Sample records for chronically txnrd 1-deficient

  1. COMMD1-deficient dogs accumulate copper in hepatocytes and provide a good model for chronic hepatitis and fibrosis.

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    Robert P Favier

    Full Text Available New therapeutic concepts developed in rodent models should ideally be evaluated in large animal models prior to human clinical application. COMMD1-deficiency in dogs leads to hepatic copper accumulation and chronic hepatitis representing a Wilson's disease like phenotype. Detailed understanding of the pathogenesis and time course of this animal model is required to test its feasibility as a large animal model for chronic hepatitis. In addition to mouse models, true longitudinal studies are possible due to the size of these dogs permitting detailed analysis of the sequence of events from initial insult to final cirrhosis. Therefore, liver biopsies were taken each half year from five new born COMMD1-deficient dogs over a period of 42 months. Biopsies were used for H&E, reticulin, and rubeanic acid (copper staining. Immunohistochemistry was performed on hepatic stellate cell (HSC activation marker (alpha-smooth muscle actin, α-SMA, proliferation (Ki67, apoptosis (caspase-3, and bile duct and liver progenitor cell (LPC markers keratin (K 19 and 7. Quantitative RT-PCR and Western Blots were performed on gene products involved in the regenerative and fibrotic pathways. Maximum copper accumulation was reached at 12 months of age, which coincided with the first signs of hepatitis. HSCs were activated (α-SMA from 18 months onwards, with increasing reticulin deposition and hepatocytic proliferation in later stages. Hepatitis and caspase-3 activity (first noticed at 18 months increased over time. Both HGF and TGF-β1 gene expression peaked at 24 months, and thereafter decreased gradually. Both STAT3 and c-MET showed an increased time-dependent activation. Smad2/3 phosphorylation, indicative for fibrogenesis, was present at all time-points. COMMD1-deficient dogs develop chronic liver disease and cirrhosis comparable to human chronic hepatitis, although at much higher pace. Therefore they represent a genetically-defined large animal model to test clinical

  2. Commensal microbiota contributes to chronic endocarditis in TAX1BP1 deficient mice.

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    Satoko Nakano

    Full Text Available Tax1-binding protein 1 (Tax1bp1 negatively regulates NF-κB by editing the ubiquitylation of target molecules by its catalytic partner A20. Genetically engineered TAX1BP1-deficient (KO mice develop age-dependent inflammatory constitutions in multiple organs manifested as valvulitis or dermatitis and succumb to premature death. Laser capture dissection and gene expression microarray analysis on the mitral valves of TAX1BP1-KO mice (8 and 16 week old revealed 588 gene transcription alterations from the wild type. SAA3 (serum amyloid A3, CHI3L1, HP, IL1B and SPP1/OPN were induced 1,180-, 361-, 187-, 122- and 101-fold respectively. WIF1 (Wnt inhibitory factor 1 exhibited 11-fold reduction. Intense Saa3 staining and significant I-κBα reduction were reconfirmed and massive infiltration of inflammatory lymphocytes and edema formation were seen in the area. Antibiotics-induced 'germ free' status or the additional MyD88 deficiency significantly ameliorated TAX1BP1-KO mice's inflammatory lesions. These pathological conditions, as we named 'pseudo-infective endocarditis' were boosted by the commensal microbiota who are usually harmless by their nature. This experimental outcome raises a novel mechanistic linkage between endothelial inflammation caused by the ubiquitin remodeling immune regulators and fatal cardiac dysfunction.

  3. Decay-accelerating factor 1 deficiency exacerbates leptospiral-induced murine chronic nephritis and renal fibrosis.

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    María F Ferrer

    Full Text Available Leptospirosis is a global zoonosis caused by pathogenic Leptospira, which can colonize the proximal renal tubules and persist for long periods in the kidneys of infected hosts. Here, we characterized the infection of C57BL/6J wild-type and Daf1-/- mice, which have an enhanced host response, with a virulent Leptospira interrogans strain at 14 days post-infection, its persistence in the kidney, and its link to kidney fibrosis at 90 days post-infection. We found that Leptospira interrogans can induce acute moderate nephritis in wild-type mice and is able to persist in some animals, inducing fibrosis in the absence of mortality. In contrast, Daf1-/- mice showed acute mortality, with a higher bacterial burden. At the chronic stage, Daf1-/- mice showed greater inflammation and fibrosis than at 14 days post-infection and higher levels at all times than the wild-type counterpart. Compared with uninfected mice, infected wild-type mice showed higher levels of IL-4, IL-10 and IL-13, with similar levels of α-smooth muscle actin, galectin-3, TGF-β1, IL-17, IFN-γ, and lower IL-12 levels at 90 days post-infection. In contrast, fibrosis in Daf1-/- mice was accompanied by high expression of α-smooth muscle actin, galectin-3, IL-10, IL-13, and IFN-γ, similar levels of TGF-β1, IL-12, and IL-17 and lower IL-4 levels. This study demonstrates the link between Leptospira-induced murine chronic nephritis with renal fibrosis and shows a protective role of Daf1.

  4. Decay-accelerating factor 1 deficiency exacerbates leptospiral-induced murine chronic nephritis and renal fibrosis. (United States)

    Ferrer, María F; Scharrig, Emilia; Alberdi, Lucrecia; Cedola, Maia; Pretre, Gabriela; Drut, Ricardo; Song, Wen-Chao; Gomez, Ricardo M


    Leptospirosis is a global zoonosis caused by pathogenic Leptospira, which can colonize the proximal renal tubules and persist for long periods in the kidneys of infected hosts. Here, we characterized the infection of C57BL/6J wild-type and Daf1-/- mice, which have an enhanced host response, with a virulent Leptospira interrogans strain at 14 days post-infection, its persistence in the kidney, and its link to kidney fibrosis at 90 days post-infection. We found that Leptospira interrogans can induce acute moderate nephritis in wild-type mice and is able to persist in some animals, inducing fibrosis in the absence of mortality. In contrast, Daf1-/- mice showed acute mortality, with a higher bacterial burden. At the chronic stage, Daf1-/- mice showed greater inflammation and fibrosis than at 14 days post-infection and higher levels at all times than the wild-type counterpart. Compared with uninfected mice, infected wild-type mice showed higher levels of IL-4, IL-10 and IL-13, with similar levels of α-smooth muscle actin, galectin-3, TGF-β1, IL-17, IFN-γ, and lower IL-12 levels at 90 days post-infection. In contrast, fibrosis in Daf1-/- mice was accompanied by high expression of α-smooth muscle actin, galectin-3, IL-10, IL-13, and IFN-γ, similar levels of TGF-β1, IL-12, and IL-17 and lower IL-4 levels. This study demonstrates the link between Leptospira-induced murine chronic nephritis with renal fibrosis and shows a protective role of Daf1.

