WorldWideScience

Sample records for c1 inhibitor deficiency

  1. C1-esterase inhibitor deficiency and elective caesarean section.

    Science.gov (United States)

    Griffiths, R J; O'Sullivan, G

    2005-07-01

    C1-esterase inhibitor deficiency is a rare disorder of the complement system characterised by episodes of cutaneous and mucosal oedema. Life-threatening airway oedema can follow airway instrumentation or minor trauma. We describe the successful management of a 37-year-old primiparous woman with inherited C1-esterase inhibitor deficiency who was admitted at 38 weeks' gestation for elective caesarean section. Whilst undergoing general anaesthesia 18 months previously she had experienced facial and pharyngeal oedema despite prophylaxis (one unit of fresh frozen plasma). On this occasion she underwent elective caesarean section following intrathecal anaesthesia with 0.5% hyperbaric bupivacaine 2 mL and diamorphine 300 microg. Cardiovascular stability was ensured using glycopyrolate and intravenous Hartmann's solution 2 L; a live female infant was delivered successfully. There were no peri- or postoperative complications. Regional anaesthesia is the safest method for providing surgical anaesthesia in the obstetric patient. We believe elective caesarean section under regional anaesthesia should be considered if there are predicted difficulties with vaginal delivery.

  2. Pediatric hereditary angioedema due to C1-inhibitor deficiency

    Directory of Open Access Journals (Sweden)

    Farkas Henriette

    2010-07-01

    Full Text Available Abstract Hereditary angioedema (HAE resulting from the deficiency of the C1 inhibitor (C1-INH is a rare, life-threatening disorder. It is characterized by attacks of angioedema involving the skin and/or the mucosa of the upper airways, as well as the intestinal mucosa. In approximately 50 per cent of cases, clinical manifestations may appear during childhood. The complex management of HAE in pediatric patients is in many respects different from the management of adults. Establishing the diagnosis early, preferably before the onset of clinical symptoms, is essential in cases with a positive family history. Complement studies usually afford accurate diagnosis, whereas molecular genetics tests may prove helpful in uncertain cases. Appropriate therapy, supported by counselling, suitable modification of lifestyle, and avoidance of triggering factors (which primarily include mechanical trauma, mental stress and airway infections in children may spare the patient unnecessary surgery and may prevent mortality. Prompt control of edematous attacks, short-term prophylaxis and intermittent therapy are recommended as the primary means for the management of pediatric cases. Medicinal products currently used for the treatment of children with hereditary angioedema include antifibrinolytics, attenuated androgens, and C1-INH replacement therapy. Current guidelines favour antifibrinolytics for long-term prophylaxis because of their favorable safety profile but efficacy may be lacking. Attenuated androgens administered in the lowest effective dose are another option. C1-INH replacement therapy is also an effective and safe agent for children. Regular monitoring and follow-up of patients are necessary.

  3. The role of ficolins and MASPs in hereditary angioedema due to C1-inhibitor deficiency

    DEFF Research Database (Denmark)

    Csuka, Dorottya; Munthe-Fog, Lea; Skjoedt, Mikkel-Ole

    2013-01-01

    Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1-INH) causes disturbances in the complement system. However, the influence of HAE-C1-INH on the lectin pathway of complement is unresolved. Thus, we studied the main initiator molecules, enzymes and regulators in the lectin pathway...... in patients with HAE-C1-INH....

  4. Mutational spectrum and phenotypes in Danish families with hereditary angioedema because of C1 inhibitor deficiency

    DEFF Research Database (Denmark)

    Bygum, A; Fagerberg, C R; Ponard, D

    2011-01-01

    Hereditary angioedema (HAE), type I and II, is an autosomal dominant disease with deficiency of functional C1 inhibitor protein causing episodic swellings of skin, mucosa and viscera. HAE is a genetically heterogeneous disease with more than 200 different mutations in the SERPING1 gene. A genotype......-phenotype relationship does not seem to exist in HAE, although the polymorphism c.-21T>C of exon 2 has been reported to be associated with a more severe phenotype. We aimed to establish the mutational spectrum of C1 inhibitor deficiency in Denmark and investigate the possible disease-aggravating effect of the c.-21T...

  5. Alterations of coagulation and fibrinolysis in patients with angioedema due to C1-inhibitor deficiency

    Science.gov (United States)

    van Geffen, M; Cugno, M; Lap, P; Loof, A; Cicardi, M; van Heerde, W

    2012-01-01

    Patients with functional deficiency of C1-inhibitor (C1-INH) suffer from recurrent acute attacks (AA) of localized oedema associated with activation of the contact system, complement and fibrinolysis. To unravel further the role of coagulation and fibrinolysis in the pathophysiology of C1-INH deficiency, we performed simultaneous thrombin and plasmin generation measurements in plasma from patients with hereditary angioedema (HAE) due to C1-INH deficiency during AA (n = 23), in remission (R) (n = 20) and in controls (n = 20). During AA thrombin generation after in-vitro activation of plasma was higher than in controls, as demonstrated by shorter thrombin peak-time (P fibrinolysis inhibitor (TAFI) in patients during AA providing possible evidence for a regulatory effect on fibrinolysis. Plasminogen activator inhibitor-1 (PAI-1) was reduced in patients during AA indicating, together with the observed reduction of plasmin generation, the consumption of fibrinolytic factors. In conclusion, our results support the involvement of coagulation and fibrinolysis in the pathophysiology of HAE and show the possible application of simultaneous measurement of thrombin and plasmin generation to evaluate different clinical conditions in HAE patients. PMID:22288590

  6. Endocan: A Novel Marker of Endothelial Dysfunction in C1-Inhibitor-Deficient Hereditary Angioedema.

    Science.gov (United States)

    Demirturk, Mustafa; Akpinar, Timur Selcuk; Kose, Murat; Gelincik, Aslı; Colakoğlu, Bahattin; Buyukozturk, Suna

    2017-10-24

    Hereditary angioedema (HAE) related to C1-inhibitor deficiency is a rare autosomal dominant disorder. Vascular cell adhesion molecules (VCAM) are known as endothelial activation markers. Endocan (also called ESM-1) is proposed as an endothelial dysfunction indicator. We aimed to investigate endothelial activation in attack-free periods in HAE patients by measuring their levels of endocan and VCAM-1. Twenty-six HAE patients (22 female, mean age 40 ± 13 years) and 38 healthy control patients (13 female, mean age 36.9 ± 12 years) were included in the study. Peripheral blood samples were collected from HAE patients during symptom-free periods and control subjects. Endocan and VCAM-1 levels were measured using the enzyme-linked immunosorbent assay method. The median serum levels of endocan (647 ± 101 ng/mL) and VCAM-1 (500 ± 79 ng/mL) in the HAE patients were significantly higher than in the control patients (391 ± 41 and 325 ± 4; p < 0.001 for both). The increased endocan and VCAM-1 levels may reflect an endothelial activation even in attack-free periods in HAE patients. © 2017 S. Karger AG, Basel.

  7. Human parvovirus infection: rheumatic manifestations, angioedema, C1 esterase inhibitor deficiency, ANA positivity, and possible onset of systemic lupus erythematosus.

    Science.gov (United States)

    Fawaz-Estrup, F

    1996-07-01

    To investigate the clinical and serological characteristics of parvovirus infection. during 1993-4, 9 adult patients presented with polyarthralgias/polyarthritis. Clinical evaluation and serological studies of antinuclear antibodies, rheumatoid factor (RF), IgM and IgG antibodies to human parvovirus were done in all patients. Other serologies including anti-DNA, serum complement, and C1 esterase inhibitor levels were obtained in some patients. All 9 patients had polyarthralgias/polyarthritis, serological evidence of parvovirus B19 IgM and IgG antibodies, and normal sedimentation rate. All patients were seronegative for RF. Four women had positive ANA titers. In 2 of them the ANA positivity was transient. One developed systemic lupus erythematosus (SLE). Three women had angioedema of the face and tongue; one had transient C1 esterase inhibitor deficiency and another a transient decrease in C4 levels. Parvovirus may be implicated in the development of SLE as well as other chronic arthropathies. This is the first reported case of angioedema and decreased C1 esterase inhibitor levels associated with parvovirus infection.

  8. Clinical Pattern and Acute and Long-term Management of Hereditary Angioedema Due to C1-Esterase Inhibitor Deficiency.

    Science.gov (United States)

    Gómez-Traseira, C; Pérez-Fernández, E; López-Serrano, M C; García-Ara, M C; Pedrosa, M; López-Trascasa, M; Caballero, T

    2015-01-01

    Hereditary angioedema due to C1-esterase inhibitor deficiency (HAE-C1-INH) is a life-threatening disease. To describe the clinical characteristics and management of patients with HAE-C1-INH during routine clinical practice. An observational, retrospective study was performed in patients with HAE-C1-INH. Demographic, clinical, and analytical data were collected from 2 periods: period A (October 2009-September 2010) and period B (October 2007-September 2009). We studied 112 patients with HAE-C1-INH (57.1% females). Age at onset of symptoms was 14.4 years (lower in patients who had experienced attacks in the previous year). In period B (n=87), 62.1% of patients presented at least 1 edema attack (median, 3.5 attacks/patient/2 years), and 19.1% of attacks were treated. In period A (n=77), 58.4% of patients were on maintenance therapy. Stanozolol was the most widely used drug (48.9%), with a mean weekly dose of 6.7 mg. At least 1 attack was recorded in 72.7% of patients (median, 3.0 attacks/patient/year), and 31.5% of the attacks were treated. Treatment of acute attacks increased by 12.4%. Age at onset of symptoms is associated with clinical expression of disease. The higher age at onset of symptoms, the fewer number of attacks per patient and year, and the lower dose of attenuated androgens necessary to control the disease than in other series lead us to hypothesize that HAE-C1-INH could have a less severe expression in Spain. Acute attacks seem to be treated increasingly often.

  9. Treatment of hereditary angioedema due to C1 inhibitor deficiency in Argentina

    Directory of Open Access Journals (Sweden)

    Eloisa Malbrán

    2017-08-01

    Full Text Available The benefits of the worldwide approval of new drugs for the treatment of acute C1-INH-HAE attacks may still not reach all patients. Identifying the current barriers in the access to medication, as well as conducting a detailed assessment of the progress in this area, is essential to achieve universal treatment. Two hundred and twenty five patients registered in the Argentina Hereditary Angioedema Patient Association (AHAEPA were randomly selected and invited to participate in a web based questionnaire on accessibility to icatibant and pdC1-INH, self-treatment, delay to treatment, and coverage. The data retrieved was compared to our previous reports in 2008 and 2013. We collected 156/225 answers. One hundred and eighteen (76% patients have either pdC1-INH (n = 86, icatibant (n = 10 or both (n = 22, while 38 (24% do not have access to treatment. In 2008, 26% had access while 82% had it in 2013. Thirty-two subjects (22% self-inject themselves, similar to 29% in 2013, even though between studies, widespread self-injection training activities have taken place. However, considering injections by proxy, home treatment reached 56%. Only half of the patients decide to receive treatment early during the attack. Ninety-nine patients (63% have full coverage, thirty (19% have no coverage at all and the rest only obtain partial reimbursement. Twenty-nine families (31% share a single treatment dose of the medication, better than 36% in 2013. Argentina's C1-INH-HAE patients had a sustained improvement in their access to medication. Efforts should continue to further improve accessibility and optimal management of HAE acute attacks to all patients in the country.

  10. C1 esterase inhibitor

    Science.gov (United States)

    ... protein called C1, which is part of the complement system. This system is a group of proteins that ... 2013:chap 20. Sullivan KE, Grumach AS. The complement system. In: Adkinson NF, Bochner BS, Burks AW, et ...

  11. Strong correlation of high EBNA-1-IgG levels with edematous attacks involving upper airway mucosa in hereditary angioedema due to C1-inhibitor deficiency.

    Science.gov (United States)

    Csuka, Dorottya; Varga, Lilian; Farkas, Henriette; Füst, George

    2012-01-01

    Elevated level of IgG-type antibodies against Type 1 nuclear antigen (anti-EBNA-1-IgG) of the Epstein-Barr virus is a strong risk factor for certain autoimmune diseases. We measured anti-EBNA-1 IgG titers in 107 patients with hereditary angioedema due to C1-inhibitor deficiency (HAE-C1-INH). In the sera from 33 longitudinally tested patients, we found a very strong correlation (R>0.75, p=0.0005) between anti-EBNA-1-IgG titers measured in 2004 and 2010, respectively. High (>200 U/ml) anti-EBNA-1 levels were strongly correlated with the frequency of upper airway attacks (p=0.003) and the dose requirement of C1-inhibitor concentrate (p=0.008), while no significant association with the frequency of subcutaneous and abdominal attacks was found. These novel findings indicate that the underlying/triggering mechanisms of upper airway attacks in HAE-C1-INH may differ from that of other types of attacks and measurement of the anti-EBNA-1 IgG levels may be suitable for the prediction of upper airway attacks and C1-inhibitor concentrate requirement in HAE-C1-INH patients. Copyright © 2011 Elsevier Ltd. All rights reserved.

  12. International consensus on the diagnosis and management of pediatric patients with hereditary angioedema with C1 inhibitor deficiency

    DEFF Research Database (Denmark)

    Farkas, H; Martinez-Saguer, I; Bork, K

    2017-01-01

    -HAE information card and medicine for emergency use. The regulatory approval status of the drugs for prophylaxis and for acute treatment is different in each country. Plasma-derived C1-INH, recombinant C1-INH, and ecallantide are the only agents licensed for the acute treatment of pediatric patients. Clinical...

  13. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency

    DEFF Research Database (Denmark)

    Caballero, Teresa; Farkas, Henriette; Bouillet, Laurence

    2012-01-01

    section. Regional anesthesia is preferred to endotracheal intubation. Breast cancer: Attenuated androgens should be avoided. Antiestrogens can worsen angioedema symptoms. In these cases anastrozole might be an alternative. Other issues addressed include special features of HAE-C1-INH treatment in female...... devices, and progestins can be used. Pregnancy: Attenuated androgens are contraindicated and should be discontinued before attempting conception. Plasma-derived human C1 inhibitor concentrate (pdhC1INH) is preferred for acute treatment, short-term prophylaxis, or long-term prophylaxis. Tranexamic acid...... labor and delivery might not be clinically indicated, but pdhC1INH therapeutic doses (20 U/kg) should be available. Nevertheless, each case should be treated based on HAE-C1-INH symptoms during pregnancy and previous labors. pdhC1INH prophylaxis is advised before forceps or vacuum extraction or cesarean...

  14. Viral safety of C1-inhibitor NF

    NARCIS (Netherlands)

    Terpstra, F. G.; Kleijn, M.; Koenderman, A. H. L.; Over, J.; van Engelenburg, F. A. C.; Schuitemaker, H.; van 't Wout, A. B.

    2007-01-01

    We studied the efficacy of virus reduction by three process steps (polyethylene glycol 4000 (PEG) precipitation, pasteurization, and 15nm virus filtration) in the manufacturing of C1-inhibitor NF. The potential prion removing capacity in this process was estimated based on data from the literature.

  15. Association of celiac disease and hereditary angioedema due to C1-inhibitor deficiency. Screening patients with hereditary angioedema for celiac disease: is it worth the effort?

    Science.gov (United States)

    Csuka, Dorottya; Kelemen, Zsuzsanna; Czaller, Ibolya; Molnár, Katalin; Füst, George; Varga, Lilian; Rajczy, Katalin; Szabó, Zsófia; Miklós, Kata; Bors, András; Farkas, Henriette

    2011-03-01

    Hereditary angioedema due to C1-inhibitor deficiency is a life-threatening condition, which manifests as edematous attacks involving subcutaneous tissues and/or the upper airway/gastrointestinal mucosa. Celiac disease is a gluten-sensitive small intestinal disorder that can lead to severe villous atrophy, malabsorption, and malignancy. Both hereditary angioedema and celiac disease may present with abdominal symptoms. Our aim was to study the occurrence of celiac disease in the hereditary angioedema population, as well as to analyze the clinical course of cases with both diseases. One hundred and twenty-eight patients with hereditary angioedema were screened for celiac disease, using serological methods [antiendomysial antibodies-immunoglobulin A (IgA), antiendomysial antibodies-IgG and tissue transglutaminase-IgA, tissue transglutaminase-IgG]. Clinical data of a child with hereditary angioedema and celiac disease diagnosed earlier were added to the dataset to be analyzed. Thus, the total number of patients was 129, comprising 107 adults and 22 pediatric patients. In patients with celiac disease, molecular genetics analysis (human leukocyte antigen-DQA1, human leukocyte antigen-DQB1) was carried out along with the introduction of a gluten-free diet and regular follow-up. Four out of the 22 children were diagnosed with celiac disease in our hereditary angioedema population. The prevalence of celiac disease among our pediatric patients with hereditary angioedema (22 children) was higher than in the general population (18.1 vs. 1.2%). Switching from the wheat starch-containing tranexamic acid product to danazol and introducing a gluten-free diet mitigated abdominal symptoms of hereditary angioedema. Similarities between the symptoms of hereditary angioedema and celiac disease may cause difficulties in differential diagnosis, as well as in choosing the appropriate therapy. In our opinion, screening hereditary angioedema patients for celiac disease is warranted if

  16. Functional C1-inhibitor diagnostics in hereditary angioedema: assay evaluation and recommendations

    DEFF Research Database (Denmark)

    Wagenaar-Bos, Ineke G A; Drouet, Christian; Aygören-Pursun, Emel

    2008-01-01

    Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent episodes of potentially life-threatening angioedema. The most widespread underlying genetic deficiency is a heterozygous deficiency of the serine protease inhibitor C1 esterase inhibitor (C1-Inh). In addition ...

  17. Safety and Usage of C1-Inhibitor in Hereditary Angioedema

    DEFF Research Database (Denmark)

    Riedl, Marc A; Bygum, Anette; Lumry, William

    2016-01-01

    BACKGROUND: The plasma-derived, highly purified, nanofiltered C1-inhibitor concentrate (Berinert; "pnfC1-INH") is approved in the United States for treating hereditary angioedema (HAE) attacks and in many European countries for attack treatment and short-term prophylaxis. OBJECTIVE: The objective...... of this study was to describe safety and usage patterns of pnfC1-INH. METHODS: A multicenter, observational, registry was conducted between 2010 and 2014 at 30 United States and 7 European sites to obtain both prospective (occurring after enrollment) and retrospective (occurring before enrollment) safety...... and usage data on subjects receiving pnfC1-INH for any reason. RESULTS: Of 343 enrolled patients, 318 received 1 or more doses of pnfC1-INH for HAE attacks (11,848 infusions) or for prophylaxis (3142 infusions), comprising the safety population. Median dosages per infusion were 10.8 IU/kg (attack treatment...

  18. Successful C1 inhibitor short-term prophylaxis during redo mitral valve replacement in a patient with hereditary angioedema

    Directory of Open Access Journals (Sweden)

    Coleman Suzanne

    2010-10-01

    Full Text Available Abstract Hereditary angioedema is characterized by sudden episodes of nonpitting edema that cause discomfort and pain. Typically the extremities, genitalia, trunk, gastrointestinal tract, face, and larynx are affected by attacks of swelling. Laryngeal swelling carries significant risk for asphyxiation. The disease results from mutations in the C1 esterase inhibitor gene that cause C1 esterase inhibitor deficiency. Attacks of hereditary angioedema result from contact, complement, and fibrinolytic plasma cascade activation, where C1 esterase inhibitor irreversibly binds substrates. Patients with hereditary angioedema cannot replenish C1 esterase inhibitor levels on pace with its binding. When C1 esterase inhibitor is depleted in these patients, vasoactive plasma cascade products cause swelling attacks. Trauma is a known trigger for hereditary angioedema attacks, and patients have been denied surgical procedures because of this risk. However, uncomplicated surgeries have been reported. Appropriate prophylaxis can reduce peri-operative morbidity in these patients, despite proteolytic cascade and complement activation during surgical trauma. We report a case of successful short-term prophylaxis with C1 esterase inhibitor in a 51-year-old man with hereditary angioedema who underwent redo mitral valve reconstructive surgery.

  19. Presence of C1-Inhibitor Polymers in a Subset of Patients Suffering from Hereditary Angioedema

    DEFF Research Database (Denmark)

    Elenius Madsen, Daniel; Hansen, Søren Werner Karlskov; Gram, Jørgen Brodersen

    2014-01-01

    Hereditary angioedema (HAE) is a potentially life-threatening disease caused by mutations in the gene encoding the serine protease inhibitor (serpin) C1 inhibitor (C1-inh). The mutations cause decreased functional plasma levels of C1-inh, which triggers unpredictable recurrent edema attacks...

  20. The Use of Plasma-Derived Complement C1-Esterase Inhibitor Concentrate (Berinert®) in the Treatment of Angiotensin Converting Enzyme-Inhibitor Related Angioedema

    DEFF Research Database (Denmark)

    Hermanrud, Thorbjørn; Duus, Nicolaj; Bygum, Anette

    2016-01-01

    concentrate is a well-established treatment option of hereditary and acquired complement C1-esterase inhibitor deficiency, which are also mediated by an increased level of bradykinin resulting in recurrent angioedema. We here present a case of severe angiotensin converting enzyme-inhibitor related angioedema...... (ACEi-AE) of the hypopharynx that completely resolved rapidly after the infusion of plasma-derived C1-inhibitor concentrate adding to the sparse reports in the existing literature.......Angioedema of the upper airways is a severe and potentially life-threatening condition. The incidence has been increasing in the past two decades, primarily due to pharmaceuticals influencing the generation or degradation of the vasoactive molecule bradykinin. Plasma-derived C1-esterase inhibitor...

  1. Genetic analysis of complement C1s deficiency associated with systemic lupus erythematosus highlights alternative splicing of normal C1s gene

    DEFF Research Database (Denmark)

    Armano, MT; Ferriani, VP; Florido, MP

    2008-01-01

    Deficiencies of complement proteins of the classical pathway are strongly associated with the development of autoimmune diseases. Deficiency of C1r has been observed to occur concomitantly with deficiency in C1s and 9 out of 15 reported cases presented systemic lupus erythematosus (SLE). Here, we...

  2. Endogenous C1-inhibitor production and expression in the heart after acute myocardial infarction.

    Science.gov (United States)

    Emmens, Reindert W; Baylan, Umit; Juffermans, Lynda J M; Karia, Rashmi V; Ylstra, Bauke; Wouters, Diana; Zeerleder, Sacha; Simsek, Suat; van Ham, Marieke; Niessen, Hans W M; Krijnen, Paul A J

    2016-01-01

    Complement activation contributes significantly to inflammation-related damage in the heart after acute myocardial infarction. Knowledge on factors that regulate postinfraction complement activation is incomplete however. In this study, we investigated whether endogenous C1-inhibitor, a well-known inhibitor of complement activation, is expressed in the heart after acute myocardial infarction. C1-inhibitor and complement activation products C3d and C4d were analyzed immunohistochemically in the hearts of patients who died at different time intervals after acute myocardial infarction (n=28) and of control patients (n=8). To determine putative local C1-inhibitor production, cardiac transcript levels of the C1-inhibitor-encoding gene serping1 were determined in rats after induction of acute myocardial infarction (microarray). Additionally, C1-inhibitor expression was analyzed (fluorescence microscopy) in human endothelial cells and rat cardiomyoblasts in vitro. C1-inhibitor was found predominantly in and on jeopardized cardiomyocytes in necrotic infarct cores between 12h and 5days old. C1-inhibitor protein expression coincided in time and colocalized with C3d and C4d. In the rat heart, serping1 transcript levels were increased from 2h up until 7days after acute myocardial infarction. Both endothelial cells and cardiomyoblasts showed increased intracellular expression of C1-inhibitor in response to ischemia in vitro (n=4). These observations suggest that endogenous C1-inhibitor is likely involved in the regulation of complement activity in the myocardium following acute myocardial infarction. Observations in rat and in vitro suggest that C1-inhibitor is produced locally in the heart after acute myocardial infarction. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. C1-inhibitor polymers activate the FXII-dependent kallikrein-kinin system

    DEFF Research Database (Denmark)

    Elenius Madsen, Daniel; Sidelmann, Johannes Jakobsen; Biltoft, Daniel

    2015-01-01

    BACKGROUND: The FXII-dependent kallikrein-kinin system (KKS) is tightly regulated by the serine protease inhibitor (serpin) C1-inhibitor (C1-inh). When regulation of the FXII-dependent KKS fails, which is the case in hereditary angioedema (HAE), patients consequently experience invalidating edema...... attacks. HAE is caused by mutations in the C1-inh encoding gene, and we recently demonstrated that some mutations give rise to the presence of polymerized C1-inh in the plasma of HAE patients. METHODS: C1-inh polymers corresponding to the size of polymers observed in vivo were produced using heat...

  4. Safety of C1-Esterase Inhibitor in Acute and Prophylactic Therapy of Hereditary Angioedema

    DEFF Research Database (Denmark)

    Busse, Paula; Bygum, Anette; Edelman, Jonathan

    2014-01-01

    BACKGROUND: The plasma-derived, pasteurized C1-inhibitor (C1-INH) concentrate, Berinert has a 4-decade history of use in hereditary angioedema (HAE), with a substantial literature base that demonstrates safety and efficacy. Thromboembolic events have rarely been reported with C1-INH products, typ...

  5. C1-esterase inhibitor blocks T lymphocyte proliferation and cytotoxic T lymphocyte generation in vitro

    DEFF Research Database (Denmark)

    Nissen, Mogens Holst; Bregenholt, S; Nording, J A

    1998-01-01

    We have previously shown that activated C1s complement and activated T cells cleave beta2-microglobulin (beta2m) in vitro leading to the formation of desLys58 beta2m. This process can specifically be inhibited by C1-esterase inhibitor (C1-inh). Furthermore we showed that exogenously added desLys58...... beta2m in nanomolar amounts to a one-way allogenic mixed lymphocyte culture (MLC) increased the endogenous production of IL-2 and the generation of allo-specific cytotoxic T lymphocytes. C1-inh was purified from fresh human plasma and added to human or murine MLC and mitogen-stimulated lymphocyte...... cultures grown in the presence of complement-inactivated serum. Read-outs were cell proliferation, lymphokine production and development of T cell-mediated cytotoxicity. We found that addition of C1-inh to MLC and mitogen-exposed murine and human lymphocyte cultures inhibited proliferation, the development...

  6. Clinical presentation of human C1q deficiency: How much of a lupus?

    Science.gov (United States)

    Stegert, Mihaela; Bock, Merete; Trendelenburg, Marten

    2015-09-01

    Hereditary human C1q deficiency has been well described to be associated with high susceptibility for the development of systemic lupus erythematosus (SLE). The majority of subjects present a clinical syndrome closely related to SLE. However, limited information is available about the primary diagnosis and particular clinical manifestations of SLE in this specific subgroup of patients. In this review, we performed a comprehensive search of electronic databases up to November 2014 to identify and analyze reports on patients with C1q deficiency. We identified 71 C1q-deficient patients descending from 45 families that had been published. According to the American College of Rheumatology (ACR) diagnostic criteria for SLE 39/71 (55%) subjects could be classified as having SLE. Another 16/71 (22.5%) presented a SLE-like syndrome (defined as 3 positive ACR criteria) whereas in 16/71 (22.5%) no SLE could be diagnosed at time of publication. Symptoms began at a median age of 5 years, male and females being equally affected. Discoid rash (56% versus 10%, poral ulcers (49% versus 24%, pmanifestations were found to occur similarly frequent. The severe course of disease in some patients seemed to be mostly due to severe infections at early ages and not in particular due to more aggressive SLE manifestations. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Homozygosity for a novel mutation in the C1q C chain gene in a Turkish family with hereditary C1q deficiency

    DEFF Research Database (Denmark)

    Gulez, N; Genel, F; Atlihan, F

    2010-01-01

    Hereditary complete deficiency of complement component C1q is associated with a high prevalence of systemic lupus erythematosus and increased susceptibility to severe recurrent infections. An 11-year-old girl was screened for immunodeficiency due to a history of recurrent meningitis and pneumonia....... Immunologic studies revealed absence of classic pathway hemolytic activity and undetectable levels of Clq. Exon-specific amplification of genomic DNA by polymerase chain reaction followed by direct sequence analysis revealed a novel homozygous missense mutation at codon 48 in the C1q C gene causing a glycine......-to-arginine substitution affecting the collagen-like region of C1q. No changes were seen in the exons of the A and B chains. The mutation affected both the formation and the secretion of C1q variant molecules. We describe a novel mutation in the C1q C chain gene that leads to an interchange in amino acids resulting...

  8. Molecular basis of hereditary C1q deficiency-revisited: identification of several novel disease-causing mutations

    DEFF Research Database (Denmark)

    Schejbel, L; Skattum, L; Hagelberg, S

    2011-01-01

    C1q is the central pattern-recognition molecule in the classical pathway of the complement system and is known to have a key role in the crossroads between adaptive and innate immunity. Hereditary C1q deficiency is a rare genetic condition strongly associated with systemic lupus erythematosus and...

  9. Molecular basis of hereditary C1q deficiency-revisited: identification of several novel disease-causing mutations

    DEFF Research Database (Denmark)

    Schejbel, L; Skattum, L; Hagelberg, S

    2011-01-01

    C1q is the central pattern-recognition molecule in the classical pathway of the complement system and is known to have a key role in the crossroads between adaptive and innate immunity. Hereditary C1q deficiency is a rare genetic condition strongly associated with systemic lupus erythematosus...

  10. Use of a C1 Inhibitor Concentrate in Adults ≥65 Years of Age with Hereditary Angioedema

    DEFF Research Database (Denmark)

    Bygum, Anette; Martinez-Saguer, Inmaculada; Bas, Murat

    2016-01-01

    BACKGROUND: Treatment of hereditary angioedema (HAE) in 'older adults' (those aged ≥65 years) has not been well studied. The international Berinert Patient Registry collected data on the use of intravenous plasma-derived, pasteurized, nanofiltered C1-inhibitor concentrate (pnfC1-INH; Berinert(®)/...

  11. C1q nephropathy and isolated CD59 deficiency manifesting as necrotizing crescentic glomerulonephritis: A rare association of two diseases

    Directory of Open Access Journals (Sweden)

    Ruchika Gupta

    2015-01-01

    Full Text Available C1q nephropathy is a recently described clinico-pathologic entity with a variable clinical presentation and pathology. Crescentic glomerulonephritis (GN has been reported in only two patients in the available literature. CD59 deficiency, along with lack of CD55, is responsible for paroxysmal nocturnal hemoglobinuria (PNH. Few cases of isolated CD59 deficiency have been described with PNH-like features. A middle-aged adult male presented with rapidly progressive renal failure. Serological investigations were negative. A renal biopsy revealed necrotizing crescentic GN with rupture of Bowman′s capsule. Immunofluorescence on the frozen sections showed dominant mesangial deposits of C1q along with IgM. Hematological work-up of the patient revealed isolated CD59 deficiency. Hence, a final diagnosis of C1q nephropathy and CD59 deficiency manifesting as crescentic GN and hemolytic anemia was made. The co-existence of two rare disorders, C1q nephropathy and CD59 deficiency, in a patient with necrotizing crescentic GN is described for the first time to the best of our knowledge. The pathogenetic link of these two entities with the clinical manifestation requires further study.

  12. Peptide Inhibitor of Complement C1 Inhibits the Peroxidase Activity of Hemoglobin and Myoglobin

    Directory of Open Access Journals (Sweden)

    Pamela S. Hair

    2017-01-01

    Full Text Available Hemoglobin is the natural carrier of oxygen in red blood cells (RBCs. While intracellular hemoglobin provides life-sustaining oxygen transport, extracellular free hemoglobin displays toxicity due to inherent peroxidase activity generating reactive oxygen species that subsequently react with the hemoglobin molecule to produce toxic heme degradation products resulting in free radicals, oxidative stress damage, and lipid peroxidation. We have recently demonstrated that Peptide Inhibitor of Complement C1 (PIC1 inhibits peroxidase activity of the heme-based enzyme myeloperoxidase. To elucidate whether PIC1 could inhibit peroxidase activity of hemoglobin, we evaluated the consequence of PIC1 on RBC lysates, methemoglobin, and myoglobin using tetramethylbenzidine (TMB as an oxidation target. PIC1 reversibly and dose-dependently prevented TMB oxidation to tetramethylbenzidine diimine by RBC lysates, methemoglobin, and myoglobin, having comparable activity to the inhibitor 4-aminobenzoic acid hydrazide. PIC1 inhibited TMB oxidation of RBC lysates similar to L-cysteine suggesting that the two cysteine residues contained in PIC1 may mediate peroxidase activity. PIC1 also inhibited heme destruction by NaOCl for RBC lysates, hemoglobin, and myoglobin as assayed by preservation of the Soret absorbance peak in the presence of NaOCl and reduction in free iron release. In conclusion, PIC1 inhibits peroxidase activity of hemoglobin and myoglobin likely via an antioxidant mechanism.

  13. Potential therapeutic benefit of C1-esterase inhibitor in neuromyelitis optica evaluated in vitro and in an experimental rat model.

    Directory of Open Access Journals (Sweden)

    Lukmanee Tradtrantip

    Full Text Available Neuromyelitis optica (NMO is an autoimmune demyelinating disease of the central nervous system in which binding of anti-aquaporin-4 (AQP4 autoantibodies (NMO-IgG to astrocytes causes complement-dependent cytotoxicity (CDC and inflammation resulting in oligodendrocyte and neuronal injury. There is compelling evidence for a central role of complement in NMO pathogenesis. Here, we evaluated the potential of C1-esterase inhibitor (C1-inh for complement-targeted therapy of NMO. C1-inh is an anti-inflammatory plasma protein with serine protease inhibition activity that has a broad range of biological activities on the contact (kallikrein, coagulation, fibrinolytic and complement systems. C1-inh is approved for therapy of hereditary angioedema (HAE and has been studied in a small safety trial in acute NMO relapses (NCT 01759602. In vitro assays of NMO-IgG-dependent CDC showed C1-inh inhibition of human and rat complement, but with predicted minimal complement inhibition activity at a dose of 2000 units in humans. Inhibition of complement by C1-inh was potentiated by ∼10-fold by polysulfated macromolecules including heparin and dextran sulfate. In rats, intravenous C1-inh at a dose 30-fold greater than that approved to treat HAE inhibited serum complement activity by <5%, even when supplemented with heparin. Also, high-dose C1-inh did not reduce pathology in a rat model of NMO produced by intracerebral injection of NMO-IgG. Therefore, although C1r and C1s are targets of C1-inh, our in vitro data with human serum and in vivo data in rats suggest that the complement inhibition activity of C1-inh in serum is too low to confer clinical benefit in NMO.

  14. High-affinity, noninhibitory pathogenic C1 domain antibodies are present in patients with hemophilia A and inhibitors.

    Science.gov (United States)

    Batsuli, Glaivy; Deng, Wei; Healey, John F; Parker, Ernest T; Baldwin, W Hunter; Cox, Courtney; Nguyen, Brenda; Kahle, Joerg; Königs, Christoph; Li, Renhao; Lollar, Pete; Meeks, Shannon L

    2016-10-20

    Inhibitor formation in hemophilia A is the most feared treatment-related complication of factor VIII (fVIII) therapy. Most inhibitor patients with hemophilia A develop antibodies against the fVIII A2 and C2 domains. Recent evidence demonstrates that the C1 domain contributes to the inhibitor response. Inhibitory anti-C1 monoclonal antibodies (mAbs) have been identified that bind to putative phospholipid and von Willebrand factor (VWF) binding epitopes and block endocytosis of fVIII by antigen presenting cells. We now demonstrate by competitive enzyme-linked immunosorbent assay and hydrogen-deuterium exchange mass spectrometry that 7 of 9 anti-human C1 mAbs tested recognize an epitope distinct from the C1 phospholipid binding site. These mAbs, designated group A, display high binding affinities for fVIII, weakly inhibit fVIII procoagulant activity, poorly inhibit fVIII binding to phospholipid, and exhibit heterogeneity with respect to blocking fVIII binding to VWF. Another mAb, designated group B, inhibits fVIII procoagulant activity, fVIII binding to VWF and phospholipid, fVIIIa incorporation into the intrinsic Xase complex, thrombin generation in plasma, and fVIII uptake by dendritic cells. Group A and B epitopes are distinct from the epitope recognized by the canonical, human-derived inhibitory anti-C1 mAb, KM33, whose epitope overlaps both groups A and B. Antibodies recognizing group A and B epitopes are present in inhibitor plasmas from patients with hemophilia A. Additionally, group A and B mAbs increase fVIII clearance and are pathogenic in a hemophilia A mouse tail snip bleeding model. Group A anti-C1 mAbs represent the first identification of pathogenic, weakly inhibitory antibodies that increase fVIII clearance. © 2016 by The American Society of Hematology.

  15. Allergenicity and safety of recombinant human C1 esterase inhibitor in patients with allergy to rabbit or cow's milk.

    Science.gov (United States)

    van den Elzen, Mignon T; van Os-Medendorp, Harmieke; Röckmann-Helmbach, Heike; van Hoffen, Els; Lebens, Ans F M; van Doorn, Helma; Klemans, Rob J B; Bruijnzeel-Koomen, Carla A F M; Hack, C Erik; Kaufman, Leonard; Relan, Anurag; Knulst, André C

    2016-08-01

    Recombinant human C1 inhibitor (rhC1INH) for on-demand treatment of hereditary angioedema is purified from milk of transgenic rabbits. It contains low amounts (cow's milk allergy (CMA). This study is an assessment of allergenicity and safety of rhC1INH in patients with RA and/or CMA. Patients with CMA and/or RA underwent skin prick test (SPT), intracutaneous test (ICT), and, when results for both were negative, subcutaneous (SC) challenge with up to 2100U (14 mL) rhC1INH. The negative predictive value of the skin test protocol was calculated, defined as the ratio of patients without systemic symptoms of hypersensitivity following SC challenge, over the number of patients having tested negative for both the SPT and the ICT. Adverse events after exposure to rhC1INH were recorded. Twenty-six patients with RA and/or CMA were enrolled. Twenty-four had negative SPT and ICT results for rhC1INH, whereas 2 had negative SPT result but positive ICT result to rhC1INH (only the highest concentration). Twenty-two patients with negative SPT and ICT results underwent SC challenge. None developed allergic symptoms. Local treatment-emergent adverse events occurred in 7 patients (32%) after SC challenge. In 5 these were considered drug related. All were mild. None of the patients with negative SPT and ICT results for rhC1INH had allergic symptoms during rhC1INH challenge. The negative predictive value of the combination of SPT and ICT for the outcome of the SC challenge was 100% (95% CI, 84.6%-100%). SC administration of rhC1INH was well tolerated. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  16. 20 CFR 664.205 - How is the “deficient in basic literacy skills” criterion in § 664.200(c)(1) defined and documented?

    Science.gov (United States)

    2010-04-01

    ... INVESTMENT ACT Eligibility for Youth Services § 664.205 How is the “deficient in basic literacy skills... requirements regarding the “deficient in basic literacy skills” criterion in § 664.200(c)(1) may be established... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false How is the âdeficient in basic literacy...

  17. X-linked inhibitor of apoptosis (XIAP) deficiency

    DEFF Research Database (Denmark)

    Speckmann, C.; Lehmberg, K.; Albert, M.H.

    2013-01-01

    X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was initially described in patients with X-linked lymphoproliferative syndrome (XLP) who had no mutations in SH2D1A. In the initial reports, EBV-associated hemophagocytic lymphohistiocytosis (HLH) was the predominant c......, neither genotype nor protein expression nor results from cell death studies were clearly associated with the clinical phenotype. Only mutation analysis can reliably identify affected patients. XIAP deficiency must be considered in a wide range of clinical presentations....

  18. Nebulized C1-Esterase Inhibitor does not Reduce Pulmonary Complement Activation in Rats with Severe Streptococcus Pneumoniae Pneumonia.

    Science.gov (United States)

    de Beer, Friso; Lagrand, Wim; Glas, Gerie J; Beurskens, Charlotte J P; van Mierlo, Gerard; Wouters, Diana; Zeerleder, Sacha; Roelofs, Joris J T H; Juffermans, Nicole P; Horn, Janneke; Schultz, Marcus J

    2016-12-01

    Complement activation plays an important role in the pathogenesis of pneumonia. We hypothesized that inhibition of the complement system in the lungs by repeated treatment with nebulized plasma-derived human C1-esterase inhibitor reduces pulmonary complement activation and subsequently attenuates lung injury and lung inflammation. This was investigated in a rat model of severe Streptococcus pneumoniae pneumonia. Rats were intra-tracheally challenged with S. pneumoniae to induce pneumonia. Nebulized C1-esterase inhibitor or saline (control animals) was repeatedly administered to rats, 30 min before induction of pneumonia and every 6 h thereafter. Rats were sacrificed 20 or 40 h after inoculation with bacteria. Brochoalveolar lavage fluid and lung tissue were obtained for measuring levels of complement activation (C4b/c), lung injury and inflammation. Induction of pneumonia was associated with pulmonary complement activation (C4b/c at 20 h 1.24 % [0.56-2.59] and at 40 h 2.08 % [0.98-5.12], compared to 0.50 % [0.07-0.59] and 0.03 % [0.03-0.03] in the healthy control animals). The functional fraction of C1-INH was detectable in BALF, but no effect was found on pulmonary complement activation (C4b/c at 20 h 0.73 % [0.16-1.93] and at 40 h 2.38 % [0.54-4.19]). Twenty hours after inoculation, nebulized C1-esterase inhibitor treatment reduced total histology score, but this effect was no longer seen at 40 h. Nebulized C1-esterase inhibitor did not affect other markers of lung injury or lung inflammation. In this negative experimental animal study, severe S. pneumoniae pneumonia in rats is associated with pulmonary complement activation. Repeated treatment with nebulized C1-esterase inhibitor, although successfully delivered to the lungs, does not affect pulmonary complement activation, lung inflammation or lung injury.

  19. Distinctive regulation of contact activation by antithrombin and C1-inhibitor on activated platelets and material surfaces.

    Science.gov (United States)

    Bäck, Jennie; Lang, Markus Huber; Elgue, Graciela; Kalbitz, Miriam; Sanchez, Javier; Ekdahl, Kristina Nilsson; Nilsson, Bo

    2009-12-01

    Activated human plate lets trigger FXII-mediated contact activation, which leads to the generation of FXIIa-antithrombin (AT) and FXIa-AT complexes. This suggests that contact activation takes place at different sites, on activated platelets and material surfaces, during therapeutic procedures involving biomaterials in contact with blood and is differentially regulated. Here we show that activation in platelet-poor plasma, platelet-rich plasma (PRP), and whole blood induced by glass, kaolin, and polyphosphate elicited high levels of FXIIa-C1-inhibitor (C1INH), low levels of FXIa-C1INH and KK-C1INH, and almost no AT complexes. Platelet activation, in both PRP and blood, led to the formation of FXIIa-AT, FXIa-AT, and kallikrein (KK)-AT but almost no C1INH complexes. In severe trauma patients, FXIIa-AT and FXIa-AT were correlated with the release of thrombospondin-1 (TSP-1) from activated platelets. In contrast, FXIIa-C1INH complexes were detected when the FXIIa-AT levels were low. No correlations were found between FXIIa-C1INH and FXIIa-AT or TSP-1. Inhibition of FXIIa on material surfaces was also shown to affect the function of aggregating platelets. In conclusion, formation of FXIIa-AT and FXIIa-C1INH complexes can help to distinguish between contact activation triggered by biomaterial surfaces and by activated platelets. Platelet aggregation studies also demonstrated that platelet function is influenced by material surface-mediated contact activation and that generation of FXIIa-AT complexes may serve as a new biomarker for thrombotic reactions during therapeutic procedures employing biomaterial devices.

  20. Deficiency of ATP2C1, a golgi ion pump, induces secretory pathway defects in endoplasmic reticulum ( ER)-associated degradation and sensitivity to ER stress

    NARCIS (Netherlands)

    Ramos-Castaneda, J; Park, YN; Liu, M; Hauser, K; Rudolph, H; Shull, GE; Jonkman, MF; Mori, K; Ikeda, S; Ogawa, H; Arvan, P

    2005-01-01

    Relatively few clues have been uncovered to elucidate the cell biological role(s) of mammalian ATP2C1 encoding an inwardly directed secretory pathway Ca2+/Mn2+ pump that is ubiquitously expressed. Deficiency of ATP2C1 results in a human disease ( Hailey-Hailey), which primarily affects

  1. Molecular phylogeny of C1 inhibitor depicts two immunoglobulin-like domains fusion in fishes and ray-finned fishes specific intron insertion after separation from zebrafish

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Abhishek, E-mail: akumar@bot.uni-kiel.de [Department of Genetics and Molecular Biology in Botany, Institute of Botany, Christian-Albrechts-University at Kiel, Kiel (Germany); Bhandari, Anita [Molecular Physiology, Zoological Institute, Christian-Albrechts-University at Kiel, Kiel (Germany); Sarde, Sandeep J. [Department of Genetics and Molecular Biology in Botany, Institute of Botany, Christian-Albrechts-University at Kiel, Kiel (Germany); Goswami, Chandan [National Institute of Science Education and Research, Bhubaneswar, Orissa (India)

    2014-07-18

    Highlights: • C1 inhibitors of fishes have two Ig domains fused in the N-terminal end. • Spliceosomal introns gain in two Ig domains of selected ray-finned fishes. • C1 inhibitors gene is maintained from 450 MY on the same locus. • C1 inhibitors gene is missing in frog and lampreys. • C1 inhibitors of tetrapod and fishes differ in the RCL region. - Abstract: C1 inhibitor (C1IN) is a multi-facet serine protease inhibitor in the plasma cascades, inhibiting several proteases, notably, regulates both complement and contact system activation. Despite huge advancements in the understanding of C1IN based on biochemical properties and its roles in the plasma cascades, the phylogenetic history of C1IN remains uncharacterized. To date, there is no comprehensive study illustrating the phylogenetic history of C1IN. Herein, we explored phylogenetic history of C1IN gene in vertebrates. Fishes have C1IN with two immunoglobulin like domains attached in the N-terminal region. The RCL regions of CIIN from fishes and tetrapod genomes have variations at the positions P2 and P1′. Gene structures of C1IN gene from selected ray-finned fishes varied in the Ig domain region with creation of novel intron splitting exon Im2 into Im2a and Im2b. This intron is limited to ray-finned fishes with genome size reduced below 1 Gb. Hence, we suggest that genome compaction and associated double-strand break repairs are behind this intron gain. This study reveals the evolutionary history of C1IN and confirmed that this gene remains the same locus for ∼450 MY in 52 vertebrates analysed, but it is not found in frogs and lampreys.

  2. N- and O-glycans of recombinant human C1 inhibitor expressed in the milk of transgenic rabbits.

    Science.gov (United States)

    Koles, Kate; van Berkel, Patrick H C; Pieper, Frank R; Nuijens, Jan H; Mannesse, Maurice L M; Vliegenthart, Johannes F G; Kamerling, Johannis P

    2004-01-01

    Human C1 inhibitor (hC1INH) is a therapeutic N, O-glycoprotein with a growing number of clinical applications, but the current natural supplies are not likely to meet the clinical demands. Therefore, recombinant approaches are of interest, whereby specific attention has to be paid to the generated glycosylation patterns. Here, the N,O-glycoprotein was expressed in the mammary gland of transgenic rabbits and subjected to glycan analysis. After release of the N-glycans of recombinant-rabbit human C1 inhibitor (rhC1INH) by peptide-N4-(N-acetyl-beta-glucosaminyl)asparagine amidase F, the oligosaccharides were separated from the O-glycoprotein by centrifugal filtration, then fractionated by a combination of anion-exchange, normal-phase, and high-pH anion-exchange liquid chromatography. The O-glycans, released from the O-glycoprotein by alkaline borohydride treatment, were fractionated by anion-exchange high-performance liquid chromatography (HPLC). The structures of individual components were analysed by 500 MHz 1H NMR spectroscopy, in most cases combined with MALDI-TOF MS. In contrast to the structural data reported for native serum hC1INH, rhC1INH contained a broad array of different N-glycans, made up of oligomannose-, hybrid-, and complex-type structures. In the case of complex-type N-glycans (partially) (alpha2-6)-sialylated (N-acetylneuraminic acid only), mono- and diantennary chains were found; part of the diantennary structures were (alpha1-6)-core-fucosylated or (alpha1-3)-fucosylated in the lower or upper antenna (Lewis x). The manno-oligosaccharide pattern of part of the hybrid- and oligomannose-type structures indicates that besides the usual N-glycan processing route, also the alternative endo-mannosidase pathway is followed. The small core 1-type O-glycans showed the usual (alpha2-3)- and (alpha2-6)-sialylation pattern of O-glycoproteins of nonmucinous origin.

  3. Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann–Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease

    Science.gov (United States)

    Schwerd, Tobias; Pandey, Sumeet; Yang, Huei-Ting; Bagola, Katrin; Jameson, Elisabeth; Jung, Jonathan; Lachmann, Robin H; Shah, Neil; Patel, Smita Y; Booth, Claire; Runz, Heiko; Düker, Gesche; Bettels, Ruth; Rohrbach, Marianne; Kugathasan, Subra; Chapel, Helen; Keshav, Satish; Elkadri, Abdul; Platt, Nick; Muise, Alexio M; Koletzko, Sibylle; Xavier, Ramnik J; Marquardt, Thorsten; Powrie, Fiona; Wraith, James E; Gyrd-Hansen, Mads; Platt, Frances M; Uhlig, Holm H

    2017-01-01

    Objective Patients with Niemann–Pick disease type C1 (NPC1), a lysosomal lipid storage disorder that causes neurodegeneration and liver damage, can present with IBD, but neither the significance nor the functional mechanism of this association is clear. We studied bacterial handling and antibacterial autophagy in patients with NPC1. Design We characterised intestinal inflammation in 14 patients with NPC1 who developed IBD. We investigated bacterial handling and cytokine production of NPC1 monocytes or macrophages in vitro and compared NPC1-associated functional defects to those caused by IBD-associated nucleotide-binding oligomerization domain-containing protein 2 (NOD2) variants or mutations in X-linked inhibitor of apoptosis (XIAP). Results Patients with the lysosomal lipid storage disorder NPC1 have increased susceptibility to early-onset fistulising colitis with granuloma formation, reminiscent of Crohn's disease (CD). Mutations in NPC1 cause impaired autophagy due to defective autophagosome function that abolishes NOD2-mediated bacterial handling in vitro similar to variants in NOD2 or XIAP deficiency. In contrast to genetic NOD2 and XIAP variants, NPC1 mutations do not impair NOD2-receptor-interacting kinase 2 (RIPK2)-XIAP-dependent cytokine production. Pharmacological activation of autophagy can rescue bacterial clearance in macrophages in vitro by increasing the autophagic flux and bypassing defects in NPC1. Conclusions NPC1 confers increased risk of early-onset severe CD. Our data support the concept that genetic defects at different checkpoints of selective autophagy cause a shared outcome of CD-like immunopathology linking monogenic and polygenic forms of IBD. Muramyl dipeptide-driven cytokine responses and antibacterial autophagy induction are parallel and independent signalling cascades downstream of the NOD2-RIPK2-XIAP complex. PMID:26953272

  4. The effect of C1-esterase inhibitor on systemic inflammation in trauma patients with a femur fracture - The CAESAR study: study protocol for a randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Strengers Paul FW

    2011-10-01

    Full Text Available Abstract Background Systemic inflammation in response to a femur fracture and the additional fixation is associated with inflammatory complications, such as acute respiratory distress syndrome and multiple organ dysfunction syndrome. The injury itself, but also the additional procedure of femoral fixation induces a release of pro-inflammatory cytokines such as interleukin-6. This results in an aggravation of the initial systemic inflammatory response, and can cause an increased risk for the development of inflammatory complications. Recent studies have shown that administration of the serum protein C1-esterase inhibitor can significantly reduce the release of circulating pro-inflammatory cytokines in response to acute systemic inflammation. Objective Attenuation of the surgery-induced additional systemic inflammatory response by perioperative treatment with C1-esterase inhibitor of trauma patients with a femur fracture. Methods The study is designed as a double-blind randomized placebo-controlled trial. Trauma patients with a femur fracture, Injury Severity Score ≥ 18 and age 18-80 years are included after obtaining informed consent. They are randomized for administration of 200 U/kg C1-esterase inhibitor intravenously or placebo (saline 0.9% just before the start of the procedure of femoral fixation. The primary endpoint of the study is Δ interleukin-6, measured at t = 0, just before start of the femur fixation surgery and administration of C1-esterase inhibitor, and t = 6, 6 hours after administration of C1-esterase inhibitor and the femur fixation. Conclusion This study intents to identify C1-esterase inhibitor as a safe and potent anti-inflammatory agent, that is capable of suppressing systemic inflammation in trauma patients. This might facilitate early total care procedures by lowering the risk of inflammation in response to the surgical intervention. This could result in increased functional outcomes and reduced health care related

  5. Elucidating the Mechanism of Gain of Toxic Function From Mutant C1 Inhibitor Proteins in Hereditary Angioedema

    Science.gov (United States)

    2017-10-01

    antibodies to 5 specifically blot wild-type C1INH in the pathologic polymers.. A FLAG tag was placed into the wild-type C1INH cDNA located immediately... constructs . The table below shows the results of this experiment. Origin of mutation Co-Transfection Construct A1AT Equiv. Replicate 1 Replicate 2... Construct n/a WT-C1INH n/a 1.00 1.01 A1AT E429K-Mu-C1INH Z 0.74 0.68 A1AT H421D-Mu-C1INH King’s 0.66 0.67 A1AT S148F-Mu-C1INH Silyama 0.71 0.54

  6. Zebrafish slc30a10 deficiency revealed a novel compensatory mechanism of Atp2c1 in maintaining manganese homeostasis.

    Directory of Open Access Journals (Sweden)

    Zhidan Xia

    2017-07-01

    Full Text Available Recent studies found that mutations in the human SLC30A10 gene, which encodes a manganese (Mn efflux transporter, are associated with hypermanganesemia with dystonia, polycythemia, and cirrhosis (HMDPC. However, the relationship between Mn metabolism and HMDPC is poorly understood, and no specific treatments are available for this disorder. Here, we generated two zebrafish slc30a10 mutant lines using the CRISPR/Cas9 system. Compared to wild-type animals, mutant adult animals developed significantly higher systemic Mn levels, and Mn accumulated in the brain and liver of mutant embryos in response to exogenous Mn. Interestingly, slc30a10 mutants developed neurological deficits in adulthood, as well as environmental Mn-induced manganism in the embryonic stage; moreover, mutant animals had impaired dopaminergic and GABAergic signaling. Finally, mutant animals developed steatosis, liver fibrosis, and polycythemia accompanied by increased epo expression. This phenotype was rescued partially by EDTA- CaNa2 chelation therapy and iron supplementation. Interestingly, prior to the onset of slc30a10 expression, expressing ATP2C1 (ATPase secretory pathway Ca2+ transporting 1 protected mutant embryos from Mn exposure, suggesting a compensatory role for Atp2c1 in the absence of Slc30a10. Notably, expressing either wild-type or mutant forms of SLC30A10 was sufficient to inhibit the effect of ATP2C1 in response to Mn challenge in both zebrafish embryos and HeLa cells. These findings suggest that either activating ATP2C1 or restoring the Mn-induced trafficking of ATP2C1 can reduce Mn accumulation, providing a possible target for treating HMDPC.

  7. Zebrafish slc30a10 deficiency revealed a novel compensatory mechanism of Atp2c1 in maintaining manganese homeostasis

    Science.gov (United States)

    Li, Yingniang; Wang, Jia; Li, Wenwen; Wang, Kai; Hong, Xiaoli; Zhao, Lu; Chen, Caiyong; Min, Junxia

    2017-01-01

    Recent studies found that mutations in the human SLC30A10 gene, which encodes a manganese (Mn) efflux transporter, are associated with hypermanganesemia with dystonia, polycythemia, and cirrhosis (HMDPC). However, the relationship between Mn metabolism and HMDPC is poorly understood, and no specific treatments are available for this disorder. Here, we generated two zebrafish slc30a10 mutant lines using the CRISPR/Cas9 system. Compared to wild-type animals, mutant adult animals developed significantly higher systemic Mn levels, and Mn accumulated in the brain and liver of mutant embryos in response to exogenous Mn. Interestingly, slc30a10 mutants developed neurological deficits in adulthood, as well as environmental Mn-induced manganism in the embryonic stage; moreover, mutant animals had impaired dopaminergic and GABAergic signaling. Finally, mutant animals developed steatosis, liver fibrosis, and polycythemia accompanied by increased epo expression. This phenotype was rescued partially by EDTA- CaNa2 chelation therapy and iron supplementation. Interestingly, prior to the onset of slc30a10 expression, expressing ATP2C1 (ATPase secretory pathway Ca2+ transporting 1) protected mutant embryos from Mn exposure, suggesting a compensatory role for Atp2c1 in the absence of Slc30a10. Notably, expressing either wild-type or mutant forms of SLC30A10 was sufficient to inhibit the effect of ATP2C1 in response to Mn challenge in both zebrafish embryos and HeLa cells. These findings suggest that either activating ATP2C1 or restoring the Mn-induced trafficking of ATP2C1 can reduce Mn accumulation, providing a possible target for treating HMDPC. PMID:28692648

  8. Self-administration of intravenous C1-inhibitor therapy for hereditary angioedema and associated quality of life benefits

    DEFF Research Database (Denmark)

    Bygum, Anette; Andersen, Klaus Ejner; Mikkelsen, Carsten Sauer

    2009-01-01

    the impact of self-administered home therapy with intravenous C1-INH concentrate on QOL in patients with HAE. Nine patients experiencing frequent or severe debilitating HAE attacks were offered self-administration of C1-INH concentrate. QOL was assessed prior to and following home therapy using...... for the individual and combined components also improved significantly. No serious complications were documented during a follow-up period of 27 to 72 months. Self-administration of C1-INH improved QOL on both physical and psychological parameters. Patients were able to resume a normal life without restrictions...

  9. Molecular basis of multiple sulfatase deficiency, mucolipidosis II/III and Niemann-Pick C1 disease - Lysosomal storage disorders caused by defects of non-lysosomal proteins.

