A) neuropathies linked to the misexpression of peripheral myelin protein 22 (PMP22) are progressive demyelinating disorders of the peripheral nervous system. In this study we asked whether dietary restriction by intermittent fasting (IF) could alleviate the neuropathic phenotype in the Trembler J (TrJ) mouse model of CMT1A. Our results show that neuropathic mice kept on a five month long IF regimen had improved locomotor performance compared to ad libitum (AL) fed littermates. The functional benefits of this dietary intervention are associated with an increased expression of myelin proteins combined with a thicker myelin sheath, less redundant basal lamina, and a reduction in aberrant Schwann cell proliferation. These morphological improvements are accompanied by a decrease in PMP22 protein aggregates, and enhanced expression of cytosolic chaperones and constituents of the autophagy-lysosomal pathway. These results indicate that dietary restriction is beneficial for peripheral nerve function in TrJ neuropathic mice, as it promotes the maintenance of locomotor performance. PMID:19320048

  12. Behavioral Phenotyping of Murine Disease Models with the Integrated Behavioral Station (INBEST).

    Science.gov (United States)

    Sakic, Boris; Cooper, Marcella P A; Taylor, Sarah E; Stojanovic, Milica; Zagorac, Bosa; Kapadia, Minesh

    2015-04-23

    Due to rapid advances in genetic engineering, small rodents have become the preferred subjects in many disciplines of biomedical research. In studies of chronic CNS disorders, there is an increasing demand for murine models with high validity at the behavioral level. However, multiple pathogenic mechanisms and complex functional deficits often impose challenges to reliably measure and interpret behavior of chronically sick mice. Therefore, the assessment of peripheral pathology and a behavioral profile at several time points using a battery of tests are required. Video-tracking, behavioral spectroscopy, and remote acquisition of physiological measures are emerging technologies that allow for comprehensive, accurate, and unbiased behavioral analysis in a home-base-like setting. This report describes a refined phenotyping protocol, which includes a custom-made monitoring apparatus (Integrated Behavioral Station, INBEST) that focuses on prolonged measurements of basic functional outputs, such as spontaneous activity, food/water intake and motivated behavior in a relatively stress-free environment. Technical and conceptual improvements in INBEST design may further promote reproducibility and standardization of behavioral studies.

  13. Intermittent fasting alleviates the neuropathic phenotype in a mouse model of Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Madorsky, Irina; Opalach, Katherine; Waber, Amanda; Verrier, Jonathan D; Solmo, Chelsea; Foster, Thomas; Dunn, William A; Notterpek, Lucia

    2009-04-01

    Charcot-Marie-Tooth type 1A (CMT1A) neuropathies linked to the misexpression of peripheral myelin protein 22 (PMP22) are progressive demyelinating disorders of the peripheral nervous system. In this study we asked whether dietary restriction by intermittent fasting (IF) could alleviate the neuropathic phenotype in the Trembler J (TrJ) mouse model of CMT1A. Our results show that neuropathic mice kept on a five month long IF regimen had improved locomotor performance compared to ad libitum (AL) fed littermates. The functional benefits of this dietary intervention are associated with an increased expression of myelin proteins combined with a thicker myelin sheath, less redundant basal lamina, and a reduction in aberrant Schwann cell proliferation. These morphological improvements are accompanied by a decrease in PMP22 protein aggregates, and enhanced expression of cytosolic chaperones and constituents of the autophagy-lysosomal pathway. These results indicate that dietary restriction is beneficial for peripheral nerve function in TrJ neuropathic mice, as it promotes the maintenance of locomotor performance.

  14. Renin Phenotypes Characterize Vascular Disease, Autonomous Aldosteronism, and Mineralocorticoid Receptor Activity.

    Science.gov (United States)

    Hundemer, Gregory L; Baudrand, Rene; Brown, Jenifer M; Curhan, Gary; Williams, Gordon H; Vaidya, Anand

    2017-06-01

    Mild cases of autonomous aldosterone secretion may go unrecognized using current diagnostic criteria for primary aldosteronism (PA). To investigate whether the inability to stimulate renin serves as a biomarker for unrecognized autonomous aldosterone secretion and mineralocorticoid receptor (MR) activation. Six hundred sixty-three normotensive and mildly hypertensive participants, who were confirmed to not have PA using current guideline criteria and were on no antihypertensive medications. Participants had their maximally stimulated plasma renin activity (PRA) measured while standing upright after sodium restriction. Tertiles of maximally stimulated PRA were hypothesized to reflect the degree of MR activation: lowest PRA tertile = "Inappropriate/Excess MR Activity;" middle PRA tertile = "Intermediate MR Activity;"; and highest PRA tertile = "Physiologic MR Activity." All participants underwent detailed biochemical and vascular characterizations under conditions of liberalized sodium intake, and associations with stimulated PRA phenotypes were performed. Participants with lower stimulated PRA had greater autonomous aldosterone secretion [higher aldosterone-to-renin ratio (P = 0.002), higher urine aldosterone excretion rate (P = 0.003), higher systolic blood pressure (P = 0.004), and lower renal plasma flow (P = 0.04)] and a nonsignificant trend toward lower serum potassium and higher urine potassium excretion, which became significant after stratification by hypertension status. In participants without clinical PA, the inability to stimulate renin was associated with greater autonomous aldosterone secretion, impaired vascular function, and suggestive trends in potassium handling that indicate an extensive spectrum of unrecognized MR activation.

  15. Systems medicine approaches for the definition of complex phenotypes in chronic diseases and ageing. From concept to implementation and policies.

    Science.gov (United States)

    Bousquet, Jean; Jorgensen, Christian; Dauzat, Michel; Cesario, Alfredo; Camuzat, Thierry; Bourret, Rodolphe; Best, Nicolas; Anto, Josep M; Abecassis, Frederic; Aubas, Pierre; Avignon, Antoine; Badin, Melanie; Bedbrook, Anna; Blain, Hubert; Bourdin, Arnaud; Bringer, Jacques; Camu, William; Cayla, Guilhaume; Costa, David J; Courtet, Philippe; Cristol, Jean-Paul; Demoly, Pascal; de la Coussaye, Jean-Emmanuel; Fesler, Pierre; Gouzi, Fares; Gris, Jean-Christophe; Guillot, Bernard; Hayot, Maurice; Jeandel, Claude; Jonquet, Olivier; Journot, Laurent; Lehmann, Sylvain; Mathieu, Gwenaelle; Morel, Jacques; Ninot, Gregory; Pelissier, Jacques; Picot, Marie-Christine; Radier-Pontal, Francoise; Robine, Jean-Marie; Rodier, Michel; Roubille, Francois; Sultan, Ariane; Wojtusciszyn, Anne; Auffray, Charles; Balling, Rudi; Barbara, Cristina; Cambon-Thomsen, Anne; Chavannes, Niels H; Chuchalin, Alexander; Crooks, George; Dedeu, Antoni; Fabbri, Leonardo M; Garcia-Aymerich, Judith; Hajjam, Jawad; Melo Gomes, Elisabete; Palkonen, Susana; Piette, Francois; Pison, Christophe; Price, David; Samolinski, Boleslaw; Schunemann, Holger J; Sterk, Peter J; Yiallouros, Panayiotis; Roca, Josep; Van de Perre, Philippe; Mercier, Jacques

    2014-01-01

    Chronic diseases are diseases of long duration and slow progression. Major NCDs (cardiovascular diseases, cancer, chronic respiratory diseases, diabetes, rheumatologic diseases and mental health) represent the predominant health problem of the Century. The prevention and control of NCDs are the priority of the World Health Organization 2008 Action Plan, the United Nations 2010 Resolution and the European Union 2010 Council. The novel trend for the management of NCDs is evolving towards integrative, holistic approaches. NCDs are intertwined with ageing. The European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) has prioritised NCDs. To tackle them in their totality in order to reduce their burden and societal impact, it is proposed that NCDs should be considered as a single expression of disease with different risk factors and entities. An innovative integrated health system built around systems medicine and strategic partnerships is proposed to combat NCDs. It includes (i) understanding the social, economic, environmental, genetic determinants, as well as the molecular and cellular mechanisms underlying NCDs; (ii) primary care and practice-based interprofessional collaboration; (iii) carefully phenotyped patients; (iv) development of unbiased and accurate biomarkers for comorbidities, severity and follow up of patients; (v) socio-economic science; (vi) development of guidelines; (vii) training; and (viii) policy decisions. The results could be applicable to all countries and adapted to local needs, economy and health systems. This paper reviews the complexity of NCDs intertwined with ageing. It gives an overview of the problem and proposes two practical examples of systems medicine (MeDALL) applied to allergy and to NCD co-morbidities (MACVIA-LR, Reference Site of the European Innovation Partnership on Active and Healthy Ageing).

  16. Space and Time Resolved Detection of Platelet Activation and von Willebrand Factor Conformational Changes in Deep Suspensions.

    Science.gov (United States)

    Biasetti, Jacopo; Sampath, Kaushik; Cortez, Angel; Azhir, Alaleh; Gilad, Assaf A; Kickler, Thomas S; Obser, Tobias; Ruggeri, Zaverio M; Katz, Joseph

    2017-01-01

    Tracking cells and proteins' phenotypic changes in deep suspensions is critical for the direct imaging of blood-related phenomena in in vitro replica of cardiovascular systems and blood-handling devices. This paper introduces fluorescence imaging techniques for space and time resolved detection of platelet activation, von Willebrand factor (VWF) conformational changes, and VWF-platelet interaction in deep suspensions. Labeled VWF, platelets, and VWF-platelet strands are suspended in deep cuvettes, illuminated, and imaged with a high-sensitivity EM-CCD camera, allowing detection using an exposure time of 1 ms. In-house postprocessing algorithms identify and track the moving signals. Recombinant VWF-eGFP (rVWF-eGFP) and VWF labeled with an FITC-conjugated polyclonal antibody are employed. Anti-P-Selectin FITC-conjugated antibodies and the calcium-sensitive probe Indo-1 are used to detect activated platelets. A positive correlation between the mean number of platelets detected per image and the percentage of activated platelets determined through flow cytometry is obtained, validating the technique. An increase in the number of rVWF-eGFP signals upon exposure to shear stress demonstrates the technique's ability to detect breakup of self-aggregates. VWF globular and unfolded conformations and self-aggregation are also observed. The ability to track the size and shape of VWF-platelet strands in space and time provides means to detect pro- and antithrombotic processes.

  17. Natural variation of macrophage activation as disease-relevant phenotype predictive of inflammation and cancer survival.

    Science.gov (United States)

    Buscher, Konrad; Ehinger, Erik; Gupta, Pritha; Pramod, Akula Bala; Wolf, Dennis; Tweet, George; Pan, Calvin; Mills, Charles D; Lusis, Aldons J; Ley, Klaus

    2017-07-24

    Although mouse models exist for many immune-based diseases, the clinical translation remains challenging. Most basic and translational studies utilize only a single inbred mouse strain. However, basal and diseased immune states in humans show vast inter-individual variability. Here, focusing on macrophage responses to lipopolysaccharide (LPS), we use the hybrid mouse diversity panel (HMDP) of 83 inbred strains as a surrogate for human natural immune variation. Since conventional bioinformatics fail to analyse a population spectrum, we highlight how gene signatures for LPS responsiveness can be derived based on an Interleukin-12β and arginase expression ratio. Compared to published signatures, these gene markers are more robust to identify susceptibility or resilience to several macrophage-related disorders in humans, including survival prediction across many tumours. This study highlights natural activation diversity as a disease-relevant dimension in macrophage biology, and suggests the HMDP as a viable tool to increase translatability of mouse data to clinical settings.

  18. Phenotypic, genetic, and single nucleotide polymorphism marker associations between calf diseases and subsequent performance and disease occurrences of first-lactation German Holstein cows.

    Science.gov (United States)

    Mahmoud, M; Yin, T; Brügemann, K; König, S

    2017-03-01

    A total of 31,396 females born from 2010 to 2013 in 43 large-scale Holstein-Friesian herds were phenotyped for calf and cow disease traits using a veterinarian diagnosis key. Calf diseases were general disease status (cGDS), calf diarrhea (cDIA), and calf respiratory disease (cRD) recorded from birth to 2 mo of age. Incidences were 0.48 for cGDS, 0.28 for cRD, and 0.21 for cDIA. Cow disease trait recording focused on the early period directly after calving in first parity, including the interval from 10 d before calving to 200 d in lactation. For cows, at least one entry for the respective disease implied a score = 1 (sick); otherwise, score = 0 (healthy). Corresponding cow diseases were first-lactation general disease status (flGDS), first-lactation diarrhea (flDIA), and first-lactation respiratory disease (flRD). Additional cow disease categories included mastitis (flMAST), claw disorders (flCLAW), female fertility disorders (flFF), and metabolic disorders (flMET). A further cow trait category considered first-lactation test-day production traits from official test-days 1 and 2 after calving. The genotype data set included 41,256 single nucleotide polymorphisms (SNP) from 9,388 females with phenotypes. Linear and generalized linear mixed models with a logit link-function were applied to Gaussian and categorical cow traits, respectively, considering the calf disease as a fixed effect. Most of the calf diseases were not significantly associated with the occurrence of any cow disease. By trend, increasing risks for the occurrence of cow diseases were observed for healthy calves, indicating mechanisms of disease resistance with aging. Also by trend, occurrence of calf diseases was associated with decreasing milk, protein, and fat yields. Univariate linear and threshold animal models were used to estimate heritabilities and breeding values (EBV) for all calf and cow traits. Heritabilities for cGDS and cRD were 0.06 and 0.07 for cDIA. Genetic correlations among all

  19. CD28/CTLA-4/ICOS haplotypes confers susceptibility to Graves' disease and modulates clinical phenotype of disease.

    Science.gov (United States)

    Pawlak-Adamska, Edyta; Frydecka, Irena; Bolanowski, Marek; Tomkiewicz, Anna; Jonkisz, Anna; Karabon, Lidia; Partyka, Anna; Nowak, Oskar; Szalinski, Marek; Daroszewski, Jacek