  5. Adult Lysophosphatidic Acid Receptor 1-Deficient Rats with Hyperoxia-Induced Neonatal Chronic Lung Disease Are Protected against Lipopolysaccharide-Induced Acute Lung Injury (United States)

    Chen, Xueyu; Walther, Frans J.; Laghmani, El H.; Hoogeboom, Annemarie M.; Hogen-Esch, Anne C. B.; van Ark, Ingrid; Folkerts, Gert; Wagenaar, Gerry T. M.


    Aim: Survivors of neonatal chronic lung disease or bronchopulmonary dysplasia (BPD) suffer from compromised lung function and are at high risk for developing lung injury by multiple insults later in life. Because neonatal lysophosphatidic acid receptor-1 (LPAR1)-deficient rats are protected against hyperoxia-induced lung injury, we hypothesize that LPAR1-deficiency may protect adult survivors of BPD from a second hit response against lipopolysaccharides (LPS)-induced lung injury. Methods: Directly after birth, Wistar control and LPAR1-deficient rat pups were exposed to hyperoxia (90%) for 8 days followed by recovery in room air. After 7 weeks, male rats received either LPS (2 mg kg−1) or 0.9% NaCl by intraperitoneal injection. Alveolar development and lung inflammation were investigated by morphometric analysis, IL-6 production, and mRNA expression of cytokines, chemokines, coagulation factors, and an indicator of oxidative stress. Results: LPAR1-deficient and control rats developed hyperoxia-induced neonatal emphysema, which persisted into adulthood, as demonstrated by alveolar enlargement and decreased vessel density. LPAR1-deficiency protected against LPS-induced lung injury. Adult controls with BPD exhibited an exacerbated response toward LPS with an increased expression of pro-inflammatory mRNAs, whereas LPAR1-deficient rats with BPD were less sensitive to this “second hit” with a decreased pulmonary influx of macrophages and neutrophils, interleukin-6 (IL-6) production, and mRNA expression of IL-6, monocyte chemoattractant protein-1, cytokine-induced neutrophil chemoattractant 1, plasminogen activator inhibitor-1, and tissue factor. Conclusion: LPAR1-deficient rats have increased hyperoxia-induced BPD survival rates and, despite the presence of neonatal emphysema, are less sensitive to an aggravated “second hit” than Wistar controls with BPD. Intervening in LPA-LPAR1-dependent signaling may not only have therapeutic potential for neonatal chronic

  6. Strain background modifies phenotypes in the ATP8B1-deficient mouse

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    Shah, S.; Sanford, U.R.; Vargas, J.C.; Xu, H.; Groen, A.; Paulusma, C.C.; Grenert, J.P.; Pawlikowska, L.; Sen, S.; Oude Elferink, R.P.J.; Bull, L.N.


    BACKGROUND: Mutations in ATP8B1 (FIC1) underlie cases of cholestatic disease, ranging from chronic and progressive (progressive familial intrahepatic cholestasis) to intermittent (benign recurrent intrahepatic cholestasis). The ATP8B1-deficient mouse serves as an animal model of human ATP8B1 deficie

  7. Strain background modifies phenotypes in the ATP8B1-deficient mouse.

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    Sohela Shah

    Full Text Available BACKGROUND: Mutations in ATP8B1 (FIC1 underlie cases of cholestatic disease, ranging from chronic and progressive (progressive familial intrahepatic cholestasis to intermittent (benign recurrent intrahepatic cholestasis. The ATP8B1-deficient mouse serves as an animal model of human ATP8B1 deficiency. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the effect of genetic background on phenotypes of ATP8B1-deficient and wild-type mice, using C57Bl/6 (B6, 129, and (B6-129 F1 strain backgrounds. B6 background resulted in greater abnormalities in ATP8B1-deficient mice than did 129 and/or F1 background. ATP8B1-deficient pups of B6 background gained less weight. In adult ATP8B1-deficient mice at baseline, those of B6 background had lower serum cholesterol levels, higher serum alkaline phosphatase levels, and larger livers. After challenge with cholate-supplemented diet, these mice exhibited higher serum alkaline phosphatase and bilirubin levels, greater weight loss and larger livers. ATP8B1-deficient phenotypes in mice of F1 and 129 backgrounds are usually similar, suggesting that susceptibility to manifestations of ATP8B1 deficiency may be recessive. We also detected differences in hepatobiliary phenotypes between wild-type mice of differing strains. CONCLUSIONS/SIGNIFICANCE: Our results indicate that the ATP8B1-deficient mouse in a B6 background may be a better model of human ATP8B1 deficiency and highlight the importance of informed background strain selection for mouse models of liver disease.

  8. Antioxidants and Quality of Aging: Further Evidences for a Major Role of TXNRD1 Gene Variability on Physical Performance at Old Age. (United States)

    Dato, Serena; De Rango, Francesco; Crocco, Paolina; Passarino, Giuseppe; Rose, Giuseppina


    Oxidative stress is a major determinant of human aging and common hallmark of age-related diseases. A protective role against free radicals accumulation was shown for thioredoxin reductase TrxR1, a key antioxidant selenoprotein. The variability of encoding gene (TXNRD1) was previously found associated with physical status at old age and extreme survival in a Danish cohort. To further investigate the influence of the gene variability on age-related physiological decline, we analyzed 9 tagging SNPs in relation to markers of physical (Activity of Daily Living, Hand Grip, Chair stand, and Walking) and cognitive (Mini Mental State Examination) status, in a Southern-Italian cohort of 64-107 aged individuals. We replicated the association of TXNRD1 variability with physical performance, with three variants (rs4445711, rs1128446, and rs11111979) associated with physical functioning after 85 years of age (p < 0.022). In addition, we found two SNPs borderline influencing longevity (rs4964728 and rs7310505) in our cohort, the last associated with health status and survival in Northern Europeans too. Overall, the evidences of association in a different population here reported extend the proposed role of TXNRD1 gene in modulating physical decline at extreme ages, further supporting the investigation of thioredoxin pathway in relation to the quality of human aging.