    Science.gov (United States)

    Dierks, Thomas; Schlotawa, Lars; Frese, Marc-André; Radhakrishnan, Karthikeyan; von Figura, Kurt; Schmidt, Bernhard

    2009-04-01

    Multiple sulfatase deficiency (MSD), mucolipidosis (ML) II/III and Niemann-Pick type C1 (NPC1) disease are rare but fatal lysosomal storage disorders caused by the genetic defect of non-lysosomal proteins. The NPC1 protein mainly localizes to late endosomes and is essential for cholesterol redistribution from endocytosed LDL to cellular membranes. NPC1 deficiency leads to lysosomal accumulation of a broad range of lipids. The precise functional mechanism of this membrane protein, however, remains puzzling. ML II, also termed I cell disease, and the less severe ML III result from deficiencies of the Golgi enzyme N-acetylglucosamine 1-phosphotransferase leading to a global defect of lysosome biogenesis. In patient cells, newly synthesized lysosomal proteins are not equipped with the critical lysosomal trafficking marker mannose 6-phosphate, thus escaping from lysosomal sorting at the trans Golgi network. MSD affects the entire sulfatase family, at least seven members of which are lysosomal enzymes that are specifically involved in the degradation of sulfated glycosaminoglycans, sulfolipids or other sulfated molecules. The combined deficiencies of all sulfatases result from a defective post-translational modification by the ER-localized formylglycine-generating enzyme (FGE), which oxidizes a specific cysteine residue to formylglycine, the catalytic residue enabling a unique mechanism of sulfate ester hydrolysis. This review gives an update on the molecular bases of these enigmatic diseases, which have been challenging researchers since many decades and so far led to a number of surprising findings that give deeper insight into both the cell biology and the pathobiochemistry underlying these complex disorders. In case of MSD, considerable progress has been made in recent years towards an understanding of disease-causing FGE mutations. First approaches to link molecular parameters with clinical manifestation have been described and even therapeutical options have been

  10. Multi-kinase inhibitor C1 triggers mitotic catastrophe of glioma stem cells mainly through MELK kinase inhibition.

    Directory of Open Access Journals (Sweden)

    Mutsuko Minata

    Full Text Available Glioblastoma multiforme (GBM is a highly lethal brain tumor. Due to resistance to current therapies, patient prognosis remains poor and development of novel and effective GBM therapy is crucial. Glioma stem cells (GSCs have gained attention as a therapeutic target in GBM due to their relative resistance to current therapies and potent tumor-initiating ability. Previously, we identified that the mitotic kinase maternal embryonic leucine-zipper kinase (MELK is highly expressed in GBM tissues, specifically in GSCs, and its expression is inversely correlated with the post-surgical survival period of GBM patients. In addition, patient-derived GSCs depend on MELK for their survival and growth both in vitro and in vivo. Here, we demonstrate evidence that the role of MELK in the GSC survival is specifically dependent on its kinase activity. With in silico structure-based analysis for protein-compound interaction, we identified the small molecule Compound 1 (C1 is predicted to bind to the kinase-active site of MELK protein. Elimination of MELK kinase activity was confirmed by in vitro kinase assay in nano-molar concentrations. When patient-derived GSCs were treated with C1, they underwent mitotic arrest and subsequent cellular apoptosis in vitro, a phenotype identical to that observed with shRNA-mediated MELK knockdown. In addition, C1 treatment strongly induced tumor cell apoptosis in slice cultures of GBM surgical specimens and attenuated growth of mouse intracranial tumors derived from GSCs in a dose-dependent manner. Lastly, C1 treatment sensitizes GSCs to radiation treatment. Collectively, these data indicate that targeting MELK kinase activity is a promising approach to attenuate GBM growth by eliminating GSCs in tumors.

  11. Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship.

    Science.gov (United States)

    Shapiro, Irina M; Kolev, Vihren N; Vidal, Christian M; Kadariya, Yuwaraj; Ring, Jennifer E; Wright, Quentin; Weaver, David T; Menges, Craig; Padval, Mahesh; McClatchey, Andrea I; Xu, Qunli; Testa, Joseph R; Pachter, Jonathan A

    2014-05-21

    The goal of targeted therapy is to match a selective drug with a genetic lesion that predicts for drug sensitivity. In a diverse panel of cancer cell lines, we found that the cells most sensitive to focal adhesion kinase (FAK) inhibition lack expression of the neurofibromatosis type 2 (NF2) tumor suppressor gene product, Merlin. Merlin expression is often lost in malignant pleural mesothelioma (MPM), an asbestos-induced aggressive cancer with limited treatment options. Our data demonstrate that low Merlin expression predicts for increased sensitivity of MPM cells to a FAK inhibitor, VS-4718, in vitro and in tumor xenograft models. Disruption of MPM cell-cell or cell-extracellular matrix (ECM) contacts with blocking antibodies suggests that weak cell-cell adhesions in Merlin-negative MPM cells underlie their greater dependence on cell-ECM-induced FAK signaling. This provides one explanation of why Merlin-negative cells are vulnerable to FAK inhibitor treatment. Furthermore, we validated aldehyde dehydrogenase as a marker of cancer stem cells (CSCs) in MPM, a cell population thought to mediate tumor relapse after chemotherapy. Whereas pemetrexed and cisplatin, standard-of-care agents for MPM, enrich for CSCs, FAK inhibitor treatment preferentially eliminates these cells. These preclinical results provide the rationale for a clinical trial in MPM patients using a FAK inhibitor as a single agent after first-line chemotherapy. With this design, the FAK inhibitor could potentially induce a more durable clinical response through reduction of CSCs along with a strong antitumor effect. Furthermore, our data suggest that patients with Merlin-negative tumors may especially benefit from FAK inhibitor treatment. Copyright © 2014, American Association for the Advancement of Science.

  12. Histone deacetylase inhibitors correct the cholesterol storage defect in most Niemann-Pick C1 mutant cells.

    Science.gov (United States)

    Pipalia, Nina H; Subramanian, Kanagaraj; Mao, Shu; Ralph, Harold; Hutt, Darren M; Scott, Samantha M; Balch, William E; Maxfield, Frederick R

    2017-04-01

    Niemann-Pick C (NPC) disease is an autosomal recessive disorder that leads to excessive storage of cholesterol and other lipids in late endosomes and lysosomes. The large majority of NPC disease is caused by mutations in NPC1, a large polytopic membrane protein that functions in late endosomes. There are many disease-associated mutations in NPC1, and most patients are compound heterozygotes. The most common mutation, NPC1I1061T, has been shown to cause endoplasmic reticulum-associated degradation of the NPC1 protein. Treatment of patient-derived NPC1I1061T fibroblasts with histone deacetylase inhibitors (HDACis) vorinostat or panobinostat increases expression of the mutant NPC1 protein and leads to correction of the cholesterol storage. Here, we show that several other human NPC1 mutant fibroblast cell lines can also be corrected by vorinostat or panobinostat and that treatment with vorinostat extends the lifetime of the NPC1I1061T protein. To test effects of HDACi on a large number of NPC1 mutants, we engineered a U2OS cell line to suppress NPC1 expression by shRNA and then transiently transfected these cells with 60 different NPC1 mutant constructs. The mutant NPC1 did not significantly reduce cholesterol accumulation, but approximately 85% of the mutants showed reduced cholesterol accumulation when treated with vorinostat or panobinostat. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

  13. Unmasking Heavily O-Glycosylated Serum Proteins Using Perchloric Acid: Identification of Serum Proteoglycan 4 and Protease C1 Inhibitor as Molecular Indicators for Screening of Breast Cancer.

    Science.gov (United States)

    Lee, Cheng-Siang; Taib, Nur Aishah Mohd; Ashrafzadeh, Ali; Fadzli, Farhana; Harun, Faizah; Rahmat, Kartini; Hoong, See Mee; Abdul-Rahman, Puteri Shafinaz; Hashim, Onn Haji

    2016-01-01

    Heavily glycosylated mucin glycopeptides such as CA 27.29 and CA 15-3 are currently being used as biomarkers for detection and monitoring of breast cancer. However, they are not well detected at the early stages of the cancer. In the present study, perchloric acid (PCA) was used to enhance detection of mucin-type O-glycosylated proteins in the serum in an attempt to identify new biomarkers for early stage breast cancer. Sensitivity and specificity of an earlier developed sandwich enzyme-linked lectin assay were significantly improved with the use of serum PCA isolates. When a pilot case-control study was performed using the serum PCA isolates of normal participants (n = 105) and patients with stage 0 (n = 31) and stage I (n = 48) breast cancer, higher levels of total O-glycosylated proteins in sera of both groups of early stage breast cancer patients compared to the normal control women were demonstrated. Further analysis by gel-based proteomics detected significant inverse altered abundance of proteoglycan 4 and plasma protease C1 inhibitor in both the early stages of breast cancer patients compared to the controls. Our data suggests that the ratio of serum proteoglycan 4 to protease C1 inhibitor may be used for screening of early breast cancer although this requires further validation in clinically representative populations.

  14. Metastasis of transgenic breast cancer in plasminogen activator inhibitor-1 gene-deficient mice

    DEFF Research Database (Denmark)

    Almholt, Kasper; Nielsen, Boye Schnack; Frandsen, Thomas Leth

    2003-01-01

    of metastasizing breast cancer. In these tumors, the expression pattern of uPA and PAI-1 resembles that of human ductal breast cancer and plasminogen is required for efficient metastasis. In a cohort of 63 transgenic mice that were either PAI-1-deficient or wild-type sibling controls, primary tumor growth...... limiting for tumor vascularization and metastasis, or that there is a functional redundancy between PAI-1 and other inhibitors of the uPA/plasmin system, masking the effect of PAI-1 deficiency....

  15. Proton Pump Inhibitor and Histamine-2 Receptor Antagonist Use and Iron Deficiency.

    Science.gov (United States)

    Lam, Jameson R; Schneider, Jennifer L; Quesenberry, Charles P; Corley, Douglas A

    2017-03-01

    Proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) suppress gastric acid production, which can inhibit iron absorption. However, few data exist regarding whether these medications increase the risk of clinical iron deficiency. A community-based case-control study evaluated the association between acid-suppressing medication use and the subsequent risk of iron deficiency. It contrasted 77,046 patients with new iron deficiency diagnoses (January 1999-December 2013), with 389,314 controls. Medication exposures, outcomes, and potential confounders used electronic databases. We excluded patients with pre-existing risk factors for iron deficiency. Associations were estimated using conditional logistic regression. Among cases, 2343 (3.0%) received a prior ≥2-year supply of PPIs and 1063 (1.4%) received H2RAs (without PPI use). Among controls, 3354 (0.9%) received a prior ≥2-year supply of PPIs and 2247 (0.6%) H2RAs. Both ≥2 years of PPIs (adjusted odds ratio, 2.49; 95% confidence interval, 2.35-2.64) and ≥2 years of H2RAs (odds ratio, 1.58; 95% CI, 1.46-1.71) were associated with an increased subsequent risk for iron deficiency. Among PPI users, the associations were stronger for higher daily doses (>1.5 vs 1.5 pills per day for at least 10 years (odds ratio, 4.27; 95% CI, 2.53-7.21). No similar strong associations were found for other commonly used prescription medications. Among patients without known risk factors for iron deficiency, gastric acid inhibitor use for ≥2 years was associated with an increased subsequent risk of iron deficiency. The risk increased with increasing potency of acid inhibition and decreased after medication discontinuation. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

  16. Carnitine-acylcarnitine translocase deficiency with c.199-10 T>G and novel c.1A>G mutation: Two case reports and brief literature review.

    Science.gov (United States)

    Yan, Hui-Ming; Hu, Hao; Ahmed, Aisha; Feng, Bing-Bing; Liu, Jing; Jia, Zheng-Jun; Wang, Hua

    2017-11-01

    Carnitine-acylcarnitine translocate deficiency (CACTD) is a rare and life-threatening, autosomal recessive disorder of fatty acid β-oxidation characterized by hypoketotic hypoglycemia, hyperammonemia, cardiomyopathy, liver dysfunction, and muscle weakness; culminating in early death. To date, CACTD cases screened from the Chinese mainland population, especially patient with compound heterozygote with c.199-10T>G and a novel c.1A>G mutation in the SLC25A20 gene has never been described. Herein, we report 2 neonatal cases of CACTD identified from the mainland China. These 2 patients were presented with severe metabolic crisis and their clinical conditions deteriorate rapidly and both died of cardiorespiratory collapse in the first week of life. We present the clinical and biochemical features of 2 probands and a brief literature review of previously reported CACTD cases with the c.199-10T>G mutation. The acylcarnitine profiles by tandem-mass-spectrometry and the mutation analysis of SLC25A20 gene confirmed the diagnosis of CACTD in both patients. Mutation analysis demonstrated that patient No. 1 was homozygous for c.199-10T>G mutation, while patient No. 2 was a compound heterozygote for 2 mutations, a maternally-inherited c.199-10T>G and a paternally-inherited, novel c.1A>G mutation. Both patients were treated with an aggressive treatment regimen include high glucose and arginine infusion, respiratory, and circulatory support. The first proband died 3 days after delivery due to sudden cardiac arrest. The second patient's clinical condition, at one time, was improved by high glucose infusion, intravenous arginine, and circulatory support. However, the patient failed to wean from mechanical ventilation. Unfortunately, her parents refused further treatment due to fear of financial burdens. The patient died of congestive heart failure in the 6th day of life. We report the first 2 cases of CACTD identified from the mainland China. Apart from a founder mutation c.199-10T

  17. ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib.

    Science.gov (United States)

    Wang, Chen; Jette, Nicholas; Moussienko, Daniel; Bebb, D Gwyn; Lees-Miller, Susan P

    2017-04-01

    The ataxia telangiectasia mutated (ATM) protein kinase plays a central role in the cellular response to DNA damage. Loss or inactivation of both copies of the ATM gene (ATM) leads to ataxia telangiectasia, a devastating childhood condition characterized by neurodegeneration, immune deficiencies, and cancer predisposition. ATM is also absent in approximately 40% of mantle cell lymphomas (MCLs), and we previously showed that MCL cell lines with loss of ATM are sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Next-generation sequencing of patient tumors has revealed that ATM is altered in many human cancers including colorectal, lung, prostate, and breast. Here, we show that the colorectal cancer cell line SK-CO-1 lacks detectable ATM protein expression and is sensitive to the PARP inhibitor olaparib. Similarly, HCT116 colorectal cancer cells with shRNA depletion of ATM are sensitive to olaparib, and depletion of p53 enhances this sensitivity. Moreover, HCT116 cells are sensitive to olaparib in combination with the ATM inhibitor KU55933, and sensitivity is enhanced by deletion of p53. Together our studies suggest that PARP inhibitors may have potential for treating colorectal cancer with ATM dysfunction and/or colorectal cancer with mutation of p53 when combined with an ATM kinase inhibitor. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  18. C 1

    Science.gov (United States)

    Nguyen, Thien; Karčiauskas, Kęstutis; Peters, Jörg

    2016-01-01

    Geometrically continuous ( G k ) constructions naturally yield families of finite elements for isogeometric analysis (IGA) that are C k also for non-tensor-product layout. This paper describes and analyzes one such concrete C 1 geometrically generalized IGA element (short: gIGA element) that generalizes bi-quadratic splines to quad meshes with irregularities. The new gIGA element is based on a recently-developed G 1 surface construction that recommends itself by its a B-spline-like control net, low (least) polynomial degree, good shape properties and reproduction of quadratics at irregular (extraordinary) points. Remarkably, for Poisson's equation on the disk using interior vertices of valence 3 and symmetric layout, we observe O ( h 3 ) convergence in the L ∞ norm for this family of elements. Numerical experiments confirm the elements to be effective for solving the trivariate Poisson equation on the solid cylinder, deformations thereof (a turbine blade), modeling and computing geodesics on smooth free-form surfaces via the heat equation, for solving the biharmonic equation on the disk and for Koiter-type thin-shell analysis.

  19. Carbonic anhydrase inhibitors are specific openers of skeletal muscle BK channel of K+-deficient rats.

    Science.gov (United States)

    Tricarico, Domenico; Barbieri, Mariagrazia; Mele, Antonietta; Carbonara, Giuseppe; Camerino, Diana Conte

    2004-04-01

    Carbonic-anhydrase (CA) inhibitors are used in the treatment of hypokalaemic periodic paralysis (hypoPP) and related channelopathies but their mechanism of action is unknown. Patch-clamp experiments and molecular modeling investigations were performed to evaluate the mechanism of actions of CA inhibitors on skeletal muscle Ca2+-activated-K+ (BK) channel of K+-deficient rats used as animal model of hypoPP. CA inhibitors showing different degree of CA inhibition such as acetazolamide (ACTZ), dichlorphenamide (DCP), hydrochlorthiazide (HCT), etoxzolamide (ETX), methazolamide (MTZ), and bendroflumethiazide (BFT), which lacks inhibitory effects on CA enzymes, were tested in vitro on BK channels. The application of ACTZ, BFT, ETX, and DCP to excised patches activated the BK channel with potency: ACTZ(DE50=7.3x10(-6)M)>BFT(DE50=5.93x10(-5)M)>ETX(DE50=1.17x10(-4)M)>DCP. In contrast, MTZ and HCT failed to activate the BK channel. Molecular modeling studies showed that the capability of CA inhibitors to open the BK channel was related to the presence in their structures of an intra-molecular hydrogen bond with calculated inter-atomic distances ranging between 1.82 A degrees and 3.01 A degrees and of an aromatic ring poor of electrons. ACTZ, BFT, ETX, and DCP showed these pharmacofores, while MTZ and HCT did not. Our data indicate that the activation of BK channel is a property of CA inhibitors that interact with the channel subunit/s and that this effect is not related to their capability to inhibit the CA enzymes.

  20. Probing the aglycon binding site of a b-glucosidase: a collection of C-1-modified 2,5-dideoxy-2,5-imino-D-mannitol derivatives and their structure-activity relationships as competitive inhibitors

    DEFF Research Database (Denmark)

    Wrodnigg, Tanja; Diness, Frederik; Gruber, Christoph

    2004-01-01

    A range of new C-1 modified derivatives of the powerful glucosidase inhibitor 2,5-dideoxy-2,5-imino-D-mannitol has been synthesised and their biological activities probed with the b-glucosidase from Agrobacterium sp. Ki values are compared with those of previously prepared close relatives. Findin...

  1. FAD286, an aldosterone synthase inhibitor, reduced atherosclerosis and inflammation in apolipoprotein E-deficient mice.

    Science.gov (United States)

    Gamliel-Lazarovich, Aviva; Gantman, Anna; Coleman, Raymond; Jeng, Arco Y; Kaplan, Marielle; Keidar, Shlomo

    2010-09-01

    Aldosterone is known to be involved in atherosclerosis and cardiovascular disease and blockade of its receptor was shown to improve cardiovascular function. It was, therefore, hypothesized that inhibition of aldosterone synthesis would also reduce atherosclerosis development. To test this hypothesis, we examined the effect of FAD286 (FAD), an aldosterone synthase inhibitor, on the development of atherosclerosis in spontaneous atherosclerotic apolipoprotein E-deficient mice. Mice were divided into three treatment groups: normal diet, low-salt diet (LSD) and LSD treated with FAD at 30 mg/kg per day (LSD + FAD) for 10 weeks. Histomorphometry of the aortas obtained from these mice showed that atherosclerotic lesion area increased by three-fold under LSD compared with normal diet and FAD significantly reduced lesion area to values similar to normal diet. Changes in atherosclerosis were paralleled by changes in the expression of the inflammation markers (C-reactive protein, monocyte chemotactic protein-1, interleukin-6, nuclear factor kappa B and intercellular adhesion molecule-1) in peritoneal macrophages obtained from these mice. Surprisingly, whereas LSD increased serum or urine aldosterone levels, FAD did not alter these levels when evaluated at the end of the study. In J774A.1 macrophage-like cell line stimulated with lipopolysaccharide, FAD was shown to have a direct dose-dependent anti-inflammatory effect. In apolipoprotein E-deficient mice, FAD reduces atherosclerosis and inflammation. However, these actions appeared to be dissociated from its effect on inhibition of aldosterone synthesis.

  2. High-fat diet enhances and plasminogen activator inhibitor-1 deficiency attenuates bone loss in mice with Lewis Lung carcinoma

    Science.gov (United States)

    This study determined the effects of a high-fat diet and plasminogen activator inhibitor-1 deficiency (PAI-1-/-) on bone structure in mice bearing Lewis lung carcinoma (LLC) in lungs. Reduction in bone volume fraction (BV/TV) by 22% and 21%, trabecular number (Tb.N) by 8% and 4% and bone mineral de...

  3. Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann?Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease

    OpenAIRE

    Schwerd, TM; Pandey, SK; Yang, H-T; Bagola, K.; Jameson, E; Jung, J.; Lachmann, RH; Shah, N.; Patel, SY; Booth, C.; Runz, H; Düker, G; Bettels, R; Rohrbach, M.; Kugathasan, S

    2016-01-01

    Objective Patients with Niemann–Pick disease type C1 (NPC1), a lysosomal lipid storage disorder that causes neurodegeneration and liver damage, can present with IBD, but neither the significance nor the functional mechanism of this association is clear. We studied bacterial handling and antibacterial autophagy in patients with NPC1. Design We characterised intestinal inflammation in 14 patients with NPC1 who developed IBD. We investigated bacterial handling and cytokine production of...

  4. Deficiencies

    Data.gov (United States)

    U.S. Department of Health & Human Services — A list of all deficiencies currently listed on Nursing Home Compare, including the nursing home that received the deficiency, the associated inspection date,...

  5. Drug-Induced Vitamin B12 Deficiency: A Focus on Proton Pump Inhibitors and Histamine-2 Antagonists.

    Science.gov (United States)

    Linder, Lauren; Tamboue, Cynthia; Clements, Jennifer N

    2017-12-01

    To review primary literature of gastric acid suppressive agents and vitamin B12 deficiency. From the published articles, proton pump inhibitors (PPIs) are associated with a higher risk of inducing vitamin B12 deficiency than histamine-2 receptor antagonists (H2RAs). Literature suggests that there is an increased risk of developing vitamin B12 deficiency in patients who are exposed to extended durations of therapy with PPIs. There are, however, some conflicting data in elderly patients suggesting that the PPI use for more than 3 years does not increase the risk of vitamin B12 deficiency. No evidence was found to support the extended use of H2RA monotherapy causing vitamin B12 deficiency. The inconsistency of results reported could be due to the differing patient populations studied, such as Zollinger-Ellison syndrome (ZES) and elderly patients. Overall, the lack of consistent evidence shows the need for more research in this area. To investigate the clinical significance of vitamin B12 deficiency caused by acid suppression with PPIs and H2RAs, longer prospective studies are needed. These studies should focus on patient-centered outcomes to accurately determine the extended usage of PPI and H2RA and the true effects on vitamin B12 deficiency.

  6. Inhibitors

    Science.gov (United States)

    ... and exercise, immune tolerance therapy, and needs of older adults with hemophilia and an inhibitor. For more information, visit https://www.hemophilia.org/Events-Educational-Programs/Inhibitor-Education/Inhibitor-Education-Summits The NHF’s Inhibitor Education Summits ...

  7. Supplementation of Nicotinic Acid with NAMPT Inhibitors Results in Loss of In Vivo Efficacy in NAPRT1-Deficient Tumor Models

    Directory of Open Access Journals (Sweden)

    Thomas O'Brien

    2013-12-01

    Full Text Available Nicotinamide adenine dinucleotide (NAD is a metabolite essential for cell survival and generated de novo from tryptophan or recycled from nicotinamide (NAM through the nicotinamide phosphoribosyltransferase (NAMPT-dependent salvage pathway. Alternatively, nicotinic acid (NA is metabolized to NAD through the nicotinic acid phosphoribosyltransferase domain containing 1 (NAPRT1-dependent salvage pathway. Tumor cells are more reliant on the NAMPT salvage pathway making this enzyme an attractive therapeutic target. Moreover, the therapeutic index of NAMPT inhibitors may be increased by in NAPRT-deficient tumors by NA supplementation as normal tissues may regenerate NAD through NAPRT1. To confirm the latter, we tested novel NAMPT inhibitors, GNE-617 and GNE-618, in cell culture- and patient-derived tumor models. While NA did not protect NAPRT1-deficient tumor cell lines from NAMPT inhibition in vitro, it rescued efficacy of GNE-617 and GNE-618 in cell culture- and patient-derived tumor xenografts in vivo. NA co-treatment increased NAD and NAM levels in NAPRT1-deficient tumors to levels that sustained growth in vivo. Furthermore, NAM co-administration with GNE-617 led to increased tumor NAD levels and rescued in vivo efficacy as well. Importantly, tumor xenografts remained NAPRT1-deficient in the presence of NA, indicating that the NAPRT1-dependent pathway is not reactivated. Protection of NAPRT1-deficient tumors in vivo may be due to increased circulating levels of metabolites generated by mouse liver, in response to NA or through competitive reactivation of NAMPT by NAM. Our results have important implications for the development of NAMPT inhibitors when considering NA co-treatment as a rescue strategy.

  8. Deficiency of a Niemann-Pick, type C1-related protein in toxoplasma is associated with multiple lipidoses and increased pathogenicity.

    Directory of Open Access Journals (Sweden)

    Bao Lige

    2011-12-01

    Full Text Available Several proteins that play key roles in cholesterol synthesis, regulation, trafficking and signaling are united by sharing the phylogenetically conserved 'sterol-sensing domain' (SSD. The intracellular parasite Toxoplasma possesses at least one gene coding for a protein containing the canonical SSD. We investigated the role of this protein to provide information on lipid regulatory mechanisms in the parasite. The protein sequence predicts an uncharacterized Niemann-Pick, type C1-related protein (NPC1 with significant identity to human NPC1, and it contains many residues implicated in human NPC disease. We named this NPC1-related protein, TgNCR1. Mammalian NPC1 localizes to endo-lysosomes and promotes the movement of sterols and sphingolipids across the membranes of these organelles. Miscoding patient mutations in NPC1 cause overloading of these lipids in endo-lysosomes. TgNCR1, however, lacks endosomal targeting signals, and localizes to flattened vesicles beneath the plasma membrane of Toxoplasma. When expressed in mammalian NPC1 mutant cells and properly addressed to endo-lysosomes, TgNCR1 restores cholesterol and GM1 clearance from these organelles. To clarify the role of TgNCR1 in the parasite, we genetically disrupted NCR1; mutant parasites were viable. Quantitative lipidomic analyses on the ΔNCR1 strain reveal normal cholesterol levels but an overaccumulation of several species of cholesteryl esters, sphingomyelins and ceramides. ΔNCR1 parasites are also characterized by abundant storage lipid bodies and long membranous tubules derived from their parasitophorous vacuoles. Interestingly, these mutants can generate multiple daughters per single mother cell at high frequencies, allowing fast replication in vitro, and they are slightly more virulent in mice than the parental strain. These data suggest that the ΔNCR1 strain has lost the ability to control the intracellular levels of several lipids, which subsequently results in the

  9. The proton pump inhibitor lansoprazole improves the skeletal phenotype in dystrophin deficient mdx mice.

    Directory of Open Access Journals (Sweden)

    Arpana Sali

    Full Text Available In Duchenne muscular dystrophy (DMD, loss of the membrane stabilizing protein dystrophin results in myofiber damage. Microinjury to dystrophic myofibers also causes secondary imbalances in sarcolemmic ion permeability and resting membrane potential, which modifies excitation-contraction coupling and increases proinflammatory/apoptotic signaling cascades. Although glucocorticoids remain the standard of care for the treatment of DMD, there is a need to investigate the efficacy of other pharmacological agents targeting the involvement of imbalances in ion flux on dystrophic pathology.We designed a preclinical trial to investigate the effects of lansoprazole (LANZO administration, a proton pump inhibitor, on the dystrophic muscle phenotype in dystrophin deficient (mdx mice. Eight to ten week-old female mice were assigned to one of four treatment groups (n = 12 per group: (1 vehicle control; (2 5 mg/kg/day LANZO; (3 5 mg/kg/day prednisolone; and (4 combined treatment of 5 mg/kg/day prednisolone (PRED and 5 mg/kg/day LANZO. Treatment was administered orally 5 d/wk for 3 months. At the end of the study, behavioral (Digiscan and functional outcomes (grip strength and Rotarod were assessed prior to sacrifice. After sacrifice, body, tissue and organ masses, muscle histology, in vitro muscle force, and creatine kinase levels were measured. Mice in the combined treatment groups displayed significant reductions in the number of degenerating muscle fibers and number of inflammatory foci per muscle field relative to vehicle control. Additionally, mice in the combined treatment group displayed less of a decline in normalized forelimb and hindlimb grip strength and declines in in vitro EDL force after repeated eccentric contractions.Together our findings suggest that combined treatment of LANZO and prednisolone attenuates some components of dystrophic pathology in mdx mice. Our findings warrant future investigation of the clinical efficacy of LANZO and

  10. Effects of a high-fat diet on spontaneous metastasis of Lewis lung carcinoma in plasminogen activator inhibitor-1 deficient and wild-type mice

    Science.gov (United States)

    We investigated the effects of plasminogen activator inhibitor-1 (PAI-1) deficiency on spontaneous metastasis of Lewis lung carcinoma (LLC) in PAI-1 deficient (PAI-1-/-) and wildtype mice (C57BL/6J background) fed the AIN93G diet or that diet modified with 45% calories from fat. The high-fat diet i...

  11. Characterization of Crohn disease in X-linked inhibitor of apoptosis-deficient male patients and female symptomatic carriers.

    Science.gov (United States)

    Aguilar, Claire; Lenoir, Christelle; Lambert, Nathalie; Bègue, Bernadette; Brousse, Nicole; Canioni, Danielle; Berrebi, Dominique; Roy, Maryline; Gérart, Stéphane; Chapel, Helen; Schwerd, Tobias; Siproudhis, Laurent; Schäppi, Michela; Al-Ahmari, Ali; Mori, Masaaki; Yamaide, Akiko; Galicier, Lionel; Neven, Bénédicte; Routes, John; Uhlig, Holm H; Koletzko, Sibylle; Patel, Smita; Kanegane, Hirokazu; Picard, Capucine; Fischer, Alain; Bensussan, Nadine Cerf; Ruemmele, Frank; Hugot, Jean-Pierre; Latour, Sylvain

    2014-11-01

    Crohn disease is an inflammatory bowel disease (IBD) with a complex mode of inheritance. Although nucleotide binding and oligomerization domain containing 2 (NOD2) is the strongest risk factor, the cause of Crohn disease remains unknown in the majority of the cases. X-linked inhibitor of apoptosis (XIAP) deficiency causes X-linked lymphoproliferative syndrome type 2. IBD has been reported in some XIAP-deficient patients. We characterize the IBD affecting a large cohort of patients with mutations in XIAP and examine the possible pathophysiologic mechanisms. We performed a phenotypical and histologic analysis of the IBD affecting 17 patients with hemizygous mutations in XIAP, including 3 patients identified by screening 83 patients with pediatric-onset IBD. The X chromosome inactivation was analyzed in female carriers of heterozygous XIAP mutations, including 2 adults with IBD. The functional consequences of XIAP deficiency were analyzed. Clinical presentation and histology of IBD in patients with XIAP deficiency overlapped with those of patients with Crohn disease. The age at onset was variable (from 3 months to 41 years), and IBD was severe and difficult to treat. In 2 patients hematopoietic stem cell transplantation fully restored intestinal homeostasis. Monocytes of patients had impaired NOD2-mediated IL-8 and monocyte chemoattractant protein 1 (MCP-1) production, as well as IL-10, in response to NOD2 and Toll-like receptor 2/4 costimulation. Nucleotide binding and oligomerization domain containing 1 (NOD1)-mediated IL-6 and IL-8 production was defective in fibroblasts from XIAP-deficient patients. The 2 heterozygous female carriers of XIAP mutations with IBD displayed abnormal expression of the XIAP mutated allele, resulting in impaired activation of the NOD2 pathway. IBD in patients with XIAP deficiency is similar to Crohn disease and is associated with defective NOD2 function in monocytes. Importantly, we report that it is not restricted to male patients

  12. Novel Mechanisms of PARP Inhibitor Resistance in BRCA1-Deficient Breast Cancers

    Science.gov (United States)

    2015-12-01

    signifying loss of fork protection. Co-treatment with Mirin , an Mre11 inhibitor, prevents this shortening, demonstrating this degradation following ATRi... Mirin , an MRE11 inhibitor, in the parental UWB1, and resistant SYr12 and SYr14 cell lines.   19   Figure 8: A small scale DNA damage drug

  13. Cost-utility analysis of Ruconest® (conestat alfa) compared to Berinert® P (human C1 esterase inhibitor) in the treatment of acute, life-threatening angioedema attacks in patients with hereditary angioedema

    Science.gov (United States)

    Holko, Przemysław; Paszulewicz, Anna

    2013-01-01

    Introduction Administration of human C1 esterase inhibitor (Berinert® P) from target import is the most widespread treatment strategy for patients with hereditary angioedema (HAE). However, a therapeutic health program including Ruconest® (conestat alfa) could shorten a patient's expectancy for a life-saving treatment. Aim To evaluate the cost-utility of Ruconest® (conestat alfa) financed from public funds within the newly introduced therapeutic health program compared with Berinert® P (human C1 esterase inhibitor) in the treatment of acute angioedema attacks in adults with HAE. Material and methods The cost-utility analysis from the Polish healthcare payer's perspective was performed for 1 year (2012). The costs and health outcomes were simulated for three pairs of eligible HAE patient groups (active treatment and corresponding placebo). The incremental costs of each intervention compared with placebo were listed together (direct or indirect comparisons between options were impossible due to limited clinical data available). Results The incremental cost-utility ratios (ICURs) for the evaluated interventions compared with placebo were as follows: EUR 15,226 per QALY (Ruconest®) and EUR 27,786 per QALY (Berinert® P). The probability of cost-utility (ICUR < EUR 24,279 per QALY) assessed for Ruconest® administered in the case of acute angioedema attack was 61% and 41% for Berinert® P. Conclusions The administration of Ruconest® in acute life-threatening angioedema attacks is economically justified from the Polish healthcare payer's perspective, results in lower costs and is characterized by higher cost-utility probability compared with Berinert® P. PMID:24278067

  14. Overexpression of Pseudomonas aeruginosa LpxC with its inhibitors in an acrB-deficient Escherichia coli strain.

    Science.gov (United States)

    Gao, Ning; McLeod, Sarah M; Hajec, Laurel; Olivier, Nelson B; Lahiri, Sushmita D; Bryan Prince, D; Thresher, Jason; Ross, Philip L; Whiteaker, James D; Doig, Peter; Li, Amanda Haixi; Hill, Pamela J; Cornebise, Mark; Reck, Folkert; Hale, Michael R

    2014-12-01

    In Gram-negative bacteria, the cell wall is surrounded by an outer membrane, the outer leaflet of which is comprised of charged lipopolysaccharide (LPS) molecules. Lipid A, a component of LPS, anchors this molecule to the outer membrane. UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a zinc-dependent metalloamidase that catalyzes the first committed step of biosynthesis of Lipid A, making it a promising target for antibiotic therapy. Formation of soluble aggregates of Pseudomonas aeruginosa LpxC protein when overexpressed in Escherichia coli has limited the availability of high quality protein for X-ray crystallography. Expression of LpxC in the presence of an inhibitor dramatically increased protein solubility, shortened crystallization time and led to a high-resolution crystal structure of LpxC bound to the inhibitor. However, this approach required large amounts of compound, restricting its use. To reduce the amount of compound needed, an overexpression strain of E. coli was created lacking acrB, a critical component of the major efflux pump. By overexpressing LpxC in the efflux deficient strain in the presence of LpxC inhibitors, several structures of P. aeruginosa LpxC in complex with different compounds were solved to accelerate structure-based drug design. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. High-fat Diet Enhances and Plasminogen Activator Inhibitor-1 Deficiency Attenuates Bone Loss in Mice with Lewis Lung Carcinoma.

    Science.gov (United States)

    Yan, Lin; Nielsen, Forrest H; Sundaram, Sneha; Cao, Jay

    2015-07-01

    This study determined the effects of a high-fat diet and plasminogen activator inhibitor-1 deficiency (Pai1(-/-)) on the bone structure in male C57BL/6 mice bearing Lewis lung carcinoma (LLC) in lungs. Significant reduction in bone volume fraction (BV/TV), trabecular number (Tb.N) and bone mineral density (BMD) in femurs and vertebrae were found in LLC-bearing mice compared to non-tumor-bearing mice. In LLC-bearing mice, the high-fat diet compared to the AIN93G control diet significantly reduced BV/TV, Tb.N and BMD in femurs and BV/TV in vertebrae. The high-fat diet significantly reduced BMD in vertebrae in wild-type mice but not in Pai1(-/-) mice. Compared to wild-type mice, PAI1 deficiency significantly increased BV/TV and Tb.N in femurs. The plasma concentration of osteocalcin was significantly lower and that of tartrate-resistant acid phosphatase 5b (TRAP5b) was significantly higher in LLC-bearing mice. The high-fat diet significantly reduced plasma osteocalcin and increased TRAP5b. Deficiency in PAI1 prevented the high-fat diet-induced increases in plasma TRAP5b. These findings demonstrate that a high-fat diet enhances, whereas PAI1 deficiency, attenuates metastasis-associated bone loss, indicating that a high-fat diet and PAI1 contribute to metastasis-associated bone deterioration. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  16. Novel mechanisms of PARP inhibitor resistance in BRCA1 deficient cancers

    Science.gov (United States)

    2016-08-01

    essential for error-free repair of DNA double strand breaks via homologous recombination (HR) (Gudmundsdottir & Ashworth, 2006), while PARPs are...integrated plasmid reporter, DR-GFP, is cut with the rare cutter, I-SceI nuclease, resulting in a double strand break. When this break is repaired via...another cell line, BR5, a BRCA1-deficient mouse ovarian cancer cell line which is exceptionally sensitive to PARPi treatment (Figure 17C). Though BR5

  17. Histone deacetylase inhibitor upregulates peroxisomal fatty acid oxidation and inhibits apoptotic cell death in abcd1-deficient glial cells.

    Directory of Open Access Journals (Sweden)

    Jaspreet Singh

    Full Text Available In X-ALD, mutation/deletion of ALD gene (ABCD1 and the resultant very long chain fatty acid (VLCFA derangement has dramatically opposing effects in astrocytes and oligodendrocytes. While loss of Abcd1 in astrocytes produces a robust inflammatory response, the oligodendrocytes undergo cell death leading to demyelination in X-linked adrenoleukodystrophy (X-ALD. The mechanisms of these distinct pathways in the two cell types are not well understood. Here, we investigated the effects of Abcd1-knockdown and the subsequent alteration in VLCFA metabolism in human U87 astrocytes and rat B12 oligodendrocytes. Loss of Abcd1 inhibited peroxisomal β-oxidation activity and increased expression of VLCFA synthesizing enzymes, elongase of very long chain fatty acids (ELOVLs (1 and 3 in both cell types. However, higher induction of ELOVL's in Abcd1-deficient B12 oligodendrocytes than astrocytes suggests that ELOVL pathway may play a prominent role in oligodendrocytes in X-ALD. While astrocytes are able to maintain the cellular homeostasis of anti-apoptotic proteins, Abcd1-deletion in B12 oligodendrocytes downregulated the anti-apototic (Bcl-2 and Bcl-xL and cell survival (phospho-Erk1/2 proteins, and upregulated the pro-apoptotic proteins (Bad, Bim, Bax and Bid leading to cell loss. These observations provide insights into different cellular signaling mechanisms in response to Abcd1-deletion in two different cell types of CNS. The apoptotic responses were accompanied by activation of caspase-3 and caspase-9 suggesting the involvement of mitochondrial-caspase-9-dependent mechanism in Abcd1-deficient oligodendrocytes. Treatment with histone deacetylase (HDAC inhibitor suberoylanilide hydroxamic acid (SAHA corrected the VLCFA derangement both in vitro and in vivo, and inhibited the oligodendrocytes loss. These observations provide a proof-of principle that HDAC inhibitor SAHA may have a therapeutic potential for X-ALD.

  18. AZD6738, A Novel Oral Inhibitor of ATR, Induces Synthetic Lethality with ATM Deficiency in Gastric Cancer Cells.

    Science.gov (United States)

    Min, Ahrum; Im, Seock-Ah; Jang, Hyemin; Kim, Seongyeong; Lee, Miso; Kim, Debora Keunyoung; Yang, Yaewon; Kim, Hee-Jun; Lee, Kyung-Hun; Kim, Jin Won; Kim, Tae-Yong; Oh, Do-Youn; Brown, Jeff; Lau, Alan; O'Connor, Mark J; Bang, Yung-Jue

    2017-04-01

    Ataxia telangiectasia and Rad3-related (ATR) can be considered an attractive target for cancer treatment due to its deleterious effect on cancer cells harboring a homologous recombination defect. The aim of this study was to investigate the potential use of the ATR inhibitor, AZD6738, to treat gastric cancer.In SNU-601 cells with dysfunctional ATM, AZD6738 treatment led to an accumulation of DNA damage due to dysfunctional RAD51 foci formation, S phase arrest, and caspase 3-dependent apoptosis. In contrast, SNU-484 cells with functional ATM were not sensitive to AZD6738. Inhibition of ATM in SNU-484 cells enhanced AZD6738 sensitivity to a level comparable with that observed in SNU-601 cells, showing that activation of the ATM-Chk2 signaling pathway attenuates AZD6738 sensitivity. In addition, decreased HDAC1 expression was found to be associated with ATM inactivation in SNU-601 cells, demonstrating the interaction between HDAC1 and ATM can affect sensitivity to AZD6738. Furthermore, in an in vivo tumor xenograft mouse model, AZD6738 significantly suppressed tumor growth and increased apoptosis.These findings suggest synthetic lethality between ATR inhibition and ATM deficiency in gastric cancer cells. Further clinical studies on the interaction between AZD 6738 and ATM deficiency are warranted to develop novel treatment strategies for gastric cancer. Mol Cancer Ther; 16(4); 566-77. ©2017 AACR. ©2017 American Association for Cancer Research.

  19. Small-Molecule Inhibitors Targeting DNA Repair and DNA Repair Deficiency in Research and Cancer Therapy.

    Science.gov (United States)

    Hengel, Sarah R; Spies, M Ashley; Spies, Maria

    2017-09-21

    To maintain stable genomes and to avoid cancer and aging, cells need to repair a multitude of deleterious DNA lesions, which arise constantly in every cell. Processes that support genome integrity in normal cells, however, allow cancer cells to develop resistance to radiation and DNA-damaging chemotherapeutics. Chemical inhibition of the key DNA repair proteins and pharmacologically induced synthetic lethality have become instrumental in both dissecting the complex DNA repair networks and as promising anticancer agents. The difficulty in capitalizing on synthetically lethal interactions in cancer cells is that many potential targets do not possess well-defined small-molecule binding determinates. In this review, we discuss several successful campaigns to identify and leverage small-molecule inhibitors of the DNA repair proteins, from PARP1, a paradigm case for clinically successful small-molecule inhibitors, to coveted new targets, such as RAD51 recombinase, RAD52 DNA repair protein, MRE11 nuclease, and WRN DNA helicase. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Response of copper deficient rats to inhibitors of renal sodium reabsorption

    Energy Technology Data Exchange (ETDEWEB)

    Noordewier, B.; Saari, J.T. (Northwestern College, Orange City, IA (United States) USDA/ARS, Grand Forks, ND (United States))

    1991-03-11

    This study examined the effects of furosemide (Furo), a Loop diuretic, and amiloride (Am), a potassium (K)-sparing diuretic, on the excretion of sodium (Na) and K in copper-adequate (CuAdeq) and copper-deficient (CuDef) rats. Weanling male Sprague Dawley rats were fed a CuDef or CuAdeq diet ad libitum and given deionized water to drink. After 5 weeks on the diets, rats were assigned to one of four treatment regimens: Furo, Am or Furo + Am. Rats were anesthetized and electrolyte excretion was measured in 2 {times} 15 min control periods followed by 3 {times} 15 min treatment periods. Furo increased Na excretion in a dose dependent manner in both the CuAdeq and the CuDef rats. The response of the CuAdeq rats was slightly greater than that of the CuDef rats in each of the 3 treatment groups in which Furo was given. K excretion following Furo increased to the same extent in the CuAdeq and CuDef rats. The natriuretic response to Am alone was slightly greater in the CuDef than the CuAdeq rats. The antikaliuretic response of the CuDef rats was similar to that of the CuAdeq rats whether Am was given alone or in combination with Furo. These data show that CuDef rats respond to Furo and Am in a manner which is similar to that of CuAdeq rats, this indicates that the sensitivity of the Na reabsorption mechanisms to inhibition by diuretics is not markedly affected by copper deficiency.

  1. Interaction of C1q and mannan-binding lectin (MBL) with C1r, C1s, MBL-associated serine proteases 1 and 2, and the MBL-associated protein MAp19

    DEFF Research Database (Denmark)

    Thiel, S; Petersen, Steen Vang; Vorup-Jensen, T

    2000-01-01

    . There is controversy as to whether MBL can utilize C1r and C1s or, inversely, whether C1q can utilize MASP-1 and 2. Serum deficient in C1r produced no complement activation in IgG-coated microwells, whereas activation was seen in mannan-coated microwells. In serum, C1r and C1s were found to be associated only with C1q...

  2. E7449: A dual inhibitor of PARP1/2 and tankyrase1/2 inhibits growth of DNA repair deficient tumors and antagonizes Wnt signaling.

    Science.gov (United States)

    McGonigle, Sharon; Chen, Zhihong; Wu, Jiayi; Chang, Paul; Kolber-Simonds, Donna; Ackermann, Karen; Twine, Natalie C; Shie, Jue-Lon; Miu, Jingzang Tao; Huang, Kuan-Chun; Moniz, George A; Nomoto, Kenichi

    2015-12-01

    Inhibition of Poly(ADP-ribose) Polymerase1 (PARP1) impairs DNA damage repair, and early generation PARP1/2 inhibitors (olaparib, niraparib, etc.) have demonstrated clinical proof of concept for cancer treatment. Here, we describe the development of the novel PARP inhibitor E7449, a potent PARP1/2 inhibitor that also inhibits PARP5a/5b, otherwise known as tankyrase1 and 2 (TNKS1 and 2), important regulators of canonical Wnt/β-catenin signaling. E7449 inhibits PARP enzymatic activity and additionally traps PARP1 onto damaged DNA; a mechanism previously shown to augment cytotoxicity. Cells deficient in DNA repair pathways beyond homologous recombination were sensitive to E7449 treatment. Chemotherapy was potentiated by E7449 and single agent had significant antitumor activity in BRCA-deficient xenografts. Additionally, E7449 inhibited Wnt/β-catenin signaling in colon cancer cell lines, likely through TNKS inhibition. Consistent with this possibility, E7449 stabilized axin and TNKS proteins resulting in β-catenin de-stabilization and significantly altered expression of Wnt target genes. Notably, hair growth mediated by Wnt signaling was inhibited by E7449. A pharmacodynamic effect of E7449 on Wnt target genes was observed in tumors, although E7449 lacked single agent antitumor activity in vivo, a finding typical for selective TNKS inhibitors. E7449 antitumor activity was increased through combination with MEK inhibition. Particularly noteworthy was the lack of toxicity, most significantly the lack of intestinal toxicity reported for other TNKS inhibitors. E7449 represents a novel dual PARP1/2 and TNKS1/2 inhibitor which has the advantage of targeting Wnt/β-catenin signaling addicted tumors. E7449 is currently in early clinical development.

  3. Marked variability in clinical presentation and outcome of patients with C1q immunodeficiency

    DEFF Research Database (Denmark)

    van Schaarenburg, Rosanne A; Schejbel, Lone; Truedsson, Lennart

    2015-01-01

    OBJECTIVE: Globally approximately 60 cases of C1q deficiency have been described with a high prevalence of Systemic Lupus Erythematosus (SLE). So far treatment has been guided by the clinical presentation rather than the underlying C1q deficiency. Recently, it was shown that C1q production can be...

  4. Evaluation of Plaque Stability of Advanced Atherosclerotic Lesions in Apo E-Deficient Mice after Treatment with the Oral Factor Xa Inhibitor Rivaroxaban

    Directory of Open Access Journals (Sweden)

    Qianxing Zhou

    2011-01-01

    Full Text Available Aim. Thrombin not only plays a central role in thrombus formation and platelet activation, but also in induction of inflammatory processes. Activated factor X (FXa is traditionally known as an important player in the coagulation cascade responsible for thrombin generation. We assessed the hypothesis that rivaroxaban, a direct FXa inhibitor, attenuates plaque progression and promotes stability of advanced atherosclerotic lesions in an in vivo model. Methods and Results. Rivaroxaban (1 or 5 mg/kg body weight/day or standard chow diet was administered for 26 weeks to apolipoprotein E-deficient mice (n=20 per group with already established atherosclerotic lesions. There was a nonsignificant reduction of lesion progression in the high-concentration group, compared to control mice. FXa inhibition with 5 mg Rivaroxaban/kg/day resulted in increased thickness of the protective fibrous caps (12.3±3.8 μm versus 10.1±2.7 μm; P<.05, as well as in fewer medial erosions and fewer lateral xanthomas, indicating plaque stabilizing properties. Real time-PCR from thoracic aortas revealed that rivaroxaban (5 mg/kg/day treatment reduced mRNA expression of inflammatory mediators, such of IL-6, TNF-α, MCP-1, and Egr-1 (P<.05. Conclusions. Chronic administration of rivaroxaban does not affect lesion progression but downregulates expression of inflammatory mediators and promotes lesion stability in apolipoprotein E-deficient mice.

  5. Combination Therapy with c-Met and Src Inhibitors Induces Caspase-Dependent Apoptosis of Merlin-Deficient Schwann Cells and Suppresses Growth of Schwannoma Cells.

    Science.gov (United States)

    Fuse, Marisa A; Plati, Stephani Klingeman; Burns, Sarah S; Dinh, Christine T; Bracho, Olena; Yan, Denise; Mittal, Rahul; Shen, Rulong; Soulakova, Julia N; Copik, Alicja J; Liu, Xue Zhong; Telischi, Fred F; Chang, Long-Sheng; Franco, Maria Clara; Fernandez-Valle, Cristina

    2017-11-01

    Neurofibromatosis type 2 (NF2) is a nervous system tumor disorder caused by inactivation of the merlin tumor suppressor encoded by the NF2 gene. Bilateral vestibular schwannomas are a diagnostic hallmark of NF2. Mainstream treatment options for NF2-associated tumors have been limited to surgery and radiotherapy; however, off-label uses of targeted molecular therapies are becoming increasingly common. Here, we investigated drugs targeting two kinases activated in NF2-associated schwannomas, c-Met and Src. We demonstrated that merlin-deficient mouse Schwann cells (MD-MSC) treated with the c-Met inhibitor, cabozantinib, or the Src kinase inhibitors, dasatinib and saracatinib, underwent a G 1 cell-cycle arrest. However, when MD-MSCs were treated with a combination of cabozantinib and saracatinib, they exhibited caspase-dependent apoptosis. The combination therapy also significantly reduced growth of MD-MSCs in an orthotopic allograft mouse model by greater than 80% of vehicle. Moreover, human vestibular schwannoma cells with NF2 mutations had a 40% decrease in cell viability when treated with cabozantinib and saracatinib together compared with the vehicle control. This study demonstrates that simultaneous inhibition of c-Met and Src signaling in MD-MSCs triggers apoptosis and reveals vulnerable pathways that could be exploited to develop NF2 therapies. Mol Cancer Ther; 16(11); 2387-98. ©2017 AACR . ©2017 American Association for Cancer Research.

  6. Structures of C1q-like proteins reveal unique features among the C1q/TNF superfamily.

    Science.gov (United States)

    Ressl, Susanne; Vu, Brandon K; Vivona, Sandro; Martinelli, David C; Südhof, Thomas C; Brunger, Axel T

    2015-04-07

    C1q-like (C1QL) -1, -2, and -3 proteins are encoded by homologous genes that are highly expressed in brain. C1QLs bind to brain-specific angiogenesis inhibitor 3 (BAI3), an adhesion-type G-protein coupled receptor that may regulate dendritic morphology by organizing actin filaments. To begin to understand the function of C1QLs, we determined high-resolution crystal structures of the globular C1q-domains of C1QL1, C1QL2, and C1QL3. Each structure is a trimer, with each protomer forming a jelly-roll fold consisting of 10 β strands. Moreover, C1QL trimers may assemble into higher-order oligomers similar to adiponectin and contain four Ca(2+)-binding sites along the trimeric symmetry axis, as well as additional surface Ca(2+)-binding sites. Mutation of Ca(2+)-coordinating residues along the trimeric symmetry axis lowered the Ca(2+)-binding affinity and protein stability. Our results reveal unique structural features of C1QLs among C1q/TNF superfamily proteins that may be associated with their specific brain functions. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Pathogenesis of peroxisomal deficiency disorders (Zellweger syndrome may be mediated by misregulation of the GABAergic system via the diazepam binding inhibitor

    Directory of Open Access Journals (Sweden)

    Breitling Rainer

    2004-03-01

    Full Text Available Abstract Background Zellweger syndrome (ZS is a fatal inherited disease caused by peroxisome biogenesis deficiency. Patients are characterized by multiple disturbances of lipid metabolism, profound hypotonia and neonatal seizures, and distinct craniofacial malformations. Median live expectancy of ZS patients is less than one year. While the molecular basis of peroxisome biogenesis and metabolism is known in considerable detail, it is unclear how peroxisome deficiency leads to the most severe neurological symptoms. Recent analysis of ZS mouse models has all but invalidated previous hypotheses. Hypothesis We suggest that a regulatory rather than a metabolic defect is responsible for the drastic impairment of brain function in ZS patients. Testing the hypothesis Using microarray analysis we identify diazepam binding inhibitor/acyl-CoA binding protein (DBI as a candidate protein that might be involved in the pathogenic mechanism of ZS. DBI has a dual role as a neuropeptide antagonist of GABA(A receptor signaling in the brain and as a regulator of lipid metabolism. Repression of DBI in ZS patients could result in an overactivation of GABAergic signaling, thus eventually leading to the characteristic hypotonia and seizures. The most important argument for a misregulation of GABA(A in ZS is, however, provided by the striking similarity between ZS and "benzodiazepine embryofetopathy", a malformation syndrome observed after the abuse of GABA(A agonists during pregnancy. Implications of the hypothesis We present a tentative mechanistic model of the effect of DBI misregulation on neuronal function that could explain some of the aspects of the pathology of Zellweger syndrome.

  8. ACE-2/Ang1-7/Mas cascade mediates ACE inhibitor, captopril, protective effects in estrogen-deficient osteoporotic rats.

    Science.gov (United States)

    Abuohashish, Hatem M; Ahmed, Mohammed M; Sabry, Dina; Khattab, Mahmoud M; Al-Rejaie, Salim S

    2017-08-01

    The local role of the renin angiotensin system (RAS) was documented recently beside its conventional systemic functions. Studies showed that the effector angiotensin II (AngII) alters bone health, while inhibition of the angiotensin converting enzyme (ACE-1) preserved these effects. The newly identified Ang1-7 exerts numerous beneficial effects opposing the AngII. Thus, the current study examines the role of Ang1-7 in mediating the osteo-preservative effects of ACEI (captopril) through the G-protein coupled Mas receptor using an ovariectomized (OVX) rat model of osteoporosis. 8 weeks after the surgical procedures, captopril was administered orally (40mgkg-1 d-1), while the specific Mas receptor blocker (A-779) was delivered at infusion rate of 400ngkg-1min-1 for 6 weeks. Bone metabolic markers were measured in serum and urine. Minerals concentrations were quantified in serum, urine and femoral bones by inductive coupled plasma mass spectroscopy (ICP-MS). Trabecular and cortical morphometry was analyzed in the right distal femurs using micro-CT. Finally, the expressions of RAS peptides, enzymes and receptors along with the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) were determined femurs heads. OVX animals markedly showed altered bone metabolism and mineralization along with disturbed bone micro-structure. Captopril significantly restored the metabolic bone bio-markers and corrected Ca2+ and P values in urine and bones of estrogen deficient rats. Moreover, the trabecular and cortical morphometric features were repaired by captopril in OVX groups. Captopril also improved the expressions of ACE-2, Ang1-7, Mas and OPG, while abolished OVX-induced up-regulation of ACE-1, AngII, Ang type 1 receptor (AT1R) and RANKL. Inhibition of Ang1-7 cascade by A-779 significantly eradicated captopril protective effects on bone metabolism, mineralization and micro-structure. A-779 also restored OVX effects on RANKL expression and ACE-1/AngII/AT1R cascade and

  9. Accelerated turnover of taste bud cells in mice deficient for the cyclin-dependent kinase inhibitor p27Kip1

    Directory of Open Access Journals (Sweden)

    Perna Marla K

    2011-04-01

    Full Text Available Abstract Background Mammalian taste buds contain several specialized cell types that coordinately respond to tastants and communicate with sensory nerves. While it has long been appreciated that these cells undergo continual turnover, little is known concerning how adequate numbers of cells are generated and maintained. The cyclin-dependent kinase inhibitor p27Kip1 has been shown to influence cell number in several developing tissues, by coordinating cell cycle exit during cell differentiation. Here, we investigated its involvement in the control of taste cell replacement by examining adult mice with targeted ablation of the p27Kip1 gene. Results Histological and morphometric analyses of fungiform and circumvallate taste buds reveal no structural differences between wild-type and p27Kip1-null mice. However, when examined in functional assays, mutants show substantial proliferative changes. In BrdU incorporation experiments, more S-phase-labeled precursors appear within circumvallate taste buds at 1 day post-injection, the earliest time point examined. After 1 week, twice as many labeled intragemmal cells are present, but numbers return to wild-type levels by 2 weeks. Mutant taste buds also contain more TUNEL-labeled cells and 50% more apoptotic bodies than wild-type controls. In normal mice, p27 Kip1 is evident in a subset of receptor and presynaptic taste cells beginning about 3 days post-injection, correlating with the onset of taste cell maturation. Loss of gene function, however, does not alter the proportions of distinct immunohistochemically-identified cell types. Conclusions p27Kip1 participates in taste cell replacement by regulating the number of precursor cells available for entry into taste buds. This is consistent with a role for the protein in timing cell cycle withdrawal in progenitor cells. The equivalence of mutant and wild-type taste buds with regard to cell number, cell types and general structure contrasts with the hyperplasia

  10. Accelerated turnover of taste bud cells in mice deficient for the cyclin-dependent kinase inhibitor p27Kip1.

    Science.gov (United States)

    Harrison, Theresa A; Smith Adams, Lorraine B; Moore, Preston D; Perna, Marla K; Sword, Jarrod D; Defoe, Dennis M

    2011-04-20

    Mammalian taste buds contain several specialized cell types that coordinately respond to tastants and communicate with sensory nerves. While it has long been appreciated that these cells undergo continual turnover, little is known concerning how adequate numbers of cells are generated and maintained. The cyclin-dependent kinase inhibitor p27Kip1 has been shown to influence cell number in several developing tissues, by coordinating cell cycle exit during cell differentiation. Here, we investigated its involvement in the control of taste cell replacement by examining adult mice with targeted ablation of the p27Kip1 gene. Histological and morphometric analyses of fungiform and circumvallate taste buds reveal no structural differences between wild-type and p27Kip1-null mice. However, when examined in functional assays, mutants show substantial proliferative changes. In BrdU incorporation experiments, more S-phase-labeled precursors appear within circumvallate taste buds at 1 day post-injection, the earliest time point examined. After 1 week, twice as many labeled intragemmal cells are present, but numbers return to wild-type levels by 2 weeks. Mutant taste buds also contain more TUNEL-labeled cells and 50% more apoptotic bodies than wild-type controls. In normal mice, p27 Kip1 is evident in a subset of receptor and presynaptic taste cells beginning about 3 days post-injection, correlating with the onset of taste cell maturation. Loss of gene function, however, does not alter the proportions of distinct immunohistochemically-identified cell types. p27Kip1 participates in taste cell replacement by regulating the number of precursor cells available for entry into taste buds. This is consistent with a role for the protein in timing cell cycle withdrawal in progenitor cells. The equivalence of mutant and wild-type taste buds with regard to cell number, cell types and general structure contrasts with the hyperplasia and tissue disruption seen in certain developing p27Kip1

  11. Specific, sensitive, precise, and rapid functional chromogenic assay of activated first complement component (C1) in plasma

    DEFF Research Database (Denmark)

    Munkvad, S; Jespersen, J; Sidelmann, Johannes Jakobsen

    1990-01-01

    We present a new functional assay for the first complement component (C1) in plasma, based on its activation by inhibition of the C1-esterase inhibitor (C1-inh) when monospecific antiserum to C1-inh is added to the plasma. After maximal activation, we can determine the concentration of activated ...