    2017-01-01

    Graves' disease, an autoimmune disease with heterogeneous symptoms including Graves' orbitopathy, has a combined genetic/environmental background, where variations within CD28/CTLA-4/ICOS genes are considered as disease markers.Association of CD28c.17+3T>C(rs3116496), CTLA-4g.319C>T(rs5742909), CTLA-4c.49A>G(rs231775), CTLA-4g.*642AT(8_33), CT60(rs3087243), Jo31(rs11571302), ICOSc.1554+4GT(8_15) polymorphisms with susceptibility to Graves' disease and clinical outcome was investigated. The study group comprised of 561 Polish Caucasians, including 172 unrelated Graves' disease patients. CTLA-4c.49A>G, CTLA-4g.319C>T, and CT60 were genotyped by PCR-RFLP; Jo31 and CD28c.17+3C>T by minisequencing; CTLA-4g.*642AT(8_33) and ICOSc.1554+4GT(8_15)-PCR and fluorescence-based technique. CD28c.17+3T>C(rs3116496)T/CTLA-4g.319C>T(rs5742909)C/CTLA-4c.49A>G(rs231775)G/CTLA-4g.*642AT(8_33)(AT16-21)/CT60(rs3087243)G/Jo31(rs11571302)G/ICOSc.1554+4GT(8_15)(m) and TCA(ATGraves' disease, especially in males, as well as overall Graves' orbitopathy development with severe outcome. TCG(AT16-21)GG(l) haplotype increased risk of Graves' disease and reduced the chance of successful medical treatment. Although this haplotype was mainly observed in patients without signs of Graves' orbitopathy, if Graves' orbitopathy developed it favored a Graves' orbitopathy outcome. Haplotype TCA(AT>21)GT(m) increased Graves' disease risk in women and, in all patients, was linked to Graves' disease without Graves' orbitopathy. TCG(ATGraves' orbitopathy, whereas TCA(AT16-21)GG(m) was absent in those patients. TCA(AT16-21)GG(m) occurred in patients with a mild Graves' orbitopathy outcome. The marker CTLA-4g.*642AT(8_33) was the only independent Graves' disease risk factor, whereas CT60 was an independent factor for disease progression. Sporadic Graves' disease was related to presence of CTLA-4c.49A>G[A] and the rare CTLA-4g.319C>T[T] allele variant. Familial background of the disease was exclusively associated

  20. Regulatory T Cells Phenotype in Different Clinical Forms of Chagas' Disease

    Science.gov (United States)

    Teixeira-Carvalho, Andréa; Renato Zuquim Antas, Paulo; Assis Silva Gomes, Juliana; Sathler-Avelar, Renato; Otávio Costa Rocha, Manoel; Elói-Santos, Silvana Maria; Pinho, Rosa Teixeira; Correa-Oliveira, Rodrigo; Martins-Filho, Olindo Assis

    2011-01-01

    CD25High CD4+ regulatory T cells (Treg cells) have been described as key players in immune regulation, preventing infection-induced immune pathology and limiting collateral tissue damage caused by vigorous anti-parasite immune response. In this review, we summarize data obtained by the investigation of Treg cells in different clinical forms of Chagas' disease. Ex vivo immunophenotyping of whole blood, as well as after stimulation with Trypanosoma cruzi antigens, demonstrated that individuals in the indeterminate (IND) clinical form of the disease have a higher frequency of Treg cells, suggesting that an expansion of those cells could be beneficial, possibly by limiting strong cytotoxic activity and tissue damage. Additional analysis demonstrated an activated status of Treg cells based on low expression of CD62L and high expression of CD40L, CD69, and CD54 by cells from all chagasic patients after T. cruzi antigenic stimulation. Moreover, there was an increase in the frequency of the population of Foxp3+ CD25HighCD4+ cells that was also IL-10+ in the IND group, whereas in the cardiac (CARD) group, there was an increase in the percentage of Foxp3+ CD25High CD4+ cells that expressed CTLA-4. These data suggest that IL-10 produced by Treg cells is effective in controlling disease development in IND patients. However, in CARD patients, the same regulatory mechanism, mediated by IL-10 and CTLA-4 expression is unlikely to be sufficient to control the progression of the disease. These data suggest that Treg cells may play an important role in controlling the immune response in Chagas' disease and the balance between regulatory and effector T cells may be important for the progression and development of the disease. Additional detailed analysis of the mechanisms on how these cells are activated and exert their function will certainly give insights for the rational design of procedure to achieve the appropriate balance between protection and pathology during parasite

  1. Calpastatin ablation aggravates the molecular phenotype in cell and animal models of Huntington disease.

    Science.gov (United States)

    Weber, Jonasz Jeremiasz; Kloock, Simon Johannes; Nagel, Maike; Ortiz-Rios, Midea Malena; Hofmann, Julian; Riess, Olaf; Nguyen, Huu Phuc

    2018-02-02

    Deciphering the molecular pathology of Huntington disease is of particular importance, not only for a better understanding of this neurodegenerative disease, but also to identify potential therapeutic targets. The polyglutamine-expanded disease protein huntingtin was shown to undergo proteolysis, which results in the accumulation of toxic and aggregation-prone fragments. Amongst several classes of proteolytic enzymes responsible for huntingtin processing, the group of calcium-activated calpains has been found to be a significant mediator of the disease protein toxicity. To confirm the impact of calpain-mediated huntingtin cleavage in Huntington disease, we analysed the effect of depleting or overexpressing the endogenous calpain inhibitor calpastatin in HEK293T cells transfected with wild-type or polyglutamine-expanded huntingtin. Moreover, we crossbred huntingtin knock-in mice with calpastatin knockout animals to assess its effect not only on huntingtin cleavage and aggregation but also additional molecular markers. We demonstrated that a reduced or ablated expression of calpastatin triggers calpain overactivation and a consequently increased mutant huntingtin cleavage in cells and in vivo. These alterations were accompanied by an elevated formation of predominantly cytoplasmic huntingtin aggregates. On the other hand, overexpression of calpastatin in cells attenuated huntingtin fragmentation and aggregation. In addition, we observed an enhanced cleavage of DARPP-32, p35 and synapsin-1 in neuronal tissue upon calpain overactivation. Our results corroborate the important role of calpains in the molecular pathogenesis of Huntington disease and endorse targeting these proteolytic enzymes as a therapeutic approach. Copyright © 2018 Elsevier Ltd. All rights reserved.

  2. Regulatory T cells phenotype in different clinical forms of Chagas' disease.

    Directory of Open Access Journals (Sweden)

    Fernanda Fortes de Araújo

    Full Text Available CD25(High CD4+ regulatory T cells (Treg cells have been described as key players in immune regulation, preventing infection-induced immune pathology and limiting collateral tissue damage caused by vigorous anti-parasite immune response. In this review, we summarize data obtained by the investigation of Treg cells in different clinical forms of Chagas' disease. Ex vivo immunophenotyping of whole blood, as well as after stimulation with Trypanosoma cruzi antigens, demonstrated that individuals in the indeterminate (IND clinical form of the disease have a higher frequency of Treg cells, suggesting that an expansion of those cells could be beneficial, possibly by limiting strong cytotoxic activity and tissue damage. Additional analysis demonstrated an activated status of Treg cells based on low expression of CD62L and high expression of CD40L, CD69, and CD54 by cells from all chagasic patients after T. cruzi antigenic stimulation. Moreover, there was an increase in the frequency of the population of Foxp3+ CD25(HighCD4+ cells that was also IL-10+ in the IND group, whereas in the cardiac (CARD group, there was an increase in the percentage of Foxp3+ CD25(High CD4+ cells that expressed CTLA-4. These data suggest that IL-10 produced by Treg cells is effective in controlling disease development in IND patients. However, in CARD patients, the same regulatory mechanism, mediated by IL-10 and CTLA-4 expression is unlikely to be sufficient to control the progression of the disease. These data suggest that Treg cells may play an important role in controlling the immune response in Chagas' disease and the balance between regulatory and effector T cells may be important for the progression and development of the disease. Additional detailed analysis of the mechanisms on how these cells are activated and exert their function will certainly give insights for the rational design of procedure to achieve the appropriate balance between protection and pathology

  3. The markers of platelet functions and Von Willebrand factor serum content from patients with type 2 diabetes mellitus and ishemic stroke

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    Tetiana Tsarenko

    2016-03-01

    Full Text Available Introduction: The est and #1110;mated number of people with diabetes worldwide in 2015 is 415 million persons, up to 91% of adults hadtype 2 diabetes and the crude incidence of stroke among patients with diabetes of the 2ndtype can be more than 3 times that in the general population. It is known platelet activation and aggregation are critical in the pathogenesis of acute ischemic cerebrovascular diseases. Thus to examine the evidence of platelet functioning such as platelet count,aggregation in response to ADP, coagulation von Willebrand factor and serotonin content, monoamine oxidase (MAO activity in the blood of patients with ischemic stroke and with ischemic stroke complicated with the 2ndtype diabetes are the aim of the present study. Methods: The platelet aggregation was assayed for photo-optical aggregometer, von Willebrand factor was determined by Elisa, serotonin determination included ion-exchange chromatography and fluorescence spectrophotometry. Determination of monoamine-oxidase serum activity was spectophotometry. Results: The investigation has shown an increase of serotonin and Von Willebrand factor blood content in both groups of patients with ischemic stroke andtype 2 diabetes and stroke alone compared with the values of the control group. The monoamine oxidase activity and platelet count were reduced in blood of patients with diabetes of the 2ndtype with ischemic stroke against to the values from the group of healthy donors. Platelet aggregation in response to ADP increased under the investigated pathologies. Conclusions: These obtained data suggested a significant imbalance in vascular platelet element of hemostasis under the ischemic stroke and amplification of negative changes under the stroke with the 2ndtype diabetes. [Biomed Res Ther 2016; 3(3.000: 542-547

  4. Fibroblasts from phenotypically normal palmar fascia exhibit molecular profiles highly similar to fibroblasts from active disease in Dupuytren's Contracture

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    Satish Latha

    2012-05-01

    Full Text Available Abstract Background Dupuytren's contracture (DC is a fibroproliferative disorder characterized by the progressive development of a scar-like collagen-rich cord that affects the palmar fascia of the hand and leads to digital flexion contractures. DC is most commonly treated by surgical resection of the diseased tissue, but has a high reported recurrence rate ranging from 27% to 80%. We sought to determine if the transcriptomic profiles of fibroblasts derived from DC-affected palmar fascia, adjacent phenotypically normal palmar fascia, and non-DC palmar fascial tissues might provide mechanistic clues to understanding the puzzle of disease predisposition and recurrence in DC. Methods To achieve this, total RNA was obtained from fibroblasts derived from primary DC-affected palmar fascia, patient-matched unaffected palmar fascia, and palmar fascia from non-DC patients undergoing carpal tunnel release (6 patients in each group. These cells were grown on a type-1 collagen substrate (to better mimic their in vivo environments. Microarray analyses were subsequently performed using Illumina BeadChip arrays to compare the transcriptomic profiles of these three cell populations. Data were analyzed using Significance Analysis of Microarrays (SAM v3.02, hierarchical clustering, concordance mapping and Venn diagram. Results We found that the transcriptomic profiles of DC-disease fibroblasts and fibroblasts from unaffected fascia of DC patients exhibited a much greater overlap than fibroblasts derived from the palmar fascia of patients undergoing carpal tunnel release. Quantitative real time RT-PCR confirmed the differential expression of select genes validating the microarray data analyses. These data are consistent with the hypothesis that predisposition and recurrence in DC may stem, at least in part, from intrinsic similarities in the basal gene expression of diseased and phenotypically unaffected palmar fascia fibroblasts. These data also demonstrate that

  5. Fibroblasts from phenotypically normal palmar fascia exhibit molecular profiles highly similar to fibroblasts from active disease in Dupuytren's Contracture

    Science.gov (United States)

    2012-01-01

    Background Dupuytren's contracture (DC) is a fibroproliferative disorder characterized by the progressive development of a scar-like collagen-rich cord that affects the palmar fascia of the hand and leads to digital flexion contractures. DC is most commonly treated by surgical resection of the diseased tissue, but has a high reported recurrence rate ranging from 27% to 80%. We sought to determine if the transcriptomic profiles of fibroblasts derived from DC-affected palmar fascia, adjacent phenotypically normal palmar fascia, and non-DC palmar fascial tissues might provide mechanistic clues to understanding the puzzle of disease predisposition and recurrence in DC. Methods To achieve this, total RNA was obtained from fibroblasts derived from primary DC-affected palmar fascia, patient-matched unaffected palmar fascia, and palmar fascia from non-DC patients undergoing carpal tunnel release (6 patients in each group). These cells were grown on a type-1 collagen substrate (to better mimic their in vivo environments). Microarray analyses were subsequently performed using Illumina BeadChip arrays to compare the transcriptomic profiles of these three cell populations. Data were analyzed using Significance Analysis of Microarrays (SAM v3.02), hierarchical clustering, concordance mapping and Venn diagram. Results We found that the transcriptomic profiles of DC-disease fibroblasts and fibroblasts from unaffected fascia of DC patients exhibited a much greater overlap than fibroblasts derived from the palmar fascia of patients undergoing carpal tunnel release. Quantitative real time RT-PCR confirmed the differential expression of select genes validating the microarray data analyses. These data are consistent with the hypothesis that predisposition and recurrence in DC may stem, at least in part, from intrinsic similarities in the basal gene expression of diseased and phenotypically unaffected palmar fascia fibroblasts. These data also demonstrate that a collagen

  6. NAD+-Dependent Activation of Sirt1 Corrects the Phenotype in a Mouse Model of Mitochondrial Disease

    Science.gov (United States)

    Cerutti, Raffaele; Pirinen, Eija; Lamperti, Costanza; Marchet, Silvia; Sauve, Anthony A.; Li, Wei; Leoni, Valerio; Schon, Eric A.; Dantzer, Françoise; Auwerx, Johan; Viscomi, Carlo; Zeviani, Massimo

    2014-01-01

    Summary Mitochondrial disorders are highly heterogeneous conditions characterized by defects of the mitochondrial respiratory chain. Pharmacological activation of mitochondrial biogenesis has been proposed as an effective means to correct the biochemical defects and ameliorate the clinical phenotype in these severely disabling, often fatal, disorders. Pathways related to mitochondrial biogenesis are targets of Sirtuin1, a NAD+-dependent protein deacetylase. As NAD+ boosts the activity of Sirtuin1 and other sirtuins, intracellular levels of NAD+ play a key role in the homeostatic control of mitochondrial function by the metabolic status of the cell. We show here that supplementation with nicotinamide riboside, a natural NAD+ precursor, or reduction of NAD+ consumption by inhibiting the poly(ADP-ribose) polymerases, leads to marked improvement of the respiratory chain defect and exercise intolerance of the Sco2 knockout/knockin mouse, a mitochondrial disease model characterized by impaired cytochrome c oxidase biogenesis. This strategy is potentially translatable into therapy of mitochondrial disorders in humans. PMID:24814483

  7. Age-related epigenetic drift and phenotypic plasticity loss: implications in prevention of age-related human diseases.