  9. Antioxidants and Quality of Aging: Further Evidences for a Major Role of TXNRD1 Gene Variability on Physical Performance at Old Age

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    Serena Dato


    Full Text Available Oxidative stress is a major determinant of human aging and common hallmark of age-related diseases. A protective role against free radicals accumulation was shown for thioredoxin reductase TrxR1, a key antioxidant selenoprotein. The variability of encoding gene (TXNRD1 was previously found associated with physical status at old age and extreme survival in a Danish cohort. To further investigate the influence of the gene variability on age-related physiological decline, we analyzed 9 tagging SNPs in relation to markers of physical (Activity of Daily Living, Hand Grip, Chair stand, and Walking and cognitive (Mini Mental State Examination status, in a Southern-Italian cohort of 64–107 aged individuals. We replicated the association of TXNRD1 variability with physical performance, with three variants (rs4445711, rs1128446, and rs11111979 associated with physical functioning after 85 years of age (p<0.022. In addition, we found two SNPs borderline influencing longevity (rs4964728 and rs7310505 in our cohort, the last associated with health status and survival in Northern Europeans too. Overall, the evidences of association in a different population here reported extend the proposed role of TXNRD1 gene in modulating physical decline at extreme ages, further supporting the investigation of thioredoxin pathway in relation to the quality of human aging.

  10. Cited1 deficiency suppresses intestinal tumorigenesis.

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    Valérie Méniel

    Full Text Available Conditional deletion of Apc in the murine intestine alters crypt-villus architecture and function. This process is accompanied by multiple changes in gene expression, including upregulation of Cited1, whose role in colorectal carcinogenesis is unknown. Here we explore the relevance of Cited1 to intestinal tumorigenesis. We crossed Cited1 null mice with Apc(Min/+ and AhCre(+Apc(fl/fl mice and determined the impact of Cited1 deficiency on tumour growth/initiation including tumour multiplicity, cell proliferation, apoptosis and the transcriptome. We show that Cited1 is up-regulated in both human and murine tumours, and that constitutive deficiency of Cited1 increases survival in Apc(Min/+ mice from 230.5 to 515 days. However, paradoxically, Cited1 deficiency accentuated nearly all aspects of the immediate phenotype 4 days after conditional deletion of Apc, including an increase in cell death and enhanced perturbation of differentiation, including of the stem cell compartment. Transcriptome analysis revealed multiple pathway changes, including p53, PI3K and Wnt. The activation of Wnt through Cited1 deficiency correlated with increased transcription of β-catenin and increased levels of dephosphorylated β-catenin. Hence, immediately following deletion of Apc, Cited1 normally restrains the Wnt pathway at the level of β-catenin. Thus deficiency of Cited1 leads to hyper-activation of Wnt signaling and an exaggerated Wnt phenotype including elevated cell death. Cited1 deficiency decreases intestinal tumourigenesis in Apc(Min/+ mice and impacts upon a number of oncogenic signaling pathways, including Wnt. This restraint imposed by Cited1 is consistent with a requirement for Cited1 to constrain Wnt activity to a level commensurate with optimal adenoma formation and maintenance, and provides one mechanism for tumour repression in the absence of Cited1.

  11. The molecular basis of aminoacylase 1 deficiency

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    Sommer, Anke; Christensen, Ernst; Schwenger, Susanne;


    by their intramolecular localization and molecular characteristics. In contrast to aminoacylase 1 variants which showed no detectable aminoacylase 1 activity, aminoacylase 1 proteins with the mutations p.Arg378Trp, p.Arg378Gln and p.Arg393His were also detected in Western blot analysis. Investigations of the molecular...... bases of additional cases of aminoacylase 1 deficiency contribute to a better understanding of this inborn error of metabolism whose clinical significance and long-term consequences remain to be elucidated....

  12. Pannexin 1 deficiency can induce hearing loss. (United States)

    Zhao, Hong-Bo; Zhu, Yan; Liang, Chun; Chen, Jin

    Gap junctions play a critical role in hearing. Connexin gap junction gene mutations can induce a high incidence of hearing loss. Pannexin (Panx) gene also encodes gap junction proteins in vertebrates. Panx1 is a predominant pannexin isoform and has extensive expression in the cochlea. Here, we report that deletion of Panx1 in the cochlea could produce a progressive hearing loss. The auditory brainstem response (ABR) recording showed that hearing loss was moderate to severe and severe at high-frequencies. Distortion product otoacoustic emission (DPOAE), which reflects the activity of active cochlear mechanics that can amply acoustic stimulation to enhance hearing sensitivity and frequency selectivity, was also reduced. We further found that Panx1 deficiency could activate Caspase-3 cell apoptotic pathway in the cochlea to cause hair cells and other types of cells degeneration. These data indicate that like connexins Panx1 deficiency can also induce hearing loss. These data also suggest that pannexins play important rather than redundant roles in the cochlea and hearing.