  12. Bioequivalence of a Liquid Formulation of Alpha1-Proteinase Inhibitor Compared with Prolastin®-C (Lyophilized Alpha1-PI) in Alpha1-Antitrypsin Deficiency.

    Science.gov (United States)

    Barker, Alan F; Campos, Michael A; Brantly, Mark L; Stocks, James M; Sandhaus, Robert A; Lee, Douglas; Steinmann, Kimberly; Lin, Jiang; Sorrells, Susan

    2017-12-01

    This study evaluated the bioequivalence, safety, and immunogenicity of a new liquid formulation of human plasma-derived alpha1-proteinase inhibitor, Liquid Alpha1-PI, compared with the Lyophilized Alpha1-PI formulation (Prolastin®-C), for augmentation therapy in patients with alpha1-antitrypsin deficiency (AATD). In this double-blind, randomized, 20-week crossover study, 32 subjects with AATD were randomized to receive 8 weekly infusions of 60 mg/kg of Liquid Alpha1-PI or Lyophilized Alpha1-PI. Serial blood samples were drawn for 7 days after the last dose followed by 8 weeks of the alternative treatment. The primary endpoint was bioequivalence at steady state, as measured by area under the concentration versus time curve from 0 to 7 days (AUC0-7 days) postdose using an antigenic content assay. Bioequivalence was defined as 90% confidence interval (CI) for the ratio of the geometric least squares (LS) mean of AUC0-7 days for both products within the limits of 0.80 and 1.25. Safety and immunogenicity were assessed. Mean alpha1-PI concentration versus time curves for both formulations were superimposable. Mean AUC0-7 days was 20 320 versus 19 838 mg × h/dl for Liquid Alpha1-PI and Lyophilized Alpha1-PI, respectively. The LS mean ratio of AUC0-7 days (90% CI) for Liquid Alpha1-PI versus Lyophilized Alpha1-PI was 1.05 (1.03-1.08), indicating bioequivalence. Liquid Alpha1-PI was well tolerated and adverse events were consistent with Lyophilized Alpha1-PI. Immunogenicity to either product was not detected. In conclusion, Liquid Alpha1-PI is bioequivalent to Lyophilized Alpha1-PI, with a similar safety profile. The liquid formulation would eliminate the need for reconstitution and shorten preparation time for patients receiving augmentation therapy for AATD.

  13. α1-Proteinase inhibitor (human) in the treatment of hereditary emphysema secondary to α1-antitrypsin deficiency: number and costs of years of life gained.

    Science.gov (United States)

    Sclar, David Alexander; Evans, Marc A; Robison, Linda M; Skaer, Tracy L

    2012-05-01

    α(1)-Antitrypsin deficiency (α-ATD) is a disorder inherited in an autosomal recessive pattern, with co-dominant alleles known as the protease inhibitor system (Pi). The main function of α(1)-antitrypsin (α-AT) is to protect the lungs against a powerful elastase released from neutrophil leucocytes. α-ATD typically presents with a serum α-AT level of effective in raising serum α-AT levels to desired levels (>80 mg/dL), with few, if any, adverse effects. The present study was designed to discern the number of years of life gained, and the expense per year of life gained, associated with use of α-AT augmentation therapy (α(1)-proteinase inhibitor [human]), relative to 'no therapeutic intervention' in persons with α-ATD. Monte Carlo simulation (MCS) was used to: (i) estimate the number of years of life gained; and (ii) estimate the health service expenditures per year of life gained for persons receiving, or not receiving, α-AT augmentation therapy. MCS afforded a decision-analytical framework parameterized with both stochastic (random) and deterministic (fixed) components, and yielded a fiscal risk-profile for each simulated cohort of interest (eight total: by sex, smoking status [non-smoker; or past use (smoker)]; and use of α-AT augmentation therapy). The stochastic components employed in the present inquiry were: (i) age-specific body weight, and height; (ii) age-specific mortality; and (iii) the probability distribution for receipt of a lung transplant, as a function of FEV(1). The deterministic components employed in the present inquiry were: (i) age in years for the simulated cohort; (ii) outlays for α-AT augmentation therapy; (iii) health service expenditures associated with receipt of a lung transplant; (iv) annual decline in FEV(1); (v) percent predicted FEV(1); (vi) initiation of α-AT augmentation therapy as a function of percent predicted FEV(1); (vii) need for a lung transplant as a function of percent predicted FEV(1); (viii) annual rate of

  14. Emerging and novel functions of complement protein C1q

    Directory of Open Access Journals (Sweden)

    Lubna eKouser

    2015-06-01

    Full Text Available Complement protein C1q, the recognition subcomponent of the classical pathway, performs a diverse range of complement and non-complement functions. It can bind various ligands derived from self, non-self and altered-self and modulate the functions of immune and non-immune cells including dendritic cells and microglia. C1q involvement in the clearance of apoptotic cells and subsequent B cell tolerance is more established now. Recent evidence appears to suggest that C1q plays an important role in pregnancy where its deficiency and dysregulation can have adverse effects, leading to preeclampsia, missed abortion, miscarriage or spontaneous loss and various infections. C1q is also produced locally in the Central Nervous System, and has a protective role against pathogens and possible inflammatory functions while interacting with aggregated proteins leading to neurodegenerative diseases. C1q role in synaptic pruning, and thus CNS development, anti-cancer effects as an immune surveillance molecule, and possibly in ageing are areas of extensive research.

  15. Cell surface expression and function of the macromolecular C1 complex on the surface of human monocytes

    Directory of Open Access Journals (Sweden)

    Kinga K Hosszu

    2012-03-01

    Full Text Available The synthesis of the subunits of the C1 complex (C1q, C1s, C1r, and its regulator C1 inhibitor (C1-Inh by human monocytes has been previously established. However, surface expression of these molecules by monocytes has not been shown. Using flow cytometry and antigen-capture ELISA, we show here for the first time that, in addition to C1q, PB monocytes and the monocyte-derived U937 cells express C1s and C1r, as well as Factor B and C1-Inh on their surface. C1s and C1r immunoprecipitated with C1q, suggesting that at least some of the C1q on these cells is part of the C1 complex. Furthermore, the C1 complex on U937 cells was able to trigger complement activation via the classical pathway. The presence of C1-Inh may ensure that an unwarranted autoactivation of the C1 complex does not take place. Since C1-Inh closely monitors the activation of the C1 complex in a sterile or infectious inflammatory environment, further elucidation of the role of C1 complex is crucial to dissect its function in monocyte, DC and T cell activities, and its implications in host defense and tolerance.

  16. Genetic, molecular and functional analyses of complement factor I deficiency

    DEFF Research Database (Denmark)

    Nilsson, S.C.; Trouw, L.A.; Renault, N.

    2009-01-01

    Complete deficiency of complement inhibitor factor I (FI) results in secondary complement deficiency due to uncontrolled spontaneous alternative pathway activation leading to susceptibility to infections. Current genetic examination of two patients with near complete FI deficiency and three patie...

  17. Limited proteolysis of beta 2-microglobulin at Lys-58 by complement component C1s

    DEFF Research Database (Denmark)

    Nissen, Mogens Holst; Roepstorff, P; Thim, L

    1990-01-01

    a modified form of beta 2-microglobulin with a two-chain structure. The C-terminal Lys-58 in the A chain is highly susceptible to removal by a carboxypeptidase-B-like activity causing the formation of des-Lys58-beta 2-microglobulin. This is the first demonstration of a noncomplement protein substrate......We have now demonstrated that activated complement component C1s cleaves beta 2-microglobulin at the position identical to that at which beta 2-microglobulin is cleaved in serum of patients suffering from lung cancer. The main cleavage is in the disulphide loop C-terminal to Lys-58, generating...... for the proteolytic activity of C1s. The C1s-induced cleavage of beta 2-microglobulin can be inhibited in the presence of C1 esterase inhibitor, demonstrating a regulatory function of C1 esterase inhibitor in the C1s-induced cleavage of beta 2-microglobulin....

  18. Alcohol binding in the C1 (C1A + C1B) domain of protein kinase C epsilon

    Science.gov (United States)

    Pany, Satyabrata; Das, Joydip

    2015-01-01

    Background Alcohol regulates the expression and function of protein kinase C epsilon (PKCε). In a previous study we identified an alcohol binding site in the C1B, one of the twin C1 subdomains of PKCε. Methods In this study, we investigated alcohol binding in the entire C1 domain (combined C1A and C1B) of PKCε. Fluorescent phorbol ester, SAPD and fluorescent diacylglycerol (DAG) analog, dansyl-DAG were used to study the effect of ethanol, butanol, and octanol on the ligand binding using fluorescence resonance energy transfer (FRET). To identify alcohol binding site(s), PKCεC1 was photolabeled with 3-azibutanol and 3-azioctanol, and analyzed by mass spectrometry. The effects of alcohols and the azialcohols on PKCε were studied in NG108-15 cells. Results In the presence of alcohol, SAPD and dansyl-DAG showed different extent of FRET, indicating differential effects of alcohol on the C1A and C1B subdomains. Effects of alcohols and azialcohols on PKCε in NG108-15 cells were comparable. Azialcohols labeled Tyr-176 of C1A and Tyr-250 of C1B. Inspection of the model structure of PKCεC1 reveals that these residues are 40 Å apart from each other indicating that these residues form two different alcohol binding sites. Conclusions The present results provide evidence for the presence of multiple alcohol-binding sites on PKCε and underscore the importance of targeting this PKC isoform in developing alcohol antagonists. PMID:26210390

  19. Clinical utility of alpha-1 proteinase inhibitor in the management of adult patients with severe alpha-1 antitrypsin deficiency: a review of the current literature

    Directory of Open Access Journals (Sweden)

    Parr DG

    2017-07-01

    Full Text Available David G Parr, Beatriz Lara Department of Respiratory Medicine, Cardio-Respiratory Division, University Hospital Coventry, Coventry, UK Abstract: Alpha-1 antitrypsin (AAT functions primarily to inhibit neutrophil elastase, and its deficiency predisposes individuals to the development of chronic obstructive pulmonary disease (COPD. The putative protective serum concentration is generally considered to be above a threshold of 11 µM/L, and therapeutic augmentation of AAT above this value is believed to retard the progression of emphysema. Several AAT preparations, all derived from human donor plasma, have been commercialized since approval by the US Food and Drug Administration (FDA in 1987. Biochemical efficacy has been demonstrated by augmentation of pulmonary antiprotease activity, but demonstration of clinical efficacy in randomized, placebo-controlled trials has been hampered by the practical difficulties of performing conventional studies in a rare disease with a relatively long natural history. Computed tomography has been applied to measure lung density as a more specific and sensitive surrogate outcome measure of emphysema than physiologic indices, such as forced expiratory volume in 1 second, and studies consistently show a therapeutic reduction in the rate of lung density decline. However, convincing evidence of benefit using traditional clinical measures remains elusive. Intravenous administration of AAT at a dose of 60 mg/kg/week is the commonest regime in use and has well-documented safety and tolerability. International and national guidelines on the management of AAT deficiency recommend intravenous augmentation therapy to supplement optimized usual COPD treatment in patients with severe deficiency and evidence of lung function impairment. Keywords: alpha-1 antitrypsin deficiency, augmentation or replacement therapy, computed tomography, emphysema, COPD

  20. The HDAC inhibitor SAHA improves depressive-like behavior of CRTC1-deficient mice: possible relevance for treatment-resistant depression

    KAUST Repository

    Meylan, Elsa M.

    2016-03-09

    Major depression is a highly complex disabling psychiatric disorder affecting millions of people worldwide. Despite the availability of several classes of antidepressants, a substantial percentage of patients are unresponsive to these medications. A better understanding of the neurobiology of depression and the mechanisms underlying antidepressant response is thus critically needed. We previously reported that mice lacking CREB-regulated transcription coactivator 1 (CRTC1) exhibit a depressive-like phenotype and a blunted antidepressant response to the selective serotonin reuptake inhibitor fluoxetine. In this study, we similarly show that Crtc1‒/‒ mice are resistant to the antidepressant effect of chronic desipramine in a behavioral despair paradigm. Supporting the blunted response to this tricyclic antidepressant, we found that desipramine does not significantly increase the expression of Bdnf and Nr4a1-3 in the hippocampus and prefrontal cortex of Crtc1‒/‒ mice. Epigenetic regulation of neuroplasticity gene expression has been associated with depression and antidepressant response, and histone deacetylase (HDAC) inhibitors have been shown to have antidepressant-like properties. Here, we show that unlike conventional antidepressants, chronic systemic administration of the HDAC inhibitor SAHA partially rescues the depressive-like behavior of Crtc1‒/‒ mice. This behavioral effect is accompanied by an increased expression of Bdnf, but not Nr4a1-3, in the prefrontal cortex of these mice, suggesting that this epigenetic intervention restores the expression of a subset of genes by acting downstream of CRTC1. These findings suggest that CRTC1 alterations may be associated with treatment-resistant depression, and support the interesting possibility that targeting HDACs may be a useful therapeutic strategy in antidepressant development.

  1. On orientifolds of c=1 orbifolds

    Energy Technology Data Exchange (ETDEWEB)

    Dijkstra, T.P.T. [NIKHEF, PO Box 41882, 1009 DB Amsterdam (Netherlands); Gato-Rivera, B. [NIKHEF, PO Box 41882, 1009 DB Amsterdam (Netherlands); Riccioni, F. [NIKHEF, PO Box 41882, 1009 DB Amsterdam (Netherlands)]. E-mail: f.riccioni@damtp.cam.ac.uk; Schellekens, A.N. [NIKHEF, PO Box 41882, 1009 DB Amsterdam (Netherlands)

    2004-10-25

    The aim of this paper is to study orientifolds of c=1 conformal field theories. A systematic analysis of the allowed orientifold projections for c=1 orbifold conformal field theories is given. We compare the Klein bottle amplitudes obtained at rational points with the orientifold projections that we claim to be consistent for any value of the orbifold radius. We show that the recently obtained Klein bottle amplitudes corresponding to exceptional modular invariants, describing bosonic string theories at fractional square radius, are also in agreement with those orientifold projections.

  2. Anti-C1q autoantibodies

    NARCIS (Netherlands)

    Kallenberg, Cees G. M.

    Autoantibodies to complement components are associated with various diseases. Anti-C1q antibodies are present in all patients with hypocomplementemic urticarial vasculitis, but also, with varying prevalence, in other conditions. In SLE, these antibodies are neither sensitive nor specific for this

  3. CC-115, a dual inhibitor of mTOR kinase and DNA-PK, blocks DNA damage repair pathways and selectively inhibits ATM-deficient cell growth in vitro.

    Science.gov (United States)

    Tsuji, Toshiya; Sapinoso, Lisa M; Tran, Tam; Gaffney, Bonny; Wong, Lilly; Sankar, Sabita; Raymon, Heather K; Mortensen, Deborah S; Xu, Shuichan

    2017-09-26

    CC-115, a selective dual inhibitor of the mammalian target of rapamycin (mTOR) kinase and DNA-dependent protein kinase (DNA-PK), is undergoing Phase 1 clinical studies. Here we report the characterization of DNA-PK inhibitory activity of CC-115 in cancer cell lines. CC-115 inhibits auto-phosphorylation of the catalytic subunit of DNA-PK (DNA-PKcs) at the S2056 site (pDNA-PK S2056), leading to blockade of DNA-PK-mediated non-homologous end joining (NHEJ). CC-115 also indirectly reduces the phosphorylation of ataxia-telangiectasia mutated kinase (ATM) at S1981 and its substrates as well as homologous recombination (HR). The mTOR kinase and DNA-PK inhibitory activity of CC-115 leads to not only potent anti-tumor activity against a large panel of hematopoietic and solid cancer cell lines but also strong induction of apoptosis in a subset of cancer lines. Mechanistically, CC-115 prevents NHEJ by inhibiting the dissociation of DNA-PKcs, X-ray repair cross-complementing protein 4 (XRCC4), and DNA ligase IV from DNA ends. CC-115 inhibits colony formation of ATM-deficient cells more potently than ATM-proficient cells, indicating that inhibition of DNA-PK is synthetically lethal with the loss of functional ATM. In conclusion, CC-115 inhibits both mTOR signaling and NHEJ and HR by direct inhibition of DNA-PK. The mechanistic data not only provide selection of potential pharmacodynamic (PD) markers but also support CC-115 clinical development in patients with ATM-deficient tumors.

  4. ACAT inhibitor pactimibe sulfate (CS-505) reduces and stabilizes atherosclerotic lesions by cholesterol-lowering and direct effects in apolipoprotein E-deficient mice.

    Science.gov (United States)

    Terasaka, Naoki; Miyazaki, Atsuhiro; Kasanuki, Naomi; Ito, Kayoko; Ubukata, Naoko; Koieyama, Tadashi; Kitayama, Ken; Tanimoto, Tatsuo; Maeda, Naoyuki; Inaba, Toshimori

    2007-02-01

    The objective of the present study was to determine whether a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, pactimibe sulfate (CS-505), could reduce atherosclerotic lesions beyond and independent of the reduction achieved by cholesterol lowering alone from two different types of lesions. (1) Early lesion model. Twelve-week-old apolipoprotein E (apoE)(-/-) mice were treated with 0.03 or 0.1% (w/w) CS-505, 0.1 or 0.3% avasimibe (CI-1011), or 3% cholestyramine for 12 weeks. Each treatment significantly reduced plasma cholesterol by a similar degree (43-48%). The antiatherosclerotic activity of 0.1% CS-505, however, was more efficacious than the effects of the other treatments (90% versus 40-50%). (2) Advanced lesion model. Twenty-four-week-old apoE(-/-) mice were treated with 0.03 or 0.1% CS-505 or 0.1% CI-1011 for 12 weeks. CS-505 at 0.1% revealed enhanced lesion reduction compared with 0.1% CI-1011 (77% versus 54%), whereas the plasma cholesterol-lowering effect of 0.1% CS-505 was almost the same as that of 0.1% CI-1011. Furthermore, immunohistochemical analysis demonstrated that CS-505 significantly reduced the number of macrophages and expression of matrix metalloproteinase (MMP)-2, MMP-9, and MMP-13. These data indicate that CS-505 can reduce and stabilize atherosclerotic lesions. This antiatherosclerotic activity is exerted via both cholesterol lowering and direct ACAT inhibition in plaque macrophages.

  5. Complement protein C1q induces maturation of human dendritic cells.

    Science.gov (United States)

    Csomor, Eszter; Bajtay, Zsuzsa; Sándor, Noémi; Kristóf, Katalin; Arlaud, Gérard J; Thiel, Steffen; Erdei, Anna

    2007-07-01

    Maturation of dendritic cells (DCs) is known to be induced by several stimuli, including microbial products, inflammatory cytokines and immobilized IgG, as demonstrated recently. Since immune complexes formed in vivo also contain C1q, moreover apoptotic cells and several pathogens fix C1q in the absence of antibodies, we undertook to investigate whether this complement protein has an impact on various functions of human DCs. Maturation of monocyte-derived immature DCs (imMDCs) cultured on immobilized C1q was followed by monitoring expression of CD80, CD83, CD86, MHCII and CCR7. The functional activity of the cells was assessed by measuring cytokine secretion and their ability to activate allogeneic T lymphocytes. Cytokine production by T cells co-cultured with C1q-matured DCs was also investigated. C1q, but not the structurally related mannose-binding lectin was found to bind to imMDC in a dose-dependent manner and induced NF-kappaB translocation to the nucleus. Immobilized C1q induced maturation of MDCs and enhanced secretion of IL-12 and TNF-alpha, moreover, elevated their T-cell stimulating capacity. As IFN-gamma levels were increased in supernatants of MDC-T cell co-cultures, our data suggest that C1q-induced DC maturation generates a Th1-type response. Interestingly, IL-10 levels were elevated by C1q-treated MDCs but not in the supernatant of their co-cultures with allogeneic T cells. Taken together, these results indicate that C1q-opsonized antigens may play a role in the induction and regulation of immune response. Moreover our data are relevant in view of the role of C1q in removal of apoptotic cells and the association between C1q-deficiency and autoimmunity.

  6. Analysis of healthy cohorts for single nucleotide polymorphisms in C1q gene cluster

    Directory of Open Access Journals (Sweden)

    MARIA A. RADANOVA

    2015-12-01

    Full Text Available C1q is the first component of the classical pathway of complement activation. The coding region for C1q is localized on chromosome 1p34.1–36.3. Mutations or single nucleotide polymorphisms (SNPs in C1q gene cluster can cause developing of Systemic lupus erythematosus (SLE because of C1q deficiency or other unknown reason. We selected five SNPs located in 7.121 kbp region on chromosome 1, which were previously associated with SLE and/or low C1q level, but not causing C1q deficiency and analyzed them in terms of allele frequencies and genotype distribution in comparison with Hispanic, Asian, African and other Caucasian cohorts. These SNPs were: rs587585, rs292001, rs172378, rs294179 and rs631090. One hundred eighty five healthy Bulgarian volunteers were genotyped for the selected five C1q SNPs by quantative real-time PCR methods. International HapMap Project has been used for information about genotype distribution and allele frequencies of the five SNPs in, Hispanics, Asians, Africans and others Caucasian cohorts. Bulgarian healthy volunteers and another pooled Caucasian cohort had similar frequencies of genotypes and alleles of rs587585, rs292001, rs294179 and rs631090 SNPs. Nevertheless, genotype AA of rs172378 was significantly overrepresented in Bulgarians when compared to other healthy Caucasians from USA and UK (60% vs 31%. Genotype distribution of rs172378 in Bulgarians was similar to Greek-Cyriot Caucasians. For all Caucasians the major allele of rs172378 was A. This is the first study analyzing the allele frequencies and genotype distribution of C1q gene cluster SNPs in Bulgarian healthy population.

  7. Iodine Deficiency

    NARCIS (Netherlands)

    Zimmermann, M.B.

    2009-01-01

    Iodine deficiency has multiple adverse effects in humans, termed iodine deficiency disorders, due to inadequate thyroid hormone production. Globally, it is estimated that 2 billion individuals have an insufficient iodine intake, and South Asia and sub-Saharan Africa are particularly affected.

  8. Human and pneumococcal cell surface glyceraldehyde-3-phosphate dehydrogenase (GAPDH) proteins are both ligands of human C1q protein.

    Science.gov (United States)

    Terrasse, Rémi; Tacnet-Delorme, Pascale; Moriscot, Christine; Pérard, Julien; Schoehn, Guy; Vernet, Thierry; Thielens, Nicole M; Di Guilmi, Anne Marie; Frachet, Philippe

    2012-12-14

    C1q, a key component of the classical complement pathway, is a major player in the response to microbial infection and has been shown to detect noxious altered-self substances such as apoptotic cells. In this work, using complementary experimental approaches, we identified the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a C1q partner when exposed at the surface of human pathogenic bacteria Streptococcus pneumoniae and human apoptotic cells. The membrane-associated GAPDH on HeLa cells bound the globular regions of C1q as demonstrated by pulldown and cell surface co-localization experiments. Pneumococcal strains deficient in surface-exposed GAPDH harbored a decreased level of C1q recognition when compared with the wild-type strains. Both recombinant human and pneumococcal GAPDHs interacted avidly with C1q as measured by surface plasmon resonance experiments (K(D) = 0.34-2.17 nm). In addition, GAPDH-C1q complexes were observed by transmission electron microscopy after cross-linking. The purified pneumococcal GAPDH protein activated C1 in an in vitro assay unlike the human form. Deposition of C1q, C3b, and C4b from human serum at the surface of pneumococcal cells was dependent on the presence of surface-exposed GAPDH. This ability of C1q to sense both human and bacterial GAPDHs sheds new insights on the role of this important defense collagen molecule in modulating the immune response.

  9. Analysis list: Nr3c1 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Nr3c1 Adipocyte,Blood,Breast,Embryo,Embryonic fibroblast,Liver,Neural + mm9 http://...dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Nr3c1.1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Nr3c1.5.tsv http:...//dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Nr3c1.10.tsv http://dbarchive.bioscie...ncedbc.jp/kyushu-u/mm9/colo/Nr3c1.Adipocyte.tsv,http://dbarchive.biosciencedbc.jp.../kyushu-u/mm9/colo/Nr3c1.Blood.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Nr3c1.Breast.tsv,http:

  10. Analysis list: NR3C1 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available NR3C1 Blood,Bone,Breast,Liver,Others,Prostate,Uterus + hg19 http://dbarchive.bioscience...dbc.jp/kyushu-u/hg19/target/NR3C1.1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/NR3C1.5.t...sv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/NR3C1.10.tsv http://dbarchive.biosciencedbc.jp/kyu...shu-u/hg19/colo/NR3C1.Blood.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/c...olo/NR3C1.Bone.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/NR3C1.Breast.tsv,http://dbarchive.bioscience

  11. [Acquired coagulant factor inhibitors].

    Science.gov (United States)

    Nogami, Keiji

    2015-02-01

    Acquired coagulation factor inhibitors are an autoimmune disease causing bleeding symptoms due to decreases in the corresponding factor (s) which result from the appearance of autoantibodies against coagulation factors (inhibitor). This disease is quite different from congenital coagulation factor deficiencies based on genetic abnormalities. In recent years, cases with this disease have been increasing, and most have anti-factor VIII autoantibodies. The breakdown of the immune control mechanism is speculated to cause this disease since it is common in the elderly, but the pathology and pathogenesis are presently unclear. We herein describe the pathology and pathogenesis of factor VIII and factor V inhibitors. Characterization of these inhibitors leads to further analysis of the coagulation process and the activation mechanisms of clotting factors. In the future, with the development of new clotting examination method (s), we anticipate that further novel findings will be obtained in this field through inhibitor analysis. In addition, detailed elucidation of the coagulation inhibitory mechanism possibly leading to hemostatic treatment strategies for acquired coagulation factor disorders will be developed.

  12. Recombinant human C1-inhibitor prevents acute antibody-mediated rejection in alloimmunized baboons

    NARCIS (Netherlands)

    Tillou, Xavier; Poirier, Nicolas; Le Bas-Bernardet, Stephanie; Hervouet, Jeremy; Minault, David; Renaudin, Karine; Vistoli, Fabio; Karam, Georges; Daha, Mohamed; Soulillou, Jean Paul; Blancho, Gilles

    Acute antibody-mediated rejection is an unsolved issue in transplantation, especially in the context of pretransplant immunization. The deleterious effect of preformed cytotoxic anti-HLA antibodies through complement activation is well proven, but very little is known concerning complement blockade

  13. C1 inhibitor treatment improves host defense in pneumococcal meningitis in rats and mice

    NARCIS (Netherlands)

    Zwijnenburg, Petra J. G.; van der Poll, Tom; Florquin, Sandrine; Polfliet, Machteld M. J.; van den Berg, Timo K.; Dijkstra, Christine D.; Roord, John J.; Hack, C. Erik; van Furth, A. Marceline

    2007-01-01

    In spite of antibiotic treatment, pneumococcal meningitis continues to be associated with significant morbidity and mortality. The complement system is a key component of innate immunity against invading pathogens. However, activation of complement is also involved in tissue damage, and complement

  14. Anti-C1q antibodies in systemic lupus erythematosus

    DEFF Research Database (Denmark)

    Orbai, A-M; Truedsson, L; Sturfelt, G

    2015-01-01

    OBJECTIVE: Anti-C1q has been associated with systemic lupus erythematosus (SLE) and lupus nephritis in previous studies. We studied anti-C1q specificity for SLE (vs rheumatic disease controls) and the association with SLE manifestations in an international multicenter study. METHODS: Information...... in combination with anti-dsDNA and low complement was the strongest serological association with renal involvement. These data support the usefulness of anti-C1q in SLE, especially in lupus nephritis....

  15. Direct interaction between CD91 and C1q

    DEFF Research Database (Denmark)

    Duus, Karen; Hansen, Erik W; Tacnet, Pascale

    2010-01-01

    . C1q binding to monocytes was shown to be correlated with CD91 expression and could be inhibited by the CD91 chaperone, receptor-associated protein. We also report data showing a direct interaction between CD91 and C1q. The interaction was investigated using various protein interaction assays....... A direct interaction between purified C1q and CD91 was observed both by ELISA and a surface plasmon resonance assay, with either C1q or CD91 immobilized. The interaction showed characteristics of specificity because it was time-dependent, saturable and could be inhibited by known ligands of both CD91 and C...

  16. Frequency and epitope specificity of anti-factor VIII C1 domain antibodies in acquired and congenital hemophilia A.

    Science.gov (United States)

    Kahle, Joerg; Orlowski, Aleksander; Stichel, Diana; Healey, John F; Parker, Ernest T; Jacquemin, Marc; Krause, Manuela; Tiede, Andreas; Schwabe, Dirk; Lollar, Pete; Königs, Christoph

    2017-08-10

    Several studies showed that neutralizing anti-factor VIII (anti-fVIII) antibodies (inhibitors) in patients with acquired hemophilia A (AHA) and congenital hemophilia A (HA) are primarily directed to the A2 and C2 domains. In this study, the frequency and epitope specificity of anti-C1 antibodies were analyzed in acquired and congenital hemophilia inhibitor patients (n = 178). The domain specificity of antibodies was studied by homolog-scanning mutagenesis (HSM) with single human domain human/porcine fVIII proteins and antibody binding to human A2, C1, and C2 domains presented as human serum albumin (HSA) fusion proteins. The analysis with HSA-fVIII domain proteins confirmed the results of the HSM approach but resulted in higher detection levels. The higher detection levels with HSA-fVIII domain proteins are a result of antibody cross-reactivity with human and porcine fVIII leading to false-negative HSM results. Overall, A2-, C1-, and C2-specific antibodies were detected in 23%, 78%, and 68% of patients with AHA (n = 115) and in 52%, 57%, and 81% of HA inhibitor patients (n = 63). Competitive binding of the human monoclonal antibody (mAb) LE2E9 revealed overlapping epitopes with murine C1-specific group A mAbs including 2A9. Mutational analyses identified distinct crucial binding residues for LE2E9 (E2066) and 2A9 (F2068) that are also recognized by anti-C1 antibodies present in patients with hemophilia. A strong contribution of LE2E9- and 2A9-like antibodies was particularly observed in patients with AHA. Overall, our study demonstrates that the C1 domain, in addition to the A2 and C2 domains, contributes significantly to the humoral anti-fVIII immune response in acquired and congenital hemophilia inhibitor patients. © 2017 by The American Society of Hematology.

  17. Cyclic nucleotide phosphodiesterase PDE1C1 in human cardiac myocytes.

    Science.gov (United States)

    Vandeput, Fabrice; Wolda, Sharon L; Krall, Judith; Hambleton, Ryan; Uher, Lothar; McCaw, Kim N; Radwanski, Przemyslaw B; Florio, Vincent; Movsesian, Matthew A

    2007-11-09

    Isoforms in the PDE1 family of cyclic nucleotide phosphodiesterases were recently found to comprise a significant portion of the cGMP-inhibited cAMP hydrolytic activity in human hearts. We examined the expression of PDE1 isoforms in human myocardium, characterized their catalytic activity, and quantified their contribution to cAMP hydrolytic and cGMP hydrolytic activity in subcellular fractions of this tissue. Western blotting with isoform-selective anti-PDE1 monoclonal antibodies showed PDE1C1 to be the principal isoform expressed in human myocardium. Immunohistochemical analysis showed that PDE1C1 is distributed along the Z-lines and M-lines of cardiac myocytes in a striated pattern that differs from that of the other major dual-specificity cyclic nucleotide phosphodiesterase in human myocardium, PDE3A. Most of the PDE1C1 activity was recovered in soluble fractions of human myocardium. It binds both cAMP and cGMP with K(m) values of approximately 1 microm and hydrolyzes both substrates with similar catalytic rates. PDE1C1 activity in subcellular fractions was quantified using a new PDE1-selective inhibitor, IC295. At substrate concentrations of 0.1 microm, PDE1C1 constitutes the great majority of cAMP hydrolytic and cGMP hydrolytic activity in soluble fractions and the majority of cGMP hydrolytic activity in microsomal fractions, whereas PDE3 constitutes the majority of cAMP hydrolytic activity in microsomal fractions. These results indicate that PDE1C1 is expressed at high levels in human cardiac myocytes with an intracellular distribution distinct from that of PDE3A and that it may have a role in the integration of cGMP-, cAMP- and Ca(2+)-mediated signaling in these cells.

  18. 17 CFR 240.16c-1 - Brokers.

    Science.gov (United States)

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Brokers. 240.16c-1 Section 240... Act of 1934 Exemption of Certain Transactions from Section 16(c) § 240.16c-1 Brokers. Any transaction... a broker of an order for an account in which the broker has no direct or indirect interest. ...

  19. Iron deficiency

    DEFF Research Database (Denmark)

    Schou, Morten; Bosselmann, Helle; Gaborit, Freja

    2015-01-01

    BACKGROUND: Both iron deficiency (ID) and cardiovascular biomarkers are associated with a poor outcome in heart failure (HF). The relationship between different cardiovascular biomarkers and ID is unknown, and the true prevalence of ID in an outpatient HF clinic is probably overlooked. OBJECTIVES.......043). CONCLUSION: ID is frequent in an outpatient HF clinic. ID is not associated with cardiovascular biomarkers after adjustment for traditional confounders. Inflammation, but not neurohormonal activation is associated with ID in systolic HF. Further studies are needed to understand iron metabolism in elderly HF...

  20. 17 CFR 270.3c-1 - Definition of beneficial ownership for certain 3(c)(1) funds.

    Science.gov (United States)

    2010-04-01

    ... Covered Company, the value of all securities owned by the Covered Company of all issuers that are Section... AND EXCHANGE COMMISSION (CONTINUED) RULES AND REGULATIONS, INVESTMENT COMPANY ACT OF 1940 § 270.3c-1... Covered Company means a company that is an investment company, a Section 3(c)(1) Company or a Section 3(c...

  1. VLCAD deficiency

    DEFF Research Database (Denmark)

    Boneh, A; Andresen, B S; Gregersen, N

    2006-01-01

    We diagnosed six newborn babies with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) through newborn screening in three years in Victoria (prevalence rate: 1:31,500). We identified seven known and two new mutations in our patients (2/6 homozygotes; 4/6 compound heterozygotes). Blood...... samples taken at age 48-72 h were diagnostic whereas repeat samples at an older age were normal in 4/6 babies. Urine analysis was normal in 5/5. We conclude that the timing of blood sampling for newborn screening is important and that it is important to perform mutation analysis to avoid false......-negative diagnoses of VLCADD in asymptomatic newborn babies. In view of the emerging genotype-phenotype correlation in this disorder, the information derived from mutational analysis can be helpful in designing the appropriate follow-up and therapeutic regime for these patients....

  2. Unilateral extended suboccipital approach for a C1 dumbbell schwanoma

    Directory of Open Access Journals (Sweden)

    Gorgan R.M.

    2015-03-01

    Full Text Available Craniovertebral junction tumors represent a complex pathology carrying a high risk of injuring the vertebral artery and the lower cranial nerves. Dumbbell C1- C2 schannomas are very rare tumors in this location. We present a case of a 66 years old male accepted for left laterocervical localized pain, headache and vertigo, with a large C1 dumbbell schwannoma extending in lateral over the C1 arch and displacing the C3 segment of the vertebral artery superiorly and anteriorly. Complete removal of the tumor was achieved using a far lateral approach. The approach is discussed with focus on the vertebral artery anatomy as the approach should give enough space to gain control of the artery without creating instability. Safe removal of C1 nerve root schwanomas can be achieved even if they compress and displace the vertebral artery by entering a fibrous tissue plane between the tumor and the vertebral artery.

  3. [Development of new antiatherosclerotic agents--ACAT inhibitors and CETP inhibitors].

    Science.gov (United States)

    Miyazaki, A; Horiuchi, S

    1999-12-01

    Development of new antiatherosclerotic agents were reviewed focusing on ACAT inhibitors and CETP inhibitors. ACAT inhibitors enhance intracellular degradation of VLDL in hepatocytes. Cholesterol absorption in small intestine is inhibited by ACAT inhibitors. Thus, ACAT inhibitors reduce plasma cholesterol levels. In atherosclerotic lesions, ACAT inhibitors suppress foam cell formation (cholesteryl ester accumulation) in macrophages. Since ACAT inhibitors have multiple anti-atherogenic effects, they are considered future drugs controlling hypercholesterolemia and atherosclerosis. CETP inhibitors are expected to increase HDL and decrease LDL. Although the patients with CETP deficiency show high level of HDL, recent studies showed that they are not necessarily resistant to atherosclerosis. The strategy to inhibit CETP for suppressing atherosclerosis has not been established.

  4. Carnitine deficiency.

    Science.gov (United States)

    Răşanu, T; Mehedinţi-Hâncu, Mihaela; Alexianu, Marilena; Mehedinţi, T; Gheorghe, Emma; Damian, Irene

    2012-01-01

    We present the case of a female patient, aged 12 years, with fatigability and exertional myalgias, progressively developed within the last two years. Negative family history, as well as negative personal medical history, were found. At physical examination, short stature, proximal muscle weakness and mild hepatomegaly were noted. Urine ketones level was slightly decreased, serum transaminases, creatine kinase and lactate dehydrogenase levels were increased. Electromyographical examination showed a myopathic non-specific pattern. Deltoid muscle biopsy revealed: small, clear vesicles are present on Hematoxylin-Eosin and modified Gömöri trichrome stains; modified Gömöri trichrome stain also revealed muscle fibers (especially type I of muscle fibers) having mild to moderate mitochondrial proliferation (red rim and speckled sarcoplasm). The lipid storage has been well demonstrated by Sudan Black stain, which revealed small lipid droplets in type I muscle fibers. Abnormal internal architecture with a punctate pattern was showed by adenine dinucleotide tetrazolium reductase and succinate dehydrogenase stains. Electron microscopy showed small inter-myofibrillar accumulations of round, amorphous, homogeneous acellular substances that are not membrane bounded. These features indicate that these are neutral fat (lipid) droplets. Subsarcolemmal accumulations of mitochondria were also revealed. The differential diagnosis of this case is discussed, and the up to date general data concerning carnitine deficiency are presented. The aim of our case-report is to emphasize the role of muscle biopsy in carnitine deficiency, as well as to remind the necessity of keeping in mind such metabolic disorders when doing the differential diagnostic of a muscular weakness.

  5. 26 CFR 1.1402(c)-1 - Trade or business.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 12 2010-04-01 2010-04-01 false Trade or business. 1.1402(c)-1 Section 1.1402(c... (CONTINUED) INCOME TAXES Tax on Self-Employment Income § 1.1402(c)-1 Trade or business. In order for an individual to have net earnings from self-employment, he must carry on a trade or business, either as an...

  6. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Research Home / < Back To Health Topics / Iron-Deficiency Anemia Iron-Deficiency Anemia Leer en español What Is Iron-deficiency anemia ... cases, surgery may be advised. Treatments for Severe Iron-Deficiency Anemia Blood Transfusion If your iron-deficiency anemia is ...

  7. Structure and function of complement protein C1q and its role in the development of autoimmune diseases

    Directory of Open Access Journals (Sweden)

    Katarzyna Smykał-Jankowiak

    2009-09-01

    Full Text Available Complement plays an important role in the immune system. Three different pathways of complement activation are known: the classical, alternative, and lectin dependent. They involve more than 30 serum peptides. C1q is the first subcomponent of the classical pathway of complement activation. It is composed of three types of chains, A, B, and C, which form a molecule containing 18 peptides. Each of the chains has a short amino-terminal region followed by a collagen-like region (playing a role in the activation of C1r2C1s2 and a carboxy-terminal head, which binds to immune complexes. Recent studies have shown a great number of ligands for C1q, including aggregated IgG, IgM, human T-cell lymphotropic virus-I (HTLV-I, gp21 peptide, human immunodeficiency virus-1 (HIV-1 gp21 peptide, β-amyloid, fragments of bacterial walls, apoptotic cells, and many others. However, the role of C1q is not only associated with complement activation. It also helps in the removal of immune complexes and necrotic cells, stimulates the production of some cytokines, and modulates the function of lymphocytes. Complete C1q deficiency is a rare genetic disorder. The C1q gene is located on the short arm of chromosome 1. So far, only a few mutations in C1q gene have been reported. The presence of these mutations is strongly associated with recurrent bacterial infections and the development of systemic lupus erythematosus (SLE. Recent clinical studies point to the significance of anti-C1q antibodies in the diagnosis and assessment of lupus nephritis activity.

  8. Distinguishing C1q nephropathy from lupus nephritis.

    Science.gov (United States)

    Sharman, Andrew; Furness, Peter; Feehally, John

    2004-06-01

    'Seronegative lupus nephritis' describes patients with renal histology typical of lupus nephritis who have no clinical or serological evidence of systemic lupus erythematosus (SLE). We report our experience in nine patients identified as having 'seronegative lupus nephritis' who met the diagnostic criteria for C1q nephropathy. A retrospective review of clinical case notes and renal histology was carried out. We describe nine patients with C1q nephropathy in whom the diagnosis of 'seronegative lupus nephritis' was initially considered. All had renal histological features typical of lupus nephritis with 'wire loop' appearances on light microscopy, 'full house' immunoglobulin and complement deposition by immunoperoxidase, and electron-dense deposits in at least two glomerular locations. None of these nine patients developed clinical or serological evidence of SLE over a median follow-up of 6 years (range 0.1-9). There was no consistent evidence of a response to immunosuppressive therapy. In all cases, C1q staining was dominant on immunoperoxidase, and no tubuloreticular inclusions were seen. These appearances accord with previous descriptions of C1q nephropathy. The implications of a diagnosis of lupus are considerable, and we propose that the term 'seronegative lupus nephritis' is unhelpful, and should be avoided when there is diagnostic uncertainty. The term C1q nephropathy should be preferred when these histological features are seen in the absence of overt lupus, when C1q deposition is dominant and when tubuloreticular bodies are absent. The clinical course in the cases reported here does not support the use of immunosuppressive therapy in C1q nephropathy.

  9. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... To Health Topics / Iron-Deficiency Anemia Iron-Deficiency Anemia What Is Iron-deficiency anemia is a common, ... all types of anemia . Signs and Symptoms of Anemia The most common symptom of all types of ...

  10. Vitamin Deficiency Anemia

    Science.gov (United States)

    ... cancer can interfere with the metabolism of folate. Vitamin B-12 deficiency anemia risk factors include: Lack ... vitamin B-12 deficiency anemia called pernicious anemia. Vitamin C deficiency anemia risk factors include: Smoking. Smoking ...

  11. Vitamin Deficiency Anemia

    Science.gov (United States)

    ... are unique to specific vitamin deficiencies. Folate-deficiency anemia risk factors include: Undergoing hemodialysis for kidney failure. ... the metabolism of folate. Vitamin B-12 deficiency anemia risk factors include: Lack of intrinsic factor. Most ...

  12. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Deficiency Anemia Explore Iron-Deficiency Anemia What Is... CAUSES WHO IS AT RISK SIGNS & SYMPTOMS DIAGNOSIS TREATMENTS ... less hemoglobin than normal. Iron-deficiency anemia can cause fatigue (tiredness), shortness of breath, chest pain, and ...

  13. Overcoming Intrinsic Restriction Enzyme Barriers Enhances Transformation Efficiency in Arthrospira platensis C1.

    Science.gov (United States)

    Jeamton, Wattana; Dulsawat, Sudarat; Tanticharoen, Morakot; Vonshak, Avigad; Cheevadhanarak, Supapon

    2017-04-01

    The development of a reliable genetic transformation system for Arthrospira platensis has been a long-term goal, mainly for those trying either to improve its performance in large-scale cultivation systems or to enhance its value as food and feed additives. However, so far, most of the attempts to develop such a transformation system have had limited success. In this study, an efficient and stable transformation system for A. platensis C1 was successfully developed. Based on electroporation and transposon techniques, exogenous DNA could be transferred to and stably maintained in the A. platensis C1 genome. Most strains of Arthrospira possess strong restriction barriers, hampering the development of a gene transfer system for this group of cyanobacteria. By using a type I restriction inhibitor and liposomes to protect the DNA from nuclease digestion, the transformation efficiency was significantly improved. The transformants were able to grow on a selective medium for more than eight passages, and the transformed DNA could be detected from the stable transformants. We propose that the intrinsic endonuclease enzymes, particularly the type I restriction enzyme, in A. platensis C1 play an important role in the transformation efficiency of this industrial important cyanobacterium. © The Author 2017. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  14. AChE inhibitor: a regio- and stereo-selective 1,3-dipolar cycloaddition for the synthesis of novel substituted 5,6-dimethoxy spiro[5.3']-oxindole-spiro-[6.3″]-2,3-dihydro-1H-inden-1″-one-7-(substituted aryl)-tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazole.

    Science.gov (United States)

    Ashraf Ali, Mohamed; Ismail, Rusli; Choon, Tan Soo; Kumar, Raju Suresh; Osman, Hasnah; Arumugam, Natarajan; Almansour, Abdulrahman I; Elumalai, Karthikeyan; Singh, Abhimanyu

    2012-01-01

    Pyrrolothiazolyloxindole analogues share vital pharmacological properties, considered useful in Alzheimer's disease (AD). The aim of this study was synthesis and evaluate pyralothiazolyloxindole analogues if possess acetyl cholinesterase (AChE) inhibitory activity. The easily accessible one-pot synthesis of these compounds resulted to be significantly less difficult and expensive than that of donepezil. Several compounds possess anti-cholinesterase activity in the order of micro and sub-micromolar. Particularly, compound was the most potent inhibitors of the series against acetyl cholinesterase enzyme with IC(50) 0.11μmol/L. Copyright © 2011 Elsevier Ltd. All rights reserved.

  15. Chondromyxoid fibroma of C1: first case report Fibroma condromixoide de C1: primer caso Fibroma condromixóide de C1: primeiro relato de caso

    Directory of Open Access Journals (Sweden)

    Ericson Sfreddo

    2012-01-01

    Full Text Available BACKGROUND: Chondromyxoid fibroma (CMF is a rare, benign primary bone tumor. The cervical spine is an uncommon site for this tumor, with only 10 reported cases to date and none involving the first cervical vertebra (C1. CASE REPORT: Female patient, 25-year-old monozygotic female twin, presented with cervical pain. Radiographic imaging demonstrated a contrast-enhanced, right-sided lytic lesion of the insufflated type in C1, with a punched-out appearance and extending to the anterior arch. A postero-lateral and a posterior approach were performed in two steps to resect the tumor followed by occipitocervical fixation. Pathology confirmed the diagnosis of CMF. At one year, the patient remains disease free with excellent spinal stability. CONCLUSION: Spinal surgeons may need to treat rare spinal tumors. Despite the proximity to neural and vascular structures, the goal of surgery is always a radical resection due to high recurrence rates.REVISIÓN: El fibroma condromixoide (FCM es un tumor óseo primario, benigno y raro. La columna cervical es un lugar raro de este tumor, con solamente 10 casos relatados, siendo que ninguno involucra a la primera vértebra cervical (C1. RELATO DEL CASO: Paciente del sexo femenino, 25 años, gemela monozigótica, presentando dolor cervical. La imagen radiográfica demostró una lesión contrastada, predominantemente en la masa lateral de C1 con extensión hacia el arco posterior y anterior. La resección del tumor se realizó en dos tiempos, inicialmente una aproximación posterolateral, seguida por la vía posterior. En esta última, se realizó una fijación occipitocervical. El análisis anatomopatológico fue compatible con FCM. Pasado un año de los procedimientos, la paciente permanecía sin enfermedad y con estabilidad cranio-cervical. CONCLUSIÓN: Especialistas de columna deben tener el conocimiento de que estos tumores raros pueden acometer a la columna vertebral y, a pesar de su proximidad con el tejido

  16. [ALK inhibitor].

    Science.gov (United States)

    Mano, Hiroyuki

    2011-01-01

    While lung cancer is the leading cause of cancer deaths worldwide, the molecular mechanism underlying its carcinogenesis is mainly unknown. We have discovered a small, fusion-type tyrosine kinase EML4-ALK that is generated through a tiny inversion within the short arm of human chromosome 2. Transgenic mice expressing EML4-ALK in lung developed hundreds of lung cancer nodules soon after birth, but such nodules were readily eradicated upon treatment with an ALK inhibitor. Clinical trials for EML4-ALK-positive lung cancer with an ALK inhibitor is ongoing, with its interim results being highly promising.

  17. Skin wound healing in MMP2-deficient and MMP2 / plasminogen double-deficient mice

    DEFF Research Database (Denmark)

    Frøssing, Signe; Rønø, Birgitte; Hald, Andreas

    2010-01-01

    activation (PA) system and the matrix metalloproteinase (MMP) family. Treatment with the broad spectrum MMP inhibitor, galardin, delays wound healing in wildtype mice and completely arrest wound healing in plasminogen (Plg)-deficient mice, indicating a functional overlap between plasmin- and galardin......During healing of incisional skin wounds, migrating keratinocytes dissect their way under the crust to re-epithelialize the wounded area. The efficiency of this tissue remodelling process depends on the concomitant activity of several extracellular proteases, including members of the plasminogen......-sensitive MMPs during wound healing. To address whether MMP2 is accountable for the galardin-induced healing deficiency in wildtype and Plg-deficient mice, incisional skin wounds were generated in MMP2 single-deficient mice and in MMP2/Plg double-deficient mice and followed until healed. Alternatively, tissue...

  18. C1q Nephropathy: The Unique Underrecognized Pathological Entity

    Directory of Open Access Journals (Sweden)

    Joe Devasahayam

    2015-01-01

    Full Text Available C1q nephropathy is a rare glomerular disease with characteristic mesangial C1q deposition noted on immunofluorescence microscopy. It is histologically defined and poorly understood. Light microscopic features are heterogeneous and comprise minimal change disease (MCD, focal segmental glomerulosclerosis (FSGS, and proliferative glomerulonephritis. Clinical presentation is also diverse, and ranges from asymptomatic hematuria or proteinuria to frank nephritic or nephrotic syndrome in both children and adults. Hypertension and renal insufficiency at the time of diagnosis are common findings. Optimal treatment is not clear and is usually guided by the underlying light microscopic lesion. Corticosteroids are the mainstay of treatment, with immunosuppressive agents reserved for steroid resistant cases. The presence of nephrotic syndrome and FSGS appear to predict adverse outcomes as opposed to favorable outcomes in those with MCD. Further research is needed to establish C1q nephropathy as a universally recognized distinct clinical entity. In this paper, we discuss the current understanding of pathogenesis, histopathology, clinical features, therapeutic options, and outcomes of C1q nephropathy.

  19. 26 CFR 1.661(c)-1 - Limitation on deduction.

    Science.gov (United States)

    2010-04-01

    ....661(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX... any amount which is treated under section 661(b) as consisting of any item of distributable net income..., which reports on the calendar year basis, has distributable net income of $20,000, which is deemed to...

  20. Angiogenesis Inhibitors

    Science.gov (United States)

    ... blood vessels “feed” growing tumors with oxygen and nutrients , allowing the cancer cells to invade nearby tissue , to move throughout ... any angiogenesis inhibitors currently being used to treat cancer in humans? Yes. The U.S. Food and Drug Administration (FDA) has approved bevacizumab to ...

  1. ZNF32 protects against oxidative stress-induced apoptosis by modulating C1QBP transcription.

    Science.gov (United States)

    Li, Kai; Gao, Bo; Li, Jun; Chen, Haining; Li, Yanyan; Wei, Yuyan; Gong, Di; Gao, Junping; Zhang, Jie; Tan, Weiwei; Wen, Tianfu; Zhang, Le; Huang, Lugang; Xiang, Rong; Lin, Ping; Wei, Yuquan

    2015-11-10

    Reactive oxygen species (ROS)-driven oxidative stress has been recognized as a critical inducer of cancer cell death in response to therapeutic agents. Our previous studies have demonstrated that zinc finger protein (ZNF)32 is key to cell survival upon oxidant stimulation. However, the mechanisms by which ZNF32 mediates cell death remain unclear. Here, we show that at moderate levels of ROS, Sp1 directly binds to two GC boxes within the ZNF32 promoter to activate ZNF32 transcription. Alternatively, at cytotoxic ROS concentrations, ZNF32 expression is repressed due to decreased binding activity of Sp1. ZNF32 overexpression maintains mitochondrial membrane potential and enhances the antioxidant capacity of cells to detoxify ROS, and these effects promote cell survival upon pro-oxidant agent treatment. Alternatively, ZNF32-deficient cells are more sensitive and vulnerable to oxidative stress-induced cell injury. Mechanistically, we demonstrate that complement 1q-binding protein (C1QBP) is a direct target gene of ZNF32 that inactivates the p38 MAPK pathway, thereby exerting the protective effects of ZNF32 on oxidative stress-induced apoptosis. Taken together, our findings indicate a novel mechanism by which the Sp1-ZNF32-C1QBP axis protects against oxidative stress and implicate a promising strategy that ZNF32 inhibition combined with pro-oxidant anticancer agents for hepatocellular carcinoma treatment.

  2. ZNF32 protects against oxidative stress-induced apoptosis by modulating C1QBP transcription

    Science.gov (United States)

    Li, Yanyan; Wei, Yuyan; Gong, Di; Gao, Junping; Zhang, Jie; Tan, Weiwei; Wen, Tianfu; Zhang, Le; Huang, Lugang; Xiang, Rong; Lin, Ping; Wei, Yuquan

    2015-01-01

    Reactive oxygen species (ROS)-driven oxidative stress has been recognized as a critical inducer of cancer cell death in response to therapeutic agents. Our previous studies have demonstrated that zinc finger protein (ZNF)32 is key to cell survival upon oxidant stimulation. However, the mechanisms by which ZNF32 mediates cell death remain unclear. Here, we show that at moderate levels of ROS, Sp1 directly binds to two GC boxes within the ZNF32 promoter to activate ZNF32 transcription. Alternatively, at cytotoxic ROS concentrations, ZNF32 expression is repressed due to decreased binding activity of Sp1. ZNF32 overexpression maintains mitochondrial membrane potential and enhances the antioxidant capacity of cells to detoxify ROS, and these effects promote cell survival upon pro-oxidant agent treatment. Alternatively, ZNF32-deficient cells are more sensitive and vulnerable to oxidative stress-induced cell injury. Mechanistically, we demonstrate that complement 1q-binding protein (C1QBP) is a direct target gene of ZNF32 that inactivates the p38 MAPK pathway, thereby exerting the protective effects of ZNF32 on oxidative stress-induced apoptosis. Taken together, our findings indicate a novel mechanism by which the Sp1-ZNF32-C1QBP axis protects against oxidative stress and implicate a promising strategy that ZNF32 inhibition combined with pro-oxidant anticancer agents for hepatocellular carcinoma treatment. PMID:26497555

  3. Bivariate C^1 quadratic finite elements and vertex splines

    Science.gov (United States)

    Chui, Charles K.; He, Tian Xiao

    1990-01-01

    Following work of Heindl and of Powell and Sabin, each triangle of an arbitrary (regular) triangulation Δ of a polygonal region Ω in {R^2} is subdivided into twelve triangles, using the three medians, yielding the refinement hat Δ of Δ , so that {C^1} quadratic finite elements can be constructed. In this paper, we derive the Bezier nets of these elements in terms of the parameters that describe function and first partial derivative values at the vertices and values of the normal derivatives at the midpoints of the edges of Δ . Consequently, bivariate {C^1} quadratic (generalized) vertex splines on Δ have an explicit formulation. Here, a generalized vertex spline is one which is a piecewise polynomial on the refined grid partition hat Δ and has support that contains at most one vertex of the original partition Δ in its interior. The collection of all {C^1} quadratic generalized vertex splines on Δ so constructed is shown to form a basis of S_2^1(hat Δ ) , the vector space of all functions on {C^1}(Ω ) whose restrictions to each triangular cell of the partition hat Δ are quadratic polynomials. A subspace with the basis given by appropriately chosen generalized vertex splines with exactly one vertex of Δ in the interior of their supports, that reproduces all quadratic polynomials, is identified, and hence, has approximation order three. Quasi-interpolation formulas using this subspace are obtained. In addition, a constructive procedure that yields a locally supported basis of yet another subspace with dimension given by the number of vertices of Δ , that has approximation order three, is given.

  4. The topological matrix model of c=1 string

    CERN Document Server

    Imbimbo, Camillo; Imbimbo, Camillo; Mukhi, Sunil

    1995-01-01

    We derive a Kontsevich-type matrix model for the c=1 string directly from the W-infinity solution of the theory. The model that we obtain is different from previous proposals, which are proven to be incorrect. Our matrix model contains the Penner and Kontsevich cases, and we study its quantum effective action. The simplicity of our model leads to an encouraging interpretation in the context of background-independent noncritical string field theory.

  5. Spectroscopic Confirmation of DES13C1feu

    Science.gov (United States)

    Smith, M.; Okouma, P.; Bassett, B.; Kasai, E.; Crawford, S. M.; Romero-Colmenero, E.; Buckley, D.; Maartens, R.; Desai, S.; Paech, K.; Smith, R. C.; Kessler, R.; Covarrubias, R. A.; Cane, R.; Fischer, J. A.; Gladney, L.; March, M.; Sako, M.; Brown, P. J.; Krisciunas, K.; Suntzeff, N.; D'Andrea, C.; Nichol, R.; Papadopoulos, A.; Sullivan, M.; Barbary, K.; Bernstein, J. P.; Biswas, R.; Gupta, R.; Kovacs, E.; Kuhlmann, S.; Spinka, H.; Ahn, E.; Finley, D.; Frieman, J.; Marriner, J.; Wester, W.; Aldering, G.; Bloom, J. S.; Goldstein, D.; Kim, A.; Nugent, P.; Perlmutter, S.; Thomas, R. C.; Foley, R.