    Science.gov (United States)

    Li, Yuanyuan; Tollefsbol, Trygve O

    2016-12-01

    Aging is considered as one of the most important developmental processes in organisms and is closely associated with global deteriorations of epigenetic markers such as aberrant methylomic patterns. This altered epigenomic state, referred to 'epigenetic drift', reflects deficient maintenance of epigenetic marks and contributes to impaired cellular and molecular functions in aged cells. Epigenetic drift-induced abnormal changes during aging are scantily repaired by epigenetic modulators. This inflexibility in the aged epigenome may lead to an age-related decline in phenotypic plasticity at the cellular and molecular levels due to epigenetic drift. This perspective aims to provide novel concepts for understanding epigenetic effects on the aging process and to provide insights into epigenetic prevention and therapeutic strategies for age-related human disease.

  8. Progression of Tubulointerstitial Fibrosis and the Chronic Kidney Disease Phenotype – Role of Risk Factors and Epigenetics

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    Timothy D. Hewitson

    2017-08-01

    Full Text Available Although the kidney has capacity to repair after mild injury, ongoing or severe damage results in scarring (fibrosis and an associated progressive loss of kidney function. However, despite its universal significance, evidence highlights a population based heterogeneity in the trajectory of chronic kidney disease (CKD in these patients. To explain the heterogeneity of the CKD phenotype requires an understanding of the relevant risk factors for fibrosis. These factors include both the extrinsic nature of injury, and intrinsic factors such as age, gender, genetics, and perpetual activation of fibroblasts through priming. In many cases an additional level of regulation is provided by epigenetic mechanisms which integrate the various pro-fibrotic and anti-fibrotic triggers in fibrogenesis. In this review we therefore examine the various molecular and structural changes of fibrosis, and how they are influenced by extrinsic and intrinsic factors. Our aim is to provide a unifying hypothesis to help explain the transition from acute to CKD.

  9. Homocisteína plasmática total e fator von Willebrand no diabete melito experimental Total plasmatic homocysteine and von Willebrand factor in experimental diabetes mellitus

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    Renato Delascio Lopes

    2007-04-01

    Full Text Available OBJETIVOS: Determinar os valores plasmáticos de homocisteína e fator von Willebrand, como marcador de disfunção endotelial, em ratos com diabete melito induzido por estreptozotocina. MÉTODOS: Trinta e cinco ratos (rattus norvegicus albinus, machos, adultos (180-200 g, randomizados em três grupos: controle (n=10 não receberam agente ou veículo; sham (n=10 receberam solução veículo da estreptozotocina; e diabético (n=15 receberam estreptozotocina. Após oito semanas de indução do diabete melito, os animais foram pesados, anestesiados e tiveram sangue colhido da aorta abdominal para determinação dos valores de homocisteína plasmática total, fator von Willebrand e glicemia. RESULTADOS: O modelo experimental foi reprodutível em 100% dos animais. A média das concentrações plasmáticas de homocisteína foi: 7,9 µmol/l (controle; 8,6 µmol/l (sham e 6,1 µmol/l (diabético, com diferença entre os grupos (pOBJECTIVES: To determine the plasma homocysteine and von Willebrand factor levels as markers of endothelial dysfunction in rats with diabetes mellitus induced by streptozotocin. METHODS: Thirty-five adult male rats (Rattus norvegicus albinus (weight between 180-200g were randomized into three groups: control group (n=10, which received no drugs or vehicles; sham group (n=10, which received streptozotocin solution; and diabetic group (n=15, which received streptozotocin. Eight weeks after diabetes mellitus induction, the animals were weighed and anesthesized; blood samples were collected from abdominal aorta for plasma total homocysteine, von Willebrand factor and glucose levels. RESULTS: The experimental model was reproducible in 100% of animals. The mean plasma homocysteine levels were: 7.9 µmol/l (control, 8.6µmol/l (sham and 6.1µmol/l (diabetic, with difference among the groups (p<0.01. Multiple comparison analysis among the groups showed that values in the diabetic group were lower than in the sham group (p<0.01. The mean

  10. Plasma asymmetric dimethylarginine concentrations in sickle cell disease are related to the hemolytic phenotype

    NARCIS (Netherlands)

    Landburg, P. P.; Teerlink, T.; Biemond, B. J.; Brandjes, D. P. M.; Muskiet, F. A. J.; Duits, A. J.; Schnog, J. B.; Grp, C. U. R. A. M. A. Study

    2010-01-01

    Asymmetric dimethylarginine (ADMA) is associated with pulmonary hypertension (PHT) in sickle cell disease (SCD). We studied the relationship of ADMA to other SCD-related complications. Plasma ADMA and associated parameters were determined in 52 HbSS/HbS beta(0)-thalassemia and 24 HbSC/HbS

  11. Cerebrospinal fluid amyloid-beta and phenotypic heterogeneity in de novo Parkinson's disease

    NARCIS (Netherlands)

    Alves, G.; Pedersen, K.F.; Bloem, B.R.; Blennow, K.; Zetterberg, H.; Borm, G.F.; Dalaker, T.O.; Beyer, M.K.; Aarsland, D.; Andreasson, U.; Lange, J.; Tysnes, O.B.; Zivadinov, R.; Larsen, J.P.

    2013-01-01

    BACKGROUND: In Parkinson's disease (PD), the motor presentation characterised by postural instability/gait difficulties (PIGD) heralds accelerated motor, functional and cognitive decline, as compared with the more benign tremor-dominant (TD) variant. This makes the PIGD complex an attractive target

  12. Very mild disease phenotype of congenic CftrTgH(neoim)Hgu cystic fibrosis mice

    NARCIS (Netherlands)

    B. Tóth (Balázs); M. Wilke (Martina); F. Stanke (Frauke); M. Dorsch (Martina); S. Jansen (Silke); D. Wedekind (Dirk); N. Charizopoulou (Nikoletta); A.G. Bot (Alice); M. Burmester (Marion); S. Leonhard-Marek (Sabine); H.R. de Jonge (Hugo); H.J. Hedrich; G. Breves (Gerhard); B. Tümmler (Burkhard)

    2008-01-01

    textabstractBackground: A major boost to cystic fibrosis disease research was given by the generation of various mouse models using gene targeting in embryonal stem cells. Moreover, the introduction of the same mutation on different inbred strains generating congenic strains facilitated the search

  13. Elevated plasma glucosylsphingosine in Gaucher disease: relation to phenotype, storage cell markers, and therapeutic response.

    Science.gov (United States)

    Dekker, Nick; van Dussen, Laura; Hollak, Carla E M; Overkleeft, Herman; Scheij, Saskia; Ghauharali, Karen; van Breemen, Mariëlle J; Ferraz, Maria J; Groener, Johanna E M; Maas, Mario; Wijburg, Frits A; Speijer, Dave; Tylki-Szymanska, Anna; Mistry, Pramod K; Boot, Rolf G; Aerts, Johannes M

    2011-10-20

    Gaucher disease, caused by a deficiency of the lysosomal enzyme glucocerebrosidase, leads to prominent glucosylceramide accumulation in lysosomes of tissue macrophages (Gaucher cells). Here we show glucosylsphingosine, the deacylated form of glucosylceramide, to be markedly increased in plasma of symptomatic nonneuronopathic (type 1) Gaucher patients (n = 64, median = 230.7 nM, range 15.6-1035.2 nM; normal (n = 28): median 1.3 nM, range 0.8-2.7 nM). The method developed for mass spectrometric quantification of plasma glucosylsphingosine is sensitive and robust. Plasma glucosylsphingosine levels correlate with established plasma markers of Gaucher cells, chitotriosidase (ρ = 0.66) and CCL18 (ρ = 0.40). Treatment of Gaucher disease patients by supplementing macrophages with mannose-receptor targeted recombinant glucocerebrosidase results in glucosylsphingosine reduction, similar to protein markers of Gaucher cells. Since macrophages prominently accumulate the lysoglycosphingolipid on glucocerebrosidase inactivation, Gaucher cells seem a major source of the elevated plasma glucosylsphingosine. Our findings show that plasma glucosylsphingosine can qualify as a biomarker for type 1 Gaucher disease, but that further investigations are warranted regarding its relationship with clinical manifestations of Gaucher disease.

  14. Mutations in Hirschsprung disease : When does a mutation contribute to the phenotype

    NARCIS (Netherlands)

    Hofstra, RMW; Osinga, J; Buys, CHCM

    1997-01-01

    Hirschsprung disease is a congenital disorder clinically characterized by the absence of colonic ganglia and genetically by extensive heterogeneity. Genes involved include RET, GDNF, EDNRB and EDN3. Mutations of these genes may give dominant, recessive, or polygenic patterns of inheritance. In

  15. Phenotypic spectrum of Charcot-Marie-Tooth disease due to LITAF/SIMPLE mutations: a study of 18 patients.

    Science.gov (United States)

    Guimarães-Costa, R; Iancu Ferfoglia, R; Leonard-Louis, S; Ziegler, F; Magy, L; Fournier, E; Dubourg, O; Bouche, P; Maisonobe, T; Lacour, A; Moerman, A; Latour, P; Stojkovic, T

    2017-03-01

    Charcot-Marie-Tooth (CMT) 1C due to mutations in LITAF/SIMPLE is a rare subtype amongst the autosomal dominant demyelinating forms of CMT. Our objective was to report the clinical and electrophysiological characteristics of 18 CMT1C patients and compare them to 20 patients with PMP22 mutations: 10 CMT1A patients and 10 patients with hereditary neuropathy with liability to pressure palsies (HNPP). Charcot-Marie-Tooth 1C patients were followed-up in referral centres for neuromuscular diseases or were identified by familial survey. All CMT1A and HNPP patients were recruited at the referral centre for neuromuscular diseases of Pitié-Salpêtrière Hospital. Two phenotypes were identified amongst 18 CMT1C patients: the classical CMT form ('CMT-like', 11 cases) and a predominantly sensory form ('sensory form', seven cases). The mean CMT neuropathy score was 4.45 in CMT1C patients. Motor nerve conduction velocities in the upper limbs were significantly more reduced in CMT1A than in CMT1C patients. On the other hand, the motor nerve conduction velocity of the median nerve was significantly lower in CMT1C compared to the HNPP group. Distal motor latency was significantly more prolonged in CMT1A patients compared to the CMT1C and HNPP groups, the latter two groups having similar distal motor latency values. Molecular analysis revealed five new LITAF/SIMPLE mutations (Ala111Thr, Gly112Ala, Trp116Arg, Pro135Leu, Arg160Cys). Our study delineates CMT1C as mostly a mild form of neuropathy, and gives clinical and electrophysiological clues differentiating CMT1C from CMT1A and HNPP. Delineating phenotypes in CMT subtypes is important to orient molecular diagnosis and to help to interpret complex molecular findings. © 2017 EAN.

  16. Hyperpolarized {sup 3}He magnetic resonance imaging: Preliminary evaluation of phenotyping potential in chronic obstructive pulmonary disease

    Energy Technology Data Exchange (ETDEWEB)

    Mathew, Lindsay, E-mail: lmathew@imaging.robarts.ca [Imaging Research Laboratories, Robarts Research Institute, London (Canada); Department of Medical Biophysics, University of Western Ontario, London (Canada); Kirby, Miranda, E-mail: mkirby@imaging.robarts.ca [Imaging Research Laboratories, Robarts Research Institute, London (Canada); Department of Medical Biophysics, University of Western Ontario, London (Canada); Etemad-Rezai, Roya, E-mail: Roya.EtemadRezai@lhsc.on.ca [Department of Medical Imaging, University of Western Ontario (Canada); Wheatley, Andrew, E-mail: awheat@imaging.robarts.ca [Imaging Research Laboratories, Robarts Research Institute, London (Canada); McCormack, David G., E-mail: David.McCormack@lhsc.on.ca [Imaging Research Laboratories, Robarts Research Institute, London (Canada); Division of Respirology, Department of Medicine, University of Western Ontario, London (Canada); Lawson Health Research Institute, London (Canada); Parraga, Grace, E-mail: gep@imaging.robarts.ca [Imaging Research Laboratories, Robarts Research Institute, London (Canada); Department of Medical Biophysics, University of Western Ontario, London (Canada); Department of Medical Imaging, University of Western Ontario (Canada); Lawson Health Research Institute, London (Canada)

    2011-07-15

    Rationale and objectives: Emphysema and small airway obstruction are the pathological hallmarks of chronic obstructive pulmonary disease (COPD). The aim of this pilot study in a small group of chronic obstructive pulmonary disease (COPD) patients was to quantify hyperpolarized helium-3 ({sup 3}He) magnetic resonance imaging (MRI) functional and structural measurements and to explore the potential role for {sup 3}He MRI in detecting the lung structural and functional COPD phenotypes. Materials and methods: We evaluated 20 ex-smokers with stage I (n = 1), stage II (n = 9) and stage III COPD (n = 10). All subjects underwent same-day plethysmography, spirometry, {sup 1}H MRI and hyperpolarized {sup 3}He MRI at 3.0 T. {sup 3}He ventilation defect percent (VDP) was generated from {sup 3}He static ventilation images and {sup 1}H thoracic images and the {sup 3}He apparent diffusion coefficient (ADC) was derived from diffusion-weighted MRI. Results: Based on the relative contribution of normalized ADC and VDP, there was evidence of a predominant {sup 3}He MRI measurement in seven patients (n = 3 mainly ventilation defects or VDP dominant (VD), n = 4 mainly increased ADC or ADC dominant (AD)). Analysis of variance (ANOVA) showed significantly lower ADC for subjects with predominantly elevated VDP (p = 0.02 compared to subjects with predominantly elevated ADC; p = 0.008 compared to mixed group) and significantly decreased VDP for subjects with predominantly elevated ADC (p = 0.003, compared to mixed group). Conclusion: In this small pilot study, a preliminary analysis shows the potential for {sup 3}He MRI to categorize or phenotype COPD ex-smokers, providing good evidence of feasibility for larger prospective studies.