  13. Sustained beta-cell dysfunction but normalized islet mass in aged thrombospondin-1 deficient mice.

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    Carl Johan Drott

    Full Text Available Pancreatic islet endothelial cells have in recent years been shown to support beta-cell mass and function by paracrine interactions. Recently, we identified an islets endothelial-specific glycoprotein, thrombospondin-1 (TSP-1, that showed to be of importance for islet angiogenesis and beta-cell function in young mice. The present study aimed to investigate long-term consequences for islet morphology and beta-cell function of TSP-1 deficiency. Islet and beta-cell mass were observed increased at 10-12 weeks of age in TSP-1 deficient mice, but were normalized before 16 weeks of age when compared to wild-type controls. Islet vascularity was normal in 10-12 and 16-week-old TSP-1 deficient animals, whereas islets of one-year-old animals lacking TSP-1 were hypervascular. Beta-cell dysfunction in TSP-1 deficient animals was present at similar magnitudes between 10-12 and 52 weeks of age, as evaluated by glucose tolerance tests. The insulin secretion capacity in vivo of islets in one-year-old TSP-1 deficient animals was only ∼15% of that in wild-type animals. Using a transplantation model, we reconstituted TSP-1 in adult TSP-deficient islets. In contrast to neonatal TSP-1 deficient islets that we previously reported to regain function after TSP-1 reconstitution, adult islets failed to recover. We conclude that TSP-1 deficiency in islets causes changing vascular and endocrine morphological alterations postnatally, but is coupled to a chronic beta-cell dysfunction. The beta-cell dysfunction induced by TSP-1 deficiency is irreversible if not substituted early in life.

  14. Metformin administration induces hepatotoxic effects in paraoxonase-1-deficient mice. (United States)

    García-Heredia, Anabel; Riera-Borrull, Marta; Fort-Gallifa, Isabel; Luciano-Mateo, Fedra; Cabré, Noemí; Hernández-Aguilera, Anna; Joven, Jorge; Camps, Jordi


    Metformin is the first-line pharmacological treatment of diabetes. In these patients, metformin reduces body weight and decreases the risk of diabetes-related complications such as cardiovascular disease. However, whether metformin elicits beneficial effects on liver histology is a controversial issue and, as yet, there is no consensus. Paraoxonase-1 (PON1), an enzyme synthesized mainly by the liver, degrades lipid peroxides and reduces oxidative stress. PON1 activities are decreased in chronic liver diseases. We evaluated the effects of metformin in the liver of PON1-deficient mice which, untreated, present a mild degree of liver steatosis. Metformin administration aggravated inflammation in animals given a standard mouse chow and in those fed a high-fat diet. Also, it was associated with a higher degree of steatosis in animals fed a standard chow diet. This report is a cautionary note regarding the prescription of metformin for the treatment of diabetes in patients with concomitant liver impairment.

  15. [Glucose transporter type 1 (GLUT-1) deficiency]. (United States)

    Cano, A; Ticus, I; Chabrol, B


    Impaired glucose transport across the blood brain barrier results in glucose transporter type 1 (GLUT-1) deficiency syndrome, first described in 1991. It is characterized by infantile seizures refractory to anticonvulsive treatments, microcephaly, delays in mental and motor development, spasticity, ataxia, dysarthria and other paroxysmal neurologic phenomena, often occurring prior to meals. Affected infants are normal at birth following an uneventful pregnancy and delivery. Seizures usually begin between the age of one and four months and can be preceded by apneic episodes or abnormal eyes movements. Patients with atypical presentations such as mental retardation and intermittent ataxia without seizures, or movement disorders characterized by choreoathetosis and dystonia, have also been described. Glucose is the principal fuel source for the brain and GLUT-1 is the only vehicle by which glucose enters the brain. In case of GLUT-1 deficiency, the risk of clinical manifestations is increased in infancy and childhood, when the brain glucose demand is maximal. The hallmark of the disease is a low glucose concentration in the cerebrospinal fluid in a presence of normoglycemia (cerebrospinal fluid/blood glucose ratio less than 0.4). The GLUT-1 defect can be confirmed by molecular analysis of the SCL2A1 gene or in erythrocytes by glucose uptake studies and GLUT-1 immunoreactivity. Several heterozygous mutations, with a majority of de novo mutations, resulting in GLUT-1 haploinsufficiency, have been described. Cases with an autosomal dominant transmission have been established and adults can exhibit symptoms of this deficiency. Ketogenic diet is an effective treatment of epileptic manifestations as ketone bodies serve as an alternative fuel for the developing brain. However, this diet is not effective on cognitive impairment and other treatments are being evaluated. The physiopathology of this disorder is partially unclear and its understanding could explain the clinical

  16. SNP in TXNRD2 Associated With Radiation-Induced Fibrosis: A Study of Genetic Variation in Reactive Oxygen Species Metabolism and Signaling

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    Edvardsen, Hege, E-mail: [Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet, Oslo (Norway); K. G. Jebsen Breast cancer centre, Institute for Clinical Medicine, University of Oslo, Oslo (Norway); Landmark-Høyvik, Hege [Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet, Oslo (Norway); K. G. Jebsen Breast cancer centre, Institute for Clinical Medicine, University of Oslo, Oslo (Norway); Reinertsen, Kristin V. [National Resource Centre for Late Effects after Cancer Treatment, OUS Radiumhospitalet, Oslo (Norway); Zhao, Xi [Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet, Oslo (Norway); K. G. Jebsen Breast cancer centre, Institute for Clinical Medicine, University of Oslo, Oslo (Norway); Grenaker-Alnæs, Grethe Irene; Nebdal, Daniel [Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet, Oslo (Norway); Syvänen, Ann-Christine [Department of Medical Sciences, Uppsala University, Uppsala (Sweden); Rødningen, Olaug [Department of Medical Genetics, OUS Ullevaal, Oslo (Norway); Alsner, Jan; Overgaard, Jens [Department of Experimental Clinical Oncology, Ahus University Hospital (Norway); Borresen-Dale, Anne-Lise [Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet, Oslo (Norway); K. G. Jebsen Breast cancer centre, Institute for Clinical Medicine, University of Oslo, Oslo (Norway); Fosså, Sophie D. [K. G. Jebsen Breast cancer centre, Institute for Clinical Medicine, University of Oslo, Oslo (Norway); National Resource Centre for Late Effects after Cancer Treatment, OUS Radiumhospitalet, Oslo (Norway); Kristensen, Vessela N. [Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet, Oslo (Norway); K. G. Jebsen Breast cancer centre, Institute for Clinical Medicine, University of Oslo, Oslo (Norway); Department of Clinical Molecular Biology (EpiGen), Division of Medicine, Ahus University Hospital (Norway)