    2013-10-01

    We report optical spectroscopy of a supernova (SN) candidate discovered by the Dark Energy Survey (ATel #4668). The spectrum (400-900 nm) of DES13C1feu was obtained using the Robert Stobie Spectrograph (RSS) on the Southern African Large Telescope (SALT). A fit of the spectrum with SNID (Blondin & Tonry, 2007, ApJ, 666, 1024) reveals this event to be a type Ic supernova at z=0.06 at peak brightness.

  6. A C1qDC Protein (HcC1qDC6 with Three Tandem C1q Domains Is Involved in Immune Response of Triangle-Shell Pearl Mussel (Hyriopsis cumingii

    Directory of Open Access Journals (Sweden)

    Ying Huang

    2017-07-01

    Full Text Available C1q-domain-containing (C1qDC proteins are a family of proteins with a globular C1q (gC1q domain and participate in several immune responses. In this study, a C1qDC gene was identified from the triangle-shell pearl mussel Hyriopsis cumingii (designated as HcC1qDC6. This gene has a full-length cDNA of 1782 bp and an open reading frame of 1,335 bp that encodes a 444-amino acid polypeptide containing three gC1q domains. HcC1qDC6 contains at least five exons and four introns. The mRNA transcripts of HcC1qDC6 were found to have the highest expression levels in the mantle tissue. The expression levels in the mantle and hepatopancreas were significantly upregulated by Staphylococcus aureus and Vibrio parahaemolyticus challenges. Moreover, knockdown of HcC1qDC6 inhibits the expression of two immune-related genes (tumor necrosis factor and whey acidic protein. The recombinant proteins of C1q1, C1q2, and C1q3 all exhibit a binding activity against seven bacterial species and directly bind to peptidoglycan and lipopolysaccharide. The results indicate that HcC1qDC6 is involved in the innate immunity of H. cumingii.

  7. Efficient C1-continuous phase-potential upwind (C1-PPU) schemes for coupled multiphase flow and transport with gravity

    Science.gov (United States)

    Jiang, Jiamin; Younis, Rami M.

    2017-10-01

    In the presence of counter-current flow, nonlinear convergence problems may arise in implicit time-stepping when the popular phase-potential upwinding (PPU) scheme is used. The PPU numerical flux is non-differentiable across the co-current/counter-current flow regimes. This may lead to cycles or divergence in the Newton iterations. Recently proposed methods address improved smoothness of the numerical flux. The objective of this work is to devise and analyze an alternative numerical flux scheme called C1-PPU that, in addition to improving smoothness with respect to saturations and phase potentials, also improves the level of scalar nonlinearity and accuracy. C1-PPU involves a novel use of the flux limiter concept from the context of high-resolution methods, and allows a smooth variation between the co-current/counter-current flow regimes. The scheme is general and applies to fully coupled flow and transport formulations with an arbitrary number of phases. We analyze the consistency property of the C1-PPU scheme, and derive saturation and pressure estimates, which are used to prove the solution existence. Several numerical examples for two- and three-phase flows in heterogeneous and multi-dimensional reservoirs are presented. The proposed scheme is compared to the conventional PPU and the recently proposed Hybrid Upwinding schemes. We investigate three properties of these numerical fluxes: smoothness, nonlinearity, and accuracy. The results indicate that in addition to smoothness, nonlinearity may also be critical for convergence behavior and thus needs to be considered in the design of an efficient numerical flux scheme. Moreover, the numerical examples show that the C1-PPU scheme exhibits superior convergence properties for large time steps compared to the other alternatives.

  8. C1 Rational Quadratic Trigonometric Interpolation Spline for Data Visualization

    Directory of Open Access Journals (Sweden)

    Shengjun Liu

    2015-01-01

    Full Text Available A new C1 piecewise rational quadratic trigonometric spline with four local positive shape parameters in each subinterval is constructed to visualize the given planar data. Constraints are derived on these free shape parameters to generate shape preserving interpolation curves for positive and/or monotonic data sets. Two of these shape parameters are constrained while the other two can be set free to interactively control the shape of the curves. Moreover, the order of approximation of developed interpolant is investigated as O(h3. Numeric experiments demonstrate that our method can construct nice shape preserving interpolation curves efficiently.

  9. Reduction of CO2 to C1 products and fuel

    Science.gov (United States)

    Mill, T.; Ross, D.

    2002-01-01

    Photochemical semiconductor processes readily reduced CO2 to a broad range of C1 products. However the intrinsic and solar efficiencies for the processes were low. Improved quantum efficiencies could be realized utilizing quantum-sized particles, but at the expense of using less of the visible solar spectrum. Conversely, semiconductors with small bandgaps used more of the visible solar spectrum at the expense of quantum efficiency. Thermal reduction of CO2 with Fe(II) was thermodynamically favored for forming many kinds of organic compounds and occurred readily with olivine and other Fe(II) minerals above 200??C to form higher alkanes and alkenes. No added hydrogen was required.

  10. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... less hemoglobin than normal. Iron-deficiency anemia can cause fatigue (tiredness), shortness of breath, chest pain, and ... iron-deficiency anemia. Treatment will depend on the cause and severity of the condition. Treatments may include ...

  11. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... food. Overview Iron-deficiency anemia is a common type of anemia . The term "anemia" usually refers to ... also may lead to iron-deficiency anemia. This type of blood loss isn't always obvious, and ...

  12. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... or an inability to absorb enough iron from food. Overview Iron-deficiency anemia is a common type ... of the condition. Treatments may include dietary changes, medicines, and surgery. Severe iron-deficiency anemia may require ...

  13. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... condition. Women Women of childbearing age are at higher risk for iron-deficiency anemia because of blood ... iron-deficiency anemia. Pregnant women also are at higher risk for the condition because they need twice ...

  14. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... help prevent overdosing in children. Because recent research supports concerns that iron deficiency during infancy and childhood ... treat iron-deficiency anemia. These doctors include pediatricians, family doctors, gynecologists/obstetricians, and internal medicine specialists. A ...

  15. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... more information about diet and supplements, go to "How Is Iron-Deficiency Anemia Treated?" Infants and young ... who should be screened for iron deficiency, and how often: Girls aged 12 to 18 and women ...

  16. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... and other symptoms. Severe iron-deficiency anemia can lead to heart problems, infections, problems with growth and ... Internal bleeding (bleeding inside the body) also may lead to iron-deficiency anemia. This type of blood ...

  17. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... have iron-deficiency anemia, you'll have a high level of transferrin that has no iron. Other ... may include dietary changes and supplements, medicines, and surgery. Severe iron-deficiency anemia may require a blood ...

  18. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... deficiency anemia if they're underweight or have chronic (ongoing) illnesses. Teenage girls who have heavy periods ... factors for iron-deficiency anemia The Centers for Disease Control and Prevention (CDC) has developed guidelines for ...

  19. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... deficiency anemia apply to all types of anemia . Signs and Symptoms of Anemia The most common symptom ... appetite, slowed growth and development, and behavioral problems. Signs and Symptoms of Iron Deficiency Signs and symptoms ...

  20. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... also may help treat iron-deficiency anemia. Medical History Your doctor will ask about your signs and ... much of the transferrin in your blood isn't carrying iron. If you have iron-deficiency anemia, ...

  1. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... coped with having iron-deficiency anemia. Prior to her diagnosis, Susan had symptoms such as tiredness, poor skin tone, dizziness, and depression. After her doctor diagnosed her with iron-deficiency anemia, Susan ...

  2. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... drawings also can cause iron-deficiency anemia. Poor Diet The best sources of iron are meat, poultry, ... more likely to develop iron-deficiency anemia. Vegetarian diets can provide enough iron if you eat the ...

  3. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Deficiency Anemia What Is... CAUSES WHO IS AT RISK SIGNS & SYMPTOMS DIAGNOSIS TREATMENTS PREVENTION LIVING WITH CLINICAL ... and women are the two groups at highest risk for iron-deficiency anemia. Outlook Doctors usually can ...

  4. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... iron-deficiency anemia may require treatment in a hospital, blood transfusions , iron injections, or intravenous iron therapy. ... Treatment may need to be done in a hospital. The goals of treating iron-deficiency anemia are ...

  5. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... To Health Topics / Iron-Deficiency Anemia Iron-Deficiency Anemia Leer en español What Is Iron-deficiency anemia ... all types of anemia . Signs and Symptoms of Anemia The most common symptom of all types of ...

  6. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... page from the NHLBI on Twitter. What Is Iron-Deficiency Anemia? Español Iron-deficiency anemia is a ... Content: NEXT >> Featured Video Living With and Managing Iron-Deficiency Anemia 05/18/2011 This video—presented ...

  7. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Tumblr. Share this page from the NHLBI on Twitter. What Is Iron-Deficiency Anemia? Español Iron-deficiency ... Iron-Deficiency Anemia article. Updated: March 26, 2014 Twitter Facebook YouTube Google+ SITE INDEX ACCESSIBILITY PRIVACY STATEMENT ...

  8. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... the NHLBI on Twitter. What Is Iron-Deficiency Anemia? Español Iron-deficiency anemia is a common, easily ... Featured Video Living With and Managing Iron-Deficiency Anemia 05/18/2011 This video—presented by the ...

  9. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... iron-deficiency anemia, especially if they have: A history of iron-deficiency anemia Heavy blood loss during their monthly periods Other risk factors for iron-deficiency anemia The Centers for Disease Control and Prevention (CDC) has developed guidelines for who ...

  10. Centrosomal localisation of the cancer/testis (CT antigens NY-ESO-1 and MAGE-C1 is regulated by proteasome activity in tumour cells.

    Directory of Open Access Journals (Sweden)

    Anna Pagotto

    Full Text Available The Cancer/Testis (CT antigen family of genes are transcriptionally repressed in most human tissues but are atypically re-expressed in many malignant tumour types. Their restricted expression profile makes CT antigens ideal targets for cancer immunotherapy. As little is known about whether CT antigens may be regulated by post-translational processing, we investigated the mechanisms governing degradation of NY-ESO-1 and MAGE-C1 in selected cancer cell lines. Inhibitors of proteasome-mediated degradation induced the partitioning of NY-ESO-1 and MAGE-C1 into a detergent insoluble fraction. Moreover, this treatment also resulted in increased localisation of NY-ESO-1 and MAGE-C1 at the centrosome. Despite their interaction, relocation of either NY-ESO-1 or MAGE-C1 to the centrosome could occur independently of each other. Using a series of truncated fragments, the regions corresponding to NY-ESO-1(91-150 and MAGE-C1(900-1116 were established as important for controlling both stability and localisation of these CT antigens. Our findings demonstrate that the steady state levels of NY-ESO-1 and MAGE-C1 are regulated by proteasomal degradation and that both behave as aggregation-prone proteins upon accumulation. With proteasome inhibitors being increasingly used as front-line treatment in cancer, these data raise issues about CT antigen processing for antigenic presentation and therefore immunogenicity in cancer patients.

  11. Centrosomal localisation of the cancer/testis (CT) antigens NY-ESO-1 and MAGE-C1 is regulated by proteasome activity in tumour cells.

    Science.gov (United States)

    Pagotto, Anna; Caballero, Otavia L; Volkmar, Norbert; Devalle, Sylvie; Simpson, Andrew J G; Lu, Xin; Christianson, John C

    2013-01-01

    The Cancer/Testis (CT) antigen family of genes are transcriptionally repressed in most human tissues but are atypically re-expressed in many malignant tumour types. Their restricted expression profile makes CT antigens ideal targets for cancer immunotherapy. As little is known about whether CT antigens may be regulated by post-translational processing, we investigated the mechanisms governing degradation of NY-ESO-1 and MAGE-C1 in selected cancer cell lines. Inhibitors of proteasome-mediated degradation induced the partitioning of NY-ESO-1 and MAGE-C1 into a detergent insoluble fraction. Moreover, this treatment also resulted in increased localisation of NY-ESO-1 and MAGE-C1 at the centrosome. Despite their interaction, relocation of either NY-ESO-1 or MAGE-C1 to the centrosome could occur independently of each other. Using a series of truncated fragments, the regions corresponding to NY-ESO-1(91-150) and MAGE-C1(900-1116) were established as important for controlling both stability and localisation of these CT antigens. Our findings demonstrate that the steady state levels of NY-ESO-1 and MAGE-C1 are regulated by proteasomal degradation and that both behave as aggregation-prone proteins upon accumulation. With proteasome inhibitors being increasingly used as front-line treatment in cancer, these data raise issues about CT antigen processing for antigenic presentation and therefore immunogenicity in cancer patients.

  12. [Vitamin K: biochemistry, function, and deficiency. Review].

    Science.gov (United States)

    Mijares, M E; Nagy, E; Guerrero, B; Arocha-Piñango, C L

    1998-09-01

    Vitamin K is a cofactor for the synthesis of blood coagulation Factors II, VII, IX and X, and inhibitors such as Protein C and S and bone matrix protein. Its active form is a coenzyme in the glutamic acid carboxylation. Vitamin K-dependent factors form enzymatic complexes with calcium and membrane phospholipids. The insufficiency of gamma glutamic carboxylation impairs the hemostatic function. Hereditary deficiencies, antibiotics and oral anticoagulants, decrease the capacity of complex formation giving way to hemorrhage or thrombosis, or bone mass disturbances which are easily treated with administration of Vitamin K. The main causes of Vitamin K deficiency are lack of hepatic storage in newborns, liver insufficiency, malabsorption, dietetic deficiency, therapy with the antibiotics and coumarin administration. For the study of Vitamin K there are methods to measure the Vit K dependent proteins and as well methods to measure specifically the quinonas.

  13. Carnitine Deficiency and Pregnancy

    Directory of Open Access Journals (Sweden)

    Anouk de Bruyn

    2015-01-01

    Full Text Available We present two cases of carnitine deficiency in pregnancy. In our first case, systematic screening revealed L-carnitine deficiency in the first born of an asymptomatic mother. In the course of her second pregnancy, maternal carnitine levels showed a deficiency as well. In a second case, a mother known with carnitine deficiency under supplementation was followed throughout her pregnancy. Both pregnancies had an uneventful outcome. Because carnitine deficiency can have serious complications, supplementation with carnitine is advised. This supplementation should be continued throughout pregnancy according to plasma concentrations.

  14. 21 CFR 866.5250 - Complement C2 inhibitor (inactivator) immunological test system.

    Science.gov (United States)

    2010-04-01

    ... Test Systems § 866.5250 Complement C2 inhibitor (inactivator) immunological test system. (a) Identification. A complement C1 inhibitor (inactivator) immunological test system is a device that consists of... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Complement C2 inhibitor (inactivator...

  15. Small-molecule arginase inhibitors.

    Science.gov (United States)

    Ivanenkov, Yan A; Chufarova, Nina V

    2014-01-01

    Arginase is an enzyme that metabolizes L-arginine to L-ornithine and urea. In addition to its fundamental role in the hepatic ornithine cycle, it also influences the immune systems in humans and mice. Arginase participates in many inflammatory disorders by decreasing the synthesis of nitric oxide and inducing fibrosis and tissue regeneration. L-arginine deficiency, which is modulated by myeloid cell arginase, suppresses T-cell immune response. This mechanism plays a fundamental role in inflammation-associated immunosuppression. Pathogens can synthesize their own arginase to elude immune reaction. Small-molecule arginase inhibitors are currently described as promising therapeutics for the treatment of several diseases, including allergic asthma, inflammatory bowel disease, ulcerative colitis, cardiovascular diseases (atherosclerosis and hypertension), diseases associated with pathogens (e.g., Helicobacter pylori, Trypanosoma cruzi, Leishmania, Mycobacterium tuberculosis and Salmonella), cancer and induced or spontaneous immune disorders. This article summarizes recent patents in the area of arginase inhibitors and discusses their properties.

  16. Beta-Ketothiolase Deficiency

    Directory of Open Access Journals (Sweden)

    Elsayed Abdelkreem MD, MSc

    2016-03-01

    Full Text Available Beta-ketothiolase deficiency is an inherited disorder of ketone body metabolism and isoleucine catabolism. It typically manifests as recurrent ketoacidotic episodes with characteristic abnormalities in the urinary organic acid profile. However, several challenges in the diagnosis of beta-ketothiolase deficiency have been encountered: atypical presentations have been reported and some other disorders, such as succinyl-CoA:3-oxoacid CoA transferase and 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiencies, can mimic the clinical and/or biochemical signs of beta-ketothiolase deficiency. A final diagnosis of beta-ketothiolase deficiency requires an enzymatic assay and/or a molecular analysis, but some caveats must be considered. Despite the reported missed cases, screening programs have successfully identified an increasing number of patients with beta-ketothiolase deficiency. Early diagnosis and management of beta-ketothiolase deficiency will enable prevention of its serious acute and chronic complications and ultimately improve the prognosis.

  17. Intestinal and Hepatic Niemann-Pick C1-Like 1

    Directory of Open Access Journals (Sweden)

    Sung-Woo Park

    2013-08-01

    Full Text Available Polytopic transmembrane protein, Niemann-Pick C1-Like 1 (NPC1L1 is localized at the apical membrane of enterocytes and the canalicular membrane of hepatocytes. It mediates intestinal cholesterol absorption and prevents extensive loss of cholesterol by transporting biliary cholesterol into hepatocytes. NPC1L1 is a molecular target of ezetimibe, an agent for hypercholesterolemia. Recently, NPC1L1 inhibition has been shown to prevent metabolic disorders such as fatty liver disease, obesity, diabetes, and atherosclerosis. In this review, the identification and characterization of NPC1L1, NPC1L1-dependent cholesterol transport, the relationship with pathogenesis of metabolic disease and its newly introduced function for virus entry are discussed.

  18. Plasma enhanced C1 chemistry for green technology

    Science.gov (United States)

    Nozaki, Tomohiro

    2013-09-01

    Plasma catalysis is one of the innovative next generation green technologies that meet the needs for energy and materials conservation as well as environmental protection. Non-thermal plasma uniquely generates reactive species independently of reaction temperature, and these species are used to initiate chemical reactions at unexpectedly lower temperatures than normal thermochemical reactions. Non-thermal plasma thus broadens the operation window of existing chemical conversion processes, and ultimately allows modification of the process parameters to minimize energy and material consumption. We have been specifically focusing on dielectric barrier discharge (DBD) as one of the viable non-thermal plasma sources for practical fuel reforming. In the presentation, room temperature one-step conversion of methane to methanol and hydrogen using a miniaturized DBD reactor (microplasma reactor) is highlighted. The practical impact of plasma technology on existing C1-chemistry is introduced, and then unique characteristics of plasma fuel reforming such as non-equilibrium product distribution is discussed.

  19. A Selection of Recent Advances in C1 Chemistry.

    Science.gov (United States)

    Mesters, Carl

    2016-06-07

    This review presents a selection of recent publications related to the chemistry and catalysis of C1 molecules, including methane, methanol, carbon monoxide, and carbon dioxide. These molecules play an important role in the current supply of energy and chemicals and will likely become even more relevant because of the need to decarbonize fuels (shift from coal to natural gas) in line with CO2 capture and use to mitigate global warming, as well as a gradual shift on the supply side from crude oil to natural gas. This review includes both recent industrial developments, such as the huge increase in methanol-to-olefins-capacity build in China and the demonstration of oxidative coupling of methane, and scientific developments in these chemistries facilitated by improved capabilities in, for example, analytical tools and computational modeling.

  20. Catalytic routes to fuels from C1 and oxygenate molecules.

    Science.gov (United States)

    Wang, Shuai; Agirrezabal-Telleria, Iker; Bhan, Aditya; Simonetti, Dante; Takanabe, Kazuhiro; Iglesia, Enrique

    2017-04-28

    This account illustrates concepts in chemical kinetics underpinned by the formalism of transition state theory using catalytic processes that enable the synthesis of molecules suitable as fuels from C1 and oxygenate reactants. Such feedstocks provide an essential bridge towards a carbon-free energy future, but their volatility and low energy density require the formation of new C-C bonds and the removal of oxygen. These transformations are described here through recent advances in our understanding of the mechanisms and site requirements in catalysis by surfaces, with emphasis on enabling concepts that tackle ubiquitous reactivity and selectivity challenges. The hurdles in forming the first C-C bond from C1 molecules are illustrated by the oxidative coupling of methane, in which surface O-atoms form OH radicals from O2 and H2O molecules. These gaseous OH species act as strong H-abstractors and activate C-H bonds with earlier transition states than oxide surfaces, thus rendering activation rates less sensitive to the weaker C-H bonds in larger alkane products than in CH4 reactants. Anhydrous carbonylation of dimethyl ether forms a single C-C bond on protons residing within inorganic voids that preferentially stabilize the kinetically-relevant transition state through van der Waals interactions that compensate for the weak CO nucleophile. Similar solvation effects, but by intrapore liquids instead of inorganic hosts, also become evident as alkenes condense within MCM-41 channels containing isolated Ni(2+) active sites during dimerization reactions. Intrapore liquids preferentially stabilize transition states for C-C bond formation and product desorption, leading to unprecedented reactivity and site stability at sub-ambient temperatures and to 1-alkene dimer selectivities previously achieved only on organometallic systems with co-catalysts or activators. C1 homologation selectively forms C4 and C7 chains with a specific backbone (isobutane, triptane) on solid acids

  1. Catalytic routes to fuels from C1 and oxygenate molecules

    KAUST Repository

    Wang, Shuai

    2017-02-23

    This account illustrates concepts in chemical kinetics underpinned by the formalism of transition state theory using catalytic processes that enable the synthesis of molecules suitable as fuels from C-1 and oxygenate reactants. Such feedstocks provide an essential bridge towards a carbon-free energy future, but their volatility and low energy density require the formation of new C-C bonds and the removal of oxygen. These transformations are described here through recent advances in our understanding of the mechanisms and site requirements in catalysis by surfaces, with emphasis on enabling concepts that tackle ubiquitous reactivity and selectivity challenges. The hurdles in forming the first C-C bond from C-1 molecules are illustrated by the oxidative coupling of methane, in which surface O-atoms form OH radicals from O-2 and H2O molecules. These gaseous OH species act as strong H-abstractors and activate C-H bonds with earlier transition states than oxide surfaces, thus rendering activation rates less sensitive to the weaker C-H bonds in larger alkane products than in CH4 reactants. Anhydrous carbonylation of dimethyl ether forms a single C-C bond on protons residing within inorganic voids that preferentially stabilize the kinetically-relevant transition state through van der Waals interactions that compensate for the weak CO nucleophile. Similar solvation effects, but by intrapore liquids instead of inorganic hosts, also become evident as alkenes condense within MCM-41 channels containing isolated Ni2+ active sites during dimerization reactions. Intrapore liquids preferentially stabilize transition states for C-C bond formation and product desorption, leading to unprecedented reactivity and site stability at sub-ambient temperatures and to 1-alkene dimer selectivities previously achieved only on organometallic systems with co-catalysts or activators. C-1 homologation selectively forms C-4 and C-7 chains with a specific backbone (isobutane, triptane) on solid

  2. Biochemical aromatization of 2-methyleneandrostenedione: stereochemistry of hydrogen removal at the C-1 position.

    Science.gov (United States)

    Numazawa, Mitsuteru; Handa, Wakako; Matsuzaki, Hisao

    2006-11-01

    To explore a stereochemistry of hydrogen removal at C-1 of the powerful aromatase inhibitor 2-methyleneandrostenedione (1), of which the A-ring conformation is markedly different from that of the natural substrate androstenedione (AD), in the course of the aromatase-catalyzed A-ring aromatization producing 2-methylestrone (2), we synthesized [1alpha-2H]labeled steroid 1 and its [1beta-2H]stereoisomer, and the metabolic fate of the C-1 deuterium in aromatization was analyzed by gas chromatography-mass spectrometry (GC-MS) in each. Parallel experiments with the natural substrates [1alpha-2H] and [1beta-2H]ADs were also carried out. The GC-MS analysis indicated that 2-methyl estrogen 2 produced from [1alpha-2H]labeled substrate 1 retained completely the 1alpha-deuterium (1beta-H elimination), while product 2 obtained from [1beta-2H]isomer 1 lost completely the 1beta-deuterium. Stereospecific 1beta-hydrogen elimination was also observed in the parallel experiments with the labeled ADs as established previously. The results indicate that biochemical aromatization of the 2-methylene steroid 1 proceeds through the 1beta-hydrogen removal concomitant with cleavage of the C(10)-C(19) bond, yielding 1(10),4-dienone 9, in a similar manner to that involved in AD aromatization. This would give additional evidence for the stereomechanisms for the last step of aromatization of AD, requiring the stereospecific 1beta-hydrogen abstraction and cleavage of the C(10)-C(19) bond, and for the enolization of a carbonyl group at C-3 in the A-ring aromatization.

  3. Targeting Atp6v1c1 Prevents Inflammation and Bone Erosion Caused by Periodontitis and Reveals Its Critical Function in Osteoimmunology.

    Directory of Open Access Journals (Sweden)

    Sheng Li

    Full Text Available Periodontal disease (Periodontitis is a serious disease that affects a majority of adult Americans and is associated with other systemic diseases, including diabetes, rheumatoid arthritis, and other inflammatory diseases. While great efforts have been devoted toward understanding the pathogenesis of periodontitis, there remains a pressing need for developing potent therapeutic strategies for targeting this pervasive and destructive disease. In this study, we utilized novel adeno-associated virus (AAV-mediated Atp6v1c1 knockdown gene therapy to treat bone erosion and inflammatory caused by periodontitis in mouse model. Atp6v1c1 is a subunit of the V-ATPase complex and regulator of the assembly of the V0 and V1 domains of the V-ATPase complex. We demonstrated previously that Atp6v1c1 has an essential function in osteoclast mediated bone resorption. We hypothesized that Atp6v1c1 may be an ideal target to prevent the bone erosion and inflammation caused by periodontitis. To test the hypothesis, we employed AAV RNAi knockdown of Atp6v1c1 gene expression to prevent bone erosion and gingival inflammation simultaneously. We found that lesion-specific injection of AAV-shRNA-Atp6v1c1 into the periodontal disease lesions protected against bone erosion (>85% and gingival inflammation caused by P. gingivalis W50 infection. AAV-mediated Atp6v1c1 knockdown dramatically reduced osteoclast numbers and inhibited the infiltration of dendritic cells and macrophages in the bacteria-induced inflammatory lesions in periodontitis. Silencing of Atp6v1c1 expression also prevented the expressions of osteoclast-related genes and pro-inflammatory cytokine genes. Our data suggests that AAV-shRNA-Atp6v1c1 treatment can significantly attenuate the bone erosion and inflammation caused by periodontitis, indicating the dual function of AAV-shRNA-Atp6v1c1 as an inhibitor of bone erosion mediated by osteoclasts, and as an inhibitor of inflammation through down-regulation of pro

  4. Computing sleep deficiency.

    Science.gov (United States)

    Erren, Thomas C; Groß, J Valerie; Lewis, Philip

    2017-11-20

    Sleep deficiency is a major public health concern. Since epidemiological studies play an important role in public health evaluations, this theoretical paper pursues answers to the question: 'How can we compute sleep deficiency as informative measures of exposures or doses in observational research?' Starting from the social jetlag concept and based on the chronodisruption rationale, we illustrate and discuss five approaches (one established and four untested, each with unique strengths and limitations) to quantify sleep deficiency by focusing on the timing and duration of sleep. Hitherto, social jetlag and chronodisruption rationale were neither explicitly proposed nor developed as assessments of sleep deficiency but, as we suggest, could potentially be utilized to this end. This first foray into computing sleep deficiency in epidemiological studies makes clear that laboratory, field and epidemiological collaboration is pre-requisite to elucidating potential (co-)causal roles of sleep deficiency in disease endpoints. © 2017 European Sleep Research Society.

  5. Acquired color vision deficiency.

    Science.gov (United States)

    Simunovic, Matthew P

    2016-01-01

    Acquired color vision deficiency occurs as the result of ocular, neurologic, or systemic disease. A wide array of conditions may affect color vision, ranging from diseases of the ocular media through to pathology of the visual cortex. Traditionally, acquired color vision deficiency is considered a separate entity from congenital color vision deficiency, although emerging clinical and molecular genetic data would suggest a degree of overlap. We review the pathophysiology of acquired color vision deficiency, the data on its prevalence, theories for the preponderance of acquired S-mechanism (or tritan) deficiency, and discuss tests of color vision. We also briefly review the types of color vision deficiencies encountered in ocular disease, with an emphasis placed on larger or more detailed clinical investigations. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Manganese deficiency in plants

    DEFF Research Database (Denmark)

    Schmidt, Sidsel Birkelund; Jensen, Poul Erik; Husted, Søren

    2016-01-01

    restricting crop productivity in many places of the world. Hence, timely alleviation of latent Mn deficiency is a challenge in promoting plant growth and quality. We describe here the key mechanisms of Mn deficiency in plants by focusing on the impact of Mn on PSII stability and functionality. We also address...... the mechanisms underlying the differential tolerance towards Mn deficiency observed among plant genotypes, which enable Mn-efficient plants to grow on marginal land with poor Mn availability....

  7. Expression of organic anion transporting polypeptide 1c1 and monocarboxylate transporter 8 in the rat placental barrier and the compensatory response to thyroid dysfunction.

    Directory of Open Access Journals (Sweden)

    Yi-na Sun

    Full Text Available Thyroid hormones (THs must pass from mother to fetus for normal fetal development and require the expression of placental TH transporters. We investigate the compensatory effect of placental organic anion transporting polypeptide 1c1 (Oatp1c1 and monocarboxylate transporter 8 (Mct8 on maternal thyroid dysfunction. We describe the expressions of these two transporters in placental barriers and trophoblastic cell populations in euthyroidism and thyroid dysfunction resulting from differential iodine nutrition at gestation day (GD 16 and 20, that is, before and after the onset of fetal thyroid function. Immunohistochemistry revealed that in the blood-placenta barrier, these two TH transporters were strongly expressed in the villous interstitial substance and were weakly expressed in trophoblast cells. Levels of Oatp1c1 protein obviously increased in the placental fetal portion during maternal thyroid deficiency at GD16. Under maternal thyroid deficiency after the production of endogenous fetal TH, quantitative PCR analysis revealed down-regulation of Oatp1c1 occurred along with up-regulation of Mct8 in trophoblast cell populations isolated by laser capture microdissection (LCM; this was consistent with the protein levels in the fetal portion of the placenta. In addition, decreased D3 mRNA at GD16 and increased D2 mRNA on two gestational days were observed in trophoblast cells with thyroid dysfunction. However, levels of Oatp1c1 mRNA at GD16 and D3 mRNA at GD20 were too low to be detectable in trophoblast cells. In conclusion, placental Oatp1c1 plays an essential compensatory role when the transplacental passage of maternal THs is insufficient at the stage before the fetal TH production. In addition, the coordinated effects of Oatp1c1, Mct8, D2 and D3 in the placental barrier may regulate both transplacental TH passage and the development of trophoblast cells during thyroid dysfunction throughout the pregnancy.

  8. Cell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain.

    Science.gov (United States)

    Fonseca, Maria I; Chu, Shu-Hui; Hernandez, Michael X; Fang, Melody J; Modarresi, Lila; Selvan, Pooja; MacGregor, Grant R; Tenner, Andrea J

    2017-03-06

    The complement cascade not only provides protection from infection but can also mediate destructive inflammation. Complement is also involved in elimination of neuronal synapses which is essential for proper development, but can be detrimental during aging and disease. C1q, required for several of these complement-mediated activities, is present in the neuropil, microglia, and a subset of interneurons in the brain. To identify the source(s) of C1q in the brain, the C1qa gene was selectively inactivated in the microglia or Thy-1+ neurons in both wild type mice and a mouse model of Alzheimer's disease (AD), and C1q synthesis assessed by immunohistochemistry, QPCR, and western blot analysis. While C1q expression in the brain was unaffected after inactivation of C1qa in Thy-1+ neurons, the brains of C1qa FL/FL :Cx3cr1 CreERT2 mice in which C1qa was ablated in microglia were devoid of C1q with the exception of limited C1q in subsets of interneurons. Surprisingly, this loss of C1q occurred even in the absence of tamoxifen by 1 month of age, demonstrating that Cre activity is tamoxifen-independent in microglia in Cx3cr1 CreERT2/WganJ mice. C1q expression in C1qa FL/FL : Cx3cr1 CreERT2/WganJ mice continued to decline and remained almost completely absent through aging and in AD model mice. No difference in C1q was detected in the liver or kidney from C1qa FL/FL : Cx3cr1 CreERT2/WganJ mice relative to controls, and C1qa FL/FL : Cx3cr1 CreERT2/WganJ mice had minimal, if any, reduction in plasma C1q. Thus, microglia, but not neurons or peripheral sources, are the dominant source of C1q in the brain. While demonstrating that the Cx3cr1 CreERT2/WganJ deleter cannot be used for adult-induced deletion of genes in microglia, the model described here enables further investigation of physiological roles of C1q in the brain and identification of therapeutic targets for the selective control of complement-mediated activities contributing to neurodegenerative disorders.

  9. Structure and activation of C1, the complex initiating the classical pathway of the complement cascade.

    Science.gov (United States)

    Mortensen, Simon A; Sander, Bjoern; Jensen, Rasmus K; Pedersen, Jan Skov; Golas, Monika M; Jensenius, Jens C; Hansen, Annette G; Thiel, Steffen; Andersen, Gregers R

    2017-01-31

    The complement system is an important antimicrobial and inflammation-generating component of the innate immune system. The classical pathway of complement is activated upon binding of the 774-kDa C1 complex, consisting of the recognition molecule C1q and the tetrameric protease complex C1r2s2, to a variety of activators presenting specific molecular patterns such as IgG- and IgM-containing immune complexes. A canonical model entails a C1r2s2 with its serine protease domains tightly packed together in the center of C1 and an intricate intramolecular reaction mechanism for activation of C1r and C1s, induced upon C1 binding to the activator. Here, we show that the serine protease domains of C1r and C1s are located at the periphery of the C1r2s2 tetramer both when alone or within the nonactivated C1 complex. Our structural studies indicate that the C1 complex adopts a conformation incompatible with intramolecular activation of C1, suggesting instead that intermolecular proteolytic activation between neighboring C1 complexes bound to a complement activating surface occurs. Our results rationalize how a multitude of structurally unrelated molecular patterns can activate C1 and suggests a conserved mechanism for complement activation through the classical and the related lectin pathway.

  10. Data of evolutionary structure change: 1IB6C-1SMKC [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1IB6C-1SMKC 1IB6 1SMK C C -MKVAVLGAAGGIGQALALLLKTQLPSGSELSLYDIAPVTPGVAVDLSHIPTAVKI...TLKKDIALGQEFVNK GFKVAILGAAGGIGQPLAMLMKM-NPLVSVLHLYDVV-NAPGVTADISHMDTGAVVRGFLGQQQLEAALTG... 1SMK C 1SMKC 1SMK C 1SMKC 1SMK C 1SMKC MLMKM-NPLVS

  11. [Investigation of C1R gene frequencies in three Han populations in China].

    Science.gov (United States)

    Ji, Z; Gou, Q; Wu, J; Hou, Y

    1997-12-01

    To reveal the C1R polymorphism in Chinese, three Han populations in Guangzhou (101 samples), Jilin (105 samples) and Chengdu (111 samples) were investigated with a technique using PAGIF followed by immunoblotting. The results showed in Chengdu the C1R * 1 = 0.5676, C1R * 2 = 0.3424 and C1R * 5 = 0.0856, in Guangzhou C1R * 1 = 0.5248, C1R * 2 = 0.2663 and C1R * 5 = 0.1089, and in Jilin C1R * 1 = 0.5381, C1R * 2 = 0.2619 and C1R * 5 = 0.1714. Three rare genes C1R * 6, C1R * 7 and C1R * 8 were found in the investigation. These indicate that the frequency of C1R * 2 is elevated from north to south which may imply a geographic cline in this locus. The cumulated heterogeneity of C1R in Han population is 61.5% which means that this polymorphic system is useful in anthropolgy as well as in forensic science.

  12. Fibulin-1C, C1 Esterase Inhibitor and Glucose Regulated Protein 75 Interact with the CREC Proteins, Calumenin and Reticulocalbin

    DEFF Research Database (Denmark)

    Hansen, G. A. W.; Ludvigsen, M.; Jacobsen, C.

    2015-01-01

    with an affinity of approximately 3-7 nM with reticulocalbin as well as with calumenin. These interactions suggest functional participation of the CREC proteins in chaperone activity, cell proliferation and transformation, cellular aging, haemostasis and thrombosis as well as modulation of the complement system...... in fighting bacterial infection....

  13. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... diet. Young children who drink a lot of cow's milk may be at risk for iron-deficiency anemia. ... her risk for iron-deficiency anemia. For example, cow's milk is low in iron. For this and other ...

  14. Serine-deficiency syndromes

    NARCIS (Netherlands)

    de Koning, Tom J; Klomp, Leo W J

    PURPOSE OF REVIEW: Serine-deficiency disorders comprise a new group of neurometabolic diseases and are caused by defects in the biosynthesis of the amino acid L-serine. In contrast to most neurometabolic disorders, serine-deficiency disorders are potentially treatable. Furthermore, the severe

  15. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Organization NHLBI Director Budget, Planning, & Legislative Advisory Committees Jobs Contact Us FAQs Home » Iron-Deficiency Anemia Explore ... the body. Iron-deficiency anemia usually develops over time if your body doesn't have enough iron ...

  16. Iron deficiency anemia

    Science.gov (United States)

    Anemia - iron deficiency ... iron from old red blood cells. Iron deficiency anemia develops when your body's iron stores run low. ... You may have no symptoms if the anemia is mild. Most of the time, ... slowly. Symptoms may include: Feeling weak or tired more often ...

  17. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... have enough iron stored in your body to make up for the lost iron, you'll develop iron- ... by mouth. This therapy also is given to people who need immediate treatment for iron-deficiency ... have iron-deficiency anemia, get ongoing care to make sure your iron levels are improving. At your ...

  18. Muscle phosphorylase kinase deficiency

    DEFF Research Database (Denmark)

    Preisler, N; Orngreen, M C; Echaniz-Laguna, A

    2012-01-01

    To examine metabolism during exercise in 2 patients with muscle phosphorylase kinase (PHK) deficiency and to further define the phenotype of this rare glycogen storage disease (GSD).......To examine metabolism during exercise in 2 patients with muscle phosphorylase kinase (PHK) deficiency and to further define the phenotype of this rare glycogen storage disease (GSD)....

  19. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Blood Tests Blood Transfusion Restless Legs Syndrome Send a link to NHLBI to someone by E-MAIL | ... Iron-Deficiency Anemia? Español Iron-deficiency anemia is a common, easily treated condition that occurs if you ...

  20. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... shows how Susan, a full-time worker and student, has coped with having iron-deficiency anemia. Prior to her diagnosis, Susan had symptoms such as tiredness, poor skin tone, dizziness, and depression. After her doctor diagnosed her with iron-deficiency ...

  1. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... For more information about diet and supplements, go to "How Is Iron-Deficiency Anemia Treated?" Infants and young ... who should be screened for iron deficiency, and how often: Girls aged 12 to 18 and women of childbearing age who are ...

  2. Nutritional iron deficiency

    NARCIS (Netherlands)

    Zimmermann, M.B.; Hurrell, R.F.

    2007-01-01

    Iron deficiency is one of the leading risk factors for disability and death worldwide, affecting an estimated 2 billion people. Nutritional iron deficiency arises when physiological requirements cannot be met by iron absorption from diet. Dietary iron bioavailability is low in populations consuming

  3. Alpha1-antitrypsin deficiency

    DEFF Research Database (Denmark)

    Stolk, Jan; Seersholm, Niels; Kalsheker, Noor

    2006-01-01

    deficiency and contributes to an international database located in Malmö, Sweden. This database is designed to increase understanding of AAT deficiency. Additionally, AIR members are engaged in active, wide-ranging investigations to improve the diagnosis, monitoring, and treatment of the disease and meet...

  4. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... women of childbearing age has iron-deficiency anemia. Pregnant women also are at higher risk for the condition ... for the fetus' growth. About half of all pregnant women develop iron-deficiency anemia. The condition can increase ...

  5. Maternal vitamin D deficiency

    African Journals Online (AJOL)

    GB

    2017-05-01

    May 1, 2017 ... ABSTRACT. BACKGROUND: A rare but reversible cause of dilated cardiomyopathy occurs in infants born to vitamin D deficient mothers due to hypocalcaemia. CASE REPORT: We report a case of dilated cardiomyopathy due to hypocalcaemia secondary to maternal vitamin D deficiency in an.

  6. G6PD Deficiency

    Science.gov (United States)

    Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a genetic disorder that is most common in males. About 1 in 10 African American males in the United States has it. G6PD deficiency mainly affects red blood cells, which carry oxygen ...

  7. Iron deficiency in childhood

    NARCIS (Netherlands)

    Uijterschout, L.

    2015-01-01

    Iron deficiency (ID) is the most common micronutrient deficiency in the world. Iron is involved in oxygen transport, energy metabolism, immune response, and plays an important role in brain development. In infancy, ID is associated with adverse effects on cognitive, motor, and behavioral development

  8. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... have RLS often have a hard time sleeping. Iron-deficiency anemia can put children at greater risk for lead poisoning and infections. Some signs and symptoms of iron-deficiency anemia are related to the condition's causes. For ...

  9. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... food. Overview Iron-deficiency anemia is a common type of anemia . The term "anemia" usually refers to a condition ... symptoms of iron-deficiency anemia apply to all types of anemia . Signs and Symptoms of Anemia The most common ...

  10. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... will diagnose iron-deficiency anemia based on your medical history, a physical exam, and the results from tests and procedures. Once ... specialists also may help treat iron-deficiency anemia. Medical ... be pregnant. Physical Exam Your doctor will do a physical exam to ...

  11. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... be advised. Treatments for Severe Iron-Deficiency Anemia Blood Transfusion If your iron-deficiency anemia is severe, you ... get a transfusion of red blood cells. A blood transfusion is a safe, common procedure in which blood ...

  12. Hepcidin in obese children as a potential mediator of the association between obesity and iron deficiency.

    NARCIS (Netherlands)

    Giudice, E. Del; Santoro, N.; Amato, A.; Brienza, C.; Calabro, P.; Wiegerinck, E.T.G.; Cirillo, G.; Tartaglione, N.; Grandone, A.; Swinkels, D.W.; Perrone, L.

    2009-01-01

    CONTEXT: Obesity and iron deficiency are two of the most common nutritional disorders worldwide. Several studies found higher rates of iron deficiency in obese than in normal-weight children. Hepcidin represents the main inhibitor of intestinal iron absorption, and its expression is increased in

  13. 21 CFR 864.7290 - Factor deficiency test.

    Science.gov (United States)

    2010-04-01

    ... defects, to monitor certain types of therapy, to detect coagulation inhibitors, and to detect a carrier state (a person carrying both a recessive gene for a coagulation factor deficiency such as hemophilia and the corresponding normal gene). (b) Classification. Class II (performance standards). [45 FR 60613...

  14. Biomechanical comparison of a novel C1 posterior locking plate with the harms technique in a C1-C2 fixation model.

    Science.gov (United States)

    Kelly, Brian P; Glaser, John A; DiAngelo, Denis J

    2008-11-15

    A biomechanical testing protocol was used to study atlantoaxial fixation techniques in a human cadaveric model. To compare the in vitro biomechanics of locking plate fixation of the posterior arch of C1 to C2 laminar screw fixation, with that of conventional C1 lateral mass to C2 pars screw fixation. Current methods of atlantoaxial fixation pose a risk to neurologic and vascular structures. A novel posterior locking plate for C1 was designed, that when rigidly linked to C2 translaminar screws may offer alternative C1-C2 fixation with greatly decreased surgical risk. No comparative in vitro biomechanical testing has been previously done to evaluate the feasibility of this method. Cadaveric and CT assessments of the thickness of the C1 ring were performed. Seven spines (C0-C4) were evaluated in flexion-extension, left-right bending, and left-right axial rotation in a cadaveric C1-C2 fixation model. Three conditions were evaluated: (1) intact spine, and after odontoidectomy, (2) C1 plate to C2 laminar screw fixation, (3) C1 lateral mass to C2 pars screw fixation. Flexibility and motion data were compared using a 1-way RM analysis of variance and Student-Newman-Kuels tests. Anatomic data indicated that 6 mm of screw purchase was viable for C1 plate fixation. Both the Harms and C1-plated conditions significantly reduced global flexibility in flexion-extension and left-right axial rotation. Motion at the C1-C2 level was significantly reduced for all loading modes for both instrumented conditions with the exception of the C1 plate in right bending. No significant differences occurred between the 2 fixation methods. A novel C1 posterior locking plate was designed and tested in a C1-C2 fixation model. The C1 locking plate technique functioned in an equivalent manner to the existing Harms technique. The C1 plate may be a viable alternative that is technically less demanding with decreased surgical risk.

  15. Facial Nerve Recovery in KbDb and C1q Knockout Mice: A Role for Histocompatibility Complex 1

    Science.gov (United States)

    Akdagli, Seden; Williams, Ryan A.; Kim, Hyun J.; Yan, Yuling; Mustapha, Mirna

    2016-01-01

    Background: Understanding the mechanisms in nerve damage can lead to better outcomes for neuronal rehabilitation. The purpose of our study was to assess the effect of major histocompatibility complex I deficiency and inhibition of the classical complement pathway (C1q) on functional recovery and cell survival in the facial motor nucleus (FMN) after crush injury in adult and juvenile mice. Methods: A prospective blinded analysis of functional recovery and cell survival in the FMN after a unilateral facial nerve crush injury in juvenile and adult mice was undertaken between wild-type, C1q knockout (C1q−/−), and KbDb knockout (KbDb−/−) groups. Whisker function was quantified to assess functional recovery. Neuron counts were performed to determine neuron survival in the FMN after recovery. Results: After facial nerve injury, all adult wild-type mice fully recovered. Juvenile mice recovered incompletely corresponding to a greater neuron loss in the FMN of juveniles compared with adults. The C1q−/− juvenile and adult groups did not differ from wild type. The KbDb−/− adults demonstrated 50% recovery of whisker movement and decreased cell survival in FMN. The KbDb−/− juvenile group did not demonstrate any difference from control group. Conclusion: Histocompatibility complex I plays a role for neuroprotection and enhanced facial nerve recovery in adult mice. Inhibition of the classical complement pathway alone does not affect functional recovery or neuronal survival. The alternative and mannose binding pathways pose alternative means for activating the final components of the pathway that may lead to acute nerve damage. PMID:28293529

  16. Identifying Determinants of PARP Inhibitor Sensitivity in Ovarian Cancer

    Science.gov (United States)

    2016-10-01

    deficient in homologous recombination (HR) DNA repair, such as those lacking functional BRCA1 are highly sensitive to poly(ADP-ribose) polymerase (PARP...Identify genetic alterations essential for PARP inhibitor resistance; 3: Determine the ability of identified genetic aberrations to serve as predictive...INTRODUCTION: Cells that are deficient in homologous recombination (HR) DNA repair, such as those lacking functional BRCA1 are highly sensitive to poly

  17. C1q nephropathy in India: A single-center study

    OpenAIRE

    K V Kanodia; Vanikar, A. V.; Patel, R.D.; Suthar, K. S.; Patel, H. V.; M A Gumber; Shah, P. R.; Trivedi, H. L.

    2015-01-01

    C1q nephropathy (C1qN) is defined by conspicuous C1q deposits in the glomerular mesangial regions of patients who do not have any evidence of systemic lupus erythematosus (SLE). We present our experience with C1qN over the last three years. In total, 1775 native renal biopsies were reviewed and dominant/co-dominant C1q mesangial deposits in patients with absence of clinical and/or serological evidence of SLE were considered as C1qN. Their clinical profile and renal function status were studie...

  18. Vitamin B12 Deficiency: Recognition and Management.

    Science.gov (United States)

    Langan, Robert C; Goodbred, Andrew J

    2017-09-15

    Vitamin B12 deficiency is a common cause of megaloblastic anemia, various neuropsychiatric symptoms, and other clinical manifestations. Screening average-risk adults for vitamin B12 deficiency is not recommended. Screening may be warranted in patients with one or more risk factors, such as gastric or small intestine resections, inflammatory bowel disease, use of metformin for more than four months, use of proton pump inhibitors or histamine H2 blockers for more than 12 months, vegans or strict vegetarians, and adults older than 75 years. Initial laboratory assessment should include a complete blood count and serum vitamin B12 level. Measurement of serum methylmalonic acid should be used to confirm deficiency in asymptomatic high-risk patients with low-normal levels of vitamin B12. Oral administration of high-dose vitamin B12 (1 to 2 mg daily) is as effective as intramuscular administration for correcting anemia and neurologic symptoms. Intramuscular therapy leads to more rapid improvement and should be considered in patients with severe deficiency or severe neurologic symptoms. Absorption rates improve with supplementation; therefore, patients older than 50 years and vegans or strict vegetarians should consume foods fortified with vitamin B12 or take vitamin B12 supplements. Patients who have had bariatric surgery should receive 1 mg of oral vitamin B12 per day indefinitely. Use of vitamin B12 in patients with elevated serum homocysteine levels and cardiovascular disease does not reduce the risk of myocardial infarction or stroke, or alter cognitive decline.

  19. Immunohistochemical localization of C1 subunit of V-ATPase (ATPase C1) in oral squamous cell cancer and normal oral mucosa.

    Science.gov (United States)

    García-García, A; Pérez-Sayáns García, M; Rodríguez, M J; Antúnez-López, J; Barros-Angueira, F; Somoza-Martín, M; Gándara-Rey, J M; Aguirre-Urízar, J M

    2012-02-01

    The ATP6V1C1 gene encodes the C1 subunit of the vacuolar-ATPase (V-ATPase) proton pump. This gene is over-expressed in oral squamous cell carcinoma (OSCC) as determined by real-time quantitative polymerase chain reaction. The aim of our study was to perform an immunohistochemical study of the distribution of the C1 subunit in normal epithelium of the oral cavity and in OSCC. We analyzed the expression of the C1 subunit in eight OSCC samples and two normal oral mucosa samples using polyclonal V-ATPase C1 antibody (clone H-300). In the normal oral mucosa samples, C1 subunit staining was observed in the basal and intermediate layers of the epithelium. No staining was visible in the keratinized superficial layers. More intense staining was observed in the OSCC samples, with the predominant expression at the periphery of tumor nests and absence of expression in dyskeratotic areas. C1 subunit expression in tumor cells was predominantly cytoplasmic, although there was perinuclear and nuclear expression in some samples. These findings demonstrate that V-ATPase is necessary for proper epithelial functioning and show its importance in the development of OSCC as evidenced by the over-expression of ATP6V1C1 in OSCC.

  20. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... bleeding. Other At-Risk Groups People who get kidney dialysis treatment may develop iron-deficiency anemia. This ... because blood is lost during dialysis. Also, the kidneys are no longer able to make enough of ...

  1. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... if you have intestinal surgery (such as gastric bypass) or a disease of the intestine (such as ... produce red blood cells. People who have gastric bypass surgery also may develop iron-deficiency anemia. This ...

  2. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Safety Sleep Science and Sleep Disorders Lung Diseases Heart and Vascular Diseases Precision Medicine Activities Obesity, Nutrition, ... symptoms. Severe iron-deficiency anemia can lead to heart problems, infections, problems with growth and development in ...

  3. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... NHLBI About NHLBI Home Mission and Strategic Vision Leadership Scientific Divisions Operations and Administration Advisory Committees Budget ... include poor appetite, slowed growth and development, and behavioral problems. Signs and Symptoms of Iron Deficiency Signs ...

  4. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... also may help treat iron-deficiency anemia. Medical History Your doctor will ask about your signs and ... It must be done in a hospital or clinic by experienced staff. Iron therapy usually is given ...

  5. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... re more likely to develop iron-deficiency anemia. Vegetarian diets can provide enough iron if you eat ... which are the best sources of iron. However, vegetarian diets can provide enough iron if you eat ...

  6. Iron-Deficiency Anemia

    Science.gov (United States)

    ... re more likely to develop iron-deficiency anemia. Vegetarian diets can provide enough iron if you eat ... which are the best sources of iron. However, vegetarian diets can provide enough iron if you eat ...

  7. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... a waste product) from your body. Anemia also can occur if your red blood cells don't ... have less hemoglobin than normal. Iron-deficiency anemia can cause fatigue (tiredness), shortness of breath, chest pain, ...

  8. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... usually can successfully treat iron-deficiency anemia. Treatment will depend on the cause and severity of the ... about a healthy diet and food choices that will help your child get enough iron. Your child's ...

  9. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... or soil, or drinking water that contains lead. Teens Teens are at risk for iron-deficiency anemia if ... and bleeding ulcers, can cause blood loss. Some medicines, such as aspirin, also can cause internal bleeding. ...

  10. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... or soil, or drinking water that contains lead. Teens Teens are at risk for iron-deficiency anemia ... for increased blood volume and for the fetus' growth. About half of all pregnant women develop iron- ...

  11. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... anemia at 1 year of age. Women and Girls Women of childbearing age may be tested for ... be screened for iron deficiency, and how often: Girls aged 12 to 18 and women of childbearing ...

  12. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... condition. Treatments may include dietary changes, medicines, and surgery. Severe iron-deficiency anemia may require treatment in ... Urinary tract bleeding Blood loss from severe injuries, surgery, or frequent blood drawings also can cause iron- ...

  13. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... or soil, or drinking water that contains lead. Teens Teens are at risk for iron-deficiency anemia if ... Visit Children and Clinical Studies to hear experts, parents, and children talk about their experiences with clinical ...

  14. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... symptoms. Severe iron-deficiency anemia can lead to heart problems, infections, problems with growth and development in ... 18/2011 This video—presented by the National Heart, Lung, and Blood Institute, part of the National ...

  15. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Digg. Share this page from the NHLBI on Facebook. Add this link to the NHLBI to my ... Deficiency Anemia article. Updated: March 26, 2014 Twitter Facebook YouTube Google+ SITE INDEX ACCESSIBILITY PRIVACY STATEMENT FOIA ...

  16. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... and Blood Safety Sleep Science and Sleep Disorders Lung Diseases Heart and Vascular Diseases Precision Medicine Activities ... iron-rich protein that carries oxygen from the lungs to the rest of the body. Iron-deficiency ...

  17. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... leafy green vegetables like turnip greens and spinach. Treatment To Stop Bleeding If blood loss is causing ... flow. In some cases, surgery may be advised. Treatments for Severe Iron-Deficiency Anemia Blood Transfusion If ...

  18. Alpha-1 Antitrypsin Deficiency

    Science.gov (United States)

    ... seafood, processed soy products, nuts, seeds, beans, and peas. A healthy diet is low in sodium (salt), ... help you cope with stress. Emotional Issues and Support Living with AAT deficiency may cause fear, anxiety, ...

  19. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Disorders Lung Diseases Heart and Vascular Diseases Precision Medicine Activities Obesity, Nutrition, and Physical Activity Population and ... of the condition. Treatments may include dietary changes, medicines, and surgery. Severe iron-deficiency anemia may require ...

  20. Vitamin D Deficiency

    Science.gov (United States)

    ... disease osteoporosis. Severe vitamin D deficiency can cause rickets in children and osteomalacia in adults. Both problems cause soft, ... The oral dose is once daily or weekly. Children with rickets or at risk of this disease may get ...

  1. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... need to be done in a hospital. The goals of treating iron-deficiency anemia are to treat ... and children talk about their experiences with clinical research. More Information Related Health Topics Anemia Blood Tests ...

  2. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... low iron levels in women. Internal bleeding (bleeding inside the body) also may lead to iron-deficiency ... a diagnosis, look for a cause, and find out how severe the condition is. Complete Blood Count ...

  3. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... the body. Iron-deficiency anemia usually develops over time if your body doesn't have enough iron ... because your need for iron increases during these times of growth and development. Inability To Absorb Enough ...

  4. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... People who have RLS often have a hard time sleeping. Iron-deficiency anemia can put children at ... Reticulocytes are young, immature red blood cells. Over time, reticulocytes become mature red blood cells that carry ...

  5. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... or iron supplements, when used properly, can help prevent iron-deficiency anemia in infants and young children. ... in the diet. Too much milk also may prevent children's bodies from absorbing iron from other foods. ...

  6. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Health Topics Education & Awareness Resources Contact The Health Information Center Health Professionals Systematic Evidence Reviews & Clinical Practice ... and see the benefits of treatment. For more information about living with and managing iron-deficiency anemia, ...

  7. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... the cause and severity of the condition. Treatments may include dietary changes, medicines, and surgery. Severe iron-deficiency anemia may require treatment in a hospital, blood transfusions , iron ...

  8. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... the first prenatal visit. For pregnant women, medical care during pregnancy usually includes screening for anemia. Also, ... while checking for other problems. Specialists Involved Primary care doctors often diagnose and treat iron-deficiency anemia. ...

  9. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... green leafy vegetables. Eat poorly because of money, social, health, or other problems. Follow a very low- ... help prevent overdosing in children. Because recent research supports concerns that iron deficiency during infancy and childhood ...

  10. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... hemoglobin than normal. Iron-deficiency anemia can cause fatigue (tiredness), shortness of breath, chest pain, and other ... common symptom of all types of anemia is fatigue (tiredness). Fatigue occurs because your body doesn't ...

  11. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... treat iron-deficiency anemia. These doctors include pediatricians, family doctors, gynecologists/obstetricians, and internal medicine specialists. A ... Center for Health Information Email Alerts Jobs and Careers Site Index About NHLBI National Institute of Health ...

  12. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Follow a very low-fat diet over a long time. Some higher fat foods, like meat, are ... iron deficiency during infancy and childhood can have long-lasting, negative effects on brain health, the American ...

  13. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Anemia What Is... CAUSES WHO IS AT RISK SIGNS & SYMPTOMS DIAGNOSIS TREATMENTS PREVENTION LIVING WITH CLINICAL TRIALS LINKS Related ... with having iron-deficiency anemia. Prior to her diagnosis, Susan had symptoms such as tiredness, poor skin ...

  14. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... iron-rich protein that carries oxygen from the lungs to the rest of the body. Iron-deficiency ... 2011 This video—presented by the National Heart, Lung, and Blood Institute, part of the National Institutes ...

  15. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... can cause fatigue (tiredness), shortness of breath, chest pain, and other symptoms. Severe iron-deficiency anemia can ... colon cancer Regular use of aspirin or other pain medicines, such as nonsteroidal anti-inflammatory drugs (for ...

  16. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... or an inability to absorb enough iron from food. Overview Iron-deficiency anemia is a common type ... or an inability to absorb enough iron from food. Blood Loss When you lose blood, you lose ...

  17. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Infants and Young Children A baby's diet can affect his or her risk for iron-deficiency anemia. ... eat grapefruit or drink grapefruit juice. Grapefruit can affect the strength of a few medicines and how ...