  17. Complete phenotypic recovery of an Alzheimer's disease model by a quinone-tryptophan hybrid aggregation inhibitor.

    Directory of Open Access Journals (Sweden)

    Roni Scherzer-Attali

    Full Text Available The rational design of amyloid oligomer inhibitors is yet an unmet drug development need. Previous studies have identified the role of tryptophan in amyloid recognition, association and inhibition. Furthermore, tryptophan was ranked as the residue with highest amyloidogenic propensity. Other studies have demonstrated that quinones, specifically anthraquinones, can serve as aggregation inhibitors probably due to the dipole interaction of the quinonic ring with aromatic recognition sites within the amyloidogenic proteins. Here, using in vitro, in vivo and in silico tools we describe the synthesis and functional characterization of a rationally designed inhibitor of the Alzheimer's disease-associated beta-amyloid. This compound, 1,4-naphthoquinon-2-yl-L-tryptophan (NQTrp, combines the recognition capacities of both quinone and tryptophan moieties and completely inhibited Abeta oligomerization and fibrillization, as well as the cytotoxic effect of Abeta oligomers towards cultured neuronal cell line. Furthermore, when fed to transgenic Alzheimer's disease Drosophila model it prolonged their life span and completely abolished their defective locomotion. Analysis of the brains of these flies showed a significant reduction in oligomeric species of Abeta while immuno-staining of the 3(rd instar larval brains showed a significant reduction in Abeta accumulation. Computational studies, as well as NMR and CD spectroscopy provide mechanistic insight into the activity of the compound which is most likely mediated by clamping of the aromatic recognition interface in the central segment of Abeta. Our results demonstrate that interfering with the aromatic core of amyloidogenic peptides is a promising approach for inhibiting various pathogenic species associated with amyloidogenic diseases. The compound NQTrp can serve as a lead for developing a new class of disease modifying drugs for Alzheimer's disease.

  18. Analysis of HLA and disease susceptibility: Chromosome 6 genes and sex influence long-QT phenotype

    Energy Technology Data Exchange (ETDEWEB)

    Weitkamp, L.R.; Moss, A.J.; Hall, W.J.; Robinson, J.L.; Guttormsen, S.A. [Univ. of Rochester School of Medicine and Dentistry, NY (United States); Lewis, R.A. [Pennsylvania State Univ., University Park, PA (United States); MacCluer, J.W. [Southwest Foundation for Biomedical Research, San Antonio, TX (United States); Schwartz, P.J. [Univ. of Pavia (Italy); Locati, E.H. [Univ. of Milan (Italy); Tzivoni, D. [Shaare Zedek Medical Center, Jerusalem (Israel)

    1994-12-01

    The long-QT (LQT) syndrome is a genetically complex disorder that is characterized by syncope and fatal ventricular arrhythmias. LQT syndrome, as defined by a prolonged electrocardiographic QT interval, has a higher incidence in females than in males and does not exhibit Mendelian transmission patterns in all families. Among those families that are nearly consistent with Mendelian transmission, linkage between a locus for LQT syndrome and the H-ras-1 locus on the short arm of chromosome 11 has been reported in some families but not in others. Earlier analyses suggesting that LQT syndrome might be caused by a gene in the HLA region of chromosome 6 were not confirmed by standard linkage analyses. Here, we present an analysis of HLA haplotype sharing among affected pedigree members, showing an excess of haplotype sharing in a previously published Japanese pedigree and possibly also in 15 families of European descent. The haplotypes shared by affected individuals derive from both affected and unaffected parents. In an analysis of independent (unrelated) HLA haplotypes, we also found a nonrandom distribution of HLA-DR genes in LQT syndrome patients compared with controls, suggesting an association between the LQT phenotype and specific HLA-DR genes. Our data indicate that DR2 has a protective effect and, particularly in males, that DR7 may increase susceptibility to the LQT syndrome. Thus, LQT syndrome may be influenced by genes on chromosomes 11 and 6, possibly with a sex-specific effect. These results provide a model for an effect of HLA-region genes inherited from either parent on the expression of an illness that may be determined principally by alleles at loci not linked to HLA.

  19. Rapid visualisation of microarray copy number data for the detection of structural variations linked to a disease phenotype.

    Directory of Open Access Journals (Sweden)

    Ian M Carr

    Full Text Available Whilst the majority of inherited diseases have been found to be caused by single base substitutions, small insertions or deletions (<1Kb, a significant proportion of genetic variability is due to copy number variation (CNV. The possible role of CNV in monogenic and complex diseases has recently attracted considerable interest. However, until the development of whole genome, oligonucleotide micro-arrays, designed specifically to detect the presence of copy number variation, it was not easy to screen an individual for the presence of unknown deletions or duplications with sizes below the level of sensitivity of optical microscopy (3-5 Mb. Now that currently available oligonucleotide micro-arrays have in excess of a million probes, the problem of copy number analysis has moved from one of data production to that of data analysis. We have developed CNViewer, to identify copy number variation that co-segregates with a disease phenotype in small nuclear families, from genome-wide oligonucleotide micro-array data. This freely available program should constitute a useful addition to the diagnostic armamentarium of clinical geneticists.

  20. Axial Disease in Psoriatic Arthritis study: defining the clinical and radiographic phenotype of psoriatic spondyloarthritis.

    Science.gov (United States)

    Jadon, Deepak R; Sengupta, Raj; Nightingale, Alison; Lindsay, Mark; Korendowych, Eleanor; Robinson, Graham; Jobling, Amelia; Shaddick, Gavin; Bi, Jing; Winchester, Robert; Giles, Jon T; McHugh, Neil J

    2017-04-01

    To compare the prevalence, clinical and radiographic characteristics of psoriatic spondyloarthritis (PsSpA) in psoriatic arthritis (PsA), with ankylosing spondylitis (AS). A prospective single-centre cross-sectional observational study recruited consecutive PsA and AS cases. Participants completed outcome measures, and underwent clinical examination, axial radiographic scoring and HLA-sequencing. Multivariable analyses are presented. The 402 enrolled cases (201 PsA, 201 AS; fulfilling classification criteria for respective conditions) were reclassified based upon radiographic axial disease and psoriasis, as: 118 PsSpA, 127 peripheral-only PsA (pPsA), and 157 AS without psoriasis (AS) cases. A significant proportion of patients with radiographic axial disease had PsSpA (118/275; 42.91%), and often had symptomatically silent axial disease (30/118; 25.42%). Modified New York criteria for AS were fulfilled by 48/201 (23.88%) PsA cases, and Classification of Psoriatic Arthritis criteria by 49/201 (24.38%) AS cases. pPsA compared with PsSpA cases had a lower frequency of HLA-B*27 (OR 0.12; 95% CI 0.05 to 0.25). Disease activity, metrology and disability were comparable in PsSpA and AS. A significant proportion of PsSpA cases had spondylitis without sacroiliitis (39/118; 33.05%); they less frequently carried HLA-B*27 (OR 0.11; 95% CI 0.04 to 0.33). Sacroiliac joint complete ankylosis (adjusted OR, ORadj 2.96; 95% CI 1.42 to 6.15) and bridging syndesmophytes (ORadj 2.78; 95% CI 1.49 to 5.18) were more likely in AS than PsSpA. Radiographic axial disease was more severe in AS than PsSpA (Psoriatic Arthritis Spondylitis Radiology Index Score: adjusted incidence risk ratio 1.13; 95% CI 1.09 to 1.19). In a combined cohort of patients with either PsA or AS from a single centre, 24% fulfilled classification criteria for both conditions. The pattern of axial disease was influenced significantly by the presence of skin psoriasis and HLA-B*27. Published by the BMJ Publishing Group

  1. Gene mutations versus clinically relevant phenotypes: lyso-Gb3 defines Fabry disease.

    Science.gov (United States)

    Niemann, Markus; Rolfs, Arndt; Störk, Stefan; Bijnens, Bart; Breunig, Frank; Beer, Meinrad; Ertl, Georg; Wanner, Christoph; Weidemann, Frank

    2014-02-01

    Currently, no method is available to identify α-galactosidase A (agalA) mutations determining clinically relevant Fabry disease. In our largest European Fabry cohort, we investigated whether a biomarker, specific for the defect, could stratify persons at risk. A total of 124 individuals with agalA mutations were investigated with a comprehensive clinical workup, genetic analysis, and laboratory testing, including measurements of agalA activity and lyso-Gb3 (degradation product of the accumulating Gb3). Additionally, an extensive family screening with a clinical workup of relatives was performed. The patient population was divided into 2 samples: previously described mutations (n=72) and novel mutations (n=52). The patients with previously described mutations were subdivided into 2 groups: classical mutations, which were known to cause the classic type of Fabry disease with specific symptoms and a high risk for major events in all 3 main organs (heart, kidney, and central nervous system), and atypical mutations without the typical presentation. All patients with atypical mutations (n=17) had lower lyso-Gb3 levels than any of the patients with classical Fabry disease (n=55). A cutoff value of 2.7 ng/mL separated the 2 groups. Six out of 52 patients with novel mutations showed a lyso-Gb3 level characterization of patients with lyso-Gb3≥2.7 ng/mL suggested classical Fabry mutations in most of the patients (93%). Our data show that the biomarker lyso-Gb3 may identify the clinically relevant agalA mutations leading to Fabry disease.

  2. Chromosome 9p21 SNPs Associated with Multiple Disease Phenotypes Correlate with ANRIL Expression.

    Directory of Open Access Journals (Sweden)

    Michael S Cunnington

    2010-04-01

    Full Text Available Single nucleotide polymorphisms (SNPs on chromosome 9p21 are associated with coronary artery disease, diabetes, and multiple cancers. Risk SNPs are mainly non-coding, suggesting that they influence expression and may act in cis. We examined the association between 56 SNPs in this region and peripheral blood expression of the three nearest genes CDKN2A, CDKN2B, and ANRIL using total and allelic expression in two populations of healthy volunteers: 177 British Caucasians and 310 mixed-ancestry South Africans. Total expression of the three genes was correlated (P<0.05, suggesting that they are co-regulated. SNP associations mapped by allelic and total expression were similar (r = 0.97, P = 4.8x10(-99, but the power to detect effects was greater for allelic expression. The proportion of expression variance attributable to cis-acting effects was 8% for CDKN2A, 5% for CDKN2B, and 20% for ANRIL. SNP associations were similar in the two populations (r = 0.94, P = 10(-72. Multiple SNPs were independently associated with expression of each gene (P<0.05 after correction for multiple testing, suggesting that several sites may modulate disease susceptibility. Individual SNPs correlated with changes in expression up to 1.4-fold for CDKN2A, 1.3-fold for CDKN2B, and 2-fold for ANRIL. Risk SNPs for coronary disease, stroke, diabetes, melanoma, and glioma were all associated with allelic expression of ANRIL (all P<0.05 after correction for multiple testing, while association with the other two genes was only detectable for some risk SNPs. SNPs had an inverse effect on ANRIL and CDKN2B expression, supporting a role of antisense transcription in CDKN2B regulation. Our study suggests that modulation of ANRIL expression mediates susceptibility to several important human diseases.

  3. 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.

  4. Examining the motor phenotype of patients with both essential tremor and Parkinson's disease.

    OpenAIRE

    Simões, R.; A. Constantino; Gibadullina, E; Houghton, D.; Louis, E; Litvan, I.

    2012-01-01

    Previous reports have suggested that essential tremor (ET) represents a risk factor for the development of Parkinson's disease (PD). Patients with long-standing ET who develop PD tend to have a tremor-dominant subtype. To further clarify this association, we examined patients from kindreds with autosomal dominant ET who had signs of isolated PD but did not meet criteria for overlapping ET. We identified 22 patients with PD meeting these diagnostic criteria, and 90% (20 of 22) had tremor-predo...

  5. Gender and age peculiarities of content changes of protein C, von Willebrand factor, vascular cell adhesion molecules sVCAM-1 in patients with acute left ventricle Q-wave myocardial infarction

    Directory of Open Access Journals (Sweden)

    S. M. Kyselov

    2015-04-01

    Full Text Available Markers of hemostasis have an influence on the state of postinfarction remodeling processes. Aim. In order to study the gender and age peculiarities, to determine the predictive value of the protein C, von Willebrand factor and vascular cell adhesion molecules sVCAM-1 concentration, we examined 76 patients with acute Q-wave myocardial infarction. Methods and results. On the 1st day of the disease, higher concentrations of protein C were detected in young women, vascular cell adhesion molecules sVCAM-1 - in men of any age. On the 10th day of the disease, both in men and women increase in the content of protein C, reducing the concentration of von Willebrand factor and vascular cell adhesion molecules sVCAM-1 were detected. Conclusion. Protein C has the highest prognostic potential in relation to the formation of heart aneurysm after Q-wave myocardial infarction in women of young age, and von Willebrand factor and vascular cell adhesion molecules sVCAM-1 - in older men.

  6. Elevated plasma glucosylsphingosine in Gaucher disease: relation to phenotype, storage cell markers, and therapeutic response

    OpenAIRE

    Dekker, Nick; van Dussen, Laura; Hollak, Carla E. M.; Overkleeft, Herman; Scheij, Saskia; Ghauharali, Karen; van Breemen, Mariëlle J.; Ferraz, Maria J.; Groener, Johanna E. M.; Maas, Mario; Wijburg, Frits A.; Speijer, Dave; Tylki-Szymanska, Anna; Mistry, Pramod K.; Boot, Rolf G.

    2011-01-01

    Gaucher disease, caused by a deficiency of the lysosomal enzyme glucocerebrosidase, leads to prominent glucosylceramide accumulation in lysosomes of tissue macrophages (Gaucher cells). Here we show glucosylsphingosine, the deacylated form of glucosylceramide, to be markedly increased in plasma of symptomatic nonneuronopathic (type 1) Gaucher patients (n = 64, median = 230.7nM, range 15.6-1035.2nM; normal (n = 28): median 1.3nM, range 0.8-2.7nM). The method developed for mass spectrometric qua...

  7. Examining the Motor Phenotype of Patients with Both Essential Tremor and Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    Rita M. Simões

    2012-05-01

    Full Text Available Background: The subset of patients with essential tremor (ET that develops Parkinson's disease (PD has not been fully clinically characterized. Methods: Motor features were retrospectively reviewed in 18 ET patients who developed PD (ET→PD, 20 ET and 30 PD patients with similar ages and disease durations. Results: Fewer ET→PD than ET patients had widespread postural and/or action tremor (2/17 [11.8%] vs. 11/17 [64.7%]; p = 0.001 and marginally fewer had cerebellar signs (1/15 [6.7%] vs. 6/18 [33.3%], p = 0.06. ET→PD patients required fewer ET medications than did their counterparts with ET (p = 0.001. ET→PD patients and PD patients did not differ in UPDRS, Hoehn and Yahr, or Schwab and England scores (each p≥0.14. Discussion: ET patients who develop PD may have distinct pre-PD motor features compared to their counterparts with ET who do not develop co-existing PD. Prospective studies are needed to evaluate the predictive value of these clinical features for the emergence of PD. 