    Purpose: The aim of the study was to identify noninvasive markers of treatment-induced side effects. Reactive oxygen species (ROS) are generated after irradiation, and genetic variation in genes related to ROS metabolism might influence the level of radiation-induced adverse effects (AEs). Methods and Materials: 92 breast cancer (BC) survivors previously treated with hypofractionated radiation therapy were assessed for the AEs subcutaneous atrophy and fibrosis, costal fractures, lung fibrosis, pleural thickening, and telangiectasias (median follow-up time 17.1 years). Single-nucleotide polymorphisms (SNPs) in 203 genes were analyzed for association to AE grade. SNPs associated with subcutaneous fibrosis were validated in an independent BC survivor material (n=283). The influence of the studied genetic variation on messenger ribonucleic acid (mRNA) expression level of 18 genes previously associated with fibrosis was assessed in fibroblast cell lines from BC patients. Results: Subcutaneous fibrosis and atrophy had the highest correlation (r=0.76) of all assessed AEs. The nonsynonymous SNP rs1139793 in TXNRD2 was associated with grade of subcutaneous fibrosis, the reference T-allele being more prevalent in the group experiencing severe levels of fibrosis. This was confirmed in another sample cohort of 283 BC survivors, and rs1139793 was found significantly associated with mRNA expression level of TXNRD2 in blood. Genetic variation in 24 ROS-related genes, including EGFR, CENPE, APEX1, and GSTP1, was associated with mRNA expression of 14 genes previously linked to fibrosis (P≤.005). Conclusion: Development of subcutaneous fibrosis can be associated with genetic variation in the mitochondrial enzyme TXNRD2, critically involved in removal of ROS, and maintenance of the intracellular redox balance.

  17. Nitroglycerin tolerance in caveolin-1 deficient mice.

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    Mao Mao

    Full Text Available Nitrate tolerance developed after persistent nitroglycerin (GTN exposure limits its clinical utility. Previously, we have shown that the vasodilatory action of GTN is dependent on endothelial nitric oxide synthase (eNOS/NOS3 activity. Caveolin-1 (Cav-1 is known to interact with NOS3 on the cytoplasmic side of cholesterol-enriched plasma membrane microdomains (caveolae and to inhibit NOS3 activity. Loss of Cav-1 expression results in NOS3 hyperactivation and uncoupling, converting NOS3 into a source of superoxide radicals, peroxynitrite, and oxidative stress. Therefore, we hypothesized that nitrate tolerance induced by persistent GTN treatment results from NOS3 dysfunction and vascular toxicity. Exposure to GTN for 48-72 h resulted in nitrosation and depletion (>50% of Cav-1, NOS3 uncoupling as measured by an increase in peroxynitrite production (>100%, and endothelial toxicity in cultured cells. In the Cav-1 deficient mice, NOS3 dysfunction was accompanied by GTN tolerance (>50% dilation inhibition at low GTN concentrations. In conclusion, GTN tolerance results from Cav-1 modification and depletion by GTN that causes persistent NOS3 activation and uncoupling, preventing it from participating in GTN-medicated vasodilation.

  18. Nitroglycerin tolerance in caveolin-1 deficient mice. (United States)

    Mao, Mao; Varadarajan, Sudhahar; Fukai, Tohru; Bakhshi, Farnaz R; Chernaya, Olga; Dudley, Samuel C; Minshall, Richard D; Bonini, Marcelo G


    Nitrate tolerance developed after persistent nitroglycerin (GTN) exposure limits its clinical utility. Previously, we have shown that the vasodilatory action of GTN is dependent on endothelial nitric oxide synthase (eNOS/NOS3) activity. Caveolin-1 (Cav-1) is known to interact with NOS3 on the cytoplasmic side of cholesterol-enriched plasma membrane microdomains (caveolae) and to inhibit NOS3 activity. Loss of Cav-1 expression results in NOS3 hyperactivation and uncoupling, converting NOS3 into a source of superoxide radicals, peroxynitrite, and oxidative stress. Therefore, we hypothesized that nitrate tolerance induced by persistent GTN treatment results from NOS3 dysfunction and vascular toxicity. Exposure to GTN for 48-72 h resulted in nitrosation and depletion (>50%) of Cav-1, NOS3 uncoupling as measured by an increase in peroxynitrite production (>100%), and endothelial toxicity in cultured cells. In the Cav-1 deficient mice, NOS3 dysfunction was accompanied by GTN tolerance (>50% dilation inhibition at low GTN concentrations). In conclusion, GTN tolerance results from Cav-1 modification and depletion by GTN that causes persistent NOS3 activation and uncoupling, preventing it from participating in GTN-medicated vasodilation.

  19. Analysis of Gait Disturbance in Glut 1 Deficiency Syndrome. (United States)

    Blumenschine, Michelle; Montes, Jacqueline; Rao, Ashwini K; Engelstad, Kristin; De Vivo, Darryl C


    Anticipating potential therapies for Glut 1 deficiency syndrome (Glut1DS) emphasizes the need for effective clinical outcome measures. The 6-minute walk test is a well-established outcome measure that evaluates walking ability in neurological diseases. Twenty-one children with Glut 1 deficiency syndrome and 21 controls performed the 6-minute walk test. Fatigue was determined by comparing distance walked in the first and sixth minutes. Gait was analyzed by stride length, velocity, cadence, base of support, and percentage time in double support. Independent sample t-tests examined differences between group. Repeated-measures analysis of variance evaluated gait parameters over time. Glut 1 deficiency syndrome patients walked less (P Glut 1 deficiency syndrome patients have impaired motor performance, walk more slowly, and have poor balance. The 6-minute walk test with gait analysis may serve as a useful outcome measure in clinical trials in Glut 1 deficiency syndrome.