  18. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... carry oxygen and remove carbon dioxide (a waste product) from your body. Anemia also can occur if ... Deficiency Anemia article. Updated: March 26, 2014 Twitter Facebook YouTube Google+ SITE INDEX ACCESSIBILITY PRIVACY STATEMENT FOIA ...

  19. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... drawings also can cause iron-deficiency anemia. Poor Diet The best sources of iron are meat, poultry, ... also checks the number of red blood cells, white blood cells, and platelets in your blood. Abnormal ...

  20. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... also can cause internal bleeding. Other At-Risk Groups People who get kidney dialysis treatment may develop ... and young children and women are the two groups at highest risk for iron-deficiency anemia. Special ...

  1. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... the signs and symptoms of iron-deficiency anemia apply to all types of anemia . Signs and Symptoms ... rapid or uneven breathing Feel your abdomen to check the size of your liver and spleen Do ...

  2. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... iron-deficiency anemia may require treatment in a hospital, blood transfusions , iron injections, or intravenous iron therapy. ... beans. Other lifestyle changes, such as getting enough sleep and exercising, also have helped Susan feel better. ...

  3. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... intestine (such as Crohn's disease or celiac disease). Prescription medicines that reduce acid in the stomach also ... specialists also may help treat iron-deficiency anemia. Medical History Your doctor will ask about your signs ...

  4. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... specialists also may help treat iron-deficiency anemia. Medical History Your doctor will ask about your signs ... information, go to the Health Topics Blood Transfusion article. Iron Therapy If you have severe anemia, your ...

  5. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... drawings also can cause iron-deficiency anemia. Poor Diet The best sources of iron are meat, poultry, ... other dark green leafy vegetables Prune juice The Nutrition Facts labels on packaged foods will show how ...

  6. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Other At-Risk Groups People who get kidney dialysis treatment may develop iron-deficiency anemia. This is because blood is lost during dialysis. Also, the kidneys are no longer able to ...

  7. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... for iron-deficiency anemia The Centers for Disease Control and Prevention (CDC) has developed guidelines for who ... heavy menstrual flow, your doctor may prescribe birth control pills to help reduce your monthly blood flow. ...

  8. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... screened for iron deficiency, and how often: Girls aged 12 to 18 and women of childbearing age ... For this treatment, iron is injected into a muscle or an IV line in one of your ...

  9. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... factors for iron-deficiency anemia The Centers for Disease Control and Prevention (CDC) has developed guidelines for who should be ... or while checking for other problems. Specialists ... disease specialist), a gastroenterologist (a digestive system specialist), and ...

  10. Iron deficiency anemia

    National Research Council Canada - National Science Library

    Naigamwalla, Dinaz Z; Webb, Jinelle A; Giger, Urs

    2012-01-01

    .... The most important function is oxygen transport in hemoglobin. Iron deficiency anemia in dogs and cats is usually caused by chronic blood loss and can be discovered incidentally as animals may have adapted to the anemia...

  11. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... stomach also can interfere with iron absorption. Risk Factors Infants and Young Children Infants and young children ... blood loss during their monthly periods Other risk factors for iron-deficiency anemia The Centers for Disease ...

  12. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... some stages of life, such as pregnancy and childhood, it may be hard to get enough iron ... supports concerns that iron deficiency during infancy and childhood can have long-lasting, negative effects on brain ...

  13. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... For this treatment, iron is injected into a muscle or an IV line in one of your ... body can damage your organs. You may have fatigue (tiredness) and other symptoms of iron-deficiency anemia ...

  14. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... risk for iron-deficiency anemia if they're underweight or have chronic (ongoing) illnesses. Teenage girls who ... other dark green leafy vegetables Prune juice The Nutrition Facts labels on packaged foods will show how ...

  15. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... deficiency anemia if they're underweight or have chronic (ongoing) illnesses. Teenage girls who have heavy periods ... in your hands and feet, pale skin, chest pain, weakness, and fatigue (tiredness). If you don't ...

  16. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... intravenous iron therapy. Rate This Content: NEXT >> Featured Video Living With and Managing Iron-Deficiency Anemia 05/18/2011 This video—presented by the National Heart, Lung, and Blood ...

  17. Sleep Deprivation and Deficiency

    Science.gov (United States)

    ... adults report falling asleep during the day without meaning to at least once a month. Also, an ... Sleep deficiency also has been linked to depression, suicide, and risk-taking behavior. Children and teens who ...

  18. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... prevent children's bodies from absorbing iron from other foods. Children who have lead in their blood also may be at risk for iron-deficiency anemia. Lead can interfere with ...

  19. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Diseases Heart and Vascular Diseases Precision Medicine Activities Obesity, Nutrition, and Physical Activity Population and Epidemiology Studies ... or an inability to absorb enough iron from food. Overview Iron-deficiency anemia is a common type ...

  20. Glucose-6-phosphatase deficiency.

    OpenAIRE

    Labrune Philippe; Gajdos Vincent; Eberschweiler Pascale; Hubert-Buron Aurélie; Petit François; Vianey-Saban Christine; Boudjemline Alix; Piraud Monique; Froissart Roseline

    2011-01-01

    Abstract Glucose-6-phosphatase deficiency (G6P deficiency), or glycogen storage disease type I (GSDI), is a group of inherited metabolic diseases, including types Ia and Ib, characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver. Prevalence is unknown and annual incidence is around 1/100,000 births. GSDIa is the more frequent type, representing about 80% of GSDI patients. The disease commonly manifests, betw...

  1. 17 CFR 270.22c-1 - Pricing of redeemable securities for distribution, redemption and repurchase.

    Science.gov (United States)

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Pricing of redeemable securities for distribution, redemption and repurchase. 270.22c-1 Section 270.22c-1 Commodity and Securities... 1940 § 270.22c-1 Pricing of redeemable securities for distribution, redemption and repurchase. (a) No...

  2. 26 CFR 1.860C-1 - Taxation of holders of residual interests.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 9 2010-04-01 2010-04-01 false Taxation of holders of residual interests. 1.860C-1 Section 1.860C-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Real Estate Investment Trusts § 1.860C-1 Taxation of holders...

  3. 26 CFR 1.666(c)-1A - Pro rata portion of taxes deemed distributed.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Pro rata portion of taxes deemed distributed. 1.666(c)-1A Section 1.666(c)-1A Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Taxable Years Beginning Before January 1, 1969 § 1.666(c)-1A Pro rata portion of taxes deemed distributed...

  4. 26 CFR 1.666(c)-1 - Pro rata portion of taxes deemed distributed.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Pro rata portion of taxes deemed distributed. 1.666(c)-1 Section 1.666(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Taxable Years Beginning Before January 1, 1969 § 1.666(c)-1 Pro rata portion of taxes deemed distributed...

  5. Effects of fenofibrate on hyperlipidemia and postprandial triglyceride metabolism in human apolipoprotein C1 transgenic mice

    NARCIS (Netherlands)

    Jong, M.C.; Dahlmans, V.E.H.; Princen, H.M.G.; Hofker, M.H.; Havekes, L.M.

    1998-01-01

    To study the in vivo role of apolipoprotein (apo) C1 in lipoprotein metabolism, we have generated transgenic mice expressing the human apo C1 gene. Apo C1 is a small 6.6 kDa protein that is primarily synthesized by the liver and is present on chylomicrons, very low density lipoproteins (VLDL) and

  6. 26 CFR 1.411(c)-1 - Allocation of accrued benefits between employer and employee contributions.

    Science.gov (United States)

    2010-04-01

    ... Bonus Plans, Etc. § 1.411(c)-1 Allocation of accrued benefits between employer and employee... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Allocation of accrued benefits between employer and employee contributions. 1.411(c)-1 Section 1.411(c)-1 Internal Revenue INTERNAL REVENUE SERVICE...

  7. Prevalence and clinical significance of anti-C1q antibodies in ...

    African Journals Online (AJOL)

    Autoantibodies against C1q are strongly linked to immune-complex disorders like systemic lupus erythematosus (SLE). Although anti-C1q antibodies have received much interest in the recent years, their biological functions remain unclear. Anti-C1q antibodies are strongly associated with lupus nephritis. The aim of this ...

  8. Prevalence and clinical significance of anti-C1q antibodies in ...

    African Journals Online (AJOL)

    Asmaa Hegazy

    2012-04-21

    Apr 21, 2012 ... ponents of the complement system might be inactivated. Anti-. C1q antibodies were first identified as low-molecular weight. C1q precipitins in the sera of patients with systemic lupus erythematosus over 30years ago. Anti-C1q antibodies are strongly associated with the development of proliferative lupus.

  9. Spontaneous metastasis in matrix metalloproteinase 3-deficient mice

    DEFF Research Database (Denmark)

    Juncker-Jensen, Anna; Rømer, John; Pennington, Caroline J

    2009-01-01

    in tumorigenesis and metastatic growth. In this model the stromal expression of MMP-3 mRNA resembles the predominant MMP-3 expression pattern observed in human ductal breast carcinomas. We studied a cohort of 63 PyMT transgenic mice, either deficient for MMP-3 or wild-type controls. The degree of metastasis did...... not differ significantly between the two groups of mice, although the median lung metastasis volume was more than threefold increased in MMTV-PyMT mice deficient in MMP-3. Likewise, primary tumor growth rate and lymph node metastasis were not significantly affected by MMP-3-deficiency. By comparing m......RNA levels in MMP-3-deficient PyMT tumors with PyMT wild-type tumors we excluded compensatory transcriptional changes of other MMPs or their specific inhibitors. Thus, we conclude that genetic ablation of MMP-3 does not significantly affect tumor growth and metastasis in the MMTV-PyMT model....

  10. 1H, 13C and 15N NMR assignments of the C1A and C1B subdomains of PKC-delta.

    Science.gov (United States)

    Ziemba, Brian P; Brian, P Ziemba; Booth, Jamie C; Jamie, C Booth; Jones, David N M; David, Jones N M

    2011-10-01

    The Protein Kinase C family of enzymes is a group of serine/threonine kinases that play central roles in cell-cycle regulation, development and cancer. A key step in the activation of PKC is translocation to membranes and binding of membrane-associated activators including diacylglycerol (DAG). Interaction of novel and conventional isotypes of PKC with DAG and phorbol esters occurs through the two C1 regulatory domains (C1A and C1B), which exhibit distinct ligand binding selectivity that likely controls enzyme activation by different co-activators. PKC has also been implicated in physiological responses to alcohol consumption and it has been proposed that PKCα (Slater et al. J Biol Chem 272(10):6167-6173, 1997; Slater et al. Biochemistry 43(23):7601-7609, 2004), PKCε (Das et al. Biochem J 421(3):405-413, 2009) and PKCδ (Das et al. J Biol Chem 279(36):37964-37972, 2004; Das et al. Protein Sci 15(9):2107-2119, 2006) contain specific alcohol-binding sites in their C1 domains. We are interested in understanding how ethanol affects signal transduction processes through its affects on the structure and function of the C1 domains of PKC. Here we present the (1)H, (15)N and (13)C NMR chemical shift assignments for the Rattus norvegicus PKCδ C1A and C1B proteins.

  11. Safety Issues and Neurological Improvement following C1- C2 Fusion using C1 Lateral Mass and C2 Pedicle Screw in Atlantoaxial Instability

    Directory of Open Access Journals (Sweden)

    MK Kwan

    2010-07-01

    Full Text Available The evolution of instrumentation methods for C1-C2 fusion from the use of posterior wiring methods to transarticular screws and C1 lateral mass with C2 pedicle screw construct have improved fusion rates to almost 100%. However, the C1 lateral mass and C2 pedicle screw technique is technically demanding. This is a prospective review of a series of ten patients who was planned for C1-C2 fusion using C1 lateral mass and C2 pedicle screw technique between January 2007 and June 2009. The procedure was converted to occipital cervical fusion due to a fracture of a hypoplastic lateral mass-posterior arch complex in one patient and Gallie fusion due to a vertebral artery injury in another. Eight patients underwent the C1-C2 fusion using C1 lateral mass and C2 pedicle screw successfully without any complications. The union rate was 100% with an average union time of 5.3 months (range from 3 to 8 months. Postoperatively, the patients achieved an average of one Frankel grade neurological improvement. In conclusion, this technique provides an excellent union rate and good neurological recovery.

  12. Iron deficiency in Europe.

    Science.gov (United States)

    Hercberg, S; Preziosi, P; Galan, P

    2001-04-01

    In Europe, iron deficiency is considered to be one of the main nutritional deficiency disorders affecting large fractions of the population, particularly such physiological groups as children, menstruating women and pregnant women. Some factors such as type of contraception in women, blood donation or minor pathological blood loss (haemorrhoids, gynaecological bleeding...) considerably increase the difficulty of covering iron needs. Moreover, women, especially adolescents consuming low-energy diets, vegetarians and vegans are at high risk of iron deficiency. Although there is no evidence that an absence of iron stores has any adverse consequences, it does indicate that iron nutrition is borderline, since any further reduction in body iron is associated with a decrease in the level of functional compounds such as haemoglobin. The prevalence of iron-deficient anaemia has slightly decreased in infants and menstruating women. Some positive factors may have contributed to reducing the prevalence of iron-deficiency anaemia in some groups of population: the use of iron-fortified formulas and iron-fortified cereals; the use of oral contraceptives and increased enrichment of iron in several countries; and the use of iron supplements during pregnancy in some European countries. It is possible to prevent and control iron deficiency by counseling individuals and families about sound iron nutrition during infancy and beyond, and about iron supplementation during pregnancy, by screening persons on the basis of their risk for iron deficiency, and by treating and following up persons with presumptive iron deficiency. This may help to reduce manifestations of iron deficiency and thus improve public health. Evidence linking iron status with risk of cardiovascular disease or cancer is unconvincing and does not justify changes in food fortification or medical practice, particularly because the benefits of assuring adequate iron intake during growth and development are well established

  13. Monoamine Oxidase B Inhibitors in Parkinson's Disease.

    Science.gov (United States)

    Dezsi, Livia; Vecsei, Laszlo

    2017-01-01

    Parkinson's disease (PD) is a neurodegenerative disorder with a prevalence increasing with age. Oxidative stress and glutamate toxicity are involved in its pathomechanism. There are still many unmet needs of PD patients, including the alleviation of motor fluctuations and dyskinesias, and the development of therapies with neuroprotective potential. To give an overview of the pharmacological properties, the efficacy and safety of the monoamine oxidase B (MAO-B) inhibitors in the treatment of PD, with special focus on the results of randomized clinical trials. A literature search was conducted in PubMed for 'PD treatment', 'MAO-B inhibitors', 'selegiline', 'rasagiline', 'safinamide' and 'clinical trials' with 'MAO-B inhibitors' in 'Parkinson' disease'. MAO-B inhibitors have a favorable pharmacokinetic profile, improve the dopamine deficient state and may have neuroprotective properties. Safinamide exhibits an anti-glutamatergic effect as well. When applied as monotherapy, MAO-B inhibitors provide a modest, but significant improvement of motor function and delay the need for levodopa. Rasagiline and safinamide were proven safe and effective when added to a dopamine agonist in early PD. As add-on to levodopa, MAO-B inhibitors significantly reduced off-time and were comparable in efficacy to COMT inhibitors. Improvements were achieved as regards certain non-motor symptoms as well. Due to the efficacy shown in clinical trials and their favorable side-effect profile, MAO-B inhibitors are valuable drugs in the treatment of PD. They are recommended as monotherapy in the early stages of the disease and as add-on therapy to levodopa in advanced PD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  14. Alpha glucosidase inhibitors

    National Research Council Canada - National Science Library

    Kalra, Sanjay

    2014-01-01

    Alpha glucosidase inhibitors (AGIs) are a unique class of anti-diabetic drugs. Derived from bacteria, these oral drugs are enzyme inhibitors which do not have a pancreato -centred mechanism of action...

  15. Proton pump inhibitors

    Science.gov (United States)

    Proton pump inhibitors (PPIs) are medicines that work by reducing the amount of stomach acid made by glands in ... Proton pump inhibitors are used to: Relieve symptoms of acid reflux, or gastroesophageal reflux disease (GERD). This is a ...

  16. Suppression of methylation-mediated transcriptional gene silencing by βC1-SAHH protein interaction during geminivirus-betasatellite infection.

    Directory of Open Access Journals (Sweden)

    Xiuling Yang

    2011-10-01

    Full Text Available DNA methylation is a fundamental epigenetic modification that regulates gene expression and represses endogenous transposons and invading DNA viruses. As a counter-defense, the geminiviruses encode proteins that inhibit methylation and transcriptional gene silencing (TGS. Some geminiviruses have acquired a betasatellite called DNA β. This study presents evidence that suppression of methylation-mediated TGS by the sole betasatellite-encoded protein, βC1, is crucial to the association of Tomato yellow leaf curl China virus (TYLCCNV with its betasatellite (TYLCCNB. We show that TYLCCNB complements Beet curly top virus (BCTV L2⁻ mutants deficient for methylation inhibition and TGS suppression, and that cytosine methylation levels in BCTV and TYLCCNV genomes, as well as the host genome, are substantially reduced by TYLCCNB or βC1 expression. We also demonstrate that while TYLCCNB or βC1 expression can reverse TGS, TYLCCNV by itself is ineffective. Thus its AC2/AL2 protein, known to have suppression activity in other geminiviruses, is likely a natural mutant in this respect. A yeast two-hybrid screen of candidate proteins, followed by bimolecular fluorescence complementation analysis, revealed that βC1 interacts with S-adenosyl homocysteine hydrolase (SAHH, a methyl cycle enzyme required for TGS. We further demonstrate that βC1 protein inhibits SAHH activity in vitro. That βC1 and other geminivirus proteins target the methyl cycle suggests that limiting its product, S-adenosyl methionine, may be a common viral strategy for methylation interference. We propose that inhibition of methylation and TGS by βC1 stabilizes geminivirus/betasatellite complexes.

  17. Identification of functional elements of the GDP-fucose transporter SLC35C1 using a novel Chinese hamster ovary mutant.

    Science.gov (United States)

    Zhang, Peiqing; Haryadi, Ryan; Chan, Kah Fai; Teo, Gavin; Goh, John; Pereira, Natasha Ann; Feng, Huatao; Song, Zhiwei

    2012-07-01

    The GDP-fucose transporter SLC35C1 critically regulates the fucosylation of glycans. Elucidation of its structure-function relationships remains a challenge due to the lack of an appropriate mutant cell line. Here we report a novel Chinese hamster ovary (CHO) mutant, CHO-gmt5, generated by the zinc-finger nuclease technology, in which the Slc35c1 gene was knocked out from a previously reported CHO mutant that has a dysfunctional CMP-sialic acid transporter (CST) gene (Slc35a1). Consequently, CHO-gmt5 harbors double genetic defects in Slc35a1 and Slc35c1 and produces N-glycans deficient in both sialic acid and fucose. The structure-function relationships of SLC35C1 were studied using CHO-gmt5 cells. In contrast to the CST and UDP-galactose transporter, the C-terminal tail of SLC35C1 is not required for its Golgi localization but is essential for generating glycans that are recognized by a fucose-binding lectin, Aleuria aurantia lectin (AAL), suggesting an important role in the transport activity of SLC35C1. Furthermore, we found that this impact can be independently contributed by a cluster of three lysine residues and a Glu-Met (EM) sequence within the C terminus. We also showed that the conserved glycine residues at positions 180 and 277 of SLC35C1 have significant impacts on AAL binding to CHO-gmt5 cells, suggesting that these conserved glycine residues are required for the transport activity of Slc35 proteins. The absence of sialic acid and fucose on Fc N-glycan has been independently shown to enhance the antibody-dependent cellular cytotoxicity (ADCC) effect. By combining these features into one cell line, we postulate that CHO-gmt5 may represent a more advantageous cell line for the production of recombinant antibodies with enhanced ADCC effect.

  18. Draft Genome Sequence of a Chitinase-producing Biocontrol Bacterium Serratia sp. C-1

    Directory of Open Access Journals (Sweden)

    Seur Kee Park

    2015-09-01

    Full Text Available The chitinase-producing bacterial strain C-1 is one of the key chitinase-producing biocontrol agents used for effective bioformulations for biological control. These bioformulations are mixed cultures of various chitinolytic bacteria. However, the precise identification, biocontrol activity, and the underlying mechanisms of the strain C-1 have not been investigated so far. Therefore, we evaluated in planta biocontrol efficacies of C-1 and determined the draft genome sequence of the strain in this study. The bacterial C-1 strain was identified as a novel Serratia sp. by a phylogenic analysis of its 16S rRNA sequence. The Serratia sp. C-1 bacterial cultures showed strong in planta biocontrol efficacies against some major phytopathogenic fungal diseases. The draft genome sequence of Serratia sp. C-1 indicated that the C-1 strain is a novel strain harboring a subset of genes that may be involved in its biocontrol activities.

  19. Silencing of atp6v1c1 prevents breast cancer growth and bone metastasis.

    Science.gov (United States)

    Feng, Shengmei; Zhu, Guochun; McConnell, Matthew; Deng, Lianfu; Zhao, Qiang; Wu, Mengrui; Zhou, Qi; Wang, Jinshen; Qi, Jin; Li, Yi-Ping; Chen, Wei

    2013-01-01

    Previous studies have shown that Atp6v1c1, a regulator of the assembly of the V0 and V1 domains of the V-ATPase complex, is up-regulated in metastatic oral tumors. Despite these studies, the function of Atp6v1c1 in tumor growth and metastasis is still unknown. Atp6v1c1's expression in metastatic oral squamous cell carcinoma indicates that Atp6v1c1 has an important function in cancer growth and metastasis. We hypothesized that elevated expression of Atp6v1c1 is essential to cancer growth and metastasis and that Atp6v1c1 promotes cancer growth and metastasis through activation of V-ATPase activity. To test this hypothesis, a Lentivirus-mediated RNAi knockdown approach was used to study the function of Atp6v1c1 in mouse 4T1 mammary tumor cell proliferation and migration in vitro and cancer growth and metastasis in vivo. Our data revealed that silencing of Atp6v1c1 in 4T1 cancer cells inhibited lysosomal acidification and severely impaired 4T1 cell growth, migration, and invasion through Matrigel in vitro. We also show that Atp6v1c1 knockdown with Lenti-c1s3, a lentivirus targeting Atp6v1c1 for shRNA mediated knockdown, can significantly inhibit 4T1 xenograft tumor growth, metastasis, and osteolytic lesions in vivo. Our study demonstrates that Atp6v1c1 may promote breast cancer growth and bone metastasis through regulation of lysosomal V-ATPase activity, indicating that Atp6v1c1 may be a viable target for breast cancer therapy and silencing of Atp6v1c1 may be an innovative therapeutic approach for the treatment and prevention of breast cancer growth and metastasis.

  20. Deficiências de minerais Mineral deficiencies

    Directory of Open Access Journals (Sweden)

    Silvia Maria Franciscato Cozzolino

    2007-08-01

    Full Text Available Neste artigo procuramos relatar a situação mundial e brasileira com relação aos micronutrientes, em especial sobre os minerais. Os elementos químicos minerais desempenham funções de grande importância no organismo humano, sendo indispensáveis para o desenvolvimento e a saúde dos indivíduos. Ainda não existe uma avaliação global do estado nutricional dos indivíduos em relação a esses micronutrientes no Brasil, mas os estudos existentes apontam para a necessidade do acompanhamento das tendências alimentares que poderiam levar às suas deficiências com conseqüências adversas para a saúde da população e o desenvolvimento do nosso país.In this paper we will try to report the Brazilian micronutrients status, as well as in worldwide, specifically for minerals. Minerals have major importance on human body, becoming indispensable for the development and health of individuals. There is not yet an integral assessment of micronutrient status in the Brazilian subjects, but there are some studies pointing to the need of observation of alimentary tendencies that might lead to deficiencies, with adverse consequences to the population’s health and the development of our country

  1. Statins and fenofibrate affect skeletal muscle chloride conductance in rats by differently impairing ClC-1 channel regulation and expression

    Science.gov (United States)

    Pierno, S; Camerino, GM; Cippone, V; Rolland, J-F; Desaphy, J-F; De Luca, A; Liantonio, A; Bianco, G; Kunic, JD; George, AL; Camerino, D Conte

    2009-01-01

    Background and purpose: Statins and fibrates can produce mild to life-threatening skeletal muscle damage. Resting chloride channel conductance (gCl), carried by the ClC-1 channel, is reduced in muscles of rats chronically treated with fluvastatin, atorvastatin or fenofibrate, along with increased resting cytosolic calcium in statin-treated rats. A high gCl, controlled by the Ca2+-dependent protein kinase C (PKC), maintains sarcolemma electrical stability and its reduction alters muscle function. Here, we investigated how statins and fenofibrate impaired gCl. Experimental approach: In rats treated with fluvastatin, atorvastatin or fenofibrate, we examined the involvement of PKC in gCl reduction by the two intracellular microelectrodes technique and ClC-1 mRNA level by quantitative real time-polymerase chain reaction. Direct drug effects were tested by patch clamp analysis on human ClC-1 channels expressed in human embryonic kidney (HEK) 293 cells. Key results: Chelerythrine, a PKC inhibitor, applied in vitro on muscle dissected from atorvastatin-treated rats fully restored gCl, suggesting the involvement of this enzyme in statin action. Chelerythrine partially restored gCl in muscles from fluvastatin-treated rats but not in those from fenofibrate-treated rats, implying additional mechanisms for gCl impairment. Accordingly, a decrease of ClC-1 channel mRNA was found in both fluvastatin-and fenofibrate-treated rat muscles. Fenofibric acid, the in vivo metabolite of fenofibrate, but not fluvastatin, rapidly reduced chloride currents in HEK 293 cells. Conclusions and implications: Our data suggest multiple mechanisms underlie the effect of statins and fenofibrate on ClC-1 channel conductance. While statins promote Ca2+-mediated PKC activation, fenofibrate directly inhibits ClC-1 channels and both fluvastatin and fenofibrate impair expression of mRNA for ClC-1. PMID:19220292

  2. Vitamin deficiencies in cattle.

    Science.gov (United States)

    Frye, T M; Williams, S N; Graham, T W

    1991-03-01

    Deficiencies of vitamins A, D, K, E and thiamin can cause severe limitations in beef production. In particular, vitamin A and E can be common causes of lost profit, secondary to limitations of reproductive and growth potential. Prolonged dry periods will reduce available A and E in pasture forage, as can ensiling and prolonged storage of harvested feedstuffs. Polioencephalomalacia is a thiamin responsive disorder, associated with high concentrate feeding and lush pastures. Antimetabolites, such as amprolium, will cause thiamine deficiency when fed in excess. Recent information has shown improved performance with supplemental beta carotene and niacin. The positive responses in reproductive performance, noted with cattle fed supplemental beta carotene, was independent of vitamin A. Supplementation of vitamins above National Research Council recommendations can be justified. However, proper evaluation of feed and animal status, and documentation of a response to supplementation is necessary before diagnosing deficiencies of specific nutrients.

  3. Antepartum Ornithine Transcarbamylase Deficiency

    Directory of Open Access Journals (Sweden)

    Hitoshi Nakajima

    2014-11-01

    Full Text Available Ornithine transcarbamylase deficiency (OTCD is the most common type urea cycle enzyme deficiencies. This syndrome results from a deficiency of the mitochondrial enzyme ornithine transcarbamylase, which catalyzes the conversion of ornithine and carbamoyl phosphate to citrullin. Our case was a 28-year-old female diagnosed with OTCD following neurocognitive deficit during her first pregnancy. Although hyperammonemia was suspected as the cause of the patient's mental changes, there was no evidence of chronic liver disease. Plasma amino acid and urine organic acid analysis revealed OTCD. After combined modality treatment with arginine, sodium benzoate and hemodialysis, the patient's plasma ammonia level stabilized and her mental status returned to normal. At last she recovered without any damage left.

  4. Monoamine Reuptake Inhibitors in Parkinson's Disease

    Science.gov (United States)

    Huot, Philippe; Fox, Susan H.; Brotchie, Jonathan M.

    2015-01-01

    The motor manifestations of Parkinson's disease (PD) are secondary to a dopamine deficiency in the striatum. However, the degenerative process in PD is not limited to the dopaminergic system and also affects serotonergic and noradrenergic neurons. Because they can increase monoamine levels throughout the brain, monoamine reuptake inhibitors (MAUIs) represent potential therapeutic agents in PD. However, they are seldom used in clinical practice other than as antidepressants and wake-promoting agents. This review article summarises all of the available literature on use of 50 MAUIs in PD. The compounds are divided according to their relative potency for each of the monoamine transporters. Despite wide discrepancy in the methodology of the studies reviewed, the following conclusions can be drawn: (1) selective serotonin transporter (SERT), selective noradrenaline transporter (NET), and dual SERT/NET inhibitors are effective against PD depression; (2) selective dopamine transporter (DAT) and dual DAT/NET inhibitors exert an anti-Parkinsonian effect when administered as monotherapy but do not enhance the anti-Parkinsonian actions of L-3,4-dihydroxyphenylalanine (L-DOPA); (3) dual DAT/SERT inhibitors might enhance the anti-Parkinsonian actions of L-DOPA without worsening dyskinesia; (4) triple DAT/NET/SERT inhibitors might exert an anti-Parkinsonian action as monotherapy and might enhance the anti-Parkinsonian effects of L-DOPA, though at the expense of worsening dyskinesia. PMID:25810948

  5. HvPap-1 C1A Protease Participates Differentially in the Barley Response to a Pathogen and an Herbivore

    Science.gov (United States)

    Diaz-Mendoza, Mercedes; Velasco-Arroyo, Blanca; Santamaria, M. Estrella; Diaz, Isabel; Martinez, Manuel

    2017-01-01

    Co-evolutionary processes in plant–pathogen/herbivore systems indicate that protease inhibitors have a particular value in biotic interactions. However, little is known about the defensive role of their targets, the plant proteases. C1A cysteine proteases are the most abundant enzymes responsible for the proteolytic activity during different processes like germination, development and senescence in plants. To identify and characterize C1A cysteine proteases of barley with a potential role in defense, mRNA and protein expression patterns were analyzed in response to biotics stresses. A barley cysteine protease, HvPap-1, previously related to abiotic stresses and grain germination, was particularly induced by flagellin or chitosan elicitation, and biotic stresses such as the phytopathogenic fungus Magnaporthe oryzae or the phytophagous mite Tetranychus urticae. To elucidate the in vivo participation of this enzyme in defense, transformed barley plants overexpressing or silencing HvPap-1 encoding gene were subjected to M. oryzae infection or T. urticae infestation. Whereas overexpressing plants were less susceptible to the fungus than silencing plants, the opposite behavior occurred to the mite. This unexpected result highlights the complexity of the regulatory events leading to the response to a particular biotic stress. PMID:28955371

  6. HvPap-1 C1A Protease Participates Differentially in the Barley Response to a Pathogen and an Herbivore

    Directory of Open Access Journals (Sweden)

    Mercedes Diaz-Mendoza

    2017-09-01

    Full Text Available Co-evolutionary processes in plant–pathogen/herbivore systems indicate that protease inhibitors have a particular value in biotic interactions. However, little is known about the defensive role of their targets, the plant proteases. C1A cysteine proteases are the most abundant enzymes responsible for the proteolytic activity during different processes like germination, development and senescence in plants. To identify and characterize C1A cysteine proteases of barley with a potential role in defense, mRNA and protein expression patterns were analyzed in response to biotics stresses. A barley cysteine protease, HvPap-1, previously related to abiotic stresses and grain germination, was particularly induced by flagellin or chitosan elicitation, and biotic stresses such as the phytopathogenic fungus Magnaporthe oryzae or the phytophagous mite Tetranychus urticae. To elucidate the in vivo participation of this enzyme in defense, transformed barley plants overexpressing or silencing HvPap-1 encoding gene were subjected to M. oryzae infection or T. urticae infestation. Whereas overexpressing plants were less susceptible to the fungus than silencing plants, the opposite behavior occurred to the mite. This unexpected result highlights the complexity of the regulatory events leading to the response to a particular biotic stress.

  7. Isolated oedema of the uvula induced by intense snoring and ACE inhibitor

    DEFF Research Database (Denmark)

    Rasmussen, Eva Rye; Mey, Kristianna; Bygum, Anette

    2014-01-01

    A case of snoring-induced angioedema of uvula is described in a patient who was treated with ACE inhibitor. The patient partially responded to complement C1-inhibitor concentrate and did not suffer any recurrences after the medication was withdrawn. When encountering a patient suffering from...

  8. Vitamin B12 deficiency

    DEFF Research Database (Denmark)

    Green, Ralph; Allen, Lindsay H; Bjørke-Monsen, Anne-Lise

    2017-01-01

    Vitamin B12 (B12; also known as cobalamin) is a B vitamin that has an important role in cellular metabolism, especially in DNA synthesis, methylation and mitochondrial metabolism. Clinical B12 deficiency with classic haematological and neurological manifestations is relatively uncommon. However...... remain debated. Management depends on B12 supplementation, either via high-dose oral routes or via parenteral administration. This Primer describes the current knowledge surrounding B12 deficiency, and highlights improvements in diagnostic methods as well as shifting concepts about the prevalence, causes...

  9. Multiple sulfatase deficiency.

    Science.gov (United States)

    Soong, B W; Casamassima, A C; Fink, J K; Constantopoulos, G; Horwitz, A L

    1988-08-01

    Multiple sulfatase deficiency is an inherited disorder characterized by a deficiency of several sulfatases and the accumulation of sulfatides, glycosaminoglycans, sphingolipids, and steroid sulfates in tissues and body fluids. The clinical manifestations represent the summation of two diseases: late infantile metachromatic leukodystrophy and mucopolysaccharidosis. We present a 9-year-old girl with a phenotype similar to a mucopolysaccharidosis: short stature, microcephaly, and mild facial dysmorphism, along with dysphagia, retinal degeneration, developmental arrest, and ataxia. We discuss the importance of measuring the sulfatase activities in the leukocytes, and the instability of sulfatases in the cultured skin fibroblasts.

  10. Iodine Deficiency and Human Development

    Directory of Open Access Journals (Sweden)

    M A Sviridonova

    2014-03-01

    Full Text Available Iodine is а vital microelements that are essential for the normal human development and functions. Iodine deficiency is a global problem: about 2 billion individuals worldwide suffer from a lack of iodine. Despite goiter is the most visually noticeable manifestation of iodine deficiency, the most significant consequence of the iodine deficiency is impaired neurodevelopment, particularly early in life. Moreover, moderate to severe iodine deficiency increases the risk of spontaneous abortion, low birth weight and infant mortality. Babies in utero affected by iodine deficiency are at increased risk of mental developmental disorders, cretinism is their extreme degree. In addition, moderate to severe iodine deficiency in childhood negatively affects somatic growth. Iodine deficiency compensation improves cognitive and motor function in children. Iodine prophylaxis of deficient populations is an extremely effective approach to reduce the substantial adverse effects of iodine deficiency throughout the life cycle.

  11. Plasminogen activation independent of uPA and tPA maintains wound healing in gene-deficient mice

    DEFF Research Database (Denmark)

    Lund, Leif R; Green, Kirsty A; Stoop, Allart A

    2006-01-01

    Simultaneous ablation of the two known activators of plasminogen (Plg), urokinase-type (uPA) and the tissue-type (tPA), results in a substantial delay in skin wound healing. However, wound closure and epidermal re-epithelialization are significantly less impaired in uPA;tPA double-deficient mice...... than in Plg-deficient mice. Skin wounds in uPA;tPA-deficient mice treated with the broad-spectrum matrix metalloproteinase (MMP) inhibitor galardin (N-[(2R)-2-(hydroxamido-carbonylmethyl)-4-methylpentanoyl]-L-tryptophan methylamide) eventually heal, whereas skin wounds in galardin-treated Plg......-deficient mice do not heal. Furthermore, plasmin is biochemically detectable in wound extracts from uPA;tPA double-deficient mice. In vivo administration of a plasma kallikrein (pKal)-selective form of the serine protease inhibitor ecotin exacerbates the healing impairment of uPA;tPA double-deficient wounds...

  12. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... your red blood cells don't contain enough hemoglobin (HEE-muh-glow-bin). Hemoglobin is an iron-rich protein that carries oxygen ... red blood cells it does make have less hemoglobin than normal. Iron-deficiency anemia can cause fatigue ( ...

  13. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Every 5 to 10 years. Women who have risk factors for iron deficiency: Once a year. Pregnant women: At the first prenatal visit. For pregnant women, medical care during pregnancy usually includes screening for anemia. Also, your doctor ...

  14. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Severe iron-deficiency anemia can lead to heart problems, infections, problems with growth and development in children, and other ... poorly because of money, social, health, or other problems. Follow a very low-fat diet over a ...

  15. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... deficiency anemia if they're underweight or have chronic (ongoing) illnesses. Teenage girls who have heavy periods ... because blood is lost during dialysis. Also, the kidneys are no longer able to make ... Centers for Disease Control and Prevention (CDC) has developed guidelines for ...

  16. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... iron-rich foods in the diet. Too much milk also may prevent children's bodies from absorbing iron from other foods. Children who have lead in their blood also may be at risk for iron-deficiency anemia. Lead can interfere with the body's ability to make hemoglobin. Lead may get into the body from ...

  17. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... also may help treat iron-deficiency anemia. Medical History Your doctor will ask about your signs and symptoms and any past problems you've had with anemia or low iron. He or she also may ask about your diet and whether you're taking any medicines. If ...

  18. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Site Health Topics News & Resources Intramural Research ... Is Iron-deficiency anemia is a common, easily treated condition that occurs if you don't have enough iron in your body. Low iron levels usually are due to blood loss, ...

  19. Deficiency Report Management System

    Science.gov (United States)

    1989-09-28

    The Customer Feedback Office of the Product Assurance Directorate, MICOM has the mission to manage and analyze data in the Deficiency Reporting...capability within the Customer Feedback Office (CFO) of the MICOM Product Assurance Directorate for government comment. The objective of this program is

  20. Partial Biotinidase Deficiency

    OpenAIRE

    J Gordon Millichap

    1990-01-01

    The symptoms, biochemical features and inheritance pattern of partial biotinidase deficiency have been studied at the Departments of Human Genetics and Pediatrics, Medical College of Virginia, Richmond, VA; the State Laboratory Institute, Massachusetts Department of Public Health; Massachusetts General Hospital, Boston; the Lincoln Clinic, NB; and the Division of Human Genetics, university of Maryland School of Medicine, Baltimore.

  1. Iodine-deficiency disorders

    NARCIS (Netherlands)

    Zimmermann, M.B.; Jooste, P.L.; Pandav, C.S.

    2008-01-01

    billion individuals worldwide have insufficient iodine intake, with those in south Asia and sub-Saharan Africa particularly affected. Iodine deficiency has many adverse effects on growth and development. These effects are due to inadequate production of thyroid hormone and are termed

  2. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Activity Population and Epidemiology Studies Women’s Health All Science A-Z ... usually are due to blood loss, poor diet, or an inability to absorb enough iron from food. Overview Iron-deficiency anemia is a common type ...

  3. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... doctor may ask whether you might be pregnant. Physical Exam Your doctor will do a physical exam to look for signs of iron-deficiency ... remove the growth. If you have heavy menstrual flow, your doctor may prescribe birth control pills to ...

  4. Alpha-1 antitrypsin deficiency

    Science.gov (United States)

    ... Tools About MedlinePlus Show Search Search MedlinePlus GO GO About MedlinePlus Site Map FAQs Customer Support Health Topics Drugs & Supplements Videos & Tools Español You Are Here: Home → Medical Encyclopedia → Alpha-1 antitrypsin deficiency URL of this page: //medlineplus. ...

  5. Vitamin B12 deficiency

    Science.gov (United States)

    Vitamin B12 (B12; also known as cobalamin) is a B vitamin that has an important role in cellular metabolism, especially in DNA synthesis, methylation and mitochondrial metabolism. Clinical B12 deficiency with classic haematological and neurological manifestations is relatively uncommon. However, sub...

  6. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... hospital, blood transfusions , iron injections, or intravenous iron therapy. Causes Not having enough iron in your body causes iron-deficiency anemia. Lack of iron usually is due to blood loss, poor diet, or an inability to absorb enough iron from ...

  7. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... blood transfusions , iron injections, or intravenous iron therapy. Rate This Content: NEXT >> Featured Video Living With and Managing Iron-Deficiency Anemia 05/18/2011 This video—presented by the National Heart, Lung, and Blood Institute, part of the National ...

  8. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... who have iron-deficiency anemia develop restless legs syndrome (RLS). RLS is a disorder that causes a ... Topics Anemia Blood Tests Blood Transfusion Restless Legs Syndrome Other Resources Non-NHLBI Resources Anemia (MedlinePlus) "Dietary ...

  9. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... the body. Iron-deficiency anemia usually develops over time if your body doesn't have enough iron ... Institutes of Health—shows how Susan, a full-time worker and student, has coped with having iron- ...

  10. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... woman's risk for a premature or low-birth-weight baby. Adults Who Have Internal Bleeding Adults who have internal bleeding, such as intestinal bleeding, can develop iron-deficiency anemia due to blood loss. Certain conditions, such as colon cancer and bleeding ...

  11. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... as larger, full-term infants. Iron-fortified baby food or iron supplements, when used properly, can help prevent iron-deficiency ... Syndrome Other Resources Non-NHLBI Resources Anemia (MedlinePlus) "Dietary Supplement Fact Sheet: Iron" (Office of Dietary Supplements, National ...

  12. Placement of C1 Pedicle Screws Using Minimal Exposure: Radiographic, Clinical, and Literature Validation.

    Science.gov (United States)

    Menger, Richard P; Storey, Christopher M; Nixon, Menarvia K C; Haydel, Justin; Nanda, Anil; Sin, Anthony

    2015-01-01

    Traditional C1-2 fixation involves placement of C1 lateral mass screws. Evolving techniques have led to the placement of C1 pedicle screws to avoid exposure of the C1-C2 joint capsule. Our minimal dissection technique utilizes anatomical landmarks with isolated exposure of C2 and the inferior posterior arch of C1. We evaluate this procedure clinically and radiographically through a technical report. Consecutive cases of cranial-vertebral junction surgery were reviewed for one fellowship trained spinal surgeon from 2008-2014. Information regarding sex, age, indication for surgery, private or public hospital, intra-operative complications, post-operative neurological deterioration, death, and failure of fusion was extracted. Measurement of pre-operative axial and sagittal CT scans were performed for C1 pedicle width and C1 posterior arch height respectively. 64 patients underwent posterior cranio-vertebral junction fixation surgery. 40 of these patients underwent occipital-cervical fusion procedures. 7/9 (77.8%) C1 instrumentation cases were from trauma with the remaining two (22.2%) from oncologic lesions. The average blood loss among isolated C1-C2 fixation was 160cc. 1/9 patients (11.1%) suffered pedicle breech requiring sub-laminar wiring at the C1 level. On radiographic measurement, the average height of the C1 posterior arch was noted at 4.3mm (range 3.8mm to 5.7mm). The average width of the C1 pedicle measured at 5.3mm (range 2.8 to 8.7mm). The patient with C1 pedicle screw failure had a pedicle width of 2.78mm on pre-operative axial CT imaging. Our study directly adds to the literature with level four evidence supporting a minimal dissection of C1 arch in the placement of C1 pedicle screws with both radiographic and clinical validation. Justification of this technique avoids C2 nerve root manipulation or sacrifice, reduces bleeding associated with the venous plexus, and leaves the third segment of the vertebral artery unexplored. Pre-operative review of

  13. Estimation of immune complexes by a microplate-adapted C1q-Protein A enzyme-linked-immunosorbent-assay (C1q-PA-ELISA)

    DEFF Research Database (Denmark)

    Bjerrum, L; Glikmann, G; Jensenius, J C

    1983-01-01

    A microplate-adapted enzyme linked immunosorbent assay (ELISA) for detection of C1q-binding immune complexes (IC) and aggregated IgG (delta IgG) is described. Purified human C1q was adsorbed to the wells of flat-bottomed microtiter plates and EDTA-treated serum samples were subsequently introduced....... Bound IC was measured by use of alkaline phosphatase-labelled Protein A followed by the substrate para-nitro-phenyl-phosphate. A dose response was found for both delta IgG and BSA anti-BSA complexes, while variations in the concentration of monomer IgG did not affect the optical density. Elevated levels...... of IC were found in the majority of sera from patients with rheumatoid arthritis and SLE. The described C1q-PA-ELISA is a simple and inexpensive method for detection of C1q-binding immune complexes. The reproducibility is acceptable and the sensitivity is higher than for most IC-methods based on C1q-binding....

  14. Observation of $B^0_s\\rightarrow\\chi_{c1}\\phi$ decay and study of $B^0\\rightarrow\\chi_{c1,2}K^{*0}$ decays

    CERN Document Server

    INSPIRE-00258707; Adeva, B; Adinolfi, M; Adrover, C; Affolder, A; Ajaltouni, Z; Albrecht, J; Alessio, F; Alexander, M; Ali, S; Alkhazov, G; Alvarez Cartelle, P; Alves Jr, A A; Amato, S; Amerio, S; Amhis, Y; Anderlini, L; Anderson, J; Andreassen, R; Andrews, J E; Appleby, R B; Aquines Gutierrez, O; Archilli, F; Artamonov, A; Artuso, M; Aslanides, E; Auriemma, G; Baalouch, M; Bachmann, S; Back, J J; Baesso, C; Balagura, V; Baldini, W; Barlow, R J; Barschel, C; Barsuk, S; Barter, W; Bauer, Th; Bay, A; Beddow, J; Bedeschi, F; Bediaga, I; Belogurov, S; Belous, K; Belyaev, I; Ben-Haim, E; Bencivenni, G; Benson, S; Benton, J; Berezhnoy, A; Bernet, R; Bettler, M -O; van Beuzekom, M; Bien, A; Bifani, S; Bird, T; Bizzeti, A; Bjørnstad, P M; Blake, T; Blanc, F; Blouw, J; Blusk, S; Bocci, V; Bondar, A; Bondar, N; Bonivento, W; Borghi, S; Borgia, A; Bowcock, T J V; Bowen, E; Bozzi, C; Brambach, T; van den Brand, J; Bressieux, J; Brett, D; Britsch, M; Britton, T; Brook, N H; Brown, H; Burducea, I; Bursche, A; Busetto, G; Buytaert, J; Cadeddu, S; Callot, O; Calvi, M; Calvo Gomez, M; Camboni, A; Campana, P; Campora Perez, D; Carbone, A; Carboni, G; Cardinale, R; Cardini, A; Carranza-Mejia, H; Carson, L; Carvalho Akiba, K; Casse, G; Castillo Garcia, L; Cattaneo, M; Cauet, Ch; Cenci, R; Charles, M; Charpentier, Ph; Chen, P; Chiapolini, N; Chrzaszcz, M; Ciba, K; Cid Vidal, X; Ciezarek, G; Clarke, P E L; Clemencic, M; Cliff, H V; Closier, J; Coca, C; Coco, V; Cogan, J; Cogneras, E; Collins, P; Comerma-Montells, A; Contu, A; Cook, A; Coombes, M; Coquereau, S; Corti, G; Couturier, B; Cowan, G A; Craik, D C; Cunliffe, S; Currie, R; D'Ambrosio, C; David, P; David, P N Y; Davis, A; De Bonis, I; De Bruyn, K; De Capua, S; De Cian, M; De Miranda, J M; De Paula, L; De Silva, W; De Simone, P; Decamp, D; Deckenhoff, M; Del Buono, L; Déléage, N; Derkach, D; Deschamps, O; Dettori, F; Di Canto, A; Di Ruscio, F; Dijkstra, H; Dogaru, M; Donleavy, S; Dordei, F; Dosil Suárez, A; Dossett, D; Dovbnya, A; Dupertuis, F; Dzhelyadin, R; Dziurda, A; Dzyuba, A; Easo, S; Egede, U; Egorychev, V; Eidelman, S; van Eijk, D; Eisenhardt, S; Eitschberger, U; Ekelhof, R; Eklund, L; El Rifai, I; Elsasser, Ch; Elsby, D; Falabella, A; Färber, C; Fardell, G; Farinelli, C; Farry, S; Fave, V; Ferguson, D; Fernandez Albor, V; Ferreira Rodrigues, F; Ferro-Luzzi, M; Filippov, S; Fiore, M; Fitzpatrick, C; Fontana, M; Fontanelli, F; Forty, R; Francisco, O; Frank, M; Frei, C; Frosini, M; Furcas, S; Furfaro, E; Gallas Torreira, A; Galli, D; Gandelman, M; Gandini, P; Gao, Y; Garofoli, J; Garosi, P; Garra Tico, J; Garrido, L; Gaspar, C; Gauld, R; Gersabeck, E; Gersabeck, M; Gershon, T; Ghez, Ph; Gibson, V; Giubega, L; Gligorov, V V; Göbel, C; Golubkov, D; Golutvin, A; Gomes, A; Gordon, H; Grabalosa Gándara, M; Graciani Diaz, R; Granado Cardoso, L A; Graugés, E; Graziani, G; Grecu, A; Greening, E; Gregson, S; Griffith, P; Grünberg, O; Gui, B; Gushchin, E; Guz, Yu; Gys, T; Hadjivasiliou, C; Haefeli, G; Haen, C; Haines, S C; Hall, S; Hamilton, B; Hampson, T; Hansmann-Menzemer, S; Harnew, N; Harnew, S T; Harrison, J; Hartmann, T; He, J; Head, T; Heijne, V; Hennessy, K; Henrard, P; Hernando Morata, J A; van Herwijnen, E; Hicheur, A; Hicks, E; Hill, D; Hoballah, M; Holtrop, M; Hombach, C; Hopchev, P; Hulsbergen, W; Hunt, P; Huse, T; Hussain, N; Hutchcroft, D; Hynds, D; Iakovenko, V; Idzik, M; Ilten, P; Jacobsson, R; Jaeger, A; Jans, E; Jaton, P; Jawahery, A; Jing, F; John, M; Johnson, D; Jones, C R; Joram, C; Jost, B; Kaballo, M; Kandybei, S; Kanso, W; Karacson, M; Karbach, T M; Kenyon, I R; Ketel, T; Keune, A; Khanji, B; Kochebina, O; Komarov, I; Koopman, R F; Koppenburg, P; Korolev, M; Kozlinskiy, A; Kravchuk, L; Kreplin, K; Kreps, M; Krocker, G; Krokovny, P; Kruse, F; Kucharczyk, M; Kudryavtsev, V; Kvaratskheliya, T; La Thi, V N; Lacarrere, D; Lafferty, G; Lai, A; Lambert, D; Lambert, R W; Lanciotti, E; Lanfranchi, G; Langenbruch, C; Latham, T; Lazzeroni, C; Le Gac, R; van Leerdam, J; Lees, J -P; Lefèvre, R; Leflat, A; Lefrançois, J; Leo, S; Leroy, O; Lesiak, T; Leverington, B; Li, Y; Li Gioi, L; Liles, M; Lindner, R; Linn, C; Liu, B; Liu, G; Lohn, S; Longstaff, I; Lopes, J H; Lopez-March, N; Lu, H; Lucchesi, D; Luisier, J; Luo, H; Machefert, F; Machikhiliyan, I V; Maciuc, F; Maev, O; Malde, S; Manca, G; Mancinelli, G; Marconi, U; Märki, R; Marks, J; Martellotti, G; Martens, A; Martín Sánchez, A; Martinelli, M; Martinez Santos, D; Martins Tostes, D; Massafferri, A; Matev, R; Mathe, Z; Matteuzzi, C; Maurice, E; Mazurov, A; Mc Skelly, B; McCarthy, J; McNab, A; McNulty, R; Meadows, B; Meier, F; Meissner, M; Merk, M; Milanes, D A; Minard, M -N; Molina Rodriguez, J; Monteil, S; Moran, D; Morawski, P; Mordà, A; Morello, M J; Mountain, R; Mous, I; Muheim, F; Müller, K; Muresan, R; Muryn, B; Muster, B; Naik, P; Nakada, T; Nandakumar, R; Nasteva, I; Needham, M; Neubert, S; Neufeld, N; Nguyen, A D; Nguyen, T D; Nguyen-Mau, C; Nicol, M; Niess, V; Niet, R; Nikitin, N; Nikodem, T; Nomerotski, A; Novoselov, A; Oblakowska-Mucha, A; Obraztsov, V; Oggero, S; Ogilvy, S; Okhrimenko, O; Oldeman, R; Orlandea, M; Otalora Goicochea, J M; Owen, P; Oyanguren, A; Pal, B K; Palano, A; Palutan, M; Panman, J; Papanestis, A; Pappagallo, M; Parkes, C; Parkinson, C J; Passaleva, G; Patel, G D; Patel, M; Patrick, G N; Patrignani, C; Pavel-Nicorescu, C; Pazos Alvarez, A; Pellegrino, A; Penso, G; Pepe Altarelli, M; Perazzini, S; Perez Trigo, E; Pérez-Calero Yzquierdo, A; Perret, P; Perrin-Terrin, M; Pessina, G; Petridis, K; Petrolini, A; Phan, A; Picatoste Olloqui, E; Pietrzyk, B; Pilař, T; Pinci, D; Playfer, S; Plo Casasus, M; Polci, F; Polok, G; Poluektov, A; Polyakov, I; Polycarpo, E; Popov, A; Popov, D; Popovici, B; Potterat, C; Powell, A; Prisciandaro, J; Pritchard, A; Prouve, C; Pugatch, V; Puig Navarro, A; Punzi, G; Qian, W; Rademacker, J H; Rakotomiaramanana, B; Rangel, M S; Raniuk, I; Rauschmayr, N; Raven, G; Redford, S; Reid, M M; dos Reis, A C; Ricciardi, S; Richards, A; Rinnert, K; Rives Molina, V; Roa Romero, D A; Robbe, P; Rodrigues, E; Rodriguez Perez, P; Roiser, S; Romanovsky, V; Romero Vidal, A; Rouvinet, J; Ruf, T; Ruffini, F; Ruiz, H; Ruiz Valls, P; Sabatino, G; Saborido Silva, J J; Sagidova, N; Sail, P; Saitta, B; Salustino Guimaraes, V; Salzmann, C; Sanmartin Sedes, B; Sannino, M; Santacesaria, R; Santamarina Rios, C; Santovetti, E; Sapunov, M; Sarti, A; Satriano, C; Satta, A; Savrie, M; Savrina, D; Schaack, P; Schiller, M; Schindler, H; Schlupp, M; Schmelling, M; Schmidt, B; Schneider, O; Schopper, A; Schune, M -H; Schwemmer, R; Sciascia, B; Sciubba, A; Seco, M; Semennikov, A; Sepp, I; Serra, N; Serrano, J; Seyfert, P; Shapkin, M; Shapoval, I; Shatalov, P; Shcheglov, Y; Shears, T; Shekhtman, L; Shevchenko, O; Shevchenko, V; Shires, A; Silva Coutinho, R; Sirendi, M; Skwarnicki, T; Smith, N A; Smith, E; Smith, J; Smith, M; Sokoloff, M D; Soler, F J P; Soomro, F; Souza, D; Souza De Paula, B; Spaan, B; Sparkes, A; Spradlin, P; Stagni, F; Stahl, S; Steinkamp, O; Stoica, S; Stone, S; Storaci, B; Straticiuc, M; Straumann, U; Subbiah, V K; Sun, L; Swientek, S; Syropoulos, V; Szczekowski, M; Szczypka, P; Szumlak, T; T'Jampens, S; Teklishyn, M; Teodorescu, E; Teubert, F; Thomas, C; Thomas, E; van Tilburg, J; Tisserand, V; Tobin, M; Tolk, S; Tonelli, D; Topp-Joergensen, S; Torr, N; Tournefier, E; Tourneur, S; Tran, M T; Tresch, M; Tsaregorodtsev, A; Tsopelas, P; Tuning, N; Ubeda Garcia, M; Ukleja, A; Urner, D; Ustyuzhanin, A; Uwer, U; Vagnoni, V; Valenti, G; Vallier, A; Van Dijk, M; Vazquez Gomez, R; Vazquez Regueiro, P; Vázquez Sierra, C; Vecchi, S; Velthuis, J J; Veltri, M; Veneziano, G; Vesterinen, M; Viaud, B; Vieira, D; Vilasis-Cardona, X; Vollhardt, A; Volyanskyy, D; Voong, D; Vorobyev, A; Vorobyev, V; Voß, C; Voss, H; Waldi, R; Wallace, C; Wallace, R; Wandernoth, S; Wang, J; Ward, D R; Watson, N K; Webber, A D; Websdale, D; Whitehead, M; Wicht, J; Wiechczynski, J; Wiedner, D; Wiggers, L; Wilkinson, G; Williams, M P; Williams, M; Wilson, F F; Wimberley, J; Wishahi, J; Witek, M; Wotton, S A; Wright, S; Wu, S; Wyllie, K; Xie, Y; Xing, Z; Yang, Z; Young, R; Yuan, X; Yushchenko, O; Zangoli, M; Zavertyaev, M; Zhang, F; Zhang, L; Zhang, W C; Zhang, Y; Zhelezov, A; Zhokhov, A; Zhong, L; Zvyagin, A

    2013-01-01

    The first observation of the decay $B^0_s\\rightarrow\\chi_{c1}\\phi$ and a study of $B^0\\rightarrow\\chi_{c1,2}K^{*0}$ decays are presented. The analysis is performed using a dataset, corresponding to an integrated luminosity of 1.0 fb$^{-1}$, collected by the LHCb experiment in pp collisions at a centre-of-mass energy of 7 TeV. The following ratios of branching fractions are measured: \\begin{equation*} \\begin{array}{lll} \\dfrac{\\cal{B}(B^0_s\\rightarrow\\chi_{c1}\\phi)}{\\cal{B}(B^0_s\\rightarrow J/\\psi\\phi)} &=& (18.9 \\pm1.8\\,(stat)\\pm1.3\\,(syst)\\pm0.8\\,(\\cal{B})) \\times 10^{-2}, \\\\ \\dfrac{\\cal{B}(B^0\\rightarrow\\chi_{c1}K^{*0})}{\\cal{B}(B^0\\rightarrow J/\\psi K^{*0})} &=& (19.8 \\pm1.1\\,(stat)\\pm1.2\\,(syst)\\pm0.9\\,(\\cal{B})) \\times 10^{-2}, \\\\ \\dfrac{\\cal{B}(B^0\\rightarrow\\chi_{c2}K^{*0})}{\\cal{B}(B^0\\rightarrow\\chi_{c 1}K^{*0})} &=& (17.1 \\pm5.0\\,(stat)\\pm1.7\\,(syst)\\pm1.1\\,(\\cal{B})) \\times 10^{-2}, \\\\ \\end{array} \\end{equation*} where the third uncertainty is due to the limited knowledge o...

  15. Glucose-6-phosphate dehydrogenase deficiency

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/000528.htm Glucose-6-phosphate dehydrogenase deficiency To use the sharing features on this page, please enable JavaScript. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a condition ...