  8. Side of Onset in Parkinson’s Disease and Alterations in Religiosity: Novel Behavioral Phenotypes

    Directory of Open Access Journals (Sweden)

    Paul M. Butler

    2011-01-01

    Full Text Available Behavioral neurologists have long been interested in changes in religiosity following circumscribed brain lesions. Advances in neuroimaging and cognitive experimental techniques have been added to these classical lesion-correlational approaches in attempt to understand changes in religiosity due to brain damage. In this paper we assess processing dynamics of religious cognition in patients with Parkinson’s disease (PD. We administered a four-condition story-based priming procedure, and then covertly probed for changes in religious belief. Story-based priming emphasized mortality salience, religious ritual, and beauty in nature (Aesthetic. In neurologically intact controls, religious belief-scores significantly increased following the Aesthetic prime condition. When comparing effects of right (RO versus left onset (LO in PD patients, a double-dissociation in religious belief-scores emerged based on prime condition. RO patients exhibited a significant increase in belief following the Aesthetic prime condition and LO patients significantly increased belief in the religious ritual prime condition. Results covaried with executive function measures. This suggests lateral cerebral specialization for ritual-based (left frontal versus aesthetic-based (right frontal religious cognition. Patient-centered individualized treatment plans should take religiosity into consideration as a complex disease-associated phenomenon connected to other clinical variables and health outcomes.

  9. Modelling the tumour microenvironment in long-term microencapsulated 3D co-cultures recapitulates phenotypic features of disease progression.

    Science.gov (United States)

    Estrada, Marta F; Rebelo, Sofia P; Davies, Emma J; Pinto, Marta T; Pereira, Hugo; Santo, Vítor E; Smalley, Matthew J; Barry, Simon T; Gualda, Emilio J; Alves, Paula M; Anderson, Elizabeth; Brito, Catarina

    2016-02-01

    3D cell tumour models are generated mainly in non-scalable culture systems, using bioactive scaffolds. Many of these models fail to reflect the complex tumour microenvironment and do not allow long-term monitoring of tumour progression. To overcome these limitations, we have combined alginate microencapsulation with agitation-based culture systems, to recapitulate and monitor key aspects of the tumour microenvironment and disease progression. Aggregates of MCF-7 breast cancer cells were microencapsulated in alginate, either alone or in combination with human fibroblasts, then cultured for 15 days. In co-cultures, the fibroblasts arranged themselves around the tumour aggregates creating distinct epithelial and stromal compartments. The presence of fibroblasts resulted in secretion of pro-inflammatory cytokines and deposition of collagen in the stromal compartment. Tumour cells established cell-cell contacts and polarised around small lumina in the interior of the aggregates. Over the culture period, there was a reduction in oestrogen receptor and membranous E-cadherin alongside loss of cell polarity, increased collective cell migration and enhanced angiogenic potential in co-cultures. These phenotypic alterations, typical of advanced stages of cancer, were not observed in the mono-cultures of MCF-7 cells. The proposed model system constitutes a new tool to study tumour-stroma crosstalk, disease progression and drug resistance mechanisms. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  10. Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer's Disease Phenotypes.

    Directory of Open Access Journals (Sweden)

    Waseem K Raja

    Full Text Available The dismal success rate of clinical trials for Alzheimer's disease (AD motivates us to develop model systems of AD pathology that have higher predictive validity. The advent of induced pluripotent stem cells (iPSCs allows us to model pathology and study disease mechanisms directly in human neural cells from healthy individual as well as AD patients. However, two-dimensional culture systems do not recapitulate the complexity of neural tissue, and phenotypes such as extracellular protein aggregation are difficult to observe. We report brain organoids that use pluripotent stem cells derived from AD patients and recapitulate AD-like pathologies such as amyloid aggregation, hyperphosphorylated tau protein, and endosome abnormalities. These pathologies are observed in an age-dependent manner in organoids derived from multiple familial AD (fAD patients harboring amyloid precursor protein (APP duplication or presenilin1 (PSEN1 mutation, compared to controls. The incidence of AD pathology was consistent amongst several fAD lines, which carried different mutations. Although these are complex assemblies of neural tissue, they are also highly amenable to experimental manipulation. We find that treatment of patient-derived organoids with β- and γ-secretase inhibitors significantly reduces amyloid and tau pathology. Moreover, these results show the potential of this model system to greatly increase the translatability of pre-clinical drug discovery in AD.

  11. Age-related behavioral phenotype of an astrocytic monoamine oxidase-B transgenic mouse model of Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Christopher A Lieu

    Full Text Available We have previously shown that increases in astrocytic monoamine oxidase-B (MAO-B expression, mimicking that which occurs with aging and in neurodegenerative disease, in a doxycycline (dox-inducible transgenic mouse model evokes neuropathological similarities to what is observed in the human parkinsonian brain. Additional behavioral and neuropathological studies could provide further validation for its usage as a model for Parkinson's disease (PD. In the present study, we utilized a battery of behavioral tests to evaluate age-related phenotype in this model. In the open field test, we found that dox-induction impaired motor ability with decreases in movement and ambulatory function as well as diminished stereotypical, repetitive movement episodes in both young and old mice. Older mice also showed decreased motor performance in the pole test when compared to younger mice. Furthermore, dox-induced older mice displayed severe hindlimb clasping and the most significant loss of dopamine (DA in the striatum when compared to young and non-induced animals. Additionally, increased MAO-B activity significantly correlated with decreased expression of striatal DA. The results of our study further confirms that the dox-inducible astrocytic MAO-B transgenic mouse displays similar age-related behavioral and neuropathological features to other models of PD, and could serve as a useful tool to study PD pathophysiology and for the evaluation of therapeutic interventions.

  12. Genomic Clustering of differential DNA methylated regions (epimutations) associated with the epigenetic transgenerational inheritance of disease and phenotypic variation.

    Science.gov (United States)

    Haque, M Muksitul; Nilsson, Eric E; Holder, Lawrence B; Skinner, Michael K

    2016-06-01

    A variety of environmental factors have been shown to promote the epigenetic transgenerational inheritance of disease and phenotypic variation in numerous species. Exposure to environmental factors such as toxicants can promote epigenetic changes (epimutations) involving alterations in DNA methylation to produce specific differential DNA methylation regions (DMRs). The germline (e.g. sperm) transmission of epimutations is associated with epigenetic transgenerational inheritance phenomena. The current study was designed to determine the genomic locations of environmentally induced transgenerational DMRs and assess their potential clustering. The exposure specific DMRs (epimutations) from a number of different studies were used. The clustering approach identified areas of the genome that have statistically significant over represented numbers of epimutations. The location of DMR clusters was compared to the gene clusters of differentially expressed genes found in tissues and cells associated with the transgenerational inheritance of disease. Such gene clusters, termed epigenetic control regions (ECRs), have been previously suggested to regulate gene expression in regions spanning up to 2-5 million bases. DMR clusters were often found to associate with inherent gene clusters within the genome. The current study used a number of epigenetic datasets from previous studies to identify novel DMR clusters across the genome. Observations suggest these clustered DMR within an ECR may be susceptible to epigenetic reprogramming and dramatically influence genome activity.

  13. Integration-independent Transgenic Huntington Disease Fragment Mouse Models Reveal Distinct Phenotypes and Life Span in Vivo*

    Science.gov (United States)

    O'Brien, Robert; DeGiacomo, Francesco; Holcomb, Jennifer; Bonner, Akilah; Ring, Karen L.; Zhang, Ningzhe; Zafar, Khan; Weiss, Andreas; Lager, Brenda; Schilling, Birgit; Gibson, Bradford W.; Chen, Sylvia; Kwak, Seung; Ellerby, Lisa M.

    2015-01-01

    The cascade of events that lead to cognitive decline, motor deficits, and psychiatric symptoms in patients with Huntington disease (HD) is triggered by a polyglutamine expansion in the N-terminal region of the huntingtin (HTT) protein. A significant mechanism in HD is the generation of mutant HTT fragments, which are generally more toxic than the full-length HTT. The protein fragments observed in human HD tissue and mouse models of HD are formed by proteolysis or aberrant splicing of HTT. To systematically investigate the relative contribution of the various HTT protein proteolysis events observed in vivo, we generated transgenic mouse models of HD representing five distinct proteolysis fragments ending at amino acids 171, 463, 536, 552, and 586 with a polyglutamine length of 148. All lines contain a single integration at the ROSA26 locus, with expression of the fragments driven by the chicken β-actin promoter at nearly identical levels. The transgenic mice N171-Q148 and N552-Q148 display significantly accelerated phenotypes and a shortened life span when compared with N463-Q148, N536-Q148, and N586-Q148 transgenic mice. We hypothesized that the accelerated phenotype was due to altered HTT protein interactions/complexes that accumulate with age. We found evidence for altered HTT complexes in caspase-2 fragment transgenic mice (N552-Q148) and a stronger interaction with the endogenous HTT protein. These findings correlate with an altered HTT molecular complex and distinct proteins in the HTT interactome set identified by mass spectrometry. In particular, we identified HSP90AA1 (HSP86) as a potential modulator of the distinct neurotoxicity of the caspase-2 fragment mice (N552-Q148) when compared with the caspase-6 transgenic mice (N586-Q148). PMID:26025364

  14. Phenotypic and genomic analysis of multiple myeloma minimal residual disease tumor cells: a new model to understand chemoresistance.

    Science.gov (United States)

    Paiva, Bruno; Corchete, Luis A; Vidriales, Maria-Belen; Puig, Noemi; Maiso, Patricia; Rodriguez, Idoia; Alignani, Diego; Burgos, Leire; Sanchez, Maria-Luz; Barcena, Paloma; Echeveste, Maria-Asuncion; Hernandez, Miguel T; García-Sanz, Ramón; Ocio, Enrique M; Oriol, Albert; Gironella, Mercedes; Palomera, Luis; De Arriba, Felipe; Gonzalez, Yolanda; Johnson, Sarah K; Epstein, Joshua; Barlogie, Bart; Lahuerta, Juan José; Blade, Joan; Orfao, Alberto; Mateos, María-Victoria; San Miguel, Jesús F

    2016-04-14

    Persistence of chemoresistant minimal residual disease (MRD) plasma cells (PCs) is associated with inferior survival in multiple myeloma (MM). Thus, characterization of the minor MRD subclone may represent a unique model to understand chemoresistance, but to our knowledge, the phenotypic and genetic features of the MRD subclone have never been investigated. Here, we compared the antigenic profile of MRD vs diagnostic clonal PCs in 40 elderly MM patients enrolled in the GEM2010MAS65 study and showed that the MRD subclone is enriched in cells overexpressing integrins (CD11a/CD11c/CD29/CD49d/CD49e), chemokine receptors (CXCR4), and adhesion molecules (CD44/CD54). Genetic profiling of MRD vs diagnostic PCs was performed in 12 patients; 3 of them showed identical copy number alterations (CNAs), in another 3 cases, MRD clonal PCs displayed all genetic alterations detected at diagnosis plus additional CNAs that emerged at the MRD stage, whereas in the remaining 6 patients, there were CNAs present at diagnosis that were undetectable in MRD clonal PCs, but also a selected number of genetic alterations that became apparent only at the MRD stage. The MRD subclone showed significant downregulation of genes related to protein processing in endoplasmic reticulum, as well as novel deregulated genes such as ALCAM that is prognostically relevant in MM and may identify chemoresistant PCs in vitro. Altogether, our results suggest that therapy-induced clonal selection could be already present at the MRD stage, where chemoresistant PCs show a singular phenotypic signature that may result from the persistence of clones with different genetic and gene expression profiles. This trial was registered atwww.clinicaltrials.gov as #NCT01237249. © 2016 by The American Society of Hematology.

  15. Integration-independent Transgenic Huntington Disease Fragment Mouse Models Reveal Distinct Phenotypes and Life Span in Vivo.

    Science.gov (United States)

    O'Brien, Robert; DeGiacomo, Francesco; Holcomb, Jennifer; Bonner, Akilah; Ring, Karen L; Zhang, Ningzhe; Zafar, Khan; Weiss, Andreas; Lager, Brenda; Schilling, Birgit; Gibson, Bradford W; Chen, Sylvia; Kwak, Seung; Ellerby, Lisa M

    2015-07-31

    The cascade of events that lead to cognitive decline, motor deficits, and psychiatric symptoms in patients with Huntington disease (HD) is triggered by a polyglutamine expansion in the N-terminal region of the huntingtin (HTT) protein. A significant mechanism in HD is the generation of mutant HTT fragments, which are generally more toxic than the full-length HTT. The protein fragments observed in human HD tissue and mouse models of HD are formed by proteolysis or aberrant splicing of HTT. To systematically investigate the relative contribution of the various HTT protein proteolysis events observed in vivo, we generated transgenic mouse models of HD representing five distinct proteolysis fragments ending at amino acids 171, 463, 536, 552, and 586 with a polyglutamine length of 148. All lines contain a single integration at the ROSA26 locus, with expression of the fragments driven by the chicken β-actin promoter at nearly identical levels. The transgenic mice N171-Q148 and N552-Q148 display significantly accelerated phenotypes and a shortened life span when compared with N463-Q148, N536-Q148, and N586-Q148 transgenic mice. We hypothesized that the accelerated phenotype was due to altered HTT protein interactions/complexes that accumulate with age. We found evidence for altered HTT complexes in caspase-2 fragment transgenic mice (N552-Q148) and a stronger interaction with the endogenous HTT protein. These findings correlate with an altered HTT molecular complex and distinct proteins in the HTT interactome set identified by mass spectrometry. In particular, we identified HSP90AA1 (HSP86) as a potential modulator of the distinct neurotoxicity of the caspase-2 fragment mice (N552-Q148) when compared with the caspase-6 transgenic mice (N586-Q148). © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  16. Quantitative Fundus Autofluorescence and Optical Coherence Tomography in PRPH2/RDS- and ABCA4-Associated Disease Exhibiting Phenotypic Overlap.

    Science.gov (United States)

    Duncker, Tobias; Tsang, Stephen H; Woods, Russell L; Lee, Winston; Zernant, Jana; Allikmets, Rando; Delori, François C; Sparrow, Janet R

    2015-05-01

    To assess whether quantitative fundus autofluorescence (qAF), a measure of RPE lipofuscin, and spectral-domain optical coherence tomography (SD-OCT) can aid in the differentiation of patients with fundus features that could either be related to ABCA4 mutations or be part of the phenotypic spectrum of pattern dystrophies. Autofluorescence images (30°, 488-nm excitation) from 39 patients (67 eyes) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference and were quantified as previously described. In addition, horizontal SD-OCT images through the fovea were obtained. Patients were screened for ABCA4 and PRPH2/RDS mutations. ABCA4 mutations were identified in 19 patients (mean age, 37 ± 12 years) and PRPH2/RDS mutations in 8 patients (mean age, 48 ± 13 years); no known ABCA4 or PRPH2/RDS mutations were found in 12 patients (mean age, 48 ± 9 years). Differentiation of the groups using phenotypic SD-OCT and AF features (e.g., peripapillary sparing, foveal sparing) was not reliable. However, patients with ABCA4 mutations could be discriminated reasonably well from other patients when qAF values were corrected for age and race. In general, ABCA4 patients had higher qAF values than PRPH2/RDS patients, while most patients without mutations in PRPH2/RDS or ABCA4 had qAF levels within the normal range. The high qAF levels of ABCA4-positive patients are a hallmark of ABCA4-related disease. The reason for high qAF among many PRPH2/RDS-positive patients is not known; higher RPE lipofuscin accumulation may be a primary or secondary effect of the PRPH2/RDS mutation.