  20. Quantitative proteomics suggests metabolic reprogramming during ETHE1 deficiency

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    Sahebekhtiari, Navid; Thomsen, Michelle M.; Sloth, Jens Jørgen


    Deficiency of mitochondrial sulfur dioxygenase (ETHE1) causes the severe metabolic disorder ethylmalonic encephalopathy, which is characterized by early-onset encephalopathy and defective cytochrome C oxidase because of hydrogen sulfide accumulation. Although the severe systemic consequences...... of the disorder are becoming clear, the molecular effects are not well defined. Therefore, for further elucidating the effects of ETHE1-deficiency, we performed a large scale quantitative proteomics study on liver tissue from ETHE1-deficient mice. Our results demonstrated a clear link between ETHE1-deficiency...... and redox active proteins, as reflected by down-regulation of several proteins related to oxidation-reduction, such as different dehydrogenases and cytochrome P450 (CYP450) members. Furthermore, the protein data indicated impact of the ETHE1-deficiency on metabolic reprogramming through up...

  1. Unusual phenotype of glucose transport protein type 1 deficiency syndrome: A case report and literature review

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    Annio Posar


    Full Text Available The glucose transport protein type 1 (GLUT1 deficit causes a chronic brain energy failure. The classic phenotype of GLUT1 deficiency syndrome is characterized by: Mild to severe motor delay and mental retardation; infantile-onset epilepsy; head growth deceleration; movement disorders (ataxia, dystonia, spasticity; and non-epileptic paroxysmal events (intermittent ataxia, periodic confusion, recurrent headaches. During last years the classic phenotype of this syndrome, as originally reported, has expanded. We report the atypical phenotype of a boy with GLUT1 deficiency syndrome, characterized by mild mental retardation and drug-resistant absence seizures with onset at the age of 6 years, without movement disorders nor decrease of head circumference. A prompt diagnosis of this disorder is mandatory since the ketogenic diet might represent an effective treatment.

  2. Glut1 deficiency syndrome and novel ketogenic diets. (United States)

    Klepper, Joerg; Leiendecker, Baerbel


    The classical ketogenic diet has been used for refractory childhood epilepsy for decades. It is also the treatment of choice for disorders of brain energy metabolism, such as Glut1 deficiency syndrome. Novel ketogenic diets such as the modified Atkins diet and the low glycemic index treatment have significantly improved the therapeutic options for dietary treatment. Benefits of these novel diets are increased palatability, practicability, and thus compliance-at the expense of lower ketosis. As high ketones appear essential to meet the brain energy deficit caused by Glut1 deficiency syndrome, the use of novel ketogenic diets in this entity may be limited. This article discusses the current data on novel ketogenic diets and the implications on the use of these diets in regard to Glut1 deficiency syndrome.

  3. Viable offspring obtained from Prm1-deficient sperm in mice


    Naoki Takeda; Kazuya Yoshinaga; Kenryo Furushima; Kazufumi Takamune; Zhenghua Li; Shin-ichi Abe; Shin-ichi Aizawa; Ken-ichi Yamamura


    Protamines are expressed in the spermatid nucleus and allow denser packaging of DNA compared with histones. Disruption of the coding sequence of one allele of either protamine 1 (Prm1) or Prm2 results in failure to produce offspring, although sperm with disrupted Prm1 or Prm2 alleles are produced. Here, we produced Prm1-deficient female chimeric mice carrying Prm1-deficient oocytes. These mice successfully produced Prm1 +/− male mice. Healthy Prm1 +/− offspring were then produced by transferr...

  4. NHE1 deficiency in liver: Implications for non-alcoholic fatty liver disease

    Energy Technology Data Exchange (ETDEWEB)

    Prasad, Vikram, E-mail: [Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine (United States); Chirra, Shivani [Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine (United States); Kohli, Rohit [Department of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital, University of Cincinnati, Cincinnati, OH 45267 (United States); Shull, Gary E. [Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine (United States)


    Highlights: • FXR, PGC1α and PPARγ levels are upregulated in NHE1 deficient livers. • NHE1 deficiency downregulates expression of pro-lipogenic genes in liver. • Chronic exposure to high-fat diet upregulates hepatic NHE1 expression. • Loss of NHE1 better preserves hepatic insulin signaling in high-fat diet-fed mice. - Abstract: Non-alcoholic fatty liver disease NAFLD is closely associated with the dysregulation of lipid homeostasis. Diet-induced hepatic steatosis, which can initiate NAFLD progression, has been shown to be dramatically reduced in mice lacking the electroneutral Na{sup +}/H{sup +} exchanger NHE1 (Slc9a1). In this study, we investigated if NHE1 deficiency had effects in liver that could contribute to the apparent protection against aberrant lipid accumulation. RT-PCR and immunoblot analyses of wild-type and NHE1-null livers revealed an expression profile that strongly suggested attenuation of both de novo lipogenesis and hepatic stellate cell activation, which is implicated in liver fibrosis. This included upregulation of the farnesoid X receptor FXR, peroxisome proliferator-activated receptor PPARγ, its co-activator PGC1α, and sestrin 2, an antioxidant protein involved in hepatic metabolic homeostasis. Furthermore, expression levels of the pro-lipogenic liver X receptor LXRα, and acetyl CoA carboxylases 1 and 2 were downregulated. These changes were associated with evidence of reduced cellular stress, which persisted even upon exposure to a high-fat diet, and the better preservation of insulin signaling, as evidenced by protein kinase B/Akt phosphorylation (Ser473). These results indicate that NHE1 deficiency may protect against NAFLD pathogenesis, which is significant given the availability of highly specific NHE1 inhibitors.

  5. GLUT1 deficiency with delayed myelination responding to ketogenic diet.

    NARCIS (Netherlands)

    Klepper, J.; Engelbrecht, V.; Scheffer, H.; Knaap, M.S. van der; Fiedler, A.


    Monitoring effects of a ketogenic diet in GLUT1 deficiency syndrome without seizures is difficult. Neuroimaging is considered uninformative. We report the case of a boy with neurodevelopmental delay, severe ataxia, an E54X-mutation in the SLC2A1 gene (previously GLUT1), and neuroimaging abnormalitie

  6. GLUT-1 deficiency without epilepsy - an exceptional case

    NARCIS (Netherlands)

    Overweg-Plandsoen, WCG; Groener, JEM; Onkenhout, W; Brouwer, OF; Bakker, HD; De Vivo, DC


    The GLUT-1 deficiency is a metabolic disorder caused by a defect in glucose transport across the blood-brain barrier as a result of a defect in the glucose-transport protein. Patients present with epileptic seizures, delayed development, ataxia and hypotonia, and in many cases acquired microcephaly.