  16. Genetics Home Reference: transcobalamin deficiency

    Science.gov (United States)

    ... PH, Nordwall M, Hoffmann-Lücke E, Sorensen BS, Nexo E. Transcobalamin deficiency caused by compound heterozygosity for ... Hung C, Rupar T, Mühl A, Fowler B, Nexo E, Bodamer OA. Transcobalamin II deficiency at birth. ...

  17. Genetics Home Reference: proopiomelanocortin deficiency

    Science.gov (United States)

    ... due to pomc deficiency Orphanet: Obesity due to pro-opiomelanocortin deficiency Patient Support and Advocacy Resources (4 ... HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, ...

  18. Growth Hormone Deficiency in Children

    Science.gov (United States)

    ... c m y one in Children What is growth hormone deficiency? Growth hormone deficiency (GHD) is a rare condition in which the body does not make enough growth hormone (GH). GH is made by the pituitary gland, ...

  19. Growth Hormone Deficiency in Adults

    Science.gov (United States)

    ... Balance › Growth Hormone Deficiency in Adults Patient Guide Growth Hormone Deficiency in Adults June 2011 Download PDFs English ... depression, or moodiness What are the benefits of growth hormone therapy? Growth hormone treatment involves injections (shots) of ...

  20. Covalent binding of quinones activates the Ah receptor in Hepa1c1c7 cells.

    Science.gov (United States)

    Abiko, Yumi; Puga, Alvaro; Kumagai, Yoshito

    2015-12-01

    Highly reactive quinone species produced by photooxidation and/or metabolic activation of mono- or bi-aromatic hydrocarbons modulate cellular homeostasis and electrophilic signal transduction pathways through the covalent modification of proteins. Polycyclic aromatic hydrocarbons, but not mono- or bi-aromatic hydrocarbons, are well recognized as ligands for the aryl hydrocarbon receptor (AhR). However, quinone species produced from mono- and bi-aromatic hydrocarbons could potentially cause AhR activation. To clarify the AhR response to mono- and bi-aromatic hydrocarbon quinones, we studied Cyp1a1 (cytochrome P450 1A1) induction and AhR activation by these quinones. We detected Cyp1a1 induction during treatment with quinones in Hepa1c1c7 cells, but not their parent compounds. Nine of the twelve quinones with covalent binding capability for proteins induced Cyp1a1. Cyp1a1 induction mediated by 1,2-naphthoquinone (1,2-NQ), 1,4-NQ, 1,4-benzoquinone (1,4-BQ) and tert-butyl-1,4-BQ was suppressed by a specific AhR inhibitor and was not observed in c35 cells, which do not have a functional AhR. These quinones stimulated AhR nuclear translocation and interaction with the AhR nuclear translocator. Interestingly, 1,2-NQ covalently modified AhR, which was detected by an immunoprecipitation assay using a specific antibody against 1,2-NQ, resulting in enhancement of xenobiotic responsive element (XRE)-derived luciferase activity and binding of AhR to the Cyp1a1 promoter region. While mono- and bi-aromatic hydrocarbons are generally believed to be poor ligands for AhR and hence unable to induce Cyp1a1, our study suggests that the quinones of these molecules are able to modify AhR and activate the AhR/XRE pathway, thereby inducing Cyp1a1. Since we previously reported that 1,2-NQ and tert-butyl-1,4-BQ also activate NF-E2-related factor 2, it seems likely that some of quinones are bi-functional inducers for phase-I and phase-II reaction of xenobiotics.

  1. The C1q family of proteins: insights into the emerging non-traditional functions

    Directory of Open Access Journals (Sweden)

    Berhane eGhebrehiwet

    2012-04-01

    Full Text Available Research conducted over the past 20 years have helped us unravel not only the hidden structural and functional subtleties of human C1q, but also has catapulted the molecule from a mere recognition unit of the classical pathway to a well-recognized molecular sensor of damage modified self or non-self antigens. Thus, C1q is involved in a rapidly expanding list of pathological disorders—including autoimmunity, trophoblast migration, preeclampsia and cancer. The results of two recent reports are provided to underscore the critical role C1q plays in health and disease. First is the observation by Singh and colleagues showing that pregnant C1q-/- mice recapitulate the key features of human preeclampsia that correlate with increased fetal death. Treatment of the C1q-/- mice with pravastatin restored trophoblast invasiveness, placental blood flow, and angiogenic balance and, thus, prevented the onset of preeclampsia. Second is the report by Hong et al., which showed that C1q can induce apoptosis of prostate cancer cells by activating the tumor suppressor molecule WW-domain containing oxydoreductase (WWOX or WOX1 and destabilizing cell adhesion. Downregulation of C1q on the other hand enhanced prostate hyperplasia and cancer formation due to failure of WOX1 activation. Recent evidence also shows that C1q belongs to a family of structurally and functionally related TNFα-like family of proteins that may have arisen from a common ancestral gene. Therefore C1q not only shares the diverse functions with the TNF family of proteins, but also explains why C1q has retained some of its ancestral cytokine-like activities. This review is intended to highlight some of the structural and functional aspects of C1q by underscoring the growing list of its non-traditional functions.

  2. Testosterone: action, deficiency, substitution

    National Research Council Canada - National Science Library

    Nieschlag, E; Nieschlag, S. (Susan); Behre, H. M. (Hermann M.)

    2004-01-01

    ... reviews applications in male contraception, the role of 5 -reductase inhibitors and the controversial use of DHEA. For this book the editors have assembled the world leaders in testosterone research and clinical andrology and endocrinology. A special feature of the book is the fact that its 24 chapters were submitted simultaneously to ens...

  3. Iron deficiency and cognitive functions

    Directory of Open Access Journals (Sweden)

    Jáuregui-Lobera I

    2014-11-01

    Full Text Available Ignacio Jáuregui-Lobera Department of Nutrition and Bromatology, Pablo de Olavide University, Seville, Spain Abstract: Micronutrient deficiencies, especially those related to iodine and iron, are linked to different cognitive impairments, as well as to potential long-term behavioral changes. Among the cognitive impairments caused by iron deficiency, those referring to attention span, intelligence, and sensory perception functions are mainly cited, as well as those associated with emotions and behavior, often directly related to the presence of iron deficiency anemia. In addition, iron deficiency without anemia may cause cognitive disturbances. At present, the prevalence of iron deficiency and iron deficiency anemia is 2%–6% among European children. Given the importance of iron deficiency relative to proper cognitive development and the alterations that can persist through adulthood as a result of this deficiency, the objective of this study was to review the current state of knowledge about this health problem. The relevance of iron deficiency and iron deficiency anemia, the distinction between the cognitive consequences of iron deficiency and those affecting specifically cognitive development, and the debate about the utility of iron supplements are the most relevant and controversial topics. Despite there being methodological differences among studies, there is some evidence that iron supplementation improves cognitive functions. Nevertheless, this must be confirmed by means of adequate follow-up studies among different groups. Keywords: iron deficiency, anemia, cognitive functions, supplementation

  4. 26 CFR 1.641(c)-1 - Electing small business trust.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Electing small business trust. 1.641(c)-1...) INCOME TAX (CONTINUED) INCOME TAXES Estates, Trusts, and Beneficiaries § 1.641(c)-1 Electing small business trust. (a) In general. An electing small business trust (ESBT) within the meaning of section 1361...

  5. C1 polymerisation and related C-C bond forming ‘carbene insertion’ reactions

    NARCIS (Netherlands)

    Jellema, E.; Jongerius, A.L.; Reek, J.N.H.; de Bruin, B.

    2010-01-01

    In this critical review we summarise the currently available ‘C1 polymerisation’ techniques as valuable alternatives for ‘C2 polymerisation’ in the preparation of saturated main-chain carbon-based polymers. C1 polymerisation involves the growth of polymers from monomers delivering only one

  6. Stereoselective synthesis and absolute configuration of the C1'-C25' fragment of symbiodinolide.

    Science.gov (United States)

    Takamura, Hiroyoshi; Murata, Takeshi; Asai, Takahiro; Kadota, Isao; Uemura, Daisuke

    2009-09-04

    Stereoselective synthesis of the C1'-C25' fragment of symbiodinolide, which was obtained as a degraded product from symbiodinolide by alkaline hydrolysis, has been accomplished. The synthetic route features Kotsuki coupling and Julia-Kocienski olefination in the introduction of the side chains. This enantio- and stereoselective synthesis has established the absolute configuration of the C1'-C25' fragment.

  7. Differential regulation of Aβ42-induced neuronal C1q synthesis and microglial activation

    Directory of Open Access Journals (Sweden)

    Tenner Andrea J

    2005-01-01

    Full Text Available Abstract Expression of C1q, an early component of the classical complement pathway, has been shown to be induced in neurons in hippocampal slices, following accumulation of exogenous Aβ42. Microglial activation was also detected by surface marker expression and cytokine production. To determine whether C1q induction was correlated with intraneuronal Aβ and/or microglial activation, D-(--2-amino-5-phosphonovaleric acid (APV, an NMDA receptor antagonist and glycine-arginine-glycine-aspartic acid-serine-proline peptide (RGD, an integrin receptor antagonist, which blocks and enhances Aβ42 uptake, respectively, were assessed for their effect on neuronal C1q synthesis and microglial activation. APV inhibited, and RGD enhanced, microglial activation and neuronal C1q expression. However, addition of Aβ10–20 to slice cultures significantly reduced Aβ42 uptake and microglial activation, but did not alter the Aβ42-induced neuronal C1q expression. Furthermore, Aβ10–20 alone triggered C1q production in neurons, demonstrating that neither neuronal Aβ42 accumulation, nor microglial activation is required for neuronal C1q upregulation. These data are compatible with the hypothesis that multiple receptors are involved in Aβ injury and signaling in neurons. Some lead to neuronal C1q induction, whereas other(s lead to intraneuronal accumulation of Aβ and/or stimulation of microglia.

  8. Autoantibodies against C1q in systemic lupus erythematosus are antigen-driven

    DEFF Research Database (Denmark)

    Schaller, Monica; Bigler, Cornelia; Danner, Doris

    2009-01-01

    Autoantibodies against complement C1q (anti-C1q Abs) were shown to strongly correlate with the occurrence of severe nephritis in patients with systemic lupus erythematosus (SLE), suggesting a potential pathogenic role by interfering with the complement cascade. To analyze the humoral immune...

  9. Amplitude analysis of the chi(c1) -> eta pi(+)pi(-) decays

    NARCIS (Netherlands)

    Haddadi, Z.; Kalantar-Nayestanaki, N.; Kavatsyuk, M.; Löhner, H.; Messchendorp, J. G.; Tiemens, M.

    2017-01-01

    Using 448.0 x 10(6) psi(3686) events collected with the BESIII detector, an amplitude analysis is performed for psi(3686) -> gamma chi(c1), chi(c1) ->eta pi(+)pi(-) decays. The most dominant two- body structure observed is a(0)(980)(+/-) pi(-/+); a(0)(980)(+/-) -> eta pi(+/-.) line shape is modeled

  10. 26 CFR 31.3405(c)-1 - Withholding on eligible rollover distributions; questions and answers.

    Science.gov (United States)

    2010-04-01

    ...; questions and answers. 31.3405(c)-1 Section 31.3405(c)-1 Internal Revenue INTERNAL REVENUE SERVICE... Withholding on eligible rollover distributions; questions and answers. The following questions and answers... received in a direct rollover? Questions and Answers Q-1: What are the withholding requirements under...

  11. Replication fork stability confers chemoresistance in BRCA-deficient cells

    DEFF Research Database (Denmark)

    Chaudhuri, Arnab Ray; Callen, Elsa; Ding, Xia

    2016-01-01

    nuclease to stalled replication forks, which in turn protects nascent DNA strands from extensive degradation. More generally, acquisition of PARP inhibitors and cisplatin resistance is associated with replication fork protection in Brca2-deficient tumour cells that do not develop Brca2 reversion mutations....... Disruption of multiple proteins, including PARP1 and CHD4, leads to the same end point of replication fork protection, highlighting the complexities by which tumour cells evade chemotherapeutic interventions and acquire drug resistance....

  12. Effect of resveratrol on c-fos expression of rat trigeminal spinal nucleus caudalis and C1 dorsal horn neurons following mustard oil-induced acute inflammation.

    Science.gov (United States)

    Matsumoto, Yasuhiro; Komatsu, Kyouhei; Shimazu, Yoshihito; Takehana, Shiori; Syouji, Yumiko; Kobayashi, Ayumu; Takeda, Mamoru

    2017-10-01

    The dietary constituent, resveratrol, was recently identified as a transient receptor potential ankyrin 1 (TRPA1) antagonist, voltage-dependent sodium ion (Na+ ) channel, and cyclooxygenase-2 (COX-2) inhibitor. The aim of the present study was to investigate whether pretreatment with resveratrol attenuates acute inflammation-induced sensitization of nociceptive processing in rat spinal trigeminal nucleus caudalis (SpVc) and upper cervical (C1) dorsal horn neurons, via c-fos immunoreactivity. Mustard oil (MO), a TRPA1 channel agonist, was injected into the whisker pads of rats to induce inflammation. Pretreatment with resveratrol significantly decreased the mean thickness of inflammation-induced edema in whisker pads compared with those of untreated, inflamed rats. Ipsilateral of both the superficial and deep laminae of SpVc and C1 dorsal horn, there were significantly more c-fos-immunoreactive SpVc/C1 neurons in inflamed rats compared with naïve rats, and resveratrol pretreatment significantly decreased that number relative to untreated, inflamed rats. These results suggest that systemic administration of resveratrol attenuates acute inflammation-induced augmented nociceptive processing of trigeminal SpVc and C1 neurons. These findings support resveratrol as a potential therapeutic agent for use in alternative, complementary medicine to attenuate, or even prevent, acute trigeminal inflammatory pain. © 2017 Eur J Oral Sci.

  13. The Secreted Protein C1QL1 and Its Receptor BAI3 Control the Synaptic Connectivity of Excitatory Inputs Converging on Cerebellar Purkinje Cells

    Directory of Open Access Journals (Sweden)

    Séverine M. Sigoillot

    2015-02-01

    Full Text Available Precise patterns of connectivity are established by different types of afferents on a given target neuron, leading to well-defined and non-overlapping synaptic territories. What regulates the specific characteristics of each type of synapse, in terms of number, morphology, and subcellular localization, remains to be understood. Here, we show that the signaling pathway formed by the secreted complement C1Q-related protein C1QL1 and its receptor, the adhesion-GPCR brain angiogenesis inhibitor 3 (BAI3, controls the stereotyped pattern of connectivity established by excitatory afferents on cerebellar Purkinje cells. The BAI3 receptor modulates synaptogenesis of both parallel fiber and climbing fiber afferents. The restricted and timely expression of its ligand C1QL1 in inferior olivary neurons ensures the establishment of the proper synaptic territory for climbing fibers. Given the broad expression of C1QL and BAI proteins in the developing mouse brain, our study reveals a general mechanism contributing to the formation of a functional brain.

  14. ERP C1 is top-down modulated by orientation perceptual learning.

    Science.gov (United States)

    Zhang, Gong-Liang; Li, Hao; Song, Yan; Yu, Cong

    2015-01-01

    The brain site of perceptual learning has been frequently debated. Recent psychophysical evidence for complete learning transfer to new retinal locations and orientations/directions suggests that perceptual learning may mainly occur in high-level brain areas. Contradictorily, ERP C1 changes associated with perceptual learning are cited as evidence for training-induced plasticity in the early visual cortex. However, C1 can be top-down modulated, which suggests the possibility that C1 changes may result from top-down modulation of the early visual cortex by high-level perceptual learning. To single out the potential top-down impact, we trained observers with a peripheral orientation discrimination task and measured C1 changes at an untrained diagonal quadrant location where learning transfer was previously known to be significant. Our assumption was that any C1 changes at this untrained location would indicate top-down modulation of the early visual cortex, rather than plasticity in the early visual cortex. The expected learning transfer was indeed accompanied with significant C1 changes. Moreover, C1 changes were absent in an untrained shape discrimination task with the same stimuli. We conclude that ERP C1 can be top-down modulated in a task-specific manner by high-level perceptual learning, so that C1 changes may not necessarily indicate plasticity in the early visual cortex. Moreover, learning transfer and associated C1 changes may indicate that learning-based top-down modulation can be remapped to early visual cortical neurons at untrained locations to enable learning transfer.

  15. Similarities and dissimilarities between the binding ability of C1q and collagen.

    Science.gov (United States)

    Csákó, G; Suba, E A; Herp, A

    1981-04-01

    Based on chemical-structural similarities between C1q and collagen, we studied their activities in reactions which are typically induced in collagen or mediated by C1q. Human C1q suppressed the collagen-induced platelet aggregation in human platelet-rich plasmas. Both human C1q and a suspension in insoluble bovine collagen inhibited in time-dependent fashion the lysis of sensitized sheep erythrocytes (EA) by guinea-pig complement. They both agglutinated sheep erythrocytes (EA and EAC4) sensitized with rabbit haemolysin, mainly in the IgM type, polystyrene latex particles complexed with heat-denatured human IgG, a combination of horse, goat and sheep globulins, or deoxyribonucleoprotein. Heating of C1q and collagen (56 degrees C, 30 min), which disrupts the collagen fold into a random coil structure, almost completely abrogated all activities of C1q and considerably reduced those of collagen, suggesting that an intact triple helix is essential for their activities. In spite of their far-ranging similarities, C1q was more potent by weight in most reactions, showed evidence of a faster rate of binding to EA, and was more sensitive to heat treatment at 56 degrees C than was collagen. on the basis of the binding activities of collagen, a model is proposed according to which platelets, sensitized erythrocytes, aggregated gammaglobulins, immune complexes and deoxyribonucleoprotein might accumulate at the site of endothelial damage where blood and its components are exposed to collagenous substances. C1q is able to inhibit all these reactions, indicating that not only is C1q collagen-like in its behaviour, but that collagen also had C1q-like properties.

  16. Biotin and biotinidase deficiency

    OpenAIRE

    Zempleni, Janos; Hassan, Yousef I.; Wijeratne, Subhashinee SK

    2008-01-01

    Biotin is a water-soluble vitamin that serves as an essential coenzyme for five carboxylases in mammals. Biotin-dependent carboxylases catalyze the fixation of bicarbonate in organic acids and play crucial roles in the metabolism of fatty acids, amino acids and glucose. Carboxylase activities decrease substantially in response to biotin deficiency. Biotin is also covalently attached to histones; biotinylated histones are enriched in repeat regions in the human genome and appear to play a role...

  17. α₁-Antitrypsin protease inhibitor MZ heterozygosity is associated with airflow obstruction in two large cohorts

    DEFF Research Database (Denmark)

    Sørheim, Inga-Cecilie; Bakke, Per; Gulsvik, Amund

    2010-01-01

    Severe a1-antitrypsin deficiency is a known genetic risk factor for COPD. Heterozygous (protease inhibitor [PI] MZ) individuals have moderately reduced serum levels of a1-antitrypsin, but whether they have an increased risk of COPD is uncertain.......Severe a1-antitrypsin deficiency is a known genetic risk factor for COPD. Heterozygous (protease inhibitor [PI] MZ) individuals have moderately reduced serum levels of a1-antitrypsin, but whether they have an increased risk of COPD is uncertain....

  18. C1q/TNF-related protein 6 (CTRP6) links obesity to adipose tissue inflammation and insulin resistance.

    Science.gov (United States)

    Lei, Xia; Seldin, Marcus M; Little, Hannah C; Choy, Nicholas; Klonisch, Thomas; Wong, G William

    2017-09-08

    Obesity is associated with chronic low-grade inflammation, and metabolic regulators linking obesity to inflammation have therefore received much attention. Secreted C1q/TNF-related proteins (CTRPs) are one such group of regulators that regulate glucose and fat metabolism in peripheral tissues and modulate inflammation in adipose tissue. We have previously shown that expression of CTRP6 is up-regulated in leptin-deficient mice and, conversely, down-regulated by the anti-diabetic drug rosiglitazone. Here, we provide evidence for a novel role of CTRP6 in modulating both inflammation and insulin sensitivity. We found that in obese and diabetic humans and mouse models, CTRP6 expression was markedly up-regulated in adipose tissue and that stromal vascular cells, such as macrophages, are a major CTRP6 source. Overexpressing mouse or human CTRP6 impaired glucose disposal in peripheral tissues in response to glucose and insulin challenge in wild-type mice. Conversely, Ctrp6 gene deletion improved insulin action and increased metabolic rate and energy expenditure in diet-induced obese mice. Mechanistically, CTRP6 regulates local inflammation and glucose metabolism by targeting macrophages and adipocytes, respectively. In cultured macrophages, recombinant CTRP6 dose-dependently up-regulated the expression and production of TNF-α. Conversely, CTRP6 deficiency reduced circulating inflammatory cytokines and pro-inflammatory macrophages in adipose tissue. CTRP6-overexpressing mice or CTRP6-treated adipocytes had reduced insulin-stimulated Akt phosphorylation and glucose uptake. In contrast, loss of CTRP6 enhanced insulin-stimulated Akt activation in adipose tissue. Together, these results establish CTRP6 as a novel metabolic/immune regulator linking obesity to adipose tissue inflammation and insulin resistance. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  19. Deconstructing Lipid Kinase Inhibitors by Chemical Proteomics.

    Science.gov (United States)

    McCloud, Rebecca L; Franks, Caroline E; Campbell, Sean T; Purow, Benjamin W; Harris, Thurl E; Hsu, Ku-Lung

    2018-01-16

    Diacylglycerol kinases (DGKs) regulate lipid metabolism and cell signaling through ATP-dependent phosphorylation of diacylglycerol to biosynthesize phosphatidic acid. Selective chemical probes for studying DGKs are currently lacking and are needed to annotate isoform-specific functions of these elusive lipid kinases. Previously, we explored fragment-based approaches to discover a core fragment of DGK-α (DGKα) inhibitors responsible for selective binding to the DGKα active site. Here, we utilize quantitative chemical proteomics to deconstruct widely used DGKα inhibitors to identify structural regions mediating off-target activity. We tested the activity of a fragment (RLM001) derived from a nucleotide-like region found in the DGKα inhibitors R59022 and ritanserin and discovered that RLM001 mimics ATP in its ability to broadly compete at ATP-binding sites of DGKα as well as >60 native ATP-binding proteins (kinases and ATPases) detected in cell proteomes. Equipotent inhibition of activity-based probe labeling by RLM001 supports a contiguous ligand-binding site composed of C1, DAGKc, and DAGKa domains in the DGKα active site. Given the lack of available crystal structures of DGKs, our studies highlight the utility of chemical proteomics in revealing active-site features of lipid kinases to enable development of inhibitors with enhanced selectivity against the human proteome.

  20. DPP-4 inhibitors

    DEFF Research Database (Denmark)

    Deacon, Carolyn F.

    2016-01-01

    Dipeptidyl peptidase (DPP)-4 inhibitors inhibit the activity of the enzyme responsible for the initial rapid degradation of the incretin hormones, thereby enhancing their antihyperglycemic effects.......Dipeptidyl peptidase (DPP)-4 inhibitors inhibit the activity of the enzyme responsible for the initial rapid degradation of the incretin hormones, thereby enhancing their antihyperglycemic effects....

  1. Thyroid hormone transport and metabolism by OATP1C1 and consequences of genetic variation

    DEFF Research Database (Denmark)

    van der Deure, Wendy M; Hansen, Pia Skov; Peeters, Robin P

    2008-01-01

    with TH levels, nor did they affect transport function in vitro. In conclusion, OATP1C1 mediates transport of T4, T4S and rT3 and increases the access of these substrates to the intracellular active sites of the deiodinases. No effect of genetic variation on the function of OATP1C1 was observed.......OATP1C1 has been characterized as a specific thyroid hormone transporter. Based on its expression in capillaries in different brain regions, OATP1C1 is thought to play a key-role in transporting thyroid hormone across the blood-brain barrier. For this reason, we studied the specificity...... of iodothyronine transport by OATP1C1 in detail by analysis of thyroid hormone uptake in OATP1C1-transfected COS1 cells. Furthermore, we examined whether OATP1C1 is rate-limiting in subsequent thyroid hormone metabolism in cells co-transfected with deiodinases. We also studied the effect of genetic variation...

  2. Trichinella spiralis Paramyosin Binds Human Complement C1q and Inhibits Classical Complement Activation.

    Directory of Open Access Journals (Sweden)

    Ran Sun

    2015-12-01

    Full Text Available Trichinella spiralis expresses paramyosin (Ts-Pmy as a defense mechanism. Ts-Pmy is a functional protein with binding activity to human complement C8 and C9 and thus plays a role in evading the attack of the host's immune system. In the present study, the binding activity of Ts-Pmy to human complement C1q and its ability to inhibit classical complement activation were investigated.The binding of recombinant and natural Ts-Pmy to human C1q were determined by ELISA, Far Western blotting and immunoprecipitation, respectively. Binding of recombinant Ts-Pmy (rTs-Pmy to C1q inhibited C1q binding to IgM and consequently inhibited C3 deposition. The lysis of antibody-sensitized erythrocytes (EAs elicited by the classical complement pathway was also inhibited in the presence of rTs-Pmy. In addition to inhibiting classical complement activation, rTs-Pmy also suppressed C1q binding to THP-1-derived macrophages, thereby reducing C1q-induced macrophages migration.Our results suggest that T. spiralis paramyosin plays an important role in immune evasion by interfering with complement activation through binding to C1q in addition to C8 and C9.

  3. Differential diagnosis of human ascites: inhibitors of the contact system and total proteins.

    Science.gov (United States)

    Buø, L; Karlsrud, T S; Dyrhaug, G; Jacobsen, M B; Bell, H; Johansen, H T; Aasen, A O

    1993-09-01

    To assess their accuracies as markers for malignancy, we assayed alpha 2-macroglobulin, C1-inhibitor, alpha 1-protease inhibitor, and total proteins in ascites and plasma from patients with gastrointestinal cancer (n = 15) and non-malignant liver disease (n = 13), using functional and immunologic assays. For all inhibitors and total proteins determined in ascites, the values in the cancer group were significantly higher than the corresponding values in the group with non-malignant liver disease. The diagnostic accuracy for differentiating malignancy-related from non-malignant ascites was 93% for a alpha 1-protease inhibitor value > or = 50% of the pool plasma value and 90% for alpha 2-macroglobulin > or = 16%, C1-inhibitor > or = 40% (all functional assays), and total proteins > or = 20 g/l (biuret). In conclusion, functional assays for alpha 2-macroglobulin, C1-inhibitor, and alpha 1-protease inhibitor and determination of total proteins in ascites appeared to be very informative tests for the differential diagnosis of ascites. The test for alpha 1-protease inhibitor gave higher specificity (92% versus 77%) and likelihood ratio for a positive test (12 versus 4) compared with the other tests.

  4. Identifying a Resistance Determinant for the Antimitotic Natural Products Disorazole C1 and A1S⃞

    Science.gov (United States)

    Reese, Celeste E.; Vogt, Andreas; Vollmer, Laura L.; Kitchens, Carolyn A.; Günther, Eckhard; Graham, Thomas H.; Hopkins, Chad D.; Wipf, Peter

    2010-01-01

    Disorazoles are macrocyclic polyketides first isolated from the fermentation broth of the myxobacterium Sorangium cellulosum. Both the major fermentation product disorazole A1 and its much rarer companion disorazole C1 exhibit potent cytotoxic activity against many human tumor cells. Furthermore, the disorazoles appear to bind tubulin uniquely among known antimitotic agents, promoting apoptosis or premature senescence. It is uncertain what conveys tumor cell sensitivity to these complex natural products. Therefore, we generated and characterized human tumor cells resistant to disorazole C1. Resistant cells proved exceedingly difficult to generate and required single step mutagenesis with chronic stepwise exposure to increasing concentrations of disorazole C1. Compared with wild-type HeLa cells, disorazole C1-resistant HeLa/DZR cells were 34- and 8-fold resistant to disorazole C1 and disorazole A1 growth inhibition, respectively. HeLa/DZR cells were also remarkably cross-resistant to vinblastine (280-fold), paclitaxel (2400-fold), and doxorubicin (47-fold) but not cisplatin, suggesting a multidrug-resistant phenotype. Supporting this hypothesis, MCF7/MDR cells were 10-fold cross-resistant to disorazole C1. HeLa/DZR disorazole resistance was not durable in the absence of chronic compound exposure. Verapamil reversed HeLa/DZR resistance to disorazole C1 and disorazole A1. Moreover, HeLa/DZR cells expressed elevated levels of the drug resistance ATP-binding cassette ABCB1 transporter. Loss of ABCB1 by incubation with short interfering RNA restored sensitivity to the disorazoles. Thus, the multidrug resistance transporter ABCB1 can affect the cytotoxicity of both disorazole C1 and A1. Disorazole C1, however, retained activity against cells resistant against the clinically used microtubule-stabilizing agent epothilone B. PMID:20008956

  5. Identification of a cytochrome P4502E1/Bid/C1q-dependent axis mediating inflammation in adipose tissue after chronic ethanol feeding to mice.

    Science.gov (United States)

    Sebastian, Becky M; Roychowdhury, Sanjoy; Tang, Hui; Hillian, Antoinette D; Feldstein, Ariel E; Stahl, Gregory L; Takahashi, Kazue; Nagy, Laura E

    2011-10-14

    Chronic, heavy alcohol exposure results in inflammation in adipose tissue, insulin resistance, and liver injury. Here we have identified a CYP2E1/Bid/C1q-dependent pathway that is activated in response to chronic ethanol and is required for the development of inflammation in adipose tissue. Ethanol feeding for 25 days to wild-type (C57BL/6J) mice increased expression of multiple markers of adipose tissue inflammation relative to pair-fed controls independent of increased body weight or adipocyte size. Ethanol feeding increased the expression of CYP2E1 in adipocytes, but not stromal vascular cells, in adipose tissue and Cyp2e1(-/-) mice were protected from adipose tissue inflammation in response to ethanol. Ethanol feeding also increased the number of TUNEL-positive nuclei in adipose tissue of wild-type mice but not in Cyp2e1(-/-) or Bid (-/-) mice. Apoptosis contributed to adipose inflammation, as the expression of multiple inflammatory markers was decreased in mice lacking the Bid-dependent apoptotic pathway. The complement protein C1q binds to apoptotic cells, facilitating their clearance and activating complement. Making use of C1q-deficient mice, we found that activation of complement via C1q provided the critical link between CYP2E1/Bid-dependent apoptosis and onset of adipose tissue inflammation in response to chronic ethanol. In summary, chronic ethanol increases CYP2E1 activity in adipose, leading to Bid-mediated apoptosis and activation of complement via C1q, finally resulting in adipose tissue inflammation. Taken together, these data identify a novel mechanism for the development of adipose tissue inflammation that likely contributes to the pathophysiological effects of ethanol.

  6. PrP-C1 fragment in cattle brains reveals features of the transmissible spongiform encephalopathy associated PrPsc.

    Science.gov (United States)

    Serra, Fabienne; Müller, Joachim; Gray, John; Lüthi, Ramona; Dudas, Sandor; Czub, Stefanie; Seuberlich, Torsten

    2017-03-15

    Three different types of bovine spongiform encephalopathy (BSE) are known and supposedly caused by distinct prion strains: the classical (C-) BSE type that was typically found during the BSE epidemic, and two relatively rare atypical BSE types, termed H-BSE and L-BSE. The three BSE types differ in the molecular phenotype of the disease associated prion protein, namely the N-terminally truncated proteinase K (PK) resistant prion protein fragment (PrP res ). In this study, we report and analyze yet another PrP res type (PrP res-2011 ), which was found in severely autolytic brain samples of two cows in the framework of disease surveillance in Switzerland in 2011. Analysis of brain tissues from these animals by PK titration and PK inhibitor assays ruled out the process of autolysis as the cause for the aberrant PrP res profile. Immunochemical characterization of the PrP fragments present in the 2011 cases by epitope mapping indicated that PrP res-2011 corresponds in its primary sequence to the physiologically occurring PrP-C1 fragment. However, high speed centrifugation, sucrose gradient assay and NaPTA precipitation revealed biochemical similarities between PrP res-2011 and the disease-associated prion protein found in BSE affected cattle in terms of detergent insolubility, PK resistance and PrP aggregation. Although it remains to be established whether PrP res-2011 is associated with a transmissible disease, our results point out the need of further research on the role the PrP-C1 aggregation and misfolding in health and disease. Copyright © 2017. Published by Elsevier B.V.

  7. Inhibitors of catechol-O-methyltransferase sensitize mice to pain

    Science.gov (United States)

    Kambur, O; Talka, R; Ansah, OB; Kontinen, VK; Pertovaara, A; Kalso, E; Männistö, PT

    2010-01-01

    BACKGROUND AND PURPOSE Catechol-O-methyltransferase (COMT) inhibitors are used in Parkinson's disease in which pain is an important symptom. COMT polymorphisms modulate pain and opioid analgesia in humans. In rats, COMT inhibitors have been shown to be pro-nociceptive in acute pain models, but also to attenuate allodynia and hyperalgesia in a model of diabetic neuropathy. Here, we have assessed the effects of acute and repeated administrations of COMT inhibitors on mechanical, thermal and carrageenan-induced nociception in male mice. EXPERIMENTAL APPROACH We used single and repeated administration of a peripherally restricted, short-acting (nitecapone) and also a centrally acting (3,5-dinitrocatechol, OR-486) COMT inhibitor. We also tested CGP 28014, an indirect inhibitor of COMT enzyme. Effects of OR-486 on thermal nociception were also studied in COMT deficient mice. Effects on spinal pathways were assessed in rats given intrathecal nitecapone. KEY RESULTS After single administration, both nitecapone and OR-486 reduced mechanical nociceptive thresholds and thermal nociceptive latencies (hot plate test) at 2 and 3 h, regardless of their brain penetration. These effects were still present after chronic treatment with COMT inhibitors for 5 days. Intraplantar injection of carrageenan reduced nociceptive latencies and both COMT inhibitors potentiated this reduction without modifying inflammation. CGP 28014 shortened paw flick latencies. OR-486 did not modify hot plate times in Comt gene deficient mice. Intrathecal nitecapone modified neither thermal nor mechanical nociception. CONCLUSIONS AND IMPLICATIONS Pro-nociceptive effects of COMT inhibitors were confirmed. The pro-nociceptive effects were primarily mediated via mechanisms acting outside the brain and spinal cord. COMT protein was required for these actions. PMID:20726980

  8. Prostaglandin E2 is critical for the development of niacin-deficiency-induced photosensitivity via ROS production

    Science.gov (United States)

    Sugita, Kazunari; Ikenouchi-Sugita, Atsuko; Nakayama, Yasuko; Yoshioka, Haruna; Nomura, Takashi; Sakabe, Jun-Ichi; Nakahigashi, Kyoko; Kuroda, Etsushi; Uematsu, Satoshi; Nakamura, Jun; Akira, Shizuo; Nakamura, Motonobu; Narumiya, Shuh; Miyachi, Yoshiki; Tokura, Yoshiki; Kabashima, Kenji

    2013-10-01

    Pellagra is a photosensitivity syndrome characterized by three ``D's'': diarrhea, dermatitis, and dementia as a result of niacin deficiency. However, the molecular mechanisms of photosensitivity dermatitis, the hallmark abnormality of this syndrome, remain unclear. We prepared niacin deficient mice in order to develop a murine model of pellagra. Niacin deficiency induced photosensitivity and severe diarrhea with weight loss. In addition, niacin deficient mice exhibited elevated expressions of COX-2 and PGE syntheses (Ptges) mRNA. Consistently, photosensitivity was alleviated by a COX inhibitor, deficiency of Ptges, or blockade of EP4 receptor signaling. Moreover, enhanced PGE2 production in niacin deficiency was mediated via ROS production in keratinocytes. In line with the above murine findings, human skin lesions of pellagra patients confirmed the enhanced expression of Ptges. Niacin deficiency-induced photosensitivity was mediated through EP4 signaling in response to increased PGE2 production via induction of ROS formation.

  9. C1q/tumor necrosis factor-related protein 3 inhibits oxidative stress during intracerebral hemorrhage via PKA signaling.

    Science.gov (United States)

    Yang, Bo; Wang, Shaohua; Yu, Shanshan; Chen, Yanlin; Li, Linyu; Zhang, Hui; Zhao, Yong

    2017-02-15

    C1q/tumor necrosis factor (TNF)-related proteins (CTRPs) have been confirmed to be adiponectin (APN) paralogs and some share APN's metabolic regulatory functions. Oxidative stress contributes to brain injury after intracerebral hemorrhage (ICH) and APN can inhibit oxidative stress injury during ICH. Thus, we addressed the role of a specific CTRP-CTRP 3-after experimental ICH and studied post-ICH oxidative stress injury and the pathway involved. ICH was induced in rats via intracerebral infusion of autologous blood, and the effects of exogenous CTRP3 (lentivirus or recombinant CTRP3) replenishment on ICH injury were investigated. Rats received an intracerebral injection of H89 (a PKA inhibitor) with recombinant CTRP3 (rCTRP 3) or dibutyryl cyclic AMP (db-cAMP, a PKA activator) without rCTRP 3. Then, oxidative stress, CTRP 3, PKA, and NADPH oxidase-2 (NOX 2) were assessed, as were functional outcomes, cerebral edema, and blood-brain barrier (BBB) permeability at 24h. We found that treatment with recombinant or lentivirus CTRP3 reduced cerebral edema and BBB damage and improved neurological functions as well as reduced post-ICH elevated reactive oxygen species and malondialdehyde and increased reduced glutathione and the ratio of oxidized to reduced glutathione. CTRP 3 applied 30min after ICH increased PKA, reduced NOX 2 expression, and decreased oxidative stress. A PKA-inhibitor abolished CTRP 3-induced protective effects and increased NOX 2 expression. We conclude from our results that CTRP 3 may regulate oxidative stress injury via PKA signaling and may provide a new therapeutic strategy for ICH. Copyright © 2016. Published by Elsevier B.V.

  10. Development of the Advanced Technology Microwave Sounder (ATMS) for NPOESS C1

    Science.gov (United States)

    Brann, C.; Kunkee, D.

    2008-12-01

    The National Polar-orbiting Operational Environmental Satellite System's Advanced Technology Microwave Sounder (ATMS) is planned for flight on the first NPOESS mission (C1) in 2013. The C1 ATMS will be the second instrument of the ATMS series and will provide along with the companion Cross-track Infrared Sounder (CrIS), atmospheric temperature and moisture profiles for NPOESS. The first flight of the ATMS is scheduled in 2010 on the NPOESS Preparatory Project (NPP) satellite, which is an early instrument risk reduction component of the NPOESS mission. This poster will focus on the development of the ATMS for C1 including aspects of the sensor calibration, antenna beam and RF characteristics and scanning. New design aspects of the C1 ATMS, required primarily by parts obsolescence, will also be addressed in this poster.

  11. Methyl Chloride Measurements in the Taylor Dome M3C1 Ice Core, Version 1

    Data.gov (United States)

    National Aeronautics and Space Administration — This data set includes methyl chloride (CH3CI) measurements made on air extracted from 62 samples from the Taylor Dome M3C1 ice core in East Antarctica. CH3CI was...

  12. Synthesis of the C1-C25 southern domain of spirastrellolides B and F.

    Science.gov (United States)

    Sabitha, Gowravaram; Rao, Allu Senkara; Yadav, J S

    2013-11-07

    Synthesis of the C1-C25 ABC spiroketal ring system of spirastrellolides B and F has been executed. The synthetic strategy relied on radical cyclization, HWE olefination, (BDP)CuH conjugate reduction and spiro acetalization reactions.

  13. Expression of ATP6V1C1 during oral carcinogenesis.

    Science.gov (United States)

    Oliveira Alves, M G; Carta, C F L; Padín-Iruegas, M-E; Pérez-Sayáns, M; Suarez-Peñaranda, J M; Issa, J S; García-García, A; Almeida, J D

    2016-01-01

    We investigated the gene and protein expressions of V-type ATPase protein subunit C1 (ATP6V1C1) in cases of oral squamous cell carcinoma (OSCC) and contralateral normal mucosa in smokers, nonsmokers and former smokers. Subjects were separated into five groups of 15: group 1, smokers with OSCC; group 2, normal contralateral mucosa of OSCC patients; group 3, chronic smokers; group 4, former smokers who had stopped smoking 1 year earlier; group 5, individuals who had never smoked. Exfoliative cytology specimens from oral mucosa of smokers, former smokers and nonsmokers showed normal gene and protein expression. We found significantly greater gene expression in the OSCC group than in the nonsmoker groups. No difference in gene expression was observed between normal contralateral mucosa and nonsmoker groups, smoker and nonsmoker groups or former smoker and nonsmoker groups. We observed intense immunostaining for ATP6V1C1 protein in all cases of OSCC and weak or no staining in smoker, former smoker and nonsmoker groups. Significantly greater expression of ATP6V1C1 protein was observed in the OSCC group compared to the other groups, which supports the role of ATP6V1C1 in effecting changes associated with oral cancer. Analysis of the mucosae of chronic smokers, former smokers and the normal contralateral mucosa of patients with OSCC showed unaltered ATP6V1C1 gene and protein expression. Early stages of carcinogenesis, represented by altered epithelium of chronic smokers, had neither gene nor protein alterations as seen in OSCC. Therefore, we infer that the changes in ATP6V1C1 occur during later stages of carcinogenesis. Our preliminary study provides a basis for future studies of using ATP6V1C1 levels for detecting early stage OSCC.

  14. Aneurysmal bone cyst of clivus and C1 C2: case report and review of literature.

    Science.gov (United States)

    Rajput, Dinesh; Tungaria, Arun; Jaiswal, Avdhesh; Jain, Vijendra

    2012-01-01

    Aneurysmal bone cyst are benign rapidly expanding bone destructive lesions of any bone. They are common in the metaphysis of long bones but 10-30% involve the spine. Cervical region involvement is uncommon. We report a case of aneurysmal bone cyst of clivus C1 and C2 with minimum symptoms. Involvement of C1 and clivus separately had been reported in past, but simultaneous involvement of both is presented in this report for the very first time.

  15. Syntheses of the C1-C14 and C15-C25 fragments of amphidinolide C.

    Science.gov (United States)

    Wu, Dimao; Forsyth, Craig J

    2013-03-15

    Divergent syntheses of the C1-C14 and C15-C25 fragments of amphidinolide C have been achieved. The synthesis of the C15-C25 fragment featured cobalt-catalyzed modified Mukaiyama aerobic alkenol cyclization and sulfur-directed regiocontrolled Wacker oxidation of an internal alkene. The C1-C14 fragment was established by alkenyllithium addition to an aldehyde followed by a challenging olefination of a highly inert C9 ketone.

  16. 17 CFR 240.15c1-8 - Sales at the market.

    Science.gov (United States)

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Sales at the market. 240.15c1... Securities Exchange Act of 1934 Rules Relating to Over-The-Counter Markets § 240.15c1-8 Sales at the market... securities exchange that such security is being offered to such customer “at the market” or at a price...

  17. The 36C1 ages of the brines in the Magadi-Natron basin, East Africa

    Science.gov (United States)

    Kaufman, Aaron; Margaritz, Mordeckai; Paul, Michael; Hillaire-Marcel, Claude; Hollos, George; Boaretto, Elisabetta; Taieb, Maurice

    1990-10-01

    The depression in the East African Rift which includes both Lake Magadi and Lake Natron forms a closed basin within which almost all the dissolved chloride originates in precipitation, since there is no important source of very ancient sedimentary chloride. This provides an ideal setting for the evaluation of the 36Cl methodology as a geochemical and hydrological tracer. The main source of recent water, as represented by the most dilute samples measured, is characterized by a 36C1/C1 ratio of 2.5 × 10 -14, in agreement with the calculated value expected in precipitation. Surface evaporation increases the chlorinity of the local freshwater inflow by about a factor of 110 without changing the isotopic ratio, indicating that little chloride enters the system in the form of sediment leachate. A second type of brine found in the basin occurs in a hot deep groundwater reservoir and is characterized by lower 36C1/C1 ratios (salt accumulation age of 760 Ka which is consistent with the time of the first appearance of the lake. These older brines also have lower 18O and 2H values which indicate that they were recharged during a climatically different era. The 36C1/C1 ratios in the inflowing waters and in the accumulated brine, together with the known age of the Lake Magadi basin, may be used to estimate the importance of the hypogene and epigene, as opposed to the meteoric, mode of 36C1 production. Such a calculation shows that the hypogene and epigene processes together contribute less than 6% of the total 36C1 present in the lake.

  18. Stereocontrolled Synthesis of the C(1)-C(11) Subunit of the Iejimalides

    DEFF Research Database (Denmark)

    Mendlik, Matthew T.; Cottard, Muriel; Rein, Tobias

    1997-01-01

    An enantioselective synthesis of the C(1)-C(11) subunit of the iejimalides has been accomplished through a combination of an asymmetric Homer-Wadsworth-Emmons condensation and a chiral pool approach. (C) 1997 Elsevier Science Ltd.......An enantioselective synthesis of the C(1)-C(11) subunit of the iejimalides has been accomplished through a combination of an asymmetric Homer-Wadsworth-Emmons condensation and a chiral pool approach. (C) 1997 Elsevier Science Ltd....

  19. Complement protein C1q induces maturation of human dendritic cells

    DEFF Research Database (Denmark)

    Cosmor, E; Bajtay, Z; Sándor, N

    2007-01-01

    activity of the cells was assessed by measuring cytokine secretion and their ability to activate allogeneic T lymphocytes. Cytokine production by T cells co-cultured with C1q-matured DCs was also investigated. C1q, but not the structurally related mannose-binding lectin was found to bind to imMDC in a dose......q-induced DC maturation generates a Th1-type response. Interestingly, IL-10 levels were elevated by C1q-treated MDCs but not in the supernatant of their co-cultures with allogeneic T cells. Taken together, these results indicate that C1q-opsonized antigens may play a role in the induction......Maturation of dendritic cells (DCs) is known to be induced by several stimuli, including microbial products, inflammatory cytokines and immobilized IgG, as demonstrated recently. Since immune complexes formed in vivo also contain C1q, moreover apoptotic cells and several pathogens fix C1q...

  20. The Cyclic Peptide Ecumicin Targeting ClpC1 Is Active against Mycobacterium tuberculosis In Vivo

    Science.gov (United States)

    Gao, Wei; Kim, Jin-Yong; Anderson, Jeffrey R.; Akopian, Tatos; Hong, Seungpyo; Jin, Ying-Yu; Kandror, Olga; Kim, Jong-Woo; Lee, In-Ae; Lee, Sun-Young; McAlpine, James B.; Mulugeta, Surafel; Sunoqrot, Suhair; Wang, Yuehong; Yang, Seung-Hwan; Yoon, Tae-Mi; Goldberg, Alfred L.; Pauli, Guido F.; Cho, Sanghyun

    2014-01-01

    Drug-resistant tuberculosis (TB) has lent urgency to finding new drug leads with novel modes of action. A high-throughput screening campaign of >65,000 actinomycete extracts for inhibition of Mycobacterium tuberculosis viability identified ecumicin, a macrocyclic tridecapeptide that exerts potent, selective bactericidal activity against M. tuberculosis in vitro, including nonreplicating cells. Ecumicin retains activity against isolated multiple-drug-resistant (MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis. The subcutaneous administration to mice of ecumicin in a micellar formulation at 20 mg/kg body weight resulted in plasma and lung exposures exceeding the MIC. Complete inhibition of M. tuberculosis growth in the lungs of mice was achieved following 12 doses at 20 or 32 mg/kg. Genome mining of lab-generated, spontaneous ecumicin-resistant M. tuberculosis strains identified the ClpC1 ATPase complex as the putative target, and this was confirmed by a drug affinity response test. ClpC1 functions in protein breakdown with the ClpP1P2 protease complex. Ecumicin markedly enhanced the ATPase activity of wild-type (WT) ClpC1 but prevented activation of proteolysis by ClpC1. Less stimulation was observed with ClpC1 from ecumicin-resistant mutants. Thus, ClpC1 is a valid drug target against M. tuberculosis, and ecumicin may serve as a lead compound for anti-TB drug development. PMID:25421483

  1. Post-transplant development of C1q-positive HLA antibodies and kidney graft survival.

    Science.gov (United States)

    Piazza, Antonina; Poggi, Elvira; Ozzella, Giuseppina; Adorno, Domenico

    2013-01-01

    The development of de novo human leukocyte antigen (HLA) donor specific antibodies (DSA), detected by both cytotoxic or solid phase assays, was considered the major risk factor for allograft failure in kidney transplantation. However, it was shown that not all patients with persistent production of DSA suffered loss of their grafts. Modified Luminex-Single Antigen assays, able to identify C1q-fixing antibodies, represent a new strategy in assessing the clinical relevance of detected DSA. This study demonstrated that C1q-fixing capability of de novo DSA is a clinically relevant marker of worse outcome and inferior graft survival in kidney transplantation. In fact, our findings evidenced a very low graft survival only in the patients who developed DSA able to fix C1q during post-transplant course, while patients producing C1q-negative DSA had good graft survival, which was comparable to that found in our previous study for DSA-negative patients. Moreover, anti-HLA class II antibodies had a higher incidence than anti-HLA class I, and the ability to fix C1q was significantly more frequent among anti-DQ DSA than anti-DR DSA. Monitoring of de novo C1q-DSA production represents a useful, non-invasive tool for risk stratification and prediction of graft outcome in kidney transplantation.

  2. Antithrombin III/SerpinC1 insufficiency exacerbates renal ischemia/reperfusion injury.

    Science.gov (United States)

    Wang, Feng; Zhang, Guangyuan; Lu, Zeyuan; Geurts, Aron M; Usa, Kristie; Jacob, Howard J; Cowley, Allen W; Wang, Niansong; Liang, Mingyu

    2015-10-01

    Antithrombin III, encoded by SerpinC1, is a major anti-coagulation molecule in vivo and has anti-inflammatory effects. We found that patients with low antithrombin III activities presented a higher risk of developing acute kidney injury after cardiac surgery. To study this further, we generated SerpinC1 heterozygous knockout rats and followed the development of acute kidney injury in a model of modest renal ischemia/reperfusion injury. Renal injury, assessed by serum creatinine and renal tubular injury scores after 24 h of reperfusion, was significantly exacerbated in SerpinC1(+/-) rats compared to wild-type littermates. Concomitantly, renal oxidative stress, tubular apoptosis, and macrophage infiltration following this injury were significantly aggravated in SerpinC1(+/-) rats. However, significant thrombosis was not found in the kidneys of any group of rats. Antithrombin III is reported to stimulate the production of prostaglandin I2, a known regulator of renal cortical blood flow, in addition to having anti-inflammatory effects and to protect against renal failure. Prostaglandin F1α, an assayable metabolite of prostaglandin I2, was increased in the kidneys of the wild-type rats at 3 h after reperfusion. The increase of prostaglandin F1α was significantly blunted in SerpinC1(+/-) rats, which preceded increased tubular injury and oxidative stress. Thus, our study found a novel role of SerpinC1 insufficiency in increasing the severity of renal ischemia/reperfusion injury.

  3. Two human homeobox genes, c1 and c8: structure analysis and expression in embryonic development.

    Science.gov (United States)

    Simeone, A; Mavilio, F; Acampora, D; Giampaolo, A; Faiella, A; Zappavigna, V; D'Esposito, M; Pannese, M; Russo, G; Boncinelli, E

    1987-07-01

    Two human cDNA clones (HHO.c1.95 and HHO.c8.5111) containing a homeobox region have been characterized, and the respective genomic regions have been partially analyzed. Expression of the corresponding genes, termed c1 and c8, was evaluated in different organs and body parts during human embryonic/fetal development. HHO.c1.95 apparently encodes a 217-amino acid protein containing a class I homeodomain that shares 60 out of 61 amino acid residues with the Antennapedia homeodomain of Drosophila melanogaster. HHO.c8.5111 encodes a 153-amino acid protein containing a homeodomain identical to that of the frog AC1 gene. Clones HHO.c1 and HHO.c8 detect by blot-hydridization one and two specific polyadenylylated transcripts, respectively. These are differentially expressed in spinal cord, backbone rudiments, limb buds (or limbs), heart, and skin of human embryos and early fetuses in the 5- to 9-week postfertilization period, thus suggesting that the c1 and c8 genes play a key role in a variety of developmental processes. Together, the results of the embryonic/fetal expression of c1 and c8 and those of two previously analyzed genes (c10 and c13) indicate a coherent pattern of expression of these genes in early human ontogeny.

  4. Bilateral C1-C2 transarticular screw and C1 laminar hook fixation and bone graft fusion for reducible atlantoaxial dislocation: a seven-year analysis of outcome.

    Directory of Open Access Journals (Sweden)

    Xiang Guo

    Full Text Available BACKGROUND: Bilateral C1-2 transarticular screw and C1 laminar hook fixation was developed on the basis of transarticular screws fixation. The modified technique has showed a better biomechanical stability than established techniques in previous study. However, long-term (minimum follow-up 7 years outcomes of patients with reducible atlantoaxial dislocation who underwent this modified fixation technique have not still been reported. METHODS: A retrospective study was conducted to evaluate the outcome of 36 patients who underwent this modified technique. Myelopathy was assessed using the Ranawat myelopathy score and Myelopathy Disability Index. Pain scores were assessed using Visual Analogue Scale. Radiological imaging was assessed and the following data were extracted: the atlantodental intervals, the space available for cord, presence of spinal cord signal change on T2 weighted image, C1-C2 angle, C2-C7 angle and fusion rates. FINDINGS: All patients achieved a minimum seven-year follow up. 95% patients with neck and suboccipital pain improved after surgery; in their Visual Analogue pain scores, there was a greater than 50% improvement in their VAS scores with a drop of 5 points on the VAS (P<0.05. 92% of patients improved in the Ranawat myelopathy grade; the Myelopathy Disability Index assessment showed a preoperative mean score of 35.62 with postoperative mean 12.75(P<0.05. There was not any significant atlantoaxial instability at each follow-up time. The space available for cord increased in all patients. Postoperative sagittal kyphosis of the subaxial spine was not observed. After six months after surgery, bone grafts of all patients were fused. No complications related to surgery were found in the period of follow-up. CONCLUSIONS: The long-term outcomes of this case series demonstrate that under the condition of thorough preoperative preparations, bilateral C1-C2 transarticular screw and C1 laminar hook fixation and bone graft fusion is a

  5. Glucose-6-phosphatase deficiency

    Directory of Open Access Journals (Sweden)

    Labrune Philippe

    2011-05-01

    Full Text Available Abstract Glucose-6-phosphatase deficiency (G6P deficiency, or glycogen storage disease type I (GSDI, is a group of inherited metabolic diseases, including types Ia and Ib, characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver. Prevalence is unknown and annual incidence is around 1/100,000 births. GSDIa is the more frequent type, representing about 80% of GSDI patients. The disease commonly manifests, between the ages of 3 to 4 months by symptoms of hypoglycemia (tremors, seizures, cyanosis, apnea. Patients have poor tolerance to fasting, marked hepatomegaly, growth retardation (small stature and delayed puberty, generally improved by an appropriate diet, osteopenia and sometimes osteoporosis, full-cheeked round face, enlarged kydneys and platelet dysfunctions leading to frequent epistaxis. In addition, in GSDIb, neutropenia and neutrophil dysfunction are responsible for tendency towards infections, relapsing aphtous gingivostomatitis, and inflammatory bowel disease. Late complications are hepatic (adenomas with rare but possible transformation into hepatocarcinoma and renal (glomerular hyperfiltration leading to proteinuria and sometimes to renal insufficiency. GSDI is caused by a dysfunction in the G6P system, a key step in the regulation of glycemia. The deficit concerns the catalytic subunit G6P-alpha (type Ia which is restricted to expression in the liver, kidney and intestine, or the ubiquitously expressed G6P transporter (type Ib. Mutations in the genes G6PC (17q21 and SLC37A4 (11q23 respectively cause GSDIa and Ib. Many mutations have been identified in both genes,. Transmission is autosomal recessive. Diagnosis is based on clinical presentation, on abnormal basal values and absence of hyperglycemic response to glucagon. It can be confirmed by demonstrating a deficient activity of a G6P system component in a liver biopsy. To date, the diagnosis is most

  6. Mismatch Repair Deficiency and Response to Immune Checkpoint Blockade

    Science.gov (United States)

    Lee, Valerie; Murphy, Adrian; Le, Dung T.

    2016-01-01

    More than 1.6 million new cases of cancer will be diagnosed in the U.S. in 2016, resulting in more than 500,000 deaths. Although chemotherapy has been the mainstay of treatment in advanced cancers, immunotherapy development, particularly with PD-1 inhibitors, has changed the face of treatment for a number of tumor types. One example is the subset of tumors characterized by mismatch repair deficiency and microsatellite instability that are highly sensitive to PD-1 blockade. Hereditary forms of cancer have been noted for more than a century, but the molecular changes underlying mismatch repair-deficient tumors and subsequent microsatellite unstable tumors was not known until the early 1990s. In this review article, we discuss the history and pathophysiology of mismatch repair, the process of testing for mismatch repair deficiency and microsatellite instability, and the role of immunotherapy in this subset of cancers. Implications for Practice: Mismatch repair deficiency has contributed to our understanding of carcinogenesis for the past 2 decades and now identifies a subgroup of traditionally chemotherapy-insensitive solid tumors as sensitive to PD-1 blockade. This article seeks to educate oncologists regarding the nature of mismatch repair deficiency, its impact in multiple tumor types, and its implications for predicting the responsiveness of solid tumors to immune checkpoint blockade. PMID:27412392

  7. [Iron deficiency towards the year 2000].

    Science.gov (United States)

    Layrisse, M

    1999-09-01

    This is a non-comprehensive overview of the latest 50 years about the evolution of iron metabolism and the methodology we currently have for the diagnosis of iron deficiency and its effects on human health. In the 40's iron absorption was determined by chemistry. The amount of iron absorbed was calculated as the difference between dietary iron and excreted iron. The other methods used to measure dietary iron was hemoglobin repletion. In the 70's the measurement of plasmatic ferritin was an important contribution to iron metabolism to assess iron deficiency and iron overload. In the same decade the extrinsic and intrinsic labelled methodology was an important advancement. The 70's and 80's were years where scientists aimed at finding iron absorption inhibitors, namely coffee, calcium, tea, zinc and fiber. The 80's and 90's were characterized for the emerging knowledge an iron absorption from a food, a meal and a complete diet and for the favorable effect of food iron fortification in developing countries. Also for the effect of iron excess in overall health and myocardial infarction in developed countries were studied.

  8. [Iron deficiency and digestive disorders].