  17. Wine intake, ABO phenotype, and risk of ischemic heart disease and all-cause mortality: the Copenhagen Male Study-a 16-year follow-up

    DEFF Research Database (Denmark)

    Suadicani, P.; Hein, H.O.; Gyntelberg, F.

    2008-01-01

    The association of alcohol intake with ischemic heart disease (IHD) and all-cause mortality may depend on ABO phenotype. We tested this hypothesis in a 16-year follow-up of 3,022 Caucasian men aged 53-74 years without overt cardiovascular disease. Potential risk factors and confounders included...... were ABO phenotypes, alcohol intake (wine, beer, and spirits), tobacco smoking history, leisure-time, physical activity, social class, and age. During 16 years, 1985-1986 to end of 2001, 197 subjects (6.5%) died due to IHD, and 1,204 (39.8%) from all causes. Among non-O phenotypes (A, B, and AB......) significantly fewer men who died due to IHD were wine consumers, 43.9% versus 55.7%, P alcohol abstainers, in Cox...

  18. Subclinical Atherosclerosis in Patients with Rheumatoid Arthritis and Low Cardiovascular Risk: The Role of von Willebrand Factor Activity.

    Science.gov (United States)

    Ristić, Gorica G; Subota, Vesna; Lepić, Toplica; Stanisavljević, Dejana; Glišić, Branislava; Ristić, Arsen D; Petronijević, Milan; Stefanović, Dušan Z

    2015-01-01

    To evaluate association between von Willebrand factor (vWF) activity, inflammation markers, disease activity, and subclinical atherosclerosis in patients with rheumatoid arthritis (RA) and low cardiovascular risk. Above mentioned parameters were determined in blood samples of 74 non-diabetic, normotensive, female subjects, with no dyslipidemia(42 patients, 32 matched healthy controls, age 45.3±10.0 vs. 45.2±9.8 years). Intima-media thickness (IMT) was measured bilaterally, at common carotid, bifurcation, and internal carotid arteries. Subclinical atherosclerosis was defined as IMT>IMTmean+2SD in controlsat each carotid level and atherosclerotic plaque as IMT>1.5 mm. Majority of RA patients were on methotrexate (83.3%), none on steroids >10 mg/day or biologic drugs. All findings were analysed in the entire study population and in RA group separately. RA patients with subclinical atherosclerosis had higher vWF activity than those without (133.5±69.3% vs. 95.3±36.8%, psubclinical atherosclerosis was confirmed by logistic regression. vWF activity correlated significantly with erythrocyte sedimentation rate, fibrinogen, modified disease activity scores (mDAS28-ESR, mDAS28-CRP), modified Health Assessment Questionnaire (psubclinical atherosclerosis (130±68% vs. 97±38%, psubclinical atherosclerosis in low-risk RA patients as well as its correlation with inflammation markers, all parameters of disease activity, and seropositivity. Therefore, vWF might be a valuable marker of early atherosclerosis in RA patients.

  19. Unhealthy diet and ultrafine carbon black particles induce senescence and disease associated phenotypic changes.

    Science.gov (United States)

    Büchner, Nicole; Ale-Agha, Niloofar; Jakob, Sascha; Sydlik, Ulrich; Kunze, Kerstin; Unfried, Klaus; Altschmied, Joachim; Haendeler, Judith

    2013-01-01

    Diet and pollution are environmental factors known to compromise "healthy aging" of the cardiovascular and respiratory systems. The molecular consequences of this permanent burden in these cells are still unknown. Therefore, this study investigates the impact of unhealthy diet on aging-related signaling pathways of human, primary cardiovascular cells and of airborne particles on lung epithelial and human endothelial cells. Nutrition health reports have shown that the diet in industrialized countries contains more than 100mg/dl low density lipoprotein (LDL) and a high fraction of added sugars, especially fructose. Several studies demonstrated that ultrafine particles can enter the circulation and thus may interact with endothelial cells directly. Both, dietary compounds and pollution derived particles, have been shown to increase the risk for cardiovascular diseases. To simulate an unhealthy diet, we supplemented cell culture media of human primary endothelial cells, smooth muscle cells and cardiomyocytes with LDL and replaced 1/3 of glucose with fructose. We observed hypertrophy in cardiomyocytes, enhanced proliferation in smooth muscle cells and increased senescence, loss of endothelial nitric oxide synthase and increased nuclear FoxO3A in endothelial cells. With respect to pollution we have used ultrafine carbon black particles (ufCB), one of the major constituents of industrial and exhaust emissions, in concentrations our lungs and vessels are constantly exposed to. These concentrations of ufCB increased reactive oxygen species in lung epithelial and vascular endothelial cells and reduced the S-NO content, a marker for NO-bioavailability, in endothelial cells. NO increases activation of Telomerase Reverse Transcriptase (TERT), an enzyme essential for telomere maintenance. TERT is required for proper endothelial cell function and is inactivated by Src kinase under conditions of oxidative stress. ufCB significantly increased Src kinase activation and reduced

  20. Clinically Distinct Phenotypes of Canavan Disease Correlate with Residual Aspartoacylase Enzyme Activity.

    Science.gov (United States)

    Mendes, Marisa I; Smith, Desirée Ec; Pop, Ana; Lennertz, Pascal; Fernandez Ojeda, Matilde R; Kanhai, Warsha A; van Dooren, Silvy Jm; Anikster, Yair; Barić, Ivo; Boelen, Caroline; Campistol, Jaime; de Boer, Lonneke; Kariminejad, Ariana; Kayserili, Hulya; Roubertie, Agathe; Verbruggen, Krijn T; Vianey-Saban, Christine; Williams, Monique; Salomons, Gajja S

    2017-05-01

    We describe 14 patients with 12 novel missense mutations in ASPA, the gene causing Canavan disease (CD). We developed a method to study the effect of these 12 variants on the function of aspartoacylase-the hydrolysis of N-acetyl-l-aspartic acid (NAA) to aspartate and acetate. The wild-type ASPA open reading frame (ORF) and the ORFs containing each of the variants were transfected into HEK293 cells. Enzyme activity was determined by incubating cell lysates with NAA and measuring the released aspartic acid by LC-MS/MS. Clinical data were obtained for 11 patients by means of questionnaires. Four patients presented with a non-typical clinical picture or with the milder form of CD, whereas seven presented with severe CD. The mutations found in the mild patients corresponded to the variants with the highest residual enzyme activities, suggesting that this assay can help evaluate unknown variants found in patients with atypical presentation. We have detected a correlation between clinical presentation, enzyme activity, and genotype for CD. © 2017 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

  1. Cell-permeable parkin proteins suppress Parkinson disease-associated phenotypes in cultured cells and animals.

    Directory of Open Access Journals (Sweden)

    Tam Duong

    Full Text Available Parkinson's disease (PD is a neurodegenerative disorder of complex etiology characterized by the selective loss of dopaminergic neurons, particularly in the substantia nigra. Parkin, a tightly regulated E3 ubiquitin ligase, promotes the survival of dopaminergic neurons in both PD and Parkinsonian syndromes induced by acute exposures to neurotoxic agents. The present study assessed the potential of cell-permeable parkin (CP-Parkin as a neuroprotective agent. Cellular uptake and tissue penetration of recombinant, enzymatically active parkin was markedly enhanced by the addition of a hydrophobic macromolecule transduction domain (MTD. The resulting CP-Parkin proteins (HPM13 and PM10 suppressed dopaminergic neuronal toxicity in cells and mice exposed to 6-hydroxydopamine (6-OHDH and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP. These included enhanced survival and dopamine expression in cultured CATH.a and SH-SY5Y neuronal cells; and protection against MPTP-induced damage in mice, notably preservation of tyrosine hydroxylase-positive cells with enhanced dopamine expression in the striatum and midbrain, and preservation of gross motor function. These results demonstrate that CP-Parkin proteins can compensate for intrinsic limitations in the parkin response and provide a therapeutic strategy to augment parkin activity in vivo.

  2. Callosal microstructural abnormalities in Alzheimer's disease and alcoholism: same phenotype, different mechanisms.

    Science.gov (United States)

    Pitel, Anne-Lise; Chanraud, Sandra; Sullivan, Edith V; Pfefferbaum, Adolf

    2010-10-30

    Magnetic resonance (MRI) and diffusion tensor imaging (DTI) data were acquired in 13 Alzheimer's disease (AD) patients, 15 elderly alcoholics, and 32 elderly controls. Midsagittal area, length, dorsoventral height, fractional anisotropy (FA), and mean diffusivity (MD) of the total corpus callosum and volume of the lateral ventricles were measured; area, FA, and MD were also determined for the callosal genu, body, and splenium. On DTI, both patient groups had lower FA and higher MD than controls in all callosal regions. On MRI, both patient groups had smaller genu than controls; additional size deficits were present in the alcoholism group's callosal body and the AD group's splenium. The callosal arch was higher in the AD but not the alcoholic group compared with controls. The two patient groups had larger ventricles than controls, and the AD group had larger ventricles than the alcoholic group. Callosal area correlated with its height, and callosal FA and MD correlated with ventricular volume in AD, whereas callosal area correlated only with FA in alcoholics. In AD, the disruption of the callosal integrity, which was associated with distorted callosal shape, was related to ventricular dilation, which has been shown in twin studies to be under a multitude of genetic, polygenetic, and environmental influences. Conversely, in alcoholism, disruption of callosal microstructural integrity was related to shrinkage of the corpus callosum itself. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  3. An external quality assessment program for von Willebrand factor laboratory analysis: an overview from the European concerted action on thrombosis and disabilities foundation.

    Science.gov (United States)

    Meijer, Piet; Haverkate, Frits

    2006-07-01

    The laboratory diagnosis of von Willebrand disease (vWD) is complex and requires a panel of different laboratory tests. Because of this complexity, a proper quality control process is necessary. Since 2003, the European Concerted Action on Thrombosis and Disabilities Foundation has provided an external quality control program for several laboratory tests included in the diagnosis of vWD. Currently, ~180 different laboratories participate in this program, of which the vast majority perform both von Willebrand factor (vWF):antigen (Ag) and activity tests. The lowest between-laboratory variation was observed for the vWF antigen assay (10 to 24%), with a better performance for the latex immunoassay (8 to 24%) than the enzyme immunoassay (13 to 25%). Both the ristocetin cofactor activity assay (RCo) and the collagen-binding assay showed a higher between-laboratory variation (20 to 40% and 17 to 29%, respectively). We have observed that the within-laboratory repeatability for normal samples ranged from 0 to 40% for the antigen assay and from 0 to 86% for the ristocetin cofactor activity assay. Normal samples were interpreted correctly by the majority of the participants. However, type 1 vWD samples were wrongly interpreted by 20 to 40% of the participants, which was mainly caused by a discordance in the vWF:RCo/vWF:Ag ratio. It can be concluded that further improvement in the laboratory diagnosis of vWD is necessary.

  4. Homocisteína plasmática total e fator von Willebrand no diabete melito experimental Total plasmatic homocysteine and von Willebrand factor in experimental diabetes mellitus

    OpenAIRE

    Renato Delascio Lopes; Lindalva Batista Neves; Vânia D'Almeida; Gleice Margarete de Souza Conceição; Alexandre Gabriel Junior

    2007-01-01

    OBJETIVOS: Determinar os valores plasmáticos de homocisteína e fator von Willebrand, como marcador de disfunção endotelial, em ratos com diabete melito induzido por estreptozotocina. MÉTODOS: Trinta e cinco ratos (rattus norvegicus albinus), machos, adultos (180-200 g), randomizados em três grupos: controle (n=10) não receberam agente ou veículo; sham (n=10) receberam solução veículo da estreptozotocina; e diabético (n=15) receberam estreptozotocina. Após oito semanas de indução do diabete me...

  5. Differential effects of delayed aging on phenotype and striatal pathology in a murine model of Huntington disease.

    Science.gov (United States)

    Tallaksen-Greene, Sara J; Sadagurski, Marianna; Zeng, Li; Mauch, Roseanne; Perkins, Matthew; Banduseela, Varuna C; Lieberman, Andrew P; Miller, Richard A; Paulson, Henry L; Albin, Roger L

    2014-11-19

    The common neurodegenerative syndromes exhibit age-related incidence, and many Mendelian neurodegenerative diseases exhibit age-related penetrance. Mutations slowing aging retard age related pathologies. To assess whether delayed aging retards the effects of a mutant allele causing a Huntington's disease (HD)-like syndrome, we generated compound mutant mice, placing a dominant HD knock-in polyglutamine allele onto the slow-aging Snell dwarf genotype. The Snell genotype did not affect mutant huntingtin protein expression. Bigenic and control mice were evaluated prospectively from 10 to 100 weeks of age. Adult HD knock-in allele mice lost weight progressively with weight loss blunted significantly in male bigenic HD knock-in/Snell dwarf mice. Impaired balance beam performance developed significantly more slowly in bigenic HD knock-in/Snell dwarf mice. Striatal dopamine receptor expression was diminished significantly and similarly in all HD-like mice, regardless of the Snell genotype. Striatal neuronal intranuclear inclusion burden was similar between HD knock-in mice with and without the Snell genotype, whereas nigral neuropil aggregates were diminished in bigenic HD knock-in/Snell dwarf mice. Compared with control mice, Snell dwarf mice exhibited differences in regional benzodiazepine and cannabinoid receptor binding site expression. These results indicate that delaying aging delayed behavioral decline with little effect on the development of striatal pathology in this model of HD but may have altered synaptic pathology. These results indicate that mutations prolonging lifespan in mice delay onset of significant phenotypic features of this model and also demonstrate dissociation between striatal pathology and a commonly used behavioral measure of disease burden in HD models. Copyright © 2014 the authors 0270-6474/14/3415658-11$15.00/0.

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

    Science.gov (United States)

    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.