  7. Heme oxygenase-1 deficiency: the first autopsy case. (United States)

    Kawashima, Atsuhiro; Oda, Yoshio; Yachie, Akihiro; Koizumi, Shoichi; Nakanishi, Isao


    This article describes the first autopsy case of heme oxygenase (HO)-1 deficiency. A 6-year-old boy who presented with growth retardation; anemia; leukocytosis; thrombocytosis; coagulation abnormality; elevated levels of haptoglobin, ferritin, and heme in serum; a low serum bilirubin concentration; and hyperlipidemia was diagnosed as HO-1 deficient by gene analysis several months before death. Autopsy showed amyloid deposits in the liver and adrenal glands and mesangioproliferative glomerular changes in kidneys, in addition to an irregular distribution of foamy macrophages with iron pigments. Fatty streaks and fibrous plaques were noted in the aorta. Compared with HO-1--targeted mice, the present case seems to more severely involve endothelial cells and the reticuloendothelial system, resulting in intravascular hemolysis, disseminated intravascular coagulation, and amyloidosis with a short survival. This contrasts to the predominant iron metabolic disorders of HO-1--targeted mice with a long survival.

  8. Viable offspring obtained from Prm1-deficient sperm in mice. (United States)

    Takeda, Naoki; Yoshinaga, Kazuya; Furushima, Kenryo; Takamune, Kazufumi; Li, Zhenghua; Abe, Shin-Ichi; Aizawa, Shin-Ichi; Yamamura, Ken-Ichi


    Protamines are expressed in the spermatid nucleus and allow denser packaging of DNA compared with histones. Disruption of the coding sequence of one allele of either protamine 1 (Prm1) or Prm2 results in failure to produce offspring, although sperm with disrupted Prm1 or Prm2 alleles are produced. Here, we produced Prm1-deficient female chimeric mice carrying Prm1-deficient oocytes. These mice successfully produced Prm1(+/-) male mice. Healthy Prm1(+/-) offspring were then produced by transferring blastocysts obtained via in vitro fertilization using zona-free oocytes and sperm from Prm1(+/-) mice. This result suggests that sperm lacking Prm1 can generate offspring despite being abnormally shaped and having destabilised DNA, decondensed chromatin and a reduction in mitochondrial membrane potential. Nevertheless, these mice showed little derangement of expression profiles.

  9. Refractory absence epilepsy associated with GLUT-1 deficiency syndrome.

    LENUS (Irish Health Repository)

    Byrne, Susan


    GLUT-1 deficiency syndrome (GLUT-1 DS) is a disorder of cerebral glucose transport associated with early infantile epilepsy and microcephaly. We report two boys who presented with refractory absence epilepsy associated with hypoglycorrhachia, both of whom have genetically confirmed GLUT-1 DS. We propose that these children serve to expand the phenotype of GLUT-1 DS and suggest that this condition should be considered as a cause of refractory absence seizures in childhood.

  10. Over-expression of a human chromosome 22q11.2 segment including TXNRD2, COMT and ARVCF developmentally affects incentive learning and working memory in mice. (United States)

    Suzuki, Go; Harper, Kathryn M; Hiramoto, Takeshi; Funke, Birgit; Lee, MoonSook; Kang, Gina; Buell, Mahalah; Geyer, Mark A; Kucherlapati, Raju; Morrow, Bernice; Männistö, Pekka T; Agatsuma, Soh; Hiroi, Noboru


    Duplication of human chromosome 22q11.2 is associated with elevated rates of mental retardation, autism and many other behavioral phenotypes. However, because duplications cover 1.5-6 Mb, the precise manner in which segments of 22q11.2 causally affect behavior is not known in humans. We have now determined the developmental impact of over-expression of an approximately 190 kb segment of human 22q11.2, which includes the genes TXNRD2, COMT and ARVCF, on behaviors in bacterial artificial chromosome (BAC) transgenic (TG) mice. BAC TG mice and wild-type (WT) mice were tested for their cognitive capacities, affect- and stress-related behaviors and motor activity at 1 and 2 months of age. An enzymatic assay determined the impact of BAC over-expression on the activity level of COMT. BAC TG mice approached a rewarded goal faster (i.e. incentive learning), but were impaired in delayed rewarded alternation during development. In contrast, BAC TG and WT mice were indistinguishable in rewarded alternation without delays, spontaneous alternation, prepulse inhibition, social interaction, anxiety-, stress- and fear-related behaviors and motor activity. Compared with WT mice, BAC TG mice had an approximately 2-fold higher level of COMT activity in the prefrontal cortex, striatum and hippocampus. These data suggest that over-expression of this 22q11.2 segment enhances incentive learning and impairs the prolonged maintenance of working memory, but has no apparent effect on working memory per se, affect- and stress-related behaviors or motor capacity. High copy numbers of this 22q11.2 segment might contribute to a highly selective set of phenotypes in learning and cognition during development.