    Science.gov (United States)

    Cozon, G J N

    2014-11-01

    Iron deficiency anemia still remains problematic worldwide. Iron deficiency without anemia is often undiagnosed. We reviewed, in this study, symptoms and syndromes associated with iron deficiency with or without anemia: fatigue, cognitive functions, restless legs syndrome, hair loss, and chronic heart failure. Iron is absorbed through the digestive tract. Hepcidin and ferroportin are the main proteins of iron regulation. Pathogenic micro-organisms or intestinal dysbiosis are suspected to influence iron absorption. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  9. Autophagy induction by tetrahydrobiopterin deficiency

    OpenAIRE

    Kwak, Sang Su; Suk, Jinkyu; Choi, Ji Hye; Yang, Seungkyung; Kim, Jin Woo; Sohn, Seonghyang; Chung, Jae Hoon; Hong, Yong Hee; Lee, Dong Hwan; Ahn, Jeong Keun; Min, Hyesun; Fu, Ya-Min; Meadows, Gary G.; Joe, Cheol O.

    2011-01-01

    Tetrahydrobiopterin (BH4) deficiency is a genetic disorder associated with a variety of metabolic syndromes such as phenylketonuria (PKU). In this article, the signaling pathway by which BH4 deficiency inactivates mTORC1 leading to the activation of the autophagic pathway was studied utilizing BH4-deficient Spr-/- mice generated by the knockout of the gene encoding sepiapterin reductase (SR) catalyzing BH4 synthesis. We found that mTORC1 signaling was inactivated and autophagic pathway was ac...

  10. Nutritional deficiencies after bariatric surgery.

    Science.gov (United States)

    Bal, Bikram S; Finelli, Frederick C; Shope, Timothy R; Koch, Timothy R

    2012-09-01

    Lifestyle intervention programmes often produce insufficient weight loss and poor weight loss maintenance. As a result, an increasing number of patients with obesity and related comorbidities undergo bariatric surgery, which includes approaches such as the adjustable gastric band or the 'divided' Roux-en-Y gastric bypass (RYGB). This Review summarizes the current knowledge on nutrient deficiencies that can develop after bariatric surgery and highlights follow-up and treatment options for bariatric surgery patients who develop a micronutrient deficiency. The major macronutrient deficiency after bariatric surgery is protein malnutrition. Deficiencies in micronutrients, which include trace elements, essential minerals, and water-soluble and fat-soluble vitamins, are common before bariatric surgery and often persist postoperatively, despite universal recommendations on multivitamin and mineral supplements. Other disorders, including small intestinal bacterial overgrowth, can promote micronutrient deficiencies, especially in patients with diabetes mellitus. Recognition of the clinical presentations of micronutrient deficiencies is important, both to enable early intervention and to minimize long-term adverse effects. A major clinical concern is the relationship between vitamin D deficiency and the development of metabolic bone diseases, such as osteoporosis or osteomalacia; metabolic bone diseases may explain the increased risk of hip fracture in patients after RYGB. Further studies are required to determine the optimal levels of nutrient supplementation and whether postoperative laboratory monitoring effectively detects nutrient deficiencies. In the absence of such data, clinicians should inquire about and treat symptoms that suggest nutrient deficiencies.

  11. Presence of arylsulfatase A (ARS A) in multiple sulfatase deficiency disorder fibroblasts.

    Science.gov (United States)

    Fluharty, A L; Stevens, R L; Davis, L L; Shapiro, L J; Kihara, H

    1978-05-01

    Multiple deficiency disorder fibroblasts cultured in MEM-CO2 showed deficiencies of arylsulfatase A(ARS A) comparable to the deficiency in metachromatic leukodystrophy fibroblasts. However, the MSDD fibroblasts cultured in MEM-HEPES contained near normal levels of ARS A. Moreover, the enzyme from the latter fibroblasts was indistinguishable from ARS A of control fibroblasts on DEAE-cellulose chromatography, ratio of activity with several substrates, thermal inactivation, sensitivity to inhibitors, and precipitation by antiserum to human ARS A. These data support the conclusion that the ARS A genome is intact in MSDD fibroblasts and, by extension, in MSDD patients. Other sulfatases were present at levels ranging from mildly deficient to near normal but never as low as seen in the corresponding specific sulfatase deficient disorders.

  12. Mutants of human colon adenocarcinoma, selected for thymidylate synthase deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Houghton, P.J.; Germain, G.S.; Hazelton, B.J.; Pennington, J.W.; Houghton, J.A. (Saint Jude Children' s Research Hospital, Memphis, TN (USA))

    1989-02-01

    GC{sub 3}/c1 human colon adenocarcinoma cells were treated with the mutagen ethyl methane sulfonate, and three clones deficient in thymidylate synthase activity were selected and characterized. Growth in medium deficient in thymidine caused cell death in two clones (TS{sup {minus}}c{sub 1} and TS{sup {minus}}c{sub 3}), whereas one clone (TS{sup {minus}}c{sub 2}) showed limited growth. Growth correlated with thymidine synthase activity and 5-fluoro-2{prime}-deoxyuridine 5{prime}-monophosphate-binding capacity and with incorporation of 2{prime}-deoxy(6-{sup 3}H)uridine into DNA. In the presence of optimal thymidine, growth rates were only 5-18% that of the parental clone (GC{sub 3}/c1), which grew equally well in thymidine-deficient or -replete medium. Analysis of poly(A){sup +} RNA showed normal levels of a 1.6-kilobase transcript in TS{sup {minus}}c{sub 1} and TS{sup minus}c{sub 2} but decreased levels in TS{sup {minus}}c{sub 3}. Clone TS{sup minus}c{sub 3} was 32-, 750-, and >100,000-fold more resistant than the parental clone to 5-fluorouracil, 5-fluoro-2{prime}-deoxyuridine, and methotrexate, respectively. When inoculated into athymic nude mice, each TS{sup {minus}} clone produced tumors, demonstrating continued ability to proliferate in vivo.

  13. ClC-1 chloride channels: state-of-the-art research and future challenges

    Directory of Open Access Journals (Sweden)

    Paola eImbrici

    2015-04-01

    Full Text Available The voltage-dependent ClC-1 chloride channel belongs to the CLC channel/transporter family. It is a homodimer comprising two individual pores which can operate independently or simultaneously according to two gating modes, the fast and the slow gate of the channel. ClC-1 is preferentially expressed in the skeletal muscle fibers where the presence of an efficient Cl- homeostasis is crucial for the correct membrane repolarization and propagation of action potential. As a consequence, mutations in the CLCN1 gene cause dominant and recessive forms of Myotonia Congenita, a rare skeletal muscle channelopathy caused by abnormal membrane excitation, and clinically characterized by muscle stiffness and various degrees of transitory weakness. Elucidation of the mechanistic link between the genetic defects and the disease pathogenesis is still incomplete and, at this time, there is no specific treatment for Myotonia Congenita. Still controversial is the subcellular localization pattern of ClC-1 channels in skeletal muscle as well as its modulation by some intracellular factors. The expression of ClC-1 in other tissues such as in brain and heart and the possible assembly of ClC-1/ClC-2 heterodimers further expand the physiological properties of ClC-1 and its involvement in diseases. A recent de novo CLCN1 truncation mutation in a patient with generalized epilepsy indeed postulates an unexpected role of this channel in the control of neuronal network excitability. This review summarizes the most relevant and state-of-the-art research on ClC-1 chloride channels physiology and associated diseases.

  14. ClC-1 chloride channels: state-of-the-art research and future challenges.

    Science.gov (United States)

    Imbrici, Paola; Altamura, Concetta; Pessia, Mauro; Mantegazza, Renato; Desaphy, Jean-François; Camerino, Diana Conte

    2015-01-01

    The voltage-dependent ClC-1 chloride channel belongs to the CLC channel/transporter family. It is a homodimer comprising two individual pores which can operate independently or simultaneously according to two gating modes, the fast and the slow gate of the channel. ClC-1 is preferentially expressed in the skeletal muscle fibers where the presence of an efficient Cl(-) homeostasis is crucial for the correct membrane repolarization and propagation of action potential. As a consequence, mutations in the CLCN1 gene cause dominant and recessive forms of myotonia congenita (MC), a rare skeletal muscle channelopathy caused by abnormal membrane excitation, and clinically characterized by muscle stiffness and various degrees of transitory weakness. Elucidation of the mechanistic link between the genetic defects and the disease pathogenesis is still incomplete and, at this time, there is no specific treatment for MC. Still controversial is the subcellular localization pattern of ClC-1 channels in skeletal muscle as well as its modulation by some intracellular factors. The expression of ClC-1 in other tissues such as in brain and heart and the possible assembly of ClC-1/ClC-2 heterodimers further expand the physiological properties of ClC-1 and its involvement in diseases. A recent de novo CLCN1 truncation mutation in a patient with generalized epilepsy indeed postulates an unexpected role of this channel in the control of neuronal network excitability. This review summarizes the most relevant and state-of-the-art research on ClC-1 chloride channels physiology and associated diseases.

  15. Primary complement C5 deficiencies - molecular characterization and clinical review of two families.

    Science.gov (United States)

    Schejbel, Lone; Fadnes, Dag; Permin, Henrik; Lappegård, Knut Tore; Garred, Peter; Mollnes, Tom Eirik

    2013-10-01

    Inherited deficiency states of the terminal complement component C5 are rare and often associated with increased risk of recurrent Neisseria infections. More than 50 cases with primary C5 deficiency have been reported. In spite of this, the molecular basis has only been documented in a few cases. In the present study we investigated two unrelated Caucasian probands with C5 deficiency originating from Norway and Denmark, respectively, and found three previously undescribed mutations. With these data, thirteen mutations associated with C5 deficiency have been described. By genetic screening of the family of the Norwegian patient, previously diagnosed as homozygous C5 deficient and suffering four Neisseria infections, an additional case of C5 deficiency was discovered, who had experienced one episode of Neisseria infections. Detailed review of the clinical history of the patients and their healthy relatives did not reveal any differences between C5 deficient and sufficient individuals with regard to clinical presentation, apart from the susceptibility to Neisseria infections. Of note, one of the patients described here, and several C5 deficient patients from the literature had Neisseria meningitidis serotype B infections, which is not covered by the current vaccines. These data support the clinical guidelines for patients treated with C5 inhibitors, who are functional C5 deficient by the treatment. Copyright © 2013 Elsevier GmbH. All rights reserved.

  16. The Nature of Foot Ray Deficiency in Congenital Fibular Deficiency.

    Science.gov (United States)

    Reyes, Bryan A; Birch, John G; Hootnick, David R; Cherkashin, Alex M; Samchukov, Mikhail L

    Absent lateral osseous structures in congenital fibular deficiency, including the distal femur and fibula, have led some authors to refer to the nature of foot ray deficiency as "lateral" as well. Others have suggested that the ray deficiency is in the central portion of the midfoot and forefoot.We sought to determine whether cuboid preservation and/or cuneiform deficiency in the feet of patients with congenital fibular deficiency implied that the ray deficiency is central rather than lateral in patients with congenital fibular deficiency. We identified all patients with a clinical morphologic diagnosis of congenital fibular deficiency at our institution over a 15-year period. We reviewed the records and radiographs of patients who had radiographs of the feet to allow determination of the number of metatarsals, the presence or absence of a cuboid or calcaneocuboid fusion, the number of cuneiforms present (if possible), and any other osseous abnormalities of the foot. We excluded patients with 5-rayed feet, those who had not had radiographs of the feet, or whose radiographs were not adequate to allow accurate assessment of these radiographic features. We defined the characteristic "lateral (fifth) ray present" if there was a well-developed cuboid or calcaneocuboid coalition with which the lateral-most preserved metatarsal articulated. Twenty-six patients with 28 affected feet met radiographic criteria for inclusion in the study. All affected feet had a well-developed cuboid or calcaneocuboid coalition. The lateral-most ray of 25 patients with 26 affected feet articulated with the cuboid or calcaneocuboid coalition. One patient with bilateral fibular deficiency had bilateral partially deficient cuboids, and the lateral-most metatarsal articulated with the medial remnant of the deformed cuboids. Twenty-one of 28 feet with visible cuneiforms had 2 or 1 cuneiform. Although the embryology and pathogenesis of congenital fibular deficiency remain unknown, based on the

  17. MCAD deficiency in Denmark

    DEFF Research Database (Denmark)

    Andresen, Brage Storstein; Lund, Allan Meldgaard; Hougaard, David Michael

    2012-01-01

    Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common defect of fatty acid oxidation. Many countries have introduced newborn screening for MCADD, because characteristic acylcarnitines can easily be identified in filter paper blood spot samples by tandem mass spectrometry (MS...... analysis. This gives an incidence of MCADD detected by newborn screening in Denmark of 1/8954. In sharp contrast to this we found that the incidence of clinically presenting MCADD in Denmark in the 10 year period preceding introduction of MS/MS-based screening was only 1 in 39,691. This means that four...... lower proportion of newborns being homozygous for the prevalent disease-causing c.985A>G mutation. A significant number of the newborns have genotypes with mutations that have not been observed in patients detected clinically. Some of these mutations, like c.199T>C and c.127G>A, are always associated...

  18. Congenital fibular deficiency.

    Science.gov (United States)

    Hamdy, Reggie C; Makhdom, Asim M; Saran, Neil; Birch, John

    2014-04-01

    Congenital fibular deficiency (CFD) is characterized by a wide spectrum of manifestations ranging from mild limb length inequality (LLI) to severe shortening, with foot and ankle deformities and associated anomalies. The etiology of CFD remains unclear. Treatment goals are to achieve normal weight bearing, a functional plantigrade foot, and equal limb length. The recent Birch classification system has been proposed to provide a treatment guide: the functionality of the foot, LLI, and associated anomalies should be taken into account for decision-making. Treatment options include orthosis or epiphysiodesis, Syme or Boyd amputation and prosthetic rehabilitation, limb lengthening procedures, and foot and ankle reconstruction. The outcome of amputation for severe forms of CFD has shown favorable results and fewer complications compared with those of limb lengthening. Nevertheless, advances in the limb lengthening techniques may change our approach to treating patients with CFD and might extend the indications for reconstructive procedures to the treatment of severe LLI and foot deformities.

  19. Mortality and GH deficiency

    DEFF Research Database (Denmark)

    Stochholm, Kirstine; Gravholt, Claus Højbjerg; Laursen, Torben

    2007-01-01

    OBJECTIVE: To estimate the mortality in Denmark in patients suffering from GH deficiency (GHD). DESIGN: Mortality was analyzed in 1794 GHD patients and 8014 controls matched on age and gender. All records in GHD patients were studied and additional morbidity noted. Patients were divided...... into childhood onset (CO) and adult onset (AO), discriminated by an age cutoff below or above 18 years at onset of GHD. METHOD: Data on death were identified in national registries. Sex- and cause-specific mortalities were identified in CO and AO GHD when compared with controls. RESULTS: Mortality was increased...... versus AO males, both compared with controls (P mortality was increased due to cancer in all subgroups, due to circulatory diseases in all age groups for females and for males in the oldest age group. For CO, the increased mortality was due to cancer. CONCLUSIONS: We found...

  20. In silico Analysis of osr40c1 Promoter Sequence Isolated from Indica Variety Pokkali

    Directory of Open Access Journals (Sweden)

    W.S.I. de Silva

    2017-07-01

    Full Text Available The promoter region of a drought and abscisic acid (ABA inducible gene, osr40c1, was isolated from a salt-tolerant indica rice variety Pokkali, which is 670 bp upstream of the putative translation start codon. In silico promoter analysis of resulted sequence showed that at least 15 types of putative motifs were distributed within the sequence, including two types of common promoter elements, TATA and CAAT boxes. Additionally, several putative cis-acing regulatory elements which may be involved in regulation of osr40c1 expression under different conditions were found in the 5′-upstream region of osr40c1. These are ABA-responsive element, light-responsive elements (ATCT-motif, Box I, G-box, GT1-motif, Gap-box and Sp1, myeloblastosis oncogene response element (CCAAT-box, auxin responsive element (TGA-element, gibberellin-responsive element (GARE-motif and fungal-elicitor responsive elements (Box E and Box-W1. A putative regulatory element, required for endosperm-specific pattern of gene expression designated as Skn-1 motif, was also detected in the Pokkali osr40c1 promoter region. In conclusion, the bioinformatic analysis of osr40c1 promoter region isolated from indica rice variety Pokkali led to the identification of several important stress-responsive cis-acting regulatory elements, and therefore, the isolated promoter sequence could be employed in rice genetic transformation to mediate expression of abiotic stress induced genes.

  1. Second-order optimality conditions for problems with C1 data

    Science.gov (United States)

    Ginchev, Ivan; Ivanov, Vsevolod I.

    2008-04-01

    In this paper we obtain second-order optimality conditions of Karush-Kuhn-Tucker type and Fritz John one for a problem with inequality constraints and a set constraint in nonsmooth settings using second-order directional derivatives. In the necessary conditions we suppose that the objective function and the active constraints are continuously differentiable, but their gradients are not necessarily locally Lipschitz. In the sufficient conditions for a global minimum we assume that the objective function is differentiable at and second-order pseudoconvex at , a notion introduced by the authors [I. Ginchev, V.I. Ivanov, Higher-order pseudoconvex functions, in: I.V. Konnov, D.T. Luc, A.M. Rubinov (Eds.), Generalized Convexity and Related Topics, in: Lecture Notes in Econom. and Math. Systems, vol. 583, Springer, 2007, pp. 247-264], the constraints are both differentiable and quasiconvex at . In the sufficient conditions for an isolated local minimum of order two we suppose that the problem belongs to the class C1,1. We show that they do not hold for C1 problems, which are not C1,1 ones. At last a new notion parabolic local minimum is defined and it is applied to extend the sufficient conditions for an isolated local minimum from problems with C1,1 data to problems with C1 one.

  2. Emicizumab Prophylaxis in Hemophilia A with Inhibitors.

    Science.gov (United States)

    Oldenburg, Johannes; Mahlangu, Johnny N; Kim, Benjamin; Schmitt, Christophe; Callaghan, Michael U; Young, Guy; Santagostino, Elena; Kruse-Jarres, Rebecca; Negrier, Claude; Kessler, Craig; Valente, Nancy; Asikanius, Elina; Levy, Gallia G; Windyga, Jerzy; Shima, Midori

    2017-08-31

    Emicizumab (ACE910) bridges activated factor IX and factor X to restore the function of activated factor VIII, which is deficient in persons with hemophilia A. This phase 3, multicenter trial assessed once-weekly subcutaneous emicizumab prophylaxis in persons with hemophilia A with factor VIII inhibitors. We enrolled participants who were 12 years of age or older. Those who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point was the difference in bleeding rates between group A and group B. Participants who had previously received prophylactic treatment with bypassing agents received emicizumab prophylaxis in group C. A total of 109 male participants with hemophilia A with inhibitors were enrolled. The annualized bleeding rate was 2.9 events (95% confidence interval [CI], 1.7 to 5.0) among participants who were randomly assigned to emicizumab prophylaxis (group A, 35 participants) versus 23.3 events (95% CI, 12.3 to 43.9) among those assigned to no prophylaxis (group B, 18 participants), representing a significant difference of 87% in favor of emicizumab prophylaxis (Phemophilia A with inhibitors. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 1 ClinicalTrials.gov number, NCT02622321 .).

  3. Iron deficiency and cardiovascular disease

    NARCIS (Netherlands)

    von Haehling, Stephan; Jankowska, Ewa A.; van Veldhuisen, Dirk J.; Ponikowski, Piotr; Anker, Stefan D.

    2015-01-01

    Iron deficiency affects up to one-third of the world's population, and is particularly common in elderly individuals and those with certain chronic diseases. Iron excess can be detrimental in cardiovascular illness, and research has now also brought anaemia and iron deficiency into the focus of

  4. Vitamin B12 deficiency anemia

    Science.gov (United States)

    ... provide oxygen to body tissues. There are many types of anemia. Vitamin B12 deficiency anemia is a low red ... People with this type of anemia often do well with treatment. Long-term vitamin B12 deficiency can cause nerve damage. This may be permanent if ...

  5. Quantification of the catalytic performance of C1-cellulose-specific lytic polysaccharide monooxygenases.

    Science.gov (United States)

    Frommhagen, Matthias; Westphal, Adrie H; Hilgers, Roelant; Koetsier, Martijn J; Hinz, Sandra W A; Visser, Jaap; Gruppen, Harry; van Berkel, Willem J H; Kabel, Mirjam A

    2018-02-01

    Lytic polysaccharide monooxygenases (LPMOs) have recently been shown to significantly enhance the degradation of recalcitrant polysaccharides and are of interest for the production of biochemicals and bioethanol from plant biomass. The copper-containing LPMOs utilize electrons, provided by reducing agents, to oxidatively cleave polysaccharides. Here, we report the development of a β-glucosidase-assisted method to quantify the release of C1-oxidized gluco-oligosaccharides from cellulose by two C1-oxidizing LPMOs from Myceliophthora thermophila C1. Based on this quantification method, we demonstrate that the catalytic performance of both MtLPMOs is strongly dependent on pH and temperature. The obtained results indicate that the catalytic performance of LPMOs depends on the interaction of multiple factors, which are affected by both pH and temperature.

  6. Detection of vanC1 gene transcription in vancomycin-susceptible Enterococcus faecalis

    Science.gov (United States)

    de Moura, Tiane Martin; Cassenego, Ana Paula Vaz; Campos, Fabrício Souza; Ribeiro, Andrea Machado Leal; Franco, Ana Cláudia; d'Azevedo, Pedro Alves; Frazzon, Jeverson; Frazzon, Ana Paula Guedes

    2013-01-01

    Here we report the presence and expression levels of the vanC 1 and vanC 2/3 genes in vancomycin-susceptible strains of Enterococcus faecalis. The vanC 1 and vanC 2/3 genes were located in the plasmid DNA and on the chromosome, respectively. Specific mRNA of the vanC 1 gene was detected in one of these strains. Additionally, analysis of the vanC gene sequences showed that these genes are related to the vanC genes of Enterococcus gallinarum and Enterococcus casseliflavus. The presence of vanC genes is useful for the identification of E. gallinarum and E. casseliflavus. Moreover, this is the first report of vanC mRNA in E. faecalis. PMID:23828012

  7. Detection of vanC 1 gene transcription in vancomycin-susceptible Enterococcus faecalis

    Directory of Open Access Journals (Sweden)

    Tiane Martin de Moura

    2013-06-01

    Full Text Available Here we report the presence and expression levels of the vanC 1 and vanC 2/3 genes in vancomycin-susceptible strains of Enterococcus faecalis. The vanC 1 and vanC 2/3 genes were located in the plasmid DNA and on the chromosome, respectively. Specific mRNA of the vanC 1 gene was detected in one of these strains. Additionally, analysis of the vanC gene sequences showed that these genes are related to the vanC genes of Enterococcus gallinarum and Enterococcus casseliflavus. The presence of vanC genes is useful for the identification of E. gallinarum and E. casseliflavus. Moreover, this is the first report of vanC mRNA in E. faecalis.

  8. Carbon isotope anomaly in the major plant C1 pool and its global biogeochemical implications

    Directory of Open Access Journals (Sweden)

    F. Keppler

    2004-01-01

    Full Text Available We report that the most abundant C1 units of terrestrial plants, the methoxyl groups of pectin and lignin, have a unique carbon isotope signature exceptionally depleted in 13C. Plant-derived C1 volatile organic compounds (VOCs are also anomalously depleted in 13C compared with Cn+1 VOCs. The results confirm that the plant methoxyl pool is the predominant source of biospheric C1 compounds of plant origin such as methanol, chloromethane and bromomethane. Furthermore this pool, comprising ca 2.5% of carbon in plant biomass, could be an important substrate for methanogenesis and thus be envisaged as a possible source of isotopically light methane entering the atmosphere. Our findings have significant implications for the use of carbon isotope ratios in elucidation of global carbon cycling. Moreover methoxyl groups could act as markers for biological activity in organic matter of terrestrial and extraterrestrial origin.

  9. Characterization of two new dominant ClC-1 channel mutations associated with myotonia

    DEFF Research Database (Denmark)

    Grunnet, Morten; Jespersen, Thomas; Colding-Jørgensen, Eskild

    2003-01-01

    Voltage-gated ClC-1 chloride channels encoded by the CLCN1 gene have a major role in setting the membrane potential in skeletal muscle. More than 60 CLCN1 mutations have been associated with myotonia congenita. These mutations are traditionally classified as recessive (Becker's disease) or dominant...... revealed a change in reversal potential compared to wild-type channels. This finding supports the notion that the E193 amino acid is an important determinant in the selectivity filter of the human ClC-1 channel. The electrophysiological behavior of both mutants demonstrates a severe reduction in ClC-1...... channel conductance under physiologically relevant membrane potentials. These studies thereby explain the molecular background for the observed myotonia in patients....

  10. Identification and Analysis of the Chloroplast rpoC1 Gene Differentially Expressed in Wild Ginseng

    Directory of Open Access Journals (Sweden)

    Lee Kwang-Ho

    2012-06-01

    Full Text Available Panax ginseng is a well-known herbal medicine in traditional Asian medicine, and wild ginseng is widely accepted to be more active than cultivated ginseng in chemoprevention. However, little has actually been reported on the difference between wild ginseng and cultivated ginseng. Thus, to identify and analyze those differences, we used suppressive subtraction hybridization (SSH sequences with microarrays, realtime polymerase chain reaction (PCR, and reverse transcription PCRs (RT-PCRs. One of the clones isolated in this research was the chloroplast rpoC1 gene, a β subunit of RNA polymerase. Real-time RT-PCR results showed that the expression of the rpoC1 gene was significantly upregulated in wild ginseng as compared to cultivated ginseng, so, we conclude that the rpoC1 gene may be one of the important markers of wild ginseng.

  11. C1 Polymerization: a unique tool towards polyethylene-based complex macromolecular architectures

    KAUST Repository

    Wang, De

    2017-05-09

    The recent developments in organoborane initiated C1 polymerization (chain grows by one atom at a time) of ylides opens unique horizons towards well-defined/perfectly linear polymethylenes (equivalent to polyethylenes, PE) and PE-based complex macromolecular architectures. The general mechanism of C1 polymerization (polyhomologation) involves the formation of a Lewis complex between a methylide (monomer) and a borane (initiator), followed by migration/insertion of a methylene into the initiator and after oxidation/hydrolysis to afford OH-terminated polyethylenes. This review summarizes efforts towards conventional and newly discovered borane-initiators and ylides (monomers), as well as a combination of polyhomologation with other polymerization methods. Initial efforts dealing with C3 polymerization and the synthesis of the first C1/C3 copolymers are also given. Finally, some thoughts for the future of these polymerizations are presented.

  12. Tumor necrosis factor-alpha potentiates the cytotoxicity of amiodarone in Hepa1c1c7 cells: roles of caspase activation and oxidative stress.

    Science.gov (United States)

    Lu, Jingtao; Miyakawa, Kazuhisa; Roth, Robert A; Ganey, Patricia E

    2013-01-01

    Amiodarone (AMD), a class III antiarrhythmic drug, causes idiosyncratic hepatotoxicity in human patients. We demonstrated previously that tumor necrosis factor-alpha (TNF-α) plays an important role in a rat model of AMD-induced hepatotoxicity under inflammatory stress. In this study, we developed a model in vitro to study the roles of caspase activation and oxidative stress in TNF potentiation of AMD cytotoxicity. AMD caused cell death in Hepa1c1c7 cells, and TNF cotreatment potentiated its toxicity. Activation of caspases 9 and 3/7 was observed in AMD/TNF-cotreated cells, and caspase inhibitors provided minor protection from cytotoxicity. Intracellular reactive oxygen species (ROS) generation and lipid peroxidation were observed after treatment with AMD and were further elevated by TNF cotreatment. Adding water-soluble antioxidants (trolox, N-acetylcysteine, glutathione, or ascorbate) produced only minor attenuation of AMD/TNF-induced cytotoxicity and did not influence the effect of AMD alone. On the other hand, α-tocopherol (TOCO), which reduced lipid peroxidation and ROS generation, prevented AMD toxicity and caused pronounced reduction in cytotoxicity from AMD/TNF cotreatment. α-TOCO plus a pancaspase inhibitor completely abolished AMD/TNF-induced cytotoxicity. In summary, activation of caspases and oxidative stress were observed after AMD/TNF cotreatment, and caspase inhibitors and a lipid-soluble free-radical scavenger attenuated AMD/TNF-induced cytotoxicity.

  13. Iron deficiency anemia in children.

    Science.gov (United States)

    Subramaniam, Girish; Girish, Meenakshi

    2015-06-01

    Iron deficiency is not just anemia; it can be responsible for a long list of other manifestations. This topic is of great importance, especially in infancy and early childhood, for a variety of reasons. Firstly, iron need is maximum in this period. Secondly, diet in infancy is usually deficient in iron. Thirdly and most importantly, iron deficiency at this age can result in neurodevelopmental and cognitive deficits, which may not be reversible. Hypochromia and microcytosis in a complete blood count (CBC) makes iron deficiency anemia (IDA) most likely diagnosis. Absence of response to iron should make us look for other differential diagnosis like β thalassemia trait and anemia of chronic disease. Celiac disease is the most important cause of true IDA not responding to oral iron therapy. While oral ferrous sulphate is the cheapest and most effective therapy for IDA, simple nonpharmacological and pharmacological measures can go a long way in prevention of iron deficiency.

  14. ATM protein is deficient in over 40% of lung adenocarcinomas.

    Science.gov (United States)

    Villaruz, Liza C; Jones, Helen; Dacic, Sanja; Abberbock, Shira; Kurland, Brenda F; Stabile, Laura P; Siegfried, Jill M; Conrads, Thomas P; Smith, Neil R; O'Connor, Mark J; Pierce, Andrew J; Bakkenist, Christopher J

    2016-09-06

    Lung cancer is the leading cause of cancer-related mortality in the USA and worldwide, and of the estimated 1.2 million new cases of lung cancer diagnosed every year, over 30% are lung adenocarcinomas. The backbone of 1st-line systemic therapy in the metastatic setting, in the absence of an actionable oncogenic driver, is platinum-based chemotherapy. ATM and ATR are DNA damage signaling kinases activated at DNA double-strand breaks (DSBs) and stalled and collapsed replication forks, respectively. ATM protein is lost in a number of cancer cell lines and ATR kinase inhibitors synergize with cisplatin to resolve xenograft models of ATM-deficient lung cancer. We therefore sought to determine the frequency of ATM loss in a tissue microarray (TMA) of lung adenocarcinoma. Here we report the validation of a commercial antibody (ab32420) for the identification of ATM by immunohistochemistry and estimate that 61 of 147 (41%, 95% CI 34%-50%) cases of lung adenocarcinoma are negative for ATM protein expression. As a positive control for ATM staining, nuclear ATM protein was identified in stroma and immune infiltrate in all evaluable cases. ATM loss in lung adenocarcinoma was not associated with overall survival. However, our preclinical findings in ATM-deficient cell lines suggest that ATM could be a predictive biomarker for synergy of an ATR kinase inhibitor with standard-of-care cisplatin. This could improve clinical outcome in 100,000's of patients with ATM-deficient lung adenocarcinoma every year.

  15. Lysosomal membrane permeabilization is involved in oxidative stress-induced apoptotic cell death in LAMP2-deficient iPSCs-derived cerebral cortical neurons

    Directory of Open Access Journals (Sweden)

    Cheuk-Yiu Law

    2016-03-01

    Our results from cellular fractionation and inhibitor blockade experiments further revealed that oxidative stress-induced apoptosis in the LAMP2-deficient cortical neurons was caused by increased abundance of cytosolic cathepsin L. These results suggest the involvement of lysosomal membrane permeabilization in the LAMP2 deficiency associated neural injury.

  16. Mechanisms involved in calcium deficiency development in tomato fruit in response to gibberellins

    Science.gov (United States)

    Although gibberellins (GAs) have been shown to induce the calcium deficiency disorder, blossom-end rot (BER), development in tomato fruit (Solanum lycopersicum), the mechanisms involved remain largely unexplored. Our objectives were to better understand how GAs and a GA biosynthesis inhibitor affect...

  17. Myeloid IκBα deficiency promotes atherogenesis by enhancing leukocyte recruitment to the plaques

    NARCIS (Netherlands)

    P. Goossens (Pieter); Y. Vergouwe (Yvonne); M. Gijbels (Marion); D.M.J. Curfs (Danielle M.); J.H.G. van Woezik (Johannes H.); M.A. Hoeksema (Marten); S. Xanthoulea (Sofia); P.J. Leenen (Pieter); R.A. Rupec (Rudolf); M.A. Hofker (Marten); M.P.J. de Winther (Menno P.)

    2011-01-01

    textabstractActivation of the transcription factor NF-κB appears to be involved in different stages of atherogenesis. In this paper we investigate the role of NF-κB inhibitor IκBα in atherosclerosis. Myeloid-specific deletion of IκBα results in larger and more advanced lesions in LDL-R-deficient

  18. Myeloid IκBα deficiency promotes atherogenesis by enhancing leukocyte recruitment to the plaques

    NARCIS (Netherlands)

    Goossens, Pieter; Vergouwe, Monique N.; Gijbels, Marion J. J.; Curfs, Danielle M. J.; van Woezik, Johannes H. G.; Hoeksema, Marten A.; Xanthoulea, Sofia; Leenen, Pieter J. M.; Rupec, Rudolf A.; Hofker, Marten H.; de Winther, Menno P. J.

    2011-01-01

    Activation of the transcription factor NF-κB appears to be involved in different stages of atherogenesis. In this paper we investigate the role of NF-κB inhibitor IκBα in atherosclerosis. Myeloid-specific deletion of IκBα results in larger and more advanced lesions in LDL-R-deficient mice without

  19. Gaussian quadrature rules for C 1 quintic splines with uniform knot vectors

    KAUST Repository

    Bartoň, Michael

    2017-03-21

    We provide explicit quadrature rules for spaces of C1C1 quintic splines with uniform knot sequences over finite domains. The quadrature nodes and weights are derived via an explicit recursion that avoids numerical solvers. Each rule is optimal, that is, requires the minimal number of nodes, for a given function space. For each of nn subintervals, generically, only two nodes are required which reduces the evaluation cost by 2/32/3 when compared to the classical Gaussian quadrature for polynomials over each knot span. Numerical experiments show fast convergence, as nn grows, to the “two-third” quadrature rule of Hughes et al. (2010) for infinite domains.

  20. SYNTHESIS OF THE ISOQUINO-[2,1-c][1,3]-BENZODIAZEPINE DERIVATIVE FROM PAPAVERINE

    Directory of Open Access Journals (Sweden)

    I Made Sudarma

    2010-06-01

    Full Text Available The objective of this research was to synthesize isoquino[2,1-c][1,3]benzodiazepine from papaverine alkaloid. Functional Group Interconversion (FGI and Carbon -Nitrogen bond connection approach was investigated. Papaverine (1 was nitrated by HNO3 to compound (2 and followed by reduction with Sn and HCl to afford aminonorlaudanosine (3. Formation of cyclic benzodiazepine (4 was achieved by reaction of (3 with CS2. Products of reactions were confirmed by Nuclear Magnetic Resonances (n.m.r, Mass Spectrum, and Fourier Transform Infra Red (FTIR.   Keywords: isoquino[2,1-c][1,3]benzodiazepine, papaverine

  1. C1q binding to Dengue Virus inhibits infection of THP-1 and cellular inflammatory responses

    Science.gov (United States)

    Douradinha, Bruno; McBurney, Sean P.; de Melo, Klecia M. Soares; Smith, Amanda P.; Krishna, Neel K.; Barratt-Boyes, Simon M.; Evans, Jared D.; Nascimento, Eduardo J. M.; Marques, Ernesto T. A

    2014-01-01

    Summary Dengue virus infection elicits a spectrum of clinical presentations ranging from asymptomatic to severe disease. The mechanisms leading to severe dengue are not known, however it has been reported that the complement system is hyper-activated in severe dengue. Screening of complement proteins demonstrated that C1q, a pattern recognition molecule, can bind directly to Dengue Virus Envelope protein and to whole Dengue Virus serotype 2. Incubation of Dengue Virus serotype 2 with C1q prior to infection of THP-1 cells led to decreased virus infectivity and modulation of mRNA expression of immunoregulatory molecules suggesting reduced inflammatory responses. PMID:24246304

  2. Complement C1q activates tumor suppressor WWOX to induce apoptosis in prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Qunying Hong

    Full Text Available BACKGROUND: Tissue exudates contain low levels of serum complement proteins, and their regulatory effects on prostate cancer progression are largely unknown. We examined specific serum complement components in coordinating the activation of tumor suppressors p53 and WWOX (also named FOR or WOX1 and kinases ERK, JNK1 and STAT3 in human prostate DU145 cells. METHODOLOGY/PRINCIPAL FINDINGS: DU145 cells were cultured overnight in 1% normal human serum, or in human serum depleted of an indicated complement protein. Under complement C1q- or C6-free conditions, WOX1 and ERK were mainly present in the cytoplasm without phosphorylation, whereas phosphorylated JNK1 was greatly accumulated in the nuclei. Exogenous C1q rapidly restored the WOX1 activation (with Tyr33 phosphorylation in less than 2 hr. Without serum complement C9, p53 became activated, and hyaluronan (HA reversed the effect. Under C6-free conditions, HA induced activation of STAT3, an enhancer of metastasis. Notably, exogenous C1q significantly induced apoptosis of WOX1-overexpressing DU145 cells, but not vehicle-expressing cells. A dominant negative and Y33R mutant of WOX1 blocked the apoptotic effect. C1q did not enhance p53-mediated apoptosis. By total internal reflection fluorescence (TIRF microscopy, it was determined that C1q destabilized adherence of WOX1-expressing DU145 cells by partial detaching and inducing formation of clustered microvilli for focal adhesion particularly in between cells. These cells then underwent shrinkage, membrane blebbing and death. Remarkably, as determined by immunostaining, benign prostatic hyperplasia and prostate cancer were shown to have a significantly reduced expression of tissue C1q, compared to age-matched normal prostate tissues. CONCLUSIONS/SIGNIFICANCE: We conclude that complement C1q may induce apoptosis of prostate cancer cells by activating WOX1 and destabilizing cell adhesion. Downregulation of C1q enhances prostate hyperplasia and cancerous

  3. Interactions between copper deficiency, selenium deficiency and adriamycin toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Fischer, J.; Tackett, R.; Johnson, M.A. (Univ. of Georgia, Athens (United States))

    1991-03-15

    The objective of this study was to test the hypothesis that there are interactions between copper (Cu) and selenium (Se) status, and adriamycin (ADR) toxicity. Male Sprague Dawley rats were fed Cu,Se adequate; Cu deficient, Se adequate ({minus}Cu); Cu adequate, Se deficient; or Cu,Se deficient diets for 38-41 days. ADR or saline (SAL) were administered weekly for the last 4 weeks of the study. Cu deficiency was confirmed by a 3-fold decrease in liver Cu,Zn-superoxide dismutase and liver Cu, and a 5-fold decrease in RBC Cu,Zn-SOD. Se deficiency was confirmed by a 10-fold decrease in liver glutathione peroxidase (GSH-Px). ADR, Cu deficiency and Se deficiency all caused EKG abnormalities. However, Cu and Se deficiencies did not enhance ADR's influence on EKGs. ADR increased lipid peroxidation in liver by 15% and in heart by 18% (NS). Cu deficiency decreased ADR-induced lipid peroxidation in heart tissue by 25%. ADR influenced Se status by significantly increasing heart GSH-Px, and Cu status by increasing liver Cu, plasma ceruloplasmin and liver Cu, Zn-SOD. These elevations in Cu,Zn-SOD and GSH-Px may be a consequence of the increased lipid peroxidation initiated by ADR. In {minus}Cu rats, ADR caused severe hemolytic anemia characterized by a 19% decrease in hematocrit and a 17-fold increase in splenic Fe. These data suggest that there are numerous interactions between ADR toxicity and Cu and Se status.

  4. Genetics Home Reference: adenosine deaminase 2 deficiency

    Science.gov (United States)

    ... Twitter Home Health Conditions Adenosine deaminase 2 deficiency Adenosine deaminase 2 deficiency Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description Adenosine deaminase 2 (ADA2) deficiency is a disorder characterized ...

  5. Genetics Home Reference: lactate dehydrogenase deficiency

    Science.gov (United States)

    ... Facebook Twitter Home Health Conditions Lactate dehydrogenase deficiency Lactate dehydrogenase deficiency Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Lactate dehydrogenase deficiency is a condition that affects how the ...

  6. Genetics Home Reference: carnitine palmitoyltransferase I deficiency

    Science.gov (United States)

    ... SL, Raff ML. Novel mutations in CPT 1A define molecular heterogeneity of hepatic carnitine palmitoyltransferase I deficiency. ... What is newborn screening? New Pages type 2 diabetes mitochondrial complex I deficiency mitochondrial complex V deficiency ...

  7. Facts about Vitamin K Deficiency Bleeding

    Science.gov (United States)

    ... label> Information For… Media Policy Makers Facts about Vitamin K Deficiency Bleeding Recommend on Facebook Tweet Share Compartir ... deficient ” or has a “ vitamin deficiency ”. What is vitamin K and why is it important? Vitamin K is ...

  8. Genetics Home Reference: corticosterone methyloxidase deficiency

    Science.gov (United States)

    ... deficiency corticosterone methyloxidase deficiency Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. ... methyloxidase deficiency can cause nausea, vomiting, dehydration, low blood pressure, extreme tiredness (fatigue), and muscle weakness. Affected infants ...

  9. Cathepsin D inhibitors

    Directory of Open Access Journals (Sweden)

    M. Gacko

    2007-11-01

    Full Text Available Inhibitors of cathepsin D belong to chemical compounds that estrify carboxyl groups of the Asp33 and Asp231residues of its catalytic site, penta-peptides containing statin, i.e. the amino acid similar in structure to the tetraedric indirectproduct, and polypeptides found in the spare organs of many plants and forming permanent noncovalent complexes withcathepsin. Cathepsin D activity is also inhibited by alpha2-macroglobulin and antibodies directed against this enzyme.Methods used to determine the activity and concentration of these inhibitors and their analytical, preparative and therapeuticapplications are discussed.

  10. Morbidity and GH deficiency

    DEFF Research Database (Denmark)

    Stochholm, Kirstine; Laursen, Torben; Green, Anders

    2008-01-01

    OBJECTIVE: To estimate morbidity in Denmark in all patients with GH deficiency (GHD). DESIGN: Morbidity was analyzed in 1794 GHD patients and 8014 controls matched on age and gender. All records in the GHD patients were studied and additional morbidity noted. Diagnoses and dates of admissions were...... identified in the National Patient Registry. Lag time until first admission was used as a measure of morbidity. Patients were divided into childhood onset (CO) and adult onset (AO), discriminated by an age cut-off of 18 years at onset of GHD. METHOD: Sex- and cause-specific hazard ratios (HRs) in CO and AO...... GHD compared with controls. RESULTS: Total morbidity was significantly increased in the GHD patients. HR for CO males: 3.1 (95% confidence interval (CI): 2.7-3.7), CO females: 3.2 (95% CI: 2.6-3.9), AO males: 2.9 (95% CI: 2.6-3.2), and AO females: 3.2 (95% CI: 2.8-3.6). In 18 out of 20 chapters from...

  11. C 1 natural element method for strain gradient linear elasticity and its application to microstructures

    Science.gov (United States)

    Nie, Zhi-Feng; Zhou, Shen-Jie; Han, Ru-Jun; Xiao, Lin-Jing; Wang, Kai

    2012-02-01

    C 1 natural element method ( C 1 NEM) is applied to strain gradient linear elasticity, and size effects on microstructures are analyzed. The shape functions in C 1 NEM are built upon the natural neighbor interpolation (NNI), with interpolation realized to nodal function and nodal gradient values, so that the essential boundary conditions (EBCs) can be imposed directly in a Galerkin scheme for partial differential equations (PDEs). In the present paper, C 1 NEM for strain gradient linear elasticity is constructed, and several typical examples which have analytical solutions are presented to illustrate the effectiveness of the constructed method. In its application to microstructures, the size effects of bending stiffness and stress concentration factor (SCF) are studied for microspeciem and microgripper, respectively. It is observed that the size effects become rather strong when the width of spring for microgripper, the radius of circular perforation and the long axis of elliptical perforation for microspeciem come close to the material characteristic length scales. For the U-shaped notch, the size effects decline obviously with increasing notch radius, and decline mildly with increasing length of notch.

  12. Association of the rs3743205 variant of DYX1C1 with dyslexia in Chinese children

    Directory of Open Access Journals (Sweden)

    Waye Mary MY

    2011-05-01

    Full Text Available Abstract Background Dyslexia is a learning disability that is characterized by difficulties in the acquisition of reading and spelling skills independent of intelligence, motivation or schooling. Studies of western populations have suggested that DYX1C1 is a candidate gene for dyslexia. In view of the different languages used in Caucasian and Chinese populations, it is therefore worthwhile to investigate whether there is an association of DYX1C1 in Chinese children with dyslexia. Method and Results Eight single nucleotide polymorphisms (SNPs were genotyped from three hundred and ninety three individuals from 131 Chinese families with two which have been reported in the literature and six tag SNPs at DYX1C1. Analysis for allelic and haplotypic associations was performed with the UNPHASED program and multiple testing was corrected using false discovery rates. We replicated the previously reported association of rs3743205 in Chinese children with dyslexia (pcorrected = 0.0072. This SNP was also associated with rapid naming, phonological memory and orthographic skills in quantitative trait analysis. Conclusion Our findings suggest that DYX1C1 is associated with dyslexia in people of Chinese ethnicity in Hong Kong.

  13. Simulation of XPS C1s Spectra of Organic Monolayers by Quantum Chemical Methods

    NARCIS (Netherlands)

    Giesbers, M.; Marcelis, A.T.M.; Zuilhof, H.

    2013-01-01

    Several simple methods are presented and evaluated to simulate the X-ray photoelectron spectra (XPS) of organic monolayers and polymeric layers by density functional theory (DFT) and second-order Møller–Plesset theory (MP2) in combination with a series of basis sets. The simulated carbon (C1s) XPS

  14. C1-continuous Virtual Element Method for Poisson-Kirchhoff plate problem

    Energy Technology Data Exchange (ETDEWEB)

    Gyrya, Vitaliy [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Mourad, Hashem Mohamed [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-09-20

    We present a family of C1-continuous high-order Virtual Element Methods for Poisson-Kirchho plate bending problem. The convergence of the methods is tested on a variety of meshes including rectangular, quadrilateral, and meshes obtained by edge removal (i.e. highly irregular meshes). The convergence rates are presented for all of these tests.

  15. Methyl Bromide Measurements in the Taylor Dome M3C1 Ice Core, Version 1

    Data.gov (United States)

    National Aeronautics and Space Administration — The data set includes methyl bromide (CH3Br) measurements made on air extracted from 70 samples from the Taylor Dome M3C1 ice core. CH3Br was measured in air from...

  16. Protection from obesity and insulin resistance in mice overexpressing human apolipoprotein C1

    NARCIS (Netherlands)

    Jong, M. C.; Voshol, P. J.; Muurling, M.; Dahlmans, V. E.; Romijn, J. A.; Pijl, H.; Havekes, L. M.

    2001-01-01

    Apolipoprotein (APO) C1 is a 6.6-kDa protein present in plasma and associated with lipoproteins. Using hyperinsulinemic-euglycemic clamp tests, we previously found that in APOC1 transgenic mice, the whole-body insulin-mediated glucose uptake is increased concomitant with a decreased fatty acid

  17. C1 compounds as auxiliary substrate for engineered Pseudomonas putida S12

    NARCIS (Netherlands)

    Koopman, F.W.; Winde, J.H. de; Ruijssenaars, H.J.

    2009-01-01

    The solvent-tolerant bacterium Pseudomonas putida S12 was engineered to efficiently utilize the C1 compounds methanol and formaldehyde as auxiliary substrate. The hps and phi genes of Bacillus brevis, encoding two key steps of the ribulose monophosphate (RuMP) pathway, were introduced to construct a

  18. 26 CFR 41.4482(c)-1 - Definition of State, taxable period, use, and customarily used.

    Science.gov (United States)

    2010-04-01

    ... a private roadway, or other private property, does not constitute use of the vehicle within the... VEHICLES Tax on Use of Certain Highway Motor Vehicles § 41.4482(c)-1 Definition of State, taxable period...”, as used in the regulations in this part with reference to a highway motor vehicle, means the use of...

  19. Construction of pECFP-C1- CIRP and its effect on cold-induced ...

    African Journals Online (AJOL)

    The fluorescence microscopy, real-time polymerase chain reaction (RT-PCR) and Western blot detection were done for transient and stable expression assays. CIRP gene was successfully subcloned into eukaryotic expression vector of pECFP-C1, confirmed by restrictive enzyme digestion analysis and DNA sequencing.

  20. Crossing the c=1 barrier in 2d Lorentzian quantum gravity

    NARCIS (Netherlands)

    Ambjørn, J.; Anagnostopoulos, K.N.; Loll, R.

    1999-01-01

    In an extension of earlier work we investigate the behaviour of two-dimensional Lorentzian quantum gravity under coupling to a conformal field theory with c > 1. This is done by analyzing numerically a system of eight Ising models (corresponding to c=4) coupled to dynamically triangulated

  1. Hyperlipidemia and cutaneous abnormalities in transgenic mice overexpressing human apolipoprotein C1

    NARCIS (Netherlands)

    Jong, M. C.; Gijbels, M. J.; Dahlmans, V. E.; Gorp, P. J.; Koopman, S. J.; Ponec, M.; Hofker, M. H.; Havekes, L. M.

    1998-01-01

    Transgenic mice were generated with different levels of human apolipoprotein C1 (APOC1) expression in liver and skin. At 2 mo of age, serum levels of cholesterol, triglycerides (TG), and FFA were strongly elevated in APOC1 transgenic mice compared with wild-type mice. These elevated levels of serum

  2. Rh-mediated C1-polymerization: copolymers from diazoesters and sulfoxonium ylides

    NARCIS (Netherlands)

    Olivos Suarez, A.I.; del Río, M.P.; Remerie, K.; Reek, J.N.H.; de Bruin, B.

    2012-01-01

    In this paper, we present new results obtained in our investigations of Rh-catalyzed C1 (co)polymerization reactions using carbene units as monomers. We demonstrate here, for the first time, the use of transition metal catalysts in carbene polymerization using sulfur ylides as the carbene monomer

  3. 26 CFR 31.3406(c)-1 - Notified payee underreporting of reportable interest or dividend payments.

    Science.gov (United States)

    2010-04-01

    ..., DEPARTMENT OF THE TREASURY (CONTINUED) EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE Collection of Income Tax at Source § 31.3406(c)-1 Notified... utilizes a universal account system described in the first sentence of paragraph (c)(3)(ii) of this section...

  4. Identifying a Resistance Determinant for the Antimitotic Natural Products Disorazole C1 and A1S⃞

    OpenAIRE

    Lazo, John S; Reese, Celeste E.; Vogt, Andreas; Vollmer, Laura L.; Kitchens, Carolyn A.; Günther, Eckhard; Graham, Thomas H.; Hopkins, Chad D.; Wipf, Peter

    2010-01-01

    Disorazoles are macrocyclic polyketides first isolated from the fermentation broth of the myxobacterium Sorangium cellulosum. Both the major fermentation product disorazole A1 and its much rarer companion disorazole C1 exhibit potent cytotoxic activity against many human tumor cells. Furthermore, the disorazoles appear to bind tubulin uniquely among known antimitotic agents, promoting apoptosis or premat...

  5. Cloning and tissue expression of cytochrome P450 1B1 and 1C1 ...

    African Journals Online (AJOL)

    SAM

    2014-05-14

    May 14, 2014 ... reading frame of 1551 bp encoding a protein of 517 amino acids; while, CYP1C1 having 2601 bp consists of an open ... expression. Key words: Cytochrome P450, Javanese medaka, salinity, starvation, heavy fuel oil, cloning, expression. .... had no influence on hepatic EROD activities, (Vigano et al., 1993) ...

  6. Cloning and tissue expression of cytochrome P450 1B1 and 1C1 ...

    African Journals Online (AJOL)

    SAM

    2014-05-14

    May 14, 2014 ... cellular macromolecules like DNA, lipids and proteins. (Breimer, 1990; Romero et al., ... Starva- tion has been reported to have pro-oxidant effects, and both the inadequate ..... boxes indicate the conserved motif region and red boxes indicates substrate recognition sites (SRS). CYP1C1 shares a number of ...

  7. Cleanup Verification Package for the 118-C-1, 105-C Solid Waste Burial Ground

    Energy Technology Data Exchange (ETDEWEB)

    M. J. Appel and J. M. Capron

    2007-07-25

    This cleanup verification package documents completion of remedial action for the 118-C-1, 105-C Solid Waste Burial Ground. This waste site was the primary burial ground for general wastes from the operation of the 105-C Reactor and received process tubes, aluminum fuel spacers, control rods, reactor hardware, spent nuclear fuel and soft wastes.

  8. Probing the Paracoccus denitrificans cytochrome c1 / c552 interaction by mutagenesis and fast kinetics†

    Science.gov (United States)

    Janzon, Julia; Yuan, Quan; Malatesta, Francesco; Hellwig, Petra; Ludwig, Bernd; Durham, Bill; Millett, Francis

    2008-01-01

    Electron transfer (ET) between Paracoccus denitrificans cytochrome c1 and cytochrome c552 was studied using the soluble redox fragments cyt c1CF and cyt c552F. A new ruthenium cyt c552F derivative labeled at C23 (Ruz-23-c552F) was designed to measure rapid electron transfer with cyt c1CF in the physiological direction using flash photolysis. The bimolecular rate constant k12 decreased rapidly with ionic strength above 40 mM, consistent with a diffusional process guided by long-range electrostatic interactions between the two proteins. However, a new kinetic phase was detected below 35 mM ionic strength with the ruthenium photoexcitation technique in which k12 became very rapid (3 × 109 M−1s−1) and nearly independent of ionic strength, suggesting that the reaction became so fast that it was controlled by short-range diffusion along the protein surfaces guided by hydrophobic interactions. These results are consistent with a two-step model for formation of the final encounter complex. No intracomplex electron transfer between Ruz-23-c552F and c1CF was observed even at the lowest ionic strength, indicating that the dissociation constant of the complex was greater than 30 µM. On the other hand, the ruthenium-labeled yeast cytochrome c derivative Ruz-39-Cc formed a tight 1:1 complex with cyt c1CF at ionic strengths below 60 mM with an intracomplex electron transfer rate constant of 50,000 s−1. A group of cyt c1CF variants in the presumed docking site were generated based on information from the yeast cyt bc1/cyt c co-crystal structure. Kinetic analysis of cyt c1CF mutants located near the heme crevice provided preliminary identification of the interaction site for cyt c552F, and suggest that formation of the encounter complex is guided primarily by the overall electrostatic surface potential rather than by defined ions. PMID:19006325

  9. Genetics Home Reference: phosphoglycerate kinase deficiency

    Science.gov (United States)

    ... Genetic Testing Registry: Phosphoglycerate kinase 1 deficiency Other Diagnosis and Management Resources (1 link) Children Living with Inherited Metabolic Diseases (CLIMB) (UK): Phosphoglycerate Kinase Deficiency (PDF) General Information ...

  10. DC-SIGN, C1q, and gC1qR form a trimolecular receptor complex on the surface of monocyte-derived immature dendritic cells

    Science.gov (United States)

    Hosszu, Kinga K.; Valentino, Alisa; Vinayagasundaram, Uma; Vinayagasundaram, Rama; Joyce, M. Gordon; Ji, Yan; Peerschke, Ellinor I. B.

    2012-01-01

    C1q modulates the differentiation and function of cells committed to the monocyte-derived dendritic cell (DC) lineage. Because the 2 C1q receptors found on the DC surface—gC1qR and cC1qR—lack a direct conduit into intracellular elements, we postulated that the receptors must form complexes with transmembrane partners. In the present study, we show that DC-SIGN, a C-type lectin expressed on DCs, binds directly to C1q, as assessed by ELISA, flow cytometry, and immunoprecipitation experiments. Surface plasmon resonance analysis revealed that the interaction was specific, and both intact C1q and the globular portion of C1q bound to DC-SIGN. Whereas IgG reduced this binding significantly, the Arg residues (162-163) of the C1q-A chain, which are thought to contribute to the C1q-IgG interaction, were not required for C1q binding to DC-SIGN. Binding was reduced significantly in the absence of Ca2+ and by preincubation of DC-SIGN with mannan, suggesting that C1q binds to DC-SIGN at its principal Ca2+-binding pocket, which has increased affinity for mannose residues. Antigen-capture ELISA and immunofluorescence microscopy revealed that C1q and gC1qR associate with DC-SIGN on blood DC precursors and immature DCs. The results of the present study suggest that C1q/gC1qR may regulate DC differentiation and function through the DC-SIGN–mediated induction of cell-signaling pathways. PMID:22700724

  11. Intraoperative electrophysiological monitoring for C1-2 spinal cord stimulation.

    Science.gov (United States)

    Muncie, Laura M; Ellens, Nathaniel R; Tolod-Kemp, Emeline; Feler, Claudio A; Winestone, John S

    2017-02-01

    OBJECTIVE This study is a retrospective case series involving C1-2 spinal cord stimulation in patients with complex regional pain syndrome (CRPS) under general endotracheal anesthesia. Currently, C1-2 paddle lead placement is an accepted practice, which provides effective cervical stimulation to ameliorate upper-extremity and sometimes lower-extremity symptoms experienced by patients with CRPS. However, this technique must be performed under general endotracheal anesthesia rather than in an awake or semiconscious state due to intraoperative safety concerns and patient comfort. The authors aim to provide additional data to support the following novel technique: the use of somatosensory evoked potential (SSEP) diminution data to assist with proper midline placement of C1-2 leads under general anesthesia. METHODS SSEP median nerve (MN) and posterior tibial nerve (PTN) data were collected from 6 patients undergoing placement of C1-2 leads under general anesthesia. Fluoroscopy was used as an initial guide for proper anatomical midline placement. This was followed by the activation of the spinal cord stimulator and simultaneous collection of primarily MN SSEPs as well as PTN SSEPs for physiological midline placement. Unilateral and bilateral reductions in SSEPs assisted with the correct lateralization of the lead to ensure effective postoperative coverage according to the patient's individual preoperative symptoms. RESULTS Six patients were monitored using SSEPs and repeatable, reliable MN and PTN baseline responses were obtained from all. A reduction in amplitude ranging from 5% to 87% was observed, confirming inhibition of dorsal column conduction, and an average pain relief of 63% at short-term and 64% at long-term follow-up was recorded with 6 of 6 and 5 of 6 patients responding, respectively. CONCLUSIONS Intraoperative SSEP collision study testing appears to be a safe technique to monitor placement of C1-2 paddle leads intraoperatively under general anesthesia.

  12. Identification of IgE sequential epitopes of lentil (Len c 1) by peptide microarray immunoassay

    Science.gov (United States)

    Vereda, Andrea; Andreae, Doerthe A.; Lin, Jing; Shreffler, Wayne G.; Ibañez, Maria Dolores; Cuesta-Herranz, Javier; Bardina, Luda; Sampson, Hugh A.

    2010-01-01

    Background Lentils are oftentimes responsible for allergic reactions to legumes in Mediterranean children. Though the primary sequence of the major allergen, Len c 1 is known, the location of the IgE binding epitopes remains undefined. Objective We sought to identify IgE-binding epitopes of Len c 1 and relate epitope binding to clinical characteristics. Methods 135 peptides corresponding to the primary sequence of Len c 1 were probed with sera from 33 lentil-allergic individuals and 15 non-atopic controls by means of microarray immunoassay. Lentil-specific IgE, Skin Prick Tests and clinical reactions to lentil were determined. Epitopes were defined as overlapping signal above inter- and intra-slide cut-offs and confirmed by inhibition assays using a peptide from the respective region. Hierarchical clustering of microarray data was used to correlate binding patterns with clinical findings. Results The lentil-allergic patients specifically recognized IgE-binding epitopes located in the C-terminal region, between peptide 107 and 135. Inhibition experiments confirmed the specificity of IgE binding in this region, identifying different epitopes. Linkage of cluster results with clinical data and lentil specific IgE levels displayed a positive correlation between lentil-specific IgE levels, epitope recognition and respiratory symptoms. Modeling based on the three-dimensional structure of a homologous soy vicilin suggests that the Len c 1 epitopes identified are exposed on the surface of the molecule. Conclusion Several IgE-binding sequential epitopes of Len c 1 have been identified. Epitopes are located in the C-terminal region, and are predicted to be exposed on the surface of the protein. Epitope diversity is positively correlated with IgE levels, pointing to a more polyclonal IgE response. PMID:20816193

  13. Functional analysis of C1 family cysteine peptidases in the larval gut of Тenebrio molitor and Tribolium castaneum.

    Science.gov (United States)

    Martynov, Alexander G; Elpidina, Elena N; Perkin, Lindsey; Oppert, Brenda

    2015-02-14

    Larvae of the tenebrionids Tenebrio molitor and Tribolium castaneum have highly compartmentalized guts, with primarily cysteine peptidases in the acidic anterior midgut that contribute to the early stages of protein digestion. High throughput sequencing was used to quantify and characterize transcripts encoding cysteine peptidases from the C1 papain family in the gut of tenebrionid larvae. For T. castaneum, 25 genes and one questionable pseudogene encoding cysteine peptidases were identified, including 11 cathepsin L or L-like, 11 cathepsin B or B-like, and one each F, K, and O. The majority of transcript expression was from two cathepsin L genes on chromosome 10 (LOC659441 and LOC659502). For cathepsin B, the major expression was from genes on chromosome 3 (LOC663145 and LOC663117). Some transcripts were expressed at lower levels or not at all in the larval gut, including cathepsins F, K, and O. For T. molitor, there were 29 predicted cysteine peptidase genes, including 14 cathepsin L or L-like, 13 cathepsin B or B-like, and one each cathepsin O and F. One cathepsin L and one cathepsin B were also highly expressed, orthologous to those in T. castaneum. Peptidases lacking conservation in active site residues were identified in both insects, and sequence analysis of orthologs indicated that changes in these residues occurred prior to evolutionary divergence. Sequences from both insects have a high degree of variability in the substrate binding regions, consistent with the ability of these enzymes to degrade a variety of cereal seed storage proteins and inhibitors. Predicted cathepsin B peptidases from both insects included some with a shortened occluding loop without active site residues in the middle, apparently lacking exopeptidase activity and unique to tenebrionid insects. Docking of specific substrates with models of T. molitor cysteine peptidases indicated that some insect cathepsins B and L bind substrates with affinities similar to human cathepsin L, while

  14. Multiple sulfatase deficiency: degradation of arylsulfatase A and B after endocytosis in fibroblasts.

    Science.gov (United States)

    Steckel, F; Hasilik, A; von Figura, K

    1985-08-15

    Multiple sulfatase deficiency can be classified into group I with severe and group II with moderate deficiencies in sulfatases. In fibroblasts in both groups the stability of arylsulfatase A and of the 47000-Mr form of arylsulfatase B is decreased [F. Steckel, A. Hasilik & K. von Figura (1985) Eur. J. Biochem. 151, 141-145]. After endocytosis in control fibroblasts or those from multiple sulfatase deficiency, arylsulfatase A and B derived from the latter were subjected to enhanced degradation in both types of recipient cells. The degradation was closely linked in time to endocytosis. Whereas instability of arylsulfatase A derived from different cell lines from multiple sulfatase deficiency was comparable, a marked heterogeneity was observed for the instability of the 47000-Mr polypeptide of arylsulfatase B. Each of the cell lines from multiple sulfatase deficiency synthesized arylsulfatase A and B polypeptides with normal and with decreased stability. Treatment with benzyloxycarbonyl-Phe-Ala-CHN2, an inhibitor of cysteine proteinases, stabilized arylsulfatase A polypeptides and partially restored arylsulfatase A activity in group II fibroblasts. The inhibitor had no protective effect on the 47000-Mr polypeptide or the activity of arylsulfatase B. The bearing of these findings on the yet unknown primary defect in multiple sulfatase deficiency is discussed.

  15. 17 CFR 230.160 - Registered investment company exemption from Section 101(c)(1) of the Electronic Signatures in...

    Science.gov (United States)

    2010-04-01

    ... exemption from Section 101(c)(1) of the Electronic Signatures in Global and National Commerce Act. 230.160...(c)(1) of the Electronic Signatures in Global and National Commerce Act. A prospectus for an... 101(c)(1) of the Electronic Signatures in Global and National Commerce Act. ...

  16. A novel multi-domain C1qDC protein from Zhikong scallop Chlamys farreri provides new insights into the function of invertebrate C1qDC proteins.

    Science.gov (United States)

    Wang, Leilei; Wang, Lingling; Zhang, Daoxiang; Jiang, Qiufen; Sun, Rui; Wang, Hao; Zhang, Huan; Song, Linsheng

    2015-10-01

    The C1q domain containing (C1qDC) proteins are a family of proteins possessing globular C1q (gC1q) domains, and they rely on this domain to recognize various ligands such as PAMPs, immunoglobulins, ligands on apoptotic cell. In the present study, a novel multi-domain C1qDC protein (CfC1qDC-2) was identified from scallop Chlamys farreri, and its full length cDNA was composed of 1648 bp, encoding a signal peptide and three typical gC1q domains. BLAST analysis revealed significant sequence similarity between CfC1qDC-2 and C1qDC proteins from mollusks. Three gC1q domains were predicted in its tertiary structure to form a tightly packed bell-shaped trimer, and each one adopted a typical 10-stranded sandwich fold with a jelly-roll topology and contained six aromatic amino acids forming the hydrophobic core. The mRNA transcripts of CfC1qDC-2 were mainly detected in the tissues of hepatopancreas and gonad of adult scallops, and the expression level was up-regulated in hemocytes after stimulated by LPS, PGN and β-glucan. During the embryonic development of scallop, the mRNA transcripts of CfC1qDC-2 were presented in all the detected stages, and the expression level was up-regulated from D-hinged larvae and reached the highest at eye-spot larvae. The recombinant protein of MBP-CfC1qDC-2 (rCfC1qDC-2) could bind various PAMPs including LPS, PGN, LTA, β-glucan, mannan as well as polyI:C, and different microorganisms including three Gram-negative bacteria, three Gram-positive bacteria and two yeasts, as well as scallop apoptotic cells. Meanwhile, rCfC1qDC-2 could interact with human heat-aggregated IgG and IgM, and inhibit the C1q-dependent hemolysis of rabbit serum. All these results indicated that CfC1qDC-2 could recognize not only PAMPs as a PRR, but also the apoptotic cells. Moreover, the similar structures and functions shared by CfC1qDC-2 and complement C1q provided a new insight into the evolution of C1qDC proteins in complement system. Copyright © 2015 Elsevier Ltd

  17. Managing menorrhagia in a familial case of factor V deficiency.

    Science.gov (United States)

    Stalnaker, M; Esquivel, P

    2015-02-01

    Factor V deficiency is a rare coagulation disorder. Excessive uterine bleeding is common in affected women. We describe a case of 2 siblings with Factor V deficiency and menorrhagia who achieved control of bleeding with differing treatments. Patient 1 is a 16-year-old female with Factor V deficiency and menorrhagia which was previously controlled with oral contraceptives (OC). She developed heavy bleeding treated with fresh frozen plasma, anti-inhibitor coagulant complex (AICC), and OC taper. A levonorgestrel IUD was placed with good control of her menorrhagia. Patient 2 is the 12-year-old sister of Patient 1. She was treated with AICC, aminocaproic acid, and her menorrhagia was ultimately controlled with continuous OCs. Factor V deficiency is a rare cause of menorrhagia. Various treatment modalities are available. In these adolescent sisters desiring future fertility, menorrhagia was managed with OCs and an IUD. Copyright © 2015 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.

  18. Deficiency of Bloom syndrome helicase activity is radiomimetic.

    Science.gov (United States)

    Horowitz, David P; Topaloglu, Ozlem; Zhang, Yonggang; Bunz, Fred

    2008-11-01

    Bloom syndrome is caused by homozygous mutations in BLM, which encodes a RecQ DNA helicase. Patient-derived cells deficient in BLM helicase activity exhibit genetic instability--apparent cytogenetically as sister chromatid exchanges--and activated DNA damage signaling. In this report, we show that BLM-knockout colorectal cancer cells exhibited endogenous, ATM-dependent double-strand DNA break responses similar to those recently observed in Bloom syndrome patient-derived cells. Xenograft tumors established from BLM-deficient cancer cells were not radiosensitive, but exhibited growth impairment that was comparable to that of wild type tumors treated with a single, high dose of ionizing radiation. These results suggest that pharmacological inhibitors of BLM would have a radiomimetic effect and that transient inhibition of BLM activity might be a viable strategy for anticancer therapy.

  19. CHRONIC HEART FAILURE AND IRON-DEFICIENT ANEMIA

    Directory of Open Access Journals (Sweden)

    M. V. Melnik

    2015-12-01

    Full Text Available 62 chronic heart failure (CHF patients with iron-deficient anemia (IDA were studied. Standard CHF therapy (angiotensin converting enzyme inhibitors, β-blockers, diuretics, cardiac glycosides was accompanied with the correction of iron deficiency by intravenous injection of Venofer and subsequent Ferro-Folgamma prescription (average daily dose of iron 137,75±5mg. After treatment serum iron level increased by 95,5% and hemoglobin level – by 9,8%. Left ventricular ejection fraction increased by 32,2% and physical activity tolerance – by 47,6%. Before treatment 32 CHF patients with IDA (51,6% had III functional class (FC of CHF according to NYHA and 16 patients (25,8% – IV FC. After treatment I FC was observed in 18 CHF patients (29%, II FC – in 26 patients and only 18 patients demonstrated III FC of CHF.

  20. Protein C deficiency in a patient of acute myocardial infarction

    Directory of Open Access Journals (Sweden)

    Tamzeed Ahmed

    2009-01-01

    Full Text Available A 42-year old male presented with acute myocardial infarction with no discernable risk factors; he never smoked; did not suffer from diabetes and had a well controlled blood pressure with single medication; plasma concentration of total cholesterol was on the upper normal limit, high and low density lipoprotein, cholesterol and triglyceride being normal. In addition to a single antihypertensive he received Allupurinol(Xanthine Oxidase inhibitorfor hyperuricaemia. Coronary angiogram revealed ectatic epicardial coronary arteries. The patient developed deep vein thrombosis of right leg after four days of the coronary angiogram. Coagulation analysis revealed protein C deficiency. The recognition of protein C deficiency as a risk factor for myocardial infarction is important as anticoagulators prevent further thrombotic events whereas inhibitors of platelet aggregation are ineffective. Ibrahim Med. Coll. J. 2009; 3(1: 34-35

  1. Dilated Cardiomyopathy Induced by Chronic Starvation and Selenium Deficiency

    Directory of Open Access Journals (Sweden)

    Soham Dasgupta

    2016-01-01

    Full Text Available Protein energy malnutrition (PEM has been rarely documented as a cause of cardiovascular abnormalities, including dilated cardiomyopathy. Selenium is responsible for antioxidant defense mechanisms in cardiomyocytes, and its deficiency in the setting of PEM and disease related malnutrition (DRM may lead to exacerbation of the dilated cardiomyopathy. We report a rare case of a fourteen-year-old boy who presented with symptoms of congestive heart failure due to DRM and PEM (secondary to chronic starvation along with severe selenium deficiency. An initial echocardiogram showed severely depressed systolic function consistent with dilated cardiomyopathy. Aggressive nutritional support and replacement of selenium and congestive heart failure medications that included diuretics and ACE inhibitors with the addition of carvedilol led to normalization of the cardiac function within four weeks. He continues to have significant weight gain and is currently completely asymptomatic from a cardiovascular standpoint.

  2. Inhibitors of histone demethylases

    DEFF Research Database (Denmark)

    Lohse, Brian; Kristensen, Jesper L; Kristensen, Line H

    2011-01-01

    Methylated lysines are important epigenetic marks. The enzymes involved in demethylation have recently been discovered and found to be involved in cancer development and progression. Despite the relative recent discovery of these enzymes a number of inhibitors have already appeared. Most of the i...

  3. Protease inhibitors and beyond.

    Science.gov (United States)

    1997-03-01

    A new generation of protease inhibitors is entering studies. Abbott Lab's ABT-378 and Pharmacia/Upjohn's PNU-140690 are beginning clinical studies and both are designed to overcome resistance problems. Several companies are developing new compounds to inhibit reverse transcriptase, such as Bristol-Myers Squibb's lobucavir and Hoechst/Bayer's HBY097. Calanolide A, which will soon begin trials, has a different resistance pattern than other non-nucleoside reverse transcriptase inhibitors, which may be an important advantage. Several groups are developing compounds to inhibit the HIV zinc finger, such as Parke-Davis' compound, CI-1012; and a Dutch company who is developing Azodicarbonamide, a drug currently in phase I/II trials for people with advanced disease in Europe. HIV drugs to date have not been successful in blocking viral fusion. However, three new fusion inhibitors are showing promise within the laboratory: Pentafuside (currently in phase I trials), Fuji ImmunoPharmaceuticals' FP-21399 (currently in phase I trials), and ISIS Pharmaceuticals' ISIS 5320. A new class of drugs known as integrase inhibitors has been of interest to pharmaceutical companies for the past several years; only one drug, Aronex Pharmaceuticals' Zintevir, has reached phase I/II trials.

  4. Transglutaminase inhibitor from milk

    NARCIS (Netherlands)

    Jong, G.A.H. de; Wijngaards, G.; Koppelman, S.J.

    2003-01-01

    Cross-linking experiments of skimmed bovine milk with bacterial transglutaminase isolated from Streptoverticillium mobaraense showed only some degree of formation of high-molecular-weight casein polymers. Studies on the nature of this phenomenon revealed that bovine milk contains an inhibitor of

  5. HIV protease inhibitor resistance

    NARCIS (Netherlands)

    Wensing, Annemarie M.J.; Fun, Axel; Nijhuis, Monique

    2017-01-01

    HIV protease is pivotal in the viral replication cycle and directs the formation of mature infectious virus particles. The development of highly specific HIV protease inhibitors (PIs), based on thorough understanding of the structure of HIV protease and its substrate, serves as a prime example of

  6. Phosphodiesterase 4 inhibitors.

    Science.gov (United States)

    Zebda, Rema; Paller, Amy S

    2018-03-01

    Historically, drugs available for treating atopic dermatitis (AD) have been limited to topical corticosteroids and topical calcineurin inhibitors, with systemic immunosuppressants and phototherapy reserved for severe AD. Despite their efficacy and infrequent adverse events, phobia about the use of topical steroids and calcineurin inhibitors has limited their use. More targeted options with fewer systemic and cutaneous side effects are needed for treating AD. Phosphodiesterase 4 (PDE4) is involved in the regulation of proinflammatory cytokines via the degradation of cyclic adenosine monophosphate. PDE4 activity is increased in the inflammatory cells of patients with AD, leading to increased production of proinflammatory cytokines and chemokines. Targeting PDE4 reduces the production of these proinflammatory mediators in AD. Both topical and oral PDE4 inhibitors have a favorable safety profile. Crisaborole 2% ointment, a topical PDE4, is now US Food and Drug Administration-approved for children older than 2 years and adults in the treatment of AD. Crisaborole 2% ointment shows early and sustained improvement in disease severity and pruritus and other AD symptoms, with burning and/or stinging upon application as the only related adverse event. Other PDE4 inhibitors are currently in trials with promising efficacy and safety. Copyright © 2017. Published by Elsevier Inc.

  7. Proton-pump inhibitors

    African Journals Online (AJOL)

    Proton-pump inhibitors (PPIs) work by binding irreversibly to the. H+/K+-ATPase pump of the parietal cell, leading to inhibition of acid production in approximately 70% of active pumps.1The result is a dramatic increase in gastric pH mitigating the deleterious effects of acid in gastro-oesophageal reflux disease (GORD) and.

  8. Genetics Home Reference: CLPB deficiency

    Science.gov (United States)

    ... or severe CLPB deficiency have clouding of the lenses of the eyes ( cataracts ) from birth (congenital) or ... Lung Cancer Awareness Month Celebrating National Family Health History Day All Bulletins Features What are genome editing ...

  9. Reconstructive surgery for fibular deficiency.

    Science.gov (United States)

    Shatilov, O E; Rozkov, A V; Cheminova, T V

    1991-08-01

    Three types of fibular deficiency are described which determine the nature of the surgery and prosthesis required. The surgical management of 50 patients who had a total of 103 operations is described.

  10. [Niacin deficiency and cutaneous immunity].

    Science.gov (United States)

    Ikenouchi-Sugita, Atsuko; Sugita, Kazunari

    2015-01-01

    Niacin, also known as vitamin B3, is required for the synthesis of coenzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Niacin binds with G protein-coupled receptor (GPR) 109A on cutaneous Langerhans cells and causes vasodilation with flushing in head and neck area. Niacin deficiency due to excessive alcohol consumption, certain drugs or inadequate uptake in diet causes pellagra, a photosensitivity dermatitis. Recently several studies have revealed the mechanism of photosensitivity in niacin deficiency, which may pave a way for new therapeutic approaches. The expression level of prostaglandin E synthase (PTGES) is up-regulated in the skin of both pellagra patients and niacin deficient pellagra mouse models. In addition, pellagra is mediated through prostaglandin E₂-EP4 (PGE₂-EP4) signaling via reactive oxygen species (ROS) production in keratinocytes. In this article, we have reviewed the role of niacin in immunity and the mechanism of niacin deficiency-induced photosensitivity.

  11. Iron deficiency among blood donors

    DEFF Research Database (Denmark)

    Rigas, A. S.; Pedersen, O. B.; Magnussen, K.

    2017-01-01

    and menopausal status are the strongest predictors of iron deficiency. Only little information on the health effects of iron deficiency in blood donors exits. Possibly, after a standard full blood donation, a temporarily reduced physical performance for women is observed. However, iron deficiency among blood...... donors is not reflected in a reduced self-perceived mental and physical health. In general, the high proportion of iron-deficient donors can be alleviated either by extending the inter-donation intervals or by guided iron supplementation. The experience from Copenhagen, the Capital Region of Denmark......, is that routine ferritin measurements and iron supplementation are feasible and effective ways of reducing the proportion of donors with low haemoglobin levels....

  12. Icatibant, an inhibitor of bradykinin receptor 2, for hereditary angioedema attacks: prospective experimental single-cohort study

    Directory of Open Access Journals (Sweden)

    Regis Albuquerque Campos

    Full Text Available CONTEXT AND OBJECTIVE: Hereditary angioedema (HAE with C1 inhibitor deficiency manifests as recurrent episodes of edema involving the skin, upper respiratory tract and gastrointestinal tract. It can be lethal due to asphyxia. The aim here was to evaluate the response to therapy for these attacks using icatibant, an inhibitor of the bradykinin receptor, which was recently introduced into Brazil.DESIGN AND SETTING: Prospective experimental single-cohort study on the efficacy and safety of icatibant for HAE patients.METHODS: Patients with a confirmed HAE diagnosis were enrolled according to symptoms and regardless of the time since onset of the attack. Icatibant was administered in accordance with the protocol that has been approved in Brazil. Symptom severity was assessed continuously and adverse events were monitored.RESULTS: 24 attacks in 20 HAE patients were treated (female/male 19:1; 19-55 years; median 29 years of age. The symptoms were: subcutaneous edema (22/24; abdominal pain (15/24 and upper airway obstruction (10/24. The time taken until onset of relief was: 5-10 minutes (5/24; 20.8%; 10-20 (5/24; 20.8%; 20-30 (8/24; 33.4%; 30-60 (5/24; 20.8%; and 2 hours (1/24; 4.3%. The time taken for complete resolution of symptoms ranged from 4.3 to 33.4 hours. Adverse effects were only reported at injection sites. Mild to moderate erythema and/or feelings of burning were reported by 15/24 patients, itching by 3 and no adverse effects in 6.CONCLUSION: HAE type I patients who received icatibant responded promptly; most achieved improved symptom severity within 30 minutes. Local adverse events occurred in 75% of the patients.

  13. MicroRNA-661 Enhances TRAIL or STS Induced Osteosarcoma Cell Apoptosis by Modulating the Expression of Cytochrome c1

    Directory of Open Access Journals (Sweden)

    Lin Fan

    2017-04-01

    Full Text Available Aim: Osteosarcoma (OS is an aggressive bone malignancy that affects rapidly growing bones and is associated with a poor prognosis. Our previous study showed that cytochrome c1 (CYC1, a subunit of the cytochrome bc1 complex (complex III of the mitochondrial electron chain, is overexpressed in human OS tissues and cell lines and its silencing induces apoptosis in vitro and inhibits tumor growth in vivo. Here, we investigated the mechanism underlying the modulation of CYC1 expression in OS and its role in the resistance of OS to apoptosis. Methods: qRT-PCR, luciferase reporter assay, western blotting, fow cytometry, and animal experiments were performed in this study. Results: MicroRNA (miR-661 was identified as a downregulated miRNA in OS tissues and cells and shown to directly target CYC1. Ectopically expressed miR-661 inhibited OS cell growth, promoted apoptosis, and reduced the activity of mitochondrial complex III. miR-661 overexpression enhanced TRAIL or STS induced apoptosis and promoted the release of cytochrome c into the cytosol, which induced caspase-9 activation, and these effects were abolished by a caspase-3 inhibitor. Overexpression of CYC1 rescued the effects of miR-661 on sensitizing OS cells to TRAIL or STS induced apoptosis, indicating that the antitumor effect of miR-661 is mediated by the downregulation of CYC1. In vivo, miR-661 overexpression sensitized tumors to TRAIL or STS induced apoptosis in a xenograft mouse model, and these effects were attenuated by co-expression of CYC1. Conclusion: Taken together, our results indicate that miR-661 plays a tumor suppressor role in OS mediated by the downregulation of CYC1, suggesting a potential mechanism underlying cell death resistance in OS.

  14. Sustained Systemic Glucocerebrosidase Inhibition Induces Brain α-Synuclein Aggregation, Microglia and Complement C1q Activation in Mice.

    Science.gov (United States)

    Rocha, Emily M; Smith, Gaynor A; Park, Eric; Cao, Hongmei; Graham, Anne-Renee; Brown, Eilish; McLean, Jesse R; Hayes, Melissa A; Beagan, Jonathan; Izen, Sarah C; Perez-Torres, Eduardo; Hallett, Penelope J; Isacson, Ole

    2015-08-20

    Loss-of-function mutations in GBA1, which cause the autosomal recessive lysosomal storage disease, Gaucher disease (GD), are also a key genetic risk factor for the α-synucleinopathies, including Parkinson's disease (PD) and dementia with Lewy bodies. GBA1 encodes for the lysosomal hydrolase glucocerebrosidase and reductions in this enzyme result in the accumulation of the glycolipid substrates glucosylceramide and glucosylsphingosine. Deficits in autophagy and lysosomal degradation pathways likely contribute to the pathological accumulation of α-synuclein in PD. In this report we used conduritol-β-epoxide (CBE), a potent selective irreversible competitive inhibitor of glucocerebrosidase, to model reduced glucocerebrosidase activity in vivo, and tested whether sustained glucocerebrosidase inhibition in mice could induce neuropathological abnormalities including α-synucleinopathy, and neurodegeneration. Our data demonstrate that daily systemic CBE treatment over 28 days caused accumulation of insoluble α-synuclein aggregates in the substantia nigra, and altered levels of proteins involved in the autophagy lysosomal system. These neuropathological changes were paralleled by widespread neuroinflammation, upregulation of complement C1q, abnormalities in synaptic, axonal transport and cytoskeletal proteins, and neurodegeneration. A reduction in brain GCase activity has been linked to sporadic PD and normal aging, and may contribute to the susceptibility of vulnerable neurons to degeneration. This report demonstrates that systemic reduction of GCase activity using chemical inhibition, leads to neuropathological changes in the brain reminiscent of α-synucleinopathy. These data reveal a link between reduced glucocerebrosidase and the development of α-synucleinopathy and pathophysiological abnormalities in mice, and support the development of GCase therapeutics to reduce α-synucleinopathy in PD and related disorders.

  15. 3-Nitrobenzanthrone and 3-aminobenzanthrone induce DNA damage and cell signalling in Hepa1c1c7 cells

    Energy Technology Data Exchange (ETDEWEB)

    Landvik, N.E. [Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 404 Torshov N-4303 Oslo (Norway); Arlt, V.M.; Nagy, E. [Section of Molecular Carcinogenesis, Institute of Cancer Research, Brookes Lawley Building, Sutton, Surrey SM2 5NG (United Kingdom); Solhaug, A. [Section for Toxicology, Department of Feed and Food Safety, National Veterinary Institute Pb 750 Sentrum, N-0106 Oslo (Norway); Tekpli, X. [EA SeRAIC, Equipe labellisee Ligue contre le Cancer, IFR 140, Universite de Rennes 1, Rennes (France); Schmeiser, H.H. [Research Group Genetic Alteration in Carcinogenesis, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg (Germany); Refsnes, M. [Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 404 Torshov N-4303 Oslo (Norway); Phillips, D.H. [Section of Molecular Carcinogenesis, Institute of Cancer Research, Brookes Lawley Building, Sutton, Surrey SM2 5NG (United Kingdom); Lagadic-Gossmann, D. [EA SeRAIC, Equipe labellisee Ligue contre le Cancer, IFR 140, Universite de Rennes 1, Rennes (France); Holme, J.A., E-mail: jorn.holme@fhi.no [Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 404 Torshov N-4303 Oslo (Norway)

    2010-02-03

    3-Nitrobenzanthrone (3-NBA) is a mutagenic and carcinogenic environmental pollutant found in diesel exhaust and urban air pollution. In the present work we have characterised the effects of 3-NBA and its metabolite 3-aminobenzanthrone (3-ABA) on cell death and cytokine release in mouse hepatoma Hepa1c1c7 cells. These effects were related to induced DNA damage and changes in cell signalling pathways. 3-NBA resulted in cell death and caused most DNA damage as judged by the amount of DNA adducts ({sup 32}P-postlabelling assay), single strand (ss)DNA breaks and oxidative DNA lesions (comet assay) detected. An increased phosphorylation of H2AX, chk1, chk2 and partly ATM was observed using flow cytometry and/or Western blotting. Both compounds increased phosphorylation of p53 and MAPKs (ERK, p38 and JNK). However, only 3-NBA caused an accumulation of p53 in the nucleus and a translocation of Bax to the mitochondria. The p53 inhibitor pifithrin-alpha inhibited 3-NBA-induced apoptosis, indicating that cell death was a result of the triggering of DNA signalling pathways. The highest phosphorylation of Akt and degradation of I{kappa}B-{alpha} (suggesting activation of NF-{kappa}B) were also seen after treatment with 3-NBA. In contrast 3-ABA increased IL-6 release, but caused little or no toxicity. Cytokine release was inhibited by PD98059 and curcumin, suggesting that ERK and NF-{kappa}B play a role in this process. In conclusion, 3-NBA seems to have a higher potency to induce DNA damage compatible with its cytotoxic effects, while 3-ABA seems to have a greater effect on the immune system.

  16. Using flow cytometry to screen patients for X-linked lymphoproliferative disease due to SAP deficiency and XIAP deficiency.

    Science.gov (United States)

    Marsh, Rebecca A; Bleesing, Jack J; Filipovich, Alexandra H

    2010-10-31

    X-linked lymphoproliferative disease is a rare congenital immunodeficiency that is most often caused by mutations in SH2D1A, the gene encoding signaling lymphocyte activation molecule (SLAM)-associated protein (SAP). XLP caused by SAP deficiency is most often characterized by fulminant mononucleosis/EBV- associated hemophagocytic lymphohistiocytosis (HLH), lymphoma, and dysgammaglobulinemia. XLP has also been found to be caused by mutations in BIRC4, the gene encoding X-linked inhibitor of apoptosis (XIAP). Patients with XIAP deficiency often present with HLH or recurrent HLH, which may or may not be associated with EBV. XLP is prematurely lethal in the majority of cases. While genetic sequencing can provide a genetic diagnosis of XLP, a more rapid means of diagnosis of XLP is desirable. Rapid diagnosis is especially important in the setting of HLH, as this may hasten the initiation of life-saving medical treatments and expedite preparations for allogeneic hematopoietic cell transplantation (HCT). Flow cytometry offers a means to quickly screen patients for XLP. Flow cytometry can be used to measure lymphocyte SAP or XIAP protein expression, and can also be used to observe lymphocyte phenotypes and functional defects that are unique to XLP. This review will give a brief overview of the clinical manifestations and molecular basis of SAP deficiency and XIAP deficiency, and will focus on the use of flow cytometry for diagnosis of XLP. Copyright © 2010 Elsevier B.V. All rights reserved.

  17. Iron deficiency and cognitive functions

    OpenAIRE

    Jáuregui-Lobera, Ignacio

    2014-01-01

    Ignacio Jáuregui-Lobera Department of Nutrition and Bromatology, Pablo de Olavide University, Seville, Spain Abstract: Micronutrient deficiencies, especially those related to iodine and iron, are linked to different cognitive impairments, as well as to potential long-term behavioral changes. Among the cognitive impairments caused by iron deficiency, those referring to attention span, intelligence, and sensory perception functions are mainly cited, as well as those associated with...

  18. Autophagy induction by tetrahydrobiopterin deficiency

    Science.gov (United States)

    Kwak, Sang Su; Suk, Jinkyu; Choi, Ji Hye; Yang, Seungkyung; Kim, Jin Woo; Sohn, Seonghyang; Chung, Jae Hoon; Hong, Yong Hee; Lee, Dong Hwan; Ahn, Jeong Keun; Min, Hyesun; Fu, Ya-Min; Meadows, Gary G

    2011-01-01

    Tetrahydrobiopterin (BH4) deficiency is a genetic disorder associated with a variety of metabolic syndromes such as phenylketonuria (PKU). In this article, the signaling pathway by which BH4 deficiency inactivates mTORC1 leading to the activation of the autophagic pathway was studied utilizing BH4-deficient Spr-/- mice generated by the knockout of the gene encoding sepiapterin reductase (SR) catalyzing BH4 synthesis. We found that mTORC1 signaling was inactivated and autophagic pathway was activated in tissues from Spr-/- mice. This study demonstrates that tyrosine deficiency causes mTORC1 inactivation and subsequent activation of autophagic pathway in Spr-/- mice. Therapeutic tyrosine diet completely rescued dwarfism and mTORC1 inhibition but inactivated autophagic pathway in Spr-/- mice. Tyrosine-dependent inactivation of mTORC1 was further supported by mTORC1 inactivation in Pahenu2 mouse model lacking phenylalanine hydroxylase (Pah). NIH3T3 cells grown under the condition of tyrosine restriction exhibited autophagy induction. However, mTORC1 activation by RhebQ64L, a positive regulator of mTORC1, inactivated autophagic pathway in NIH3T3 cells under tyrosine-deficient conditions. In addition, this study first documents mTORC1 inactivation and autophagy induction in PKU patients with BH4 deficiency. PMID:21795851

  19. Post-weaning epiphysiolysis causes distal femur dysplasia and foreshortened hindlimbs in fetuin-A-deficient mice

    OpenAIRE

    Brylka, Laura J.; Köppert, Sina; Babler, Anne; Kratz, Beate; Denecke, Bernd; Yorgan, Timur A.; Etich, Julia; Costa, Ivan G.; Brachvogel, Bent; Boor, Peter; Schinke, Thorsten; Jahnen-Dechent, Willi

    2017-01-01

    Fetuin-A / α2-Heremans-Schmid-glycoprotein (gene name Ahsg) is a systemic inhibitor of ectopic calcification. Due to its high affinity for calcium phosphate, fetuin-A is highly abundant in mineralized bone matrix. Foreshortened femora in fetuin-A-deficient Ahsg -/- mice indicated a role for fetuin-A in bone formation. We studied early postnatal bone development in fetuin-A-deficient mice and discovered that femora from Ahsg -/- mice exhibited severely displaced distal epiphyses and deformed g...

  20. Complement component C1r mediated cleavage of the heavy chain of the major histocompatibility class I antigens

    DEFF Research Database (Denmark)

    Eriksson, H; Nissen, Mogens Holst

    1992-01-01

    Apart from cleaving C1s, we demonstrate for the first time that: 1) at concentrations found in serum, the activated forms of the complement components C1r in addition to C1s can cleave the heavy chain of MHC class I antigens, 2) the cleavage by C1r and C1s is seemingly dependent upon a native con......-chain of MHC class I was shown to take place between the alpha 2- and alpha 3- domains as estimated by the Con A-Sepharose precipitation pattern on SDS-PAGE. The alpha 1/alpha 2 fragment was still shown to interact with beta 2-microglobulin as shown by immunoprecipitation.......Apart from cleaving C1s, we demonstrate for the first time that: 1) at concentrations found in serum, the activated forms of the complement components C1r in addition to C1s can cleave the heavy chain of MHC class I antigens, 2) the cleavage by C1r and C1s is seemingly dependent upon a native...... configuration of the MHC class I antigen, since heat denaturation of the HLA antigens reduce the cleavage. The proteolytic fragments following C1 cleavage were characterized by precipitation with Con A-Sepharose, anti-MHC class I and anti-beta 2-microglobulin antibodies. The proteolysis of the alpha...

  1. Design of HIV Protease Inhibitors Targeting Protein Backbone: An Effective Strategy for Combating Drug Resistance

    Energy Technology Data Exchange (ETDEWEB)

    Ghosh, Arun K.; Chapsal, Bruno D.; Weber, Irene T.; Mitsuya, Hiroaki (GSU); (Kumamoto Univ., Japan); (Purdue)

    2008-06-03

    The discovery of human immunodeficiency virus (HIV) protease inhibitors (PIs) and their utilization in highly active antiretroviral therapy (HAART) have been a major turning point in the management of HIV/acquired immune-deficiency syndrome (AIDS). However, despite the successes in disease management and the decrease of HIV/AIDS-related mortality, several drawbacks continue to hamper first-generation protease inhibitor therapies. The rapid emergence of drug resistance has become the most urgent concern because it renders current treatments ineffective and therefore compels the scientific community to continue efforts in the design of inhibitors that can efficiently combat drug resistance.

  2. Fishing for biodiversity: Novel methanopterin-linked C1 transfergenes deduced from the Sargasso Sea metagenome

    Energy Technology Data Exchange (ETDEWEB)

    Kalyuzhnaya, Marina G.; Nercessian, Olivier; Lapidus, Alla; Chistoserdova, Ludmila

    2004-07-01

    The recently generated database of microbial genes from anoligotrophic environment populated by a calculated 1,800 of major phylotypes (the Sargasso Sea metagenome) presents a great source for expanding local databases of genes indicative of a specific function. In this paper we analyze the Sargasso Sea metagenome in terms of the presence of methanopterin-linked C1 transfer genes that are signature for methylotrophy. We conclude that more than 10 phylotypes possessing genes of interest are present in this environment, and a few of these are relatively abundant species. The sequences representative of the major phylotypes do not appear to belong to any known microbial group capable of methanopterin-linked C1 transfer. Instead, they separate from all known sequences on phylogenetic trees, pointing towards their affiliation with a novel microbial phylum. These data imply a broader distribution of methanopterin-linked functions in the microbial world than previously known.

  3. The C1XS X-ray Spectrometer on Chandrayaan-1

    Science.gov (United States)

    Grande, M.; Maddison, B. J.; Howe, C. J.; Kellett, B. J.; Sreekumar, P.; Huovelin, J.; Crawford, I. A.; Duston, C. L.; Smith, D.; Anand, M.; Bhandari, N.; Cook, A.; Fernandes, V.; Foing, B.; Gasnaut, O.; Goswami, J. N.; Holland, A.; Joy, K. H.; Kochney, D.; Lawrence, D.; Maurice, S.; Okada, T.; Narendranath, S.; Pieters, C.; Rothery, D.; Russell, S. S.; Shrivastava, A.; Swinyard, B.; Wilding, M.; Wieczorek, M.

    2009-06-01

    The Chandrayaan-1 X-ray Spectrometer (C1XS) is a compact X-ray spectrometer for the Indian Space Research Organisation (ISRO) Chandrayaan-1 lunar mission. It exploits heritage from the D-CIXS instrument on ESA's SMART-1 mission. As a result of detailed developments to all aspects of the design, its performance as measured in the laboratory greatly surpasses that of D-CIXS. In comparison with SMART-1, Chandrayaan-1 is a science-oriented rather than a technology mission, leading to far more favourable conditions for science measurements. C1XS is designed to measure absolute and relative abundances of major rock-forming elements (principally Mg, Al, Si, Ca and Fe) in the lunar crust with spatial resolution ⩽25 FWHM km, and to achieve relative elemental abundances of better than 10%.

  4. Cloning and tissue expression of cytochrome P450 1B1 and 1C1 ...

    African Journals Online (AJOL)

    Cytochrome P450 1 (CYP1) is widely used as an indicator of exposure to environmental contaminants. In the study, two full-length complementary DNAs encode for CYP1B1 and CYP1C1 were cloned from medaka liver exposed to 500 ppb β-naphthoflavone for 24 h. CYP1B1, having 1984 bp, contains an open reading ...

  5. Explicit Gaussian quadrature rules for C^1 cubic splines with symmetrically stretched knot sequence

    KAUST Repository

    Ait-Haddou, Rachid

    2015-06-19

    We provide explicit expressions for quadrature rules on the space of C^1 cubic splines with non-uniform, symmetrically stretched knot sequences. The quadrature nodes and weights are derived via an explicit recursion that avoids an intervention of any numerical solver and the rule is optimal, that is, it requires minimal number of nodes. Numerical experiments validating the theoretical results and the error estimates of the quadrature rules are also presented.

  6. Synthetic studies on hemicalide: development of a convergent approach toward the C1-C25 fragment.

    Science.gov (United States)

    Sorin, Geoffroy; Fleury, Etienne; Tran, Christine; Prost, Elise; Molinier, Nicolas; Sautel, François; Massiot, Georges; Specklin, Simon; Meyer, Christophe; Cossy, Janine; Lannou, Marie-Isabelle; Ardisson, Janick

    2013-09-20

    Synthetic studies on hemicalide, a recently isolated marine natural product displaying highly potent antiproliferative activity and a unique mode of action, have highlighted a reliable Horner-Wadsworth-Emmons olefination to create the C6-C7 alkene and a remarkable efficient Suzuki-Miyaura coupling to form the C15-C16 bond, resulting in the development of a convergent approach toward the C1-C25 fragment.

  7. Rapid Reactivation of Deep Subsurface Microbes in the Presence of C-1 Compounds

    Directory of Open Access Journals (Sweden)

    Pauliina Rajala

    2015-02-01

    Full Text Available Microorganisms in the deep biosphere are believed to conduct little metabolic activity due to low nutrient availability in these environments. However, destructive penetration to long-isolated bedrock environments during construction of underground waste repositories can lead to increased nutrient availability and potentially affect the long-term stability of the repository systems, Here, we studied how microorganisms present in fracture fluid from a depth of 500 m in Outokumpu, Finland, respond to simple carbon compounds (C-1 compounds in the presence or absence of sulphate as an electron acceptor. C-1 compounds such as methane and methanol are important intermediates in the deep subsurface carbon cycle, and electron acceptors such as sulphate are critical components of oxidation processes. Fracture fluid samples were incubated in vitro with either methane or methanol in the presence or absence of sulphate as an electron acceptor. Metabolic response was measured by staining the microbial cells with fluorescent dyes that indicate metabolic activity and transcriptional response with RT-qPCR. Our results show that deep subsurface microbes exist in dormant states but rapidly reactivate their transcription and respiration systems in the presence of C-1 substrates, particularly methane. Microbial activity was further enhanced by the addition of sulphate as an electron acceptor. Sulphate- and nitrate-reducing microbes were particularly responsive to the addition of C-1 compounds and sulphate. These taxa are common in deep biosphere environments and may be affected by conditions disturbed by bedrock intrusion, as from drilling and excavation for long-term storage of hazardous waste.

  8. Polygonumnolides C1-C4; minor dianthrone glycosides from the roots of Polygonum multiflorum Thunb.

    Science.gov (United States)

    Yang, Jian-Bo; Li, Li; Dai, Zhong; Wu, Yu; Geng, Xing-Chao; Li, Bo; Ma, Shuang-Cheng; Wang, Ai-Guo; Su, Ya-Lun

    2016-09-01

    Four new dianthrone glycosides, named polygonumnolides C1-C4 (1-4), were isolated from the dried roots of Polygonum multiflorum Thunb, together with two known emodin dianthrones (5-6). Their hepatotoxicities were evaluated against L-02 cell lines. Compounds 1-4 showed weak hepatotoxicity against L-02 cell lines with IC50 values of 313.05, 205.20, 294.20, and 207.35 μM, respectively.

  9. Electrodril system field test program. Phase II: Task C-1-deep drilling system demonstration. Final report for Phase II: Task C-1

    Energy Technology Data Exchange (ETDEWEB)

    Taylor, P D

    1981-04-01

    The Electrodril Deep Drilling System field test demonstrations were aborted in July 1979, due to connector problems. Subsequent post test analyses concluded that the field replacable connectors were the probable cause of the problems encountered. The designs for both the male and female connectors, together with their manufacturing processes, were subsequently modified, as was the acceptance test procedures. A total of nine male and nine female connectors were manufactured and delivered during the 2nd Quarter 1980. Exhaustive testing was then conducted on each connector as a precursor to formal qualification testing conducted during the month of October 1980, at the Brown Oil Tool test facility located in Houston, Texas. With this report, requirements under Phase II, Task C-1 are satisfied. The report documents the results of the connector qualification test program which was successfully completed October 28, 1980. In general, it was concluded that connector qualification had been achieved and plans are now in progress to resume the field test demonstration program so that Electrodril System performance predictions and economic viability can be evaluated.

  10. Reactions of water and C1 molecules on carbide and metal-modified carbide surfaces.

    Science.gov (United States)

    Wan, Weiming; Tackett, Brian M; Chen, Jingguang G

    2017-04-03

    The formation of carbides can significantly modify the physical and chemical properties of the parent metals. In the current review, we summarize the general trends in the reactions of water and C1 molecules over transition metal carbide (TMC) and metal-modified TMC surfaces and thin films. Although the primary focus of the current review is on the theoretical and experimental studies of reactions of C1 molecules (CO, CO2, CH3OH, etc.), the reactions of water will also be reviewed because water plays an important role in many of the C1 transformation reactions. This review is organized by discussing separately thermal reactions and electrochemical reactions, which provides insights into the application of TMCs in heterogeneous catalysis and electrocatalysis, respectively. In thermal reactions, we discuss the thermal decomposition of water and methanol, as well as the reactions of CO and CO2 over TMC surfaces. In electrochemical reactions, we summarize recent studies in the hydrogen evolution reaction, electrooxidation of methanol and CO, and electroreduction of CO2. Finally, future research opportunities and challenges associated with using TMCs as catalysts and electrocatalysts are also discussed.

  11. Gene Expression and Methylation Signatures of MAN2C1 are Associated with PTSD

    Directory of Open Access Journals (Sweden)

    Monica Uddin

    2011-01-01

    Full Text Available As potential regulators of DNA accessibility and activity, epigenetic modifications offer a mechanism by which the environment can moderate the effects of genes. To date, however, there have been relatively few studies assessing epigenetic modifications associated with post-traumatic stress disorder (PTSD. Here we investigate PTSD-associated methylation differences in 33 genes previously shown to differ in whole blood-derived gene expression levels between those with vs. without the disorder. Drawing on DNA samples similarly obtained from whole blood in 100 individuals, 23 with and 77 without lifetime PTSD, we used methylation microarray data to assess whether these 33 candidate genes showed epigenetic signatures indicative of increased risk for, or resilience to, PTSD. Logistic regression analyses were performed to assess the main and interacting effects of candidate genes’ methylation values and number of potentially traumatic events (PTEs, adjusting for age and other covariates. Results revealed that only one candidate gene–MAN2C1–showed a significant methylation x PTE interaction, such that those with both higher MAN2C1 methylation and greater exposure to PTEs showed a marked increase in risk of lifetime PTSD (OR 4.35, 95% CI: 1.07, 17.77, p = 0.04. These results indicate that MAN2C1 methylation levels modify cumulative traumatic burden on risk of PTSD, and suggest that both gene expression and epigenetic changes at specific loci are associated with this disorder.

  12. Initial Results from the C1XS X-Ray Spectrometer on Chandrayaan-1

    Science.gov (United States)

    Grande, M.; Kellett, B. J.; Maddison, B.. J.; Sreekumar, P.; Huovelin, J.; Howe, C. J.; Crawford, I. A.

    2009-04-01

    The Chandrayaan-1 lunar mission, which was successfully launched by the Indian Space Research Organisation (ISRO) on 22 October, carried as part of its payload the C1XS Chandrayaan-1 X-ray Spec-trometer [1]. It exploits heritage from the D-CIXS instrument [2] on ESA's SMART-1 mission. Whereas SMART-1 was a technology mission, Chandrayaan-1 is science oriented, with a far more favourable orbit for science measurements. C1XS is designed to measure abundances of major rock-forming elements (princi-pally Mg, Al, Si, Ca, Ti and Fe). The instrument has been commissioned, and is operating nominally. The Sun continues to show X-ray emission charac-teristic of the Solar minimum. As has been commented by [7], the onset of this solar maximum is significantly delayed. However, C1XS has been able to observe the Moon even in these very low illumination conditions. Figure 3 shows the result of an integration during an A class flare on the 12th Dec. 2008. Characteristic energy lines at Mg, Al and Si are clearly seen and resolved from the average extreme quiet time data background. This performance shows that the instrument is easily meeting its design requirements, and in the higher illumination conditions expected during the rest of the mission will be capable of meeting its science goals.

  13. Styloid/C1 transverse process juxtaposition as a cause of Eagle's syndrome.

    Science.gov (United States)

    Ho, Sandra; Luginbuhl, Adam; Finden, Steven; Curry, Joseph M; Cognetti, David M

    2015-11-01

    The purpose of this case report was to characterize styloid/C1 transverse process juxtaposition as a cause for Eagle's syndrome. A case series was conducted with a chart review of 5 patients with radiographic evidence of jugular vein compression who underwent styloid process excision between 2010 and 2013. There were 4 men and 1 woman, aged 35 to 62 years (mean, 46 years). Cervicalgia (4 of 5 patients) and otalgia (4 of 5 patients) were the most commonly reported symptoms. Styloid process length ranged from 2.4 to 8.5 cm. The distance between the styloid process and the transverse process of C1 ranged from 0.05 to 0.46 cm. All patients underwent a transcervical approach for the excision of the styloid process with immediate postoperative resolution of symptoms and good cosmetic results. Styloid/C1 transverse process juxtaposition can produce symptoms of cervicalgia and otalgia even in the setting of a normal length styloid process. The transcervical approach is safe and effective for excision of the styloid process and has good functional and cosmetic results. © 2015 Wiley Periodicals, Inc.

  14. Lytic polysaccharide monooxygenases from Myceliophthora thermophila C1 differ in substrate preference and reducing agent specificity.

    Science.gov (United States)

    Frommhagen, Matthias; Koetsier, Martijn J; Westphal, Adrie H; Visser, Jaap; Hinz, Sandra W A; Vincken, Jean-Paul; van Berkel, Willem J H; Kabel, Mirjam A; Gruppen, Harry

    2016-01-01

    Lytic polysaccharide monooxgygenases (LPMOs) are known to boost the hydrolytic breakdown of lignocellulosic biomass, especially cellulose, due to their oxidative mechanism. For their activity, LPMOs require an electron donor for reducing the divalent copper cofactor. LPMO activities are mainly investigated with ascorbic acid as a reducing agent, but little is known about the effect of plant-derived reducing agents on LPMOs activity. Here, we show that three LPMOs from the fungus Myceliophthora thermophila C1, MtLPMO9A, MtLPMO9B and MtLPMO9C, differ in their substrate preference, C1-/C4-regioselectivity and reducing agent specificity. MtLPMO9A generated C1- and C4-oxidized, MtLPMO9B C1-oxidized and MtLPMO9C C4-oxidized gluco-oligosaccharides from cellulose. The recently published MtLPMO9A oxidized, next to cellulose, xylan, β-(1 → 3, 1 → 4)-glucan and xyloglucan. In addition, MtLPMO9C oxidized, to a minor extent, xyloglucan and β-(1 → 3, 1 → 4)-glucan from oat spelt at the C4 position. In total, 34 reducing agents, mainly plant-derived flavonoids and lignin-building blocks, were studied for their ability to promote LPMO activity. Reducing agents with a 1,2-benzenediol or 1,2,3-benzenetriol moiety gave the highest release of oxidized and non-oxidized gluco-oligosaccharides from cellulose for all three MtLPMOs. Low activities toward cellulose were observed in the presence of monophenols and sulfur-containing compounds. Several of the most powerful LPMO reducing agents of this study serve as lignin building blocks or protective flavonoids in plant biomass. Our findings support the hypothesis that LPMOs do not only vary in their C1-/C4-regioselectivity and substrate specificity, but also in their reducing agent specificity. This work strongly supports the idea that the activity of LPMOs toward lignocellulosic biomass does not only depend on the ability to degrade plant polysaccharides like cellulose, but also on their specificity toward plant

  15. Lazarus and Group Psychotherapy: AIDS in the Era of Protease Inhibitors

    Science.gov (United States)

    Gushue, George V.; Brazaitis, Sarah J.

    2003-01-01

    A new class of medications, protease inhibitors, has dramatically improved the health of many people with Human Immunodeficiency Virus (HIV) and Acquired Immune Deficiency Syndrome (AIDS). This development has had a major impact on the lives of those affected by HIV/AIDS. This article considers how a group is affected by the larger systems of…

  16. Unilateral C-1 posterior arch screws and C-2 laminar screws combined with a 1-side C1-2 pedicle screw system as salvage fixation for atlantoaxial instability.

    Science.gov (United States)

    Guo-Xin, Jin; Huan, Wang

    2015-10-30

    OBJECT Atlantoaxial instability often requires surgery, and the current methods for fixation pose some risk to vascular and neurological tissues. Thus, new effective and safer methods are needed for salvage operations. This study sought to assess unilateral C-1 posterior arch screws (PASs) and C-2 laminar screws (LSs) combined with 1-side C1-2 pedicle screws (PSs) for posterior C1-2 fixation using biomechanical testing with bilateral C1-2 PSs in a cadaveric model. METHODS Six fresh ligamentous human cervical spines were evaluated for their biomechanics. The cadaveric specimens were tested in their intact condition, stabilization after injury, and after injury at 1.5 Nm of pure moment in 6 directions. The 3 groups tested were bilateral C1-2 PSs (Group A); left side C1-2 PSs with an ipsilateral C-1 PAS + C-2 laminar screw (Group B); and left side C1-2 PSs with a contralateral C-1 PAS + C-2 LS (Group C). During the testing, angular motion was measured using a motion capture platform. Data were recorded, and statistical analyses were performed. RESULTS Biomechanical testing showed that there was no significant difference among the stabilities of these fixation systems in flexion-extension and rotation control. In left lateral bending, the bilateral C1-2 PS group decreased flexibility by 71.9% compared with the intact condition, the unilateral C1-2 PS and ipsilateral PAS+LS group decreased flexibility by 77.6%, and the unilateral C1-2 PS and contralateral PAS+LS group by 70.0%. Each method significantly decreased C1-2 movements in right lateral bending compared with the intact condition, and the bilateral C1-2 PS system was more stable than the C1-2 PS and contralateral PAS+LS system (p = 0.036). CONCLUSIONS A unilateral C-1 PAS + C-2 LS combined with 1-side C-1 PSs provided the same acute stability as the PS, and no statistically significant difference in acute stability was found between the 2 screw techniques. These methods may constitute an alternative method for

  17. Lonafarnib is a potential inhibitor for neovascularization.

    Directory of Open Access Journals (Sweden)

    Linlin Sun

    Full Text Available Atherosclerosis is a common cardiovascular disease that involves the build-up of plaque on the inner walls of the arteries. Intraplaque neovacularization has been shown to be essential in the pathogenesis of atherosclerosis. Previous studies showed that small-molecule compounds targeting farnesyl transferase have the ability to prevent atherosclerosis in apolipoprotein E-deficient mice, but the underlying mechanism remains to be elucidated. In this study, we found that lonafarnib, a specific inhibitor of farnesyl transferase, elicits inhibitory effect on vascular endothelial capillary assembly in vitro in a dose-dependent manner. In addition, we showed that lonafarnib treatment led to a dose-dependent decrease in scratch wound closure in vitro, whereas it had little effect on endothelial cell proliferation. These data indicate that lonafarnib inhibits neovascularization via directly targeting endothelial cells and disturbing their motility. Moreover, we demonstrated that pharmacological inhibition of farnesyl transferase by lonafarnib significantly impaired centrosome reorientation toward the leading edge of endothelial cells. Mechanistically, we found that the catalytic β subunit of farnesyl transferase associated with a cytoskeletal protein important for the establishment and maintenance of cell polarity. Additionally, we showed that lonafarnib remarkably inhibited the expression of the cytoskeletal protein and interrupted its interaction with farnesyl transferase. Our findings thus offer novel mechanistic insight into the protective effect of farnesyl transferase inhibitors on atherosclerosis and provide encouraging evidence for the potential use of this group of agents in inhibiting plaque neovascularization.

  18. Characterization of a gC1qR from the giant freshwater prawn, Macrobrachium rosenbergii.

    Science.gov (United States)

    Ye, Ting; Huang, Xin; Wang, Xian-Wei; Shi, Yan-Ru; Hui, Kai-Min; Ren, Qian

    2015-03-01

    gC1qR, as a multicompartmental and a multifunctional protein, plays an important role in innate immunity. In this study, a gC1qR homolog (MrgC1qR) in the giant freshwater prawn, Macrobrachium rosenbergii was identified. MrgC1qR, a 258-amino-acid polypeptide, shares high identities with gC1qR from other species. MrgC1qR gene was expressed in different tissues and was highest expressed in the hepatopancreas. In addition, the MrgC1qR transcript was significantly enhanced after 6 h of white spot syndrome virus (WSSV) infection or post 2 h, 24 h of Vibrio anguillarum challenge compared to appropriate controls. Moreover, recombinant MrgC1qR (rMrgC1qR) had bacterial binding activity, the result also revealed that rMrgC1qR could bind pathogen-associated molecular patterns (PAMPs) such as LPS or PGN, suggesting that MrgC1qRmight function as a pathogen-recognition receptor (PRR). Furthermore, glutathione S-transferase (GST) pull-down assays showed that rMrgC1qR with GST-tag could bind to rMrFicolin1 or rMrFicolin2 with His-tag. Altogether, these results may demonstrate a role for MrgC1qR in innate immunity in the giant freshwater prawns. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. SAP deficiency mitigated atherosclerotic lesions in ApoE(-/-) mice.

    Science.gov (United States)

    Zheng, Lingyun; Wu, Teng; Zeng, Cuiling; Li, Xiangli; Li, Xiaoqiang; Wen, Dingwen; Ji, Tianxing; Lan, Tian; Xing, Liying; Li, Jiangchao; He, Xiaodong; Wang, Lijing

    2016-01-01

    Serum amyloid P conpoent (SAP), a member of the pentraxin family, interact with pathogens and cell debris to promote their removal by macrophages and neutrophils and is co-localized with atherosclerotic plaques in patients. However, the exact mechanism of SAP in atherogenesis is still unclear. We investigated whether SAP influence macrophage recruitment and foam cell formation and ultimately affect atherosclerotic progression. we generated apoE(-/-); SAP(-/-) (DKO) mice and fed them western diet for 4 and 8 weeks to characterize atherosclerosis development. SAP deficiency effectively reduced plaque size both in the aorta (p = 0.0006 for 4 wks; p = 0.0001 for 8 wks) and the aortic root (p = 0.0061 for 4 wks; p = 0.0079 for 8wks) compared with apoE(-/-) mice. Meanwhile, SAP deficiency inhibited oxLDL-induced foam cell formation (p = 0.0004) compared with apoE(-/-) mice and SAP treatment increases oxLDL-induced foam cell formation (p = 0.002) in RAW cells. Besides, SAP deficiency reduced macrophages recruitment (p = 0.035) in vivo and in vitro (p = 0.026). Furthermore, SAP treatment enhanced CD36 (p = 0.007) and FcγRI (p = 0.031) expression induced by oxLDL through upregulating JNK and p38 MAPK phosphorylation whereas specific JNK1/2 inhibitor reduced CD36 (p = 0.0005) and FcγRI (P = 0.0007) expression in RAW cell. SAP deficiency also significantly decreased the expression of M1 and M2 macrophage markers and inflammatory cytokines in oxLDL-induced macrophages. SAP deficiency mitigated foam cell formation and atherosclerotic development in apoE(-/-) mice, due to reduction in macrophages recruitment, polarization and pro-inflammatory cytokines and inhibition the CD36/FcγR-dependent signaling pathway. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. [Xanthine oxidase deficiency (hereditary xanthinuria), molybdenum cofactor deficiency].

    Science.gov (United States)

    Sumi, S; Wada, Y

    1996-12-01

    Hereditary xanthinuria is a rare autosomal recessive disorder, with xanthine oxidase deficiency. Patients often display renal symptoms because they excrete a large amounts of xanthine in urine. An high-fluid-intake, alow-purine-food, and alkalinization of urine are effective in the patients. Molybdenum cofactor is essential for xanthine oxidase, sulfite oxidase and aldehyde oxidase. Patients with molybdenum cofactor deficiency display severe neurological symptoms, such as severe convulsions. The patients increase urinary excretions of xanthine and sulfite. Treatments are ineffective for neurological symptoms.