  7. Co-existence of scrapie prion protein types 1 and 2 in sporadic Creutzfeldt-Jakob disease: its effect on the phenotype and prion-type characteristics

    NARCIS (Netherlands)

    Cali, I.; Castellani, R.; Alshekhlee, A.; Cohen, Y.; Blevins, J.; Yuan, J.; Langeveld, J.P.M.; Parchi, P.; Safar, J.G.; Zou, W.Q.; Gambetti, P.

    2009-01-01

    Five phenotypically distinct subtypes have been identified in sporadic Creutzfeldt-Jakob disease (sCJD), based on the methionine/valine polymorphic genotype of codon 129 of the prion protein (PrP) gene and the presence of either one of the two protease K-resistant scrapie prion protein (PrPSc) types

  8. Genotype-Phenotype Correlations in Multiple Sclerosis: "HLA" Genes Influence Disease Severity Inferred by [superscript 1]HMR Spectroscopy and MRI Measures

    Science.gov (United States)

    Okuda, D. T.; Srinivasan, R.; Oksenberg, J. R.; Goodin, D. S.; Baranzini, S. E.; Beheshtian, A.; Waubant, E.; Zamvil, S. S.; Leppert, D.; Qualley, P.; Lincoln, R.; Gomez, R.; Caillier, S.; George, M.; Wang, J.; Nelson, S. J.; Cree, B. A. C.; Hauser, S. L.; Pelletier, D.

    2009-01-01

    Genetic susceptibility to multiple sclerosis (MS) is associated with the human leukocyte antigen (HLA) "DRB1*1501" allele. Here we show a clear association between DRB1*1501 carrier status and four domains of disease severity in an investigation of genotype-phenotype associations in 505 robust, clinically well characterized MS patients evaluated…

  9. The interleukin 23 receptor gene does not confer risk to systemic sclerosis and is not associated with systemic sclerosis disease phenotype.

    NARCIS (Netherlands)

    Rueda, B.; Broen, J.; Torres, O.; Simeon, C.; Ortego-Centeno, N.; Schrijvenaars, M.M.; Vonk, M.C.; Fonollosa, V.; Hoogen, F.H.J. van den; Coenen, M.J.H.; Sanchez-Roman, J.; Aguirre-Zamorano, M.A.; Garcia-Portales, R.; Pros, A.; Camps, M.T.; Gonzalez-Gay, M.A.; Martin, J.; Radstake, T.R.D.J.

    2009-01-01

    OBJECTIVES: Multiple studies indicate the role of the interleukin (IL)-17/IL-23 axis in autoimmune diseases, including systemic sclerosis (SSc). The aim of the current study was to investigate the possible implication of the IL23R gene in SSc susceptibility and/or clinical phenotype. METHODS: An

  10. Phenotypic Prenatal Diagnosis of Chronic Granulomatous Disease: A Useful Tool in The Absence Of Molecular Diagnosis.

    Science.gov (United States)

    Kulkarni, M; Gupta, M; Madkaikar, M

    2017-12-01

    Chronic granulomatous disease (CGD) is an inherited immunodeficiency disorder affecting the microbicidal function of the phagocytes. It is characterized by susceptibility to recurrent infections leading to significant morbidity and mortality. Antibacterial and antifungal prophylaxis, though, has significantly reduced the rate and severity of the infections; the breakthrough infections still remain a challenge. Currently, allogenic haematopoietic stem cell transplantation is the only curative option which is very expensive and unavailable for many due to lack of suitable donor. Thus, prenatal diagnosis (PND) forms an important component of management in the affected families. PND is challenging in families approaching late in pregnancy with an uncharacterized molecular defect. In such cases, PND can be performed by analysis of NADPH activity of fetal blood (FB) neutrophils at 18-20 weeks of gestation. Cord blood samples at 18 weeks of gestation from healthy control were used to establish normal ranges for NBT and DHR. PND was offered for six pregnancies (NBT: n = 3, DHR: n = 6) with index cases of CGD confirmed by abnormal NBT and DHR analysis. NBT and DHR tests were found to be negative for all the six cases, confirming the same on samples post-delivery. NBT and DHR tests offer a rapid and sensitive PND of CGD in the absence of facilities for molecular diagnosis. It was observed that addition of CD15 along with CD45 led to an accurate DHR analysis. It is recommended to perform the diagnosis with adequate precautions only at centres with considerable experience and expertise in the diagnosis of CGD. © 2017 The Foundation for the Scandinavian Journal of Immunology.

  11. Behavioral phenotyping of Parkin-deficient mice: looking for early preclinical features of Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Daniel Rial

    Full Text Available There is considerable evidence showing that the neurodegenerative processes that lead to sporadic Parkinson's disease (PD begin many years before the appearance of the characteristic motor symptoms. Neuropsychiatric, sensorial and cognitive deficits are recognized as early non-motor manifestations of PD, and are not attenuated by the current anti-parkinsonian therapy. Although loss-of-function mutations in the parkin gene cause early-onset familial PD, Parkin-deficient mice do not display spontaneous degeneration of the nigrostriatal pathway or enhanced vulnerability to dopaminergic neurotoxins such as 6-OHDA and MPTP. Here, we employed adult homozygous C57BL/6 mice with parkin gene deletion on exon 3 (parkin-/- to further investigate the relevance of Parkin in the regulation of non-motor features, namely olfactory, emotional, cognitive and hippocampal synaptic plasticity. Parkin-/- mice displayed normal performance on behavioral tests evaluating olfaction (olfactory discrimination, anxiety (elevated plus-maze, depressive-like behavior (forced swimming and tail suspension and motor function (rotarod, grasping strength and pole. However, parkin-/- mice displayed a poor performance in the open field habituation, object location and modified Y-maze tasks suggestive of procedural and short-term spatial memory deficits. These behavioral impairments were accompanied by impaired hippocampal long-term potentiation (LTP. These findings indicate that the genetic deletion of parkin causes deficiencies in hippocampal synaptic plasticity, resulting in memory deficits with no major olfactory, emotional or motor impairments. Therefore, parkin-/- mice may represent a promising animal model to study the early stages of PD and for testing new therapeutic strategies to restore learning and memory and synaptic plasticity impairments in PD.

  12. Genetic and phenotypic characterization of Candida albicans strains isolated from infectious disease patients in Shanghai.

    Science.gov (United States)

    Hu, Lvyin; Du, Xin; Li, Tianming; Song, Yan; Zai, Shubei; Hu, Xiangnan; Zhang, Xiaonan; Li, Min

    2015-01-01

    Candida albicans, as an opportunistic pathogen, can cause superficial and life-threatening candidiasis in immunocompromised individuals. The formation of surface-associated biofilms and the appearance of drug resistance pose a significant challenge for clinical intervention. In this study, a total of 104 hospital-acquired C. alibcans clinical isolates were collected from sterile sites and mucosal lesions of 92 infectious disease patients in the Shanghai Public Health Clinical Center and analysed. The resistance rates to fluconazole, itraconazole and voriconazole were 12.5 %, 15.4 % and 11.5 % respectively. Multilocus sequence typing (MLST) analysis identified 63 diploid sequence types (DSTs) with a decentralized phylogeny, of which 37 DSTs (58.7 %) had not been reported in the online MLST database. Loss of heterozygosity was observed in ACC1 and ADP1 sequences obtained from six sequential isolates from a patient receiving antifungal treatment, which exemplified the effect of microevolution on C. albicans genetic alterations. Biofilm formation capability, an important virulence trait of C. albicans, was variable among strains isolated from different anatomical sites (P = 0.0302) and affected by genotypes (P = 0.0185). The mRNA levels of the azole antifungal target ERG11 gene and efflux pump genes (CDR1, CDR2 and MDR1) were detected in 9-18.1 % of azole-resistant and susceptible-dose dependent (S-DD) isolates. Twelve mutations encoding distinct amino acid substitutions in ERG11 were found in azole-resistant and S-DD isolates. Among them, A114S, Y132H and Y257H substitution in the ERG11 gene may be primarily related to azole resistance. Taken together, we observed a high level of diversity within C. albicans isolates. Multiple inter-related underlying mechanisms, including genetic and environmental factors, may account for high surface adhesion or azole resistance in clinical C. albicans infections. © 2015 The Authors.

  13. A Deep Phenotype Association Study Reveals Specific Phenotype Associations with Genetic Variants in Age-related Macular Degeneration: Age-Related Eye Disease Study 2 (AREDS2) Report No. 14.

    Science.gov (United States)

    van Asten, Freekje; Simmons, Michael; Singhal, Ayush; Keenan, Tiarnan D; Ratnapriya, Rinki; Agrón, Elvira; Clemons, Traci E; Swaroop, Anand; Lu, Zhiyong; Chew, Emily Y

    2017-10-30

    Age-related macular degeneration (AMD), a multifactorial disease with variable phenotypic presentation, was associated with 52 single nucleotide polymorphisms (SNPs) at 34 loci in a genome-wide association study (GWAS). These genetic variants could modulate different biological pathways involved in AMD, contributing to phenotypic variability. To better understand the effects of these SNPs, we performed a deep phenotype association study (DeePAS) in the Age-Related Eye Disease Study 2 (AREDS2), followed by replication using AREDS participants, to identify genotype associations with AMD and non-AMD ocular and systemic phenotypes. Cohort study. AREDS and AREDS2 participants. AREDS2 participants (discovery cohort) had detailed phenotyping for AMD; other eye conditions; cardiovascular, neurologic, gastrointestinal, and endocrine disease; cognitive function; serum nutrient levels; and others (total of 139 AMD and non-AMD phenotypes). Genotypes of the 52 GWAS SNPs were obtained. The DeePAS was performed by correlating the 52 SNPs to all phenotypes using logistic and linear regression models. Associations that reached Bonferroni-corrected statistical significance were replicated in AREDS. Genotype-phenotype associations. A total of 1776 AREDS2 participants had 5 years follow-up; 1435 AREDS participants had 10 years. The DeePAS revealed a significant association of the rs3750846 SNP at the ARMS2/HTRA1 locus with subretinal/sub-retinal pigment epithelial (RPE) hemorrhage related to neovascular AMD (odds ratio 1.55 [95% confidence interval 1.31-1.84], P = 2.67 × 10(-7)). This novel association remained significant after conditioning on participants with neovascular AMD (P = 2.42 × 10(-4)). Carriers of rs3750846 had poorer visual acuity during follow-up (P = 6.82 × 10(-7)) and were more likely to have a first-degree relative with AMD (P = 5.38 × 10(-6)). Two SNPs at the CFH locus, rs10922109 and rs570618, were associated with the drusen area in the Early Treatment

  14. Bax-inhibitor-1 knockdown phenotypes are suppressed by Buffy and exacerbate degeneration in a Drosophila model of Parkinson disease.

    Science.gov (United States)

    M'Angale, P Githure; Staveley, Brian E

    2017-01-01

    Bax inhibitor-1 (BI-1) is an evolutionarily conserved cytoprotective transmembrane protein that acts as a suppressor of Bax-induced apoptosis by regulation of endoplasmic reticulum stress-induced cell death. We knocked down BI-1 in the sensitive dopa decarboxylase (Ddc) expressing neurons of Drosophila melanogaster to investigate its neuroprotective functions. We additionally sought to rescue the BI-1-induced phenotypes by co-expression with the pro-survival Buffy and determined the effect of BI-1 knockdown on the neurodegenerative α-synuclein-induced Parkinson disease (PD) model. We used organismal assays to assess longevity of the flies to determine the effect of the altered expression of BI-1 in the Ddc-Gal4-expressing neurons by employing two RNAi transgenic fly lines. We measured the locomotor ability of these RNAi lines by computing the climbing indices of the climbing ability and compared them to a control line that expresses the lacZ transgene. Finally, we performed biometric analysis of the developing eye, where we counted the number of ommatidia and calculated the area of ommatidial disruption. The knockdown of BI-1 in these neurons was achieved under the direction of the Ddc-Gal4 transgene and resulted in shortened lifespan and precocious loss of locomotor ability. The co-expression of Buffy, the Drosophila anti-apoptotic Bcl-2 homologue, with BI-1-RNAi resulted in suppression of the reduced lifespan and impaired climbing ability. Expression of human α-synuclein in Drosophila dopaminergic neurons results in neuronal degeneration, accompanied by the age-dependent loss in climbing ability. We exploited this neurotoxic system to investigate possible BI-1 neuroprotective function. The co-expression of α-synuclein with BI-1-RNAi results in a slight decrease in lifespan coupled with an impairment in climbing ability. In supportive experiments, we employed the neuron-rich Drosophila compound eye to investigate subtle phenotypes that result from altered gene

  15. Bax-inhibitor-1 knockdown phenotypes are suppressed by Buffy and exacerbate degeneration in a Drosophila model of Parkinson disease

    Directory of Open Access Journals (Sweden)

    P. Githure M’Angale

    2017-02-01

    Full Text Available Background Bax inhibitor-1 (BI-1 is an evolutionarily conserved cytoprotective transmembrane protein that acts as a suppressor of Bax-induced apoptosis by regulation of endoplasmic reticulum stress-induced cell death. We knocked down BI-1 in the sensitive dopa decarboxylase (Ddc expressing neurons of Drosophila melanogaster to investigate its neuroprotective functions. We additionally sought to rescue the BI-1-induced phenotypes by co-expression with the pro-survival Buffy and determined the effect of BI-1 knockdown on the neurodegenerative α-synuclein-induced Parkinson disease (PD model. Methods We used organismal assays to assess longevity of the flies to determine the effect of the altered expression of BI-1 in the Ddc-Gal4-expressing neurons by employing two RNAi transgenic fly lines. We measured the locomotor ability of these RNAi lines by computing the climbing indices of the climbing ability and compared them to a control line that expresses the lacZ transgene. Finally, we performed biometric analysis of the developing eye, where we counted the number of ommatidia and calculated the area of ommatidial disruption. Results The knockdown of BI-1 in these neurons was achieved under the direction of the Ddc-Gal4 transgene and resulted in shortened lifespan and precocious loss of locomotor ability. The co-expression of Buffy, the Drosophila anti-apoptotic Bcl-2 homologue, with BI-1-RNAi resulted in suppression of the reduced lifespan and impaired climbing ability. Expression of human α-synuclein in Drosophila dopaminergic neurons results in neuronal degeneration, accompanied by the age-dependent loss in climbing ability. We exploited this neurotoxic system to investigate possible BI-1 neuroprotective function. The co-expression of α-synuclein with BI-1-RNAi results in a slight decrease in lifespan coupled with an impairment in climbing ability. In supportive experiments, we employed the neuron-rich Drosophila compound eye to investigate

  16. Differential proteolytic activation of factor VIII-von Willebrand factor complex by thrombin

    Energy Technology Data Exchange (ETDEWEB)

    Hill-Eubanks, D.C.; Parker, C.G.; Lollar, P. (Univ. of Vermont, Burlington (USA))

    1989-09-01

    Blood coagulation factor VIII (fVIII) is a plasma protein that is decreased or absent in hemophilia A. It is isolated as a mixture of heterodimers that contain a variably sized heavy chain and a common light chain. Thrombin catalyzes the activation of fVIII in a reaction that is associated with cleavages in both types of chain. The authors isolated a serine protease from Bothrops jararacussu snake venom that catalyzes thrombin-like heavy-chain cleavage but not light-chain cleavage in porcine fVIII as judged by NaDodSO{sub 4}/PAGE and N-terminal sequence analysis. Using a plasma-free assay of the ability of activated {sup 125}I-fVIII to function as a cofactor in the activation of factor X by factor IXa, they found that fVIII is activated by the venom enzyme. The venom enzyme-activated fVIII was isolated in stable form by cation-exchange HPLC. von Willebrand factor inhibited venom enzyme-activated fVIII but not thrombin-activated fVIII. These results suggest that the binding of fVIII to von Willebrand factor depends on the presence of an intact light chain and that activated fVIII must dissociate from von Willebrand factor to exert its cofactor effect. Thus, proteolytic activation of fVIII-von Willebrand factor complex appears to be differentially regulated by light-chain cleavage to dissociate the complex and heavy-chain cleavage to activate the cofactor function.