  11. SMARCB1 (INI-1)-deficient carcinomas of the sinonasal tract. (United States)

    Bishop, Justin A; Antonescu, Cristina R; Westra, William H


    SMARCB1 (INI-1) is a tumor-suppressor gene located on chromosome 22q11.2. Its gene product is ubiquitously expressed in nuclei of all normal tissues. SMARCB1 gene inactivation has been implicated in the pathogenesis of a diverse group of malignant neoplasms that tend to share "rhabdoid" cytomorphology. This group of SMARCB1-deficient tumors is now further expanded by a subset of carcinomas arising in the sinonasal tract. SMARCB1 immunostaining was performed on 142 sinonasal carcinomas. Tumors that showed loss of expression were further characterized for SMARCB1 deletions by fluorescence in situ hybridization. Nine of 142 (6%) primary sinonasal carcinomas showed loss of SMARCB1 expression by immunohistochemistry. Five patients were women, and patients ranged in age from 33 to 78 years (mean 59 y). The SMARCB1-deficient tumors were characterized by nests, sheets, and cords of cells without any histologic evidence of specific (eg, squamous or glandular) differentiation. The tumors comprised varying proportions of basaloid and rhabdoid cells. The SMARCB1-deficient carcinomas had been diagnosed as nonkeratinizing squamous cell carcinomas (n=3), sinonasal undifferentiated carcinomas (n=2), myoepithelial carcinoma (n=2), nonintestinal adenocarcinoma (n=1), and carcinoma, not otherwise specified (n=1). Fluorescence in situ hybridization analysis revealed SMARCB1 deletions in 6 of 8 (75%) carcinomas. The SMARCB1-deficient carcinomas did not harbor human papillomavirus or NUT-1 alterations. Six patients presented with T4 disease, 5 patients developed local recurrences and/or distant metastases, and 4 died of their disease. Inactivation of the SMARCB1 tumor-suppressor gene appears to be involved in the pathogenesis of a subset of sinonasal carcinomas, further expanding the family of SMARCB1-deficient neoplasms and further delineating a bewildering group of poorly/undifferentiated, aggressive carcinomas arising at this site. The ability to detect SMARCB1 loss by

  12. Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction. (United States)

    Thongthip, Supawat; Bellani, Marina; Gregg, Siobhan Q; Sridhar, Sunandini; Conti, Brooke A; Chen, Yanglu; Seidman, Michael M; Smogorzewska, Agata


    Deficiency of FANCD2/FANCI-associated nuclease 1 (FAN1) in humans leads to karyomegalic interstitial nephritis (KIN), a rare hereditary kidney disease characterized by chronic renal fibrosis, tubular degeneration, and characteristic polyploid nuclei in multiple tissues. The mechanism of how FAN1 protects cells is largely unknown but is thought to involve FAN1's function in DNA interstrand cross-link (ICL) repair. Here, we describe a Fan1-deficient mouse and show that FAN1 is required for cellular and organismal resistance to ICLs. We show that the ubiquitin-binding zinc finger (UBZ) domain of FAN1, which is needed for interaction with FANCD2, is not required for the initial rapid recruitment of FAN1 to ICLs or for its role in DNA ICL resistance. Epistasis analyses reveal that FAN1 has cross-link repair activities that are independent of the Fanconi anemia proteins and that this activity is redundant with the 5'-3' exonuclease SNM1A. Karyomegaly becomes prominent in kidneys and livers of Fan1-deficient mice with age, and mice develop liver dysfunction. Treatment of Fan1-deficient mice with ICL-inducing agents results in pronounced thymic and bone marrow hypocellularity and the disappearance of c-kit(+) cells. Our results provide insight into the mechanism of FAN1 in ICL repair and demonstrate that the Fan1 mouse model effectively recapitulates the pathological features of human FAN1 deficiency.

  13. BACE1-Deficient Mice Exhibit Alterations in Immune System Pathways. (United States)

    Stertz, L; Contreras-Shannon, V; Monroy-Jaramillo, N; Sun, J; Walss-Bass, C


    BACE1 encodes for the beta-site amyloid precursor protein cleaving enzyme 1 or β-secretase. Genetic deletion of Bace1 leads to behavioral alterations and affects midbrain dopaminergic signaling and memory processes. In order to further understand the role of BACE1 in brain function and behavior, we performed microarray transcriptome profiling and gene pathway analysis in the hippocampus of BACE1-deficient mice compared to wild type. We identified a total of 91 differentially expressed genes (DEGs), mostly enriched in pathways related to the immune and inflammation systems, particularly IL-9 and NF-κB activation pathways. Serum levels of IL-9 were elevated in BACE1-deficient mice. Our network analysis supports an intimate connection between immune response via NF-κB and BACE1 signaling through the NRG1/Akt1 pathway. Our findings warrant future mechanistic studies to determine if BACE1 signaling and the IL-9 pathway interact to alter behavior and brain function. This study opens new avenues in the investigation of hippocampus-related neuroimmunological and neuroinflammation-associated disorders.

  14. Fat and carbohydrate metabolism during exercise in phosphoglucomutase type 1 deficiency

    DEFF Research Database (Denmark)

    Preisler, Nicolai; Laforêt, Pascal; Echaniz-Laguna, Andoni;


    Phosphoglucomutase type 1 (PGM1) deficiency is a rare metabolic myopathy in which symptoms are provoked by exercise.......Phosphoglucomutase type 1 (PGM1) deficiency is a rare metabolic myopathy in which symptoms are provoked by exercise....

  15. Robust food anticipatory activity in BMAL1-deficient mice.

    Directory of Open Access Journals (Sweden)

    Julie S Pendergast

    Full Text Available Food availability is a potent environmental cue that directs circadian locomotor activity in rodents. Even though nocturnal rodents prefer to forage at night, daytime food anticipatory activity (FAA is observed prior to short meals presented at a scheduled time of day. Under this restricted feeding regimen, rodents exhibit two distinct bouts of activity, a nocturnal activity rhythm that is entrained to the light-dark cycle and controlled by the master clock in the suprachiasmatic nuclei (SCN and a daytime bout of activity that is phase-locked to mealtime. FAA also occurs during food deprivation, suggesting that a food-entrainable oscillator (FEO keeps time in the absence of scheduled feeding. Previous studies have demonstrated that the FEO is anatomically distinct from the SCN and that FAA is observed in mice lacking some circadian genes essential for timekeeping in the SCN. In the current study, we optimized the conditions for examining FAA during restricted feeding and food deprivation in mice lacking functional BMAL1, which is critical for circadian rhythm generation in the SCN. We found that BMAL1-deficient mice displayed FAA during restricted feeding in 12hr light:12hr dark (12L:12D and 18L:6D lighting cycles, but distinct activity during food deprivation was observed only in 18L:6D. While BMAL1-deficient mice also exhibited robust FAA during restricted feeding in constant darkness, mice were hyperactive during food deprivation so it was not clear that FAA consistently occurred at the time of previously scheduled food availability. Taken together, our findings suggest that optimization of experimental conditions such as photoperiod may be necessary to visualize FAA in genetically modified mice. Furthermore, the expression of