  17. Exercise induced hypercoagulability, increased von Willebrand factor and decreased thyroid hormone concentrations in sled dogs

    DEFF Research Database (Denmark)

    Krogh, Anne Kirstine Havnsøe; Legind, Pernille; Kjelgaard-Hansen, Mads

    2014-01-01

    Sled dogs performing endurance races have been reported to have a high incidence of gastric erosions or ulcerations and an increased risk of gastro intestinal bleeding leading to death in some cases. In addition, these dogs also become hypothyroid during training and exercise. Canine hypothyroidi......, activated partial thromboplastin time (aPTT), prothrombin time (PT), fibrinogen, von Willebrand factor (vWf), D-dimer, platelet number, thyroid hormones, hematocrit and C-reactive protein (CRP)....

  18. The impact of von Willebrand factor on factor VIII memory immune responses

    OpenAIRE

    Chen, Juan; Schroeder, Jocelyn A.; Luo, Xiaofeng; Shi, Qizhen

    2017-01-01

    Immune tolerance induction (ITI) with aggressive infusion of factor VIII (FVIII) is the current strategy used to eradicate FVIII inhibitors and restore normal FVIII pharmacokinetics in inhibitor patients. Whether the use of FVIII products containing von Willebrand factor (VWF) will affect the efficacy of ITI is still controversial. In this study, we explored the impact of VWF on FVIII memory immune responses in hemophilia A (HA) mice. A T-cell proliferation assay and cytokine profile analysis...

  19. Assembly of multimeric von Willebrand factor directs sorting of P-selectin

    NARCIS (Netherlands)

    Hop, C.; Guilliatt, A.; Daly, M.; de Leeuw, H. P.; Brinkman, H. J.; Peake, I. R.; van Mourik, J. A.; Pannekoek, H.

    2000-01-01

    We designed a model system to study the role of von Willebrand factor (vWF) in the sorting of P-selectin and the biogenesis of Weibel-Palade body (WPB)-like organelles. For that purpose, a human epithelial cell line (T24) that synthesizes P-selectin mRNA, but which is devoid of vWF mRNA synthesis

  20. Persistent CMV infection correlates with disease activity and dominates the phenotype of peripheral CD8+ T cells in psoriasis.

    Science.gov (United States)

    Weitz, Mario; Kiessling, Corinna; Friedrich, Markus; Prösch, Susanna; Höflich, Conny; Kern, Florian; Volk, Hans-Dieter; Sterry, Wolfram; Asadullah, Khusru; Döcke, Wolf-Dietrich

    2011-07-01

    Previously, we have reported a frequent association of active plaque psoriasis with inflammation-mediated cytomegalovirus (CMV) reactivation. This study aimed at characterizing the impact of CMV infection on psoriasis disease activity and peripheral cellular adaptive immune response. Twenty nine patients with active plaque psoriasis and 29 healthy controls were analysed for CMV-serostatus, CMV-antigenaemia, frequencies of peripheral CMV-specific T cells and the immunophenotype of peripheral CD8+ T cells. (i) Psoriasis severity was higher in CMV-seropositive patients and positively correlated to the severity of CMV-antigenaemia. (ii) In comparison to CMV-seropositive healthy controls, CMV-seropositive psoriasis patients showed a reduced frequency of circulating CMV-specific T cells that increased under effective antipsoriatic therapy. (iii) The immunophenotype of peripheral CD8+ T cells was dominated by CMV-seroprevalence. (iv) Selective analysis of CMV-seronegative psoriasis patients revealed a strong expansion of a - probably early activated - CD8+ T-cell population with the yet undescribed differentiation phenotype 'CD45RA-dim/CD11a-dim'. Under effective antipsoriatic therapy this population decreased in parallel to an increase of effector differentiated CD8+ T cells. Taken together with our previous results of inflammation-mediated CMV reactivation in psoriasis, our data support the concept of an interactive relationship between psoriasis and CMV infection which may be mediated by peripheral CD8+ T cells. © 2011 John Wiley & Sons A/S.

  1. NAD(+)-dependent activation of Sirt1 corrects the phenotype in a mouse model of mitochondrial disease.

    Science.gov (United States)

    Cerutti, Raffaele; Pirinen, Eija; Lamperti, Costanza; Marchet, Silvia; Sauve, Anthony A; Li, Wei; Leoni, Valerio; Schon, Eric A; Dantzer, Françoise; Auwerx, Johan; Viscomi, Carlo; Zeviani, Massimo

    2014-06-03

    Mitochondrial disorders are highly heterogeneous conditions characterized by defects of the mitochondrial respiratory chain. Pharmacological activation of mitochondrial biogenesis has been proposed as an effective means to correct the biochemical defects and ameliorate the clinical phenotype in these severely disabling, often fatal, disorders. Pathways related to mitochondrial biogenesis are targets of Sirtuin1, a NAD(+)-dependent protein deacetylase. As NAD(+) boosts the activity of Sirtuin1 and other sirtuins, intracellular levels of NAD(+) play a key role in the homeostatic control of mitochondrial function by the metabolic status of the cell. We show here that supplementation with nicotinamide riboside, a natural NAD(+) precursor, or reduction of NAD(+) consumption by inhibiting the poly(ADP-ribose) polymerases, leads to marked improvement of the respiratory chain defect and exercise intolerance of the Sco2 knockout/knockin mouse, a mitochondrial disease model characterized by impaired cytochrome c oxidase biogenesis. This strategy is potentially translatable into therapy of mitochondrial disorders in humans. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  2. A Phylogenetic and Phenotypic Analysis of Salmonella enterica Serovar Weltevreden, an Emerging Agent of Diarrheal Disease in Tropical Regions.

    Directory of Open Access Journals (Sweden)

    Carine Makendi

    2016-02-01

    Full Text Available Salmonella enterica serovar Weltevreden (S. Weltevreden is an emerging cause of diarrheal and invasive disease in humans residing in tropical regions. Despite the regional and international emergence of this Salmonella serovar, relatively little is known about its genetic diversity, genomics or virulence potential in model systems. Here we used whole genome sequencing and bioinformatics analyses to define the phylogenetic structure of a diverse global selection of S. Weltevreden. Phylogenetic analysis of more than 100 isolates demonstrated that the population of S. Weltevreden can be segregated into two main phylogenetic clusters, one associated predominantly with continental Southeast Asia and the other more internationally dispersed. Subcluster analysis suggested the local evolution of S. Weltevreden within specific geographical regions. Four of the isolates were sequenced using long read sequencing to produce high quality reference genomes. Phenotypic analysis in Hep-2 cells and in a murine infection model indicated that S. Weltevreden were significantly attenuated in these models compared to the classical S. Typhimurium reference strain SL1344. Our work outlines novel insights into this important emerging pathogen and provides a baseline understanding for future research studies.

  3. Incidence and phenotype at diagnosis of inflammatory bowel disease. Results in Spain of the EpiCom study.

    Science.gov (United States)

    Fernández, Alberto; Hernández, Vicent; Martínez-Ares, David; Sanromán, Luciano; de Castro, María Luisa; Pineda, Juan Ramón; Carmona, Amalia; González-Portela, Carlos; Salgado, Carlos; Martínez-Cadilla, Jesús; Pereira, Santos; García-Burriel, Jose Ignacio; Vázquez, Santiago; Rodríguez-Prada, Ignacio

    2015-11-01

    Incidence of inflammatory bowel disease (IBD) is increasing progressively. Few recent epidemiological prospective studies are available in Spain. The Epicom study, a population-based inception cohort of unselected IBD patients developed within the European Crohn's and Colitis Organization, was started in 2010. Vigo is the only Spanish area participating. To describe the incidence of IBD in the Vigo area and the phenotypical characteristics at diagnosis and to compare them with previous data available in Spain. Epidemiological, descriptive, prospective, and population-based study. All incident cases of IBD during 2010 and living in the Vigo area at diagnosis were included. The Copenhagen Diagnostic criteria were used to define cases. Background population at the start of the study was 579,632 inhabitants. Data were prospectively entered in the EpiCom database. A total of 106 patients were included (57.5% men, median age 39.5 years). Of them 53 were diagnosed of as Crohn's disease (CD), 47 ulcerative colitis (UC) and six IBD unclassified (IBDU). The incidence rate per 100,000 per year for patients aged 15 years or older was 21.4 (10.8 for CD, 9.4 for UC, 1.2 IBDU). Including pediatric population incidence rates were 18.3 (10.3 CD, 8.7 UC, 1.2 IBDU). Median time since onset of symptoms until diagnosis was 2 months. The incidence rate of IBD in Vigo is the highest compared to former Spanish cohorts, especially in CD patients. Median time since onset of symptoms until diagnosis is relatively short. Copyright © 2015 Elsevier España, S.L.U. and AEEH y AEG. All rights reserved.

  4. A murine model of variant late infantile ceroid lipofuscinosis recapitulates behavioral and pathological phenotypes of human disease.

    Directory of Open Access Journals (Sweden)

    Jeremy P Morgan

    Full Text Available Neuronal ceroid lipofuscinoses (NCLs; also known collectively as Batten Disease are a family of autosomal recessive lysosomal storage disorders. Mutations in as many as 13 genes give rise to ∼10 variants of NCL, all with overlapping clinical symptomatology including visual impairment, motor and cognitive dysfunction, seizures, and premature death. Mutations in CLN6 result in both a variant late infantile onset neuronal ceroid lipofuscinosis (vLINCL as well as an adult-onset form of the disease called Type A Kufs. CLN6 is a non-glycosylated membrane protein of unknown function localized to the endoplasmic reticulum (ER. In this study, we perform a detailed characterization of a naturally occurring Cln6 mutant (Cln6(nclf mouse line to validate its utility for translational research. We demonstrate that this Cln6(nclf mutation leads to deficits in motor coordination, vision, memory, and learning. Pathologically, we demonstrate loss of neurons within specific subregions and lamina of the cortex that correlate to behavioral phenotypes. As in other NCL models, this model displays selective loss of GABAergic interneuron sub-populations in the cortex and the hippocampus with profound, early-onset glial activation. Finally, we demonstrate a novel deficit in memory and learning, including a dramatic reduction in dendritic spine density in the cerebral cortex, which suggests a reduction in synaptic strength following disruption in CLN6. Together, these findings highlight the behavioral and pathological similarities between the Cln6(nclf mouse model and human NCL patients, validating this model as a reliable format for screening potential therapeutics.

  5. von Willebrand’s disease diagnosis and laboratory issues

    Science.gov (United States)

    CASTAMAN, G.; MONTGOMERY, R. R.; MESCHENGIESER, S. S.; HABERICHTER, S. L.; WOODS, A. I.; LAZZARI, M. A.

    2015-01-01

    Summary In this paper, the recent developments in the diagnosis and laboratory issues of von Willebrand’s disease (VWD) are presented. Dr. Castaman reviews the functional tests available for the diagnosis of VWD and their pathophysiological significance, focusing on which tests are best used in the diagnosis and classification of VWD. Dr Montgomery reviews an emerging issue that is accelerated clearance of von Willebrand factor (VWF) occurring in some variants of VWD. This phenotype can be suspected by the presence of an increased ratio between the VWF propeptide and the VWF antigen. These patients have typically a robust, but short-lived increase of FVIII and VWF after desmopressin. Dr Meschengieser reviews the determinants of bleeding after surgery in patients with VWD, emphasizing the role of bleeding history in predicting this risk. PMID:20590859

  6. Adiposity influences airway wall thickness and the asthma phenotype of HIV-associated obstructive lung disease: a cross-sectional study.

    Science.gov (United States)

    Barton, Julia H; Ireland, Alex; Fitzpatrick, Meghan; Kessinger, Cathy; Camp, Danielle; Weinman, Renee; McMahon, Deborah; Leader, Joseph K; Holguin, Fernando; Wenzel, Sally E; Morris, Alison; Gingo, Matthew R

    2016-08-04

    Airflow obstruction, which encompasses several phenotypes, is common among HIV-infected individuals. Obesity and adipose-related inflammation are associated with both COPD (fixed airflow obstruction) and asthma (reversible airflow obstruction) in HIV-uninfected persons, but the relationship to airway inflammation and airflow obstruction in HIV-infected persons is unknown. The objective of this study was to determine if adiposity and adipose-associated inflammation are associated with airway obstruction phenotypes in HIV-infected persons. We performed a cross-sectional analysis of 121 HIV-infected individuals assessed with pulmonary function testing, chest CT scans for measures of airway wall thickness (wall area percent [WA%]) and adipose tissue volumes (mediastinal and subcutaneous), as well as HIV- and adipose-related inflammatory markers. Participants were defined as COPD phenotype (post-bronchodilator FEV1/FVC adipose measurements, WA%, and pulmonary function. Multivariable logistic and linear regression models were used to determine associations of airflow obstruction and airway remodeling (WA%) with adipose measurements and participant characteristics. Twenty-three (19 %) participants were classified as the COPD phenotype and 33 (27 %) were classified as the asthma phenotype. Body mass index (BMI) was similar between those with and without COPD, but higher in those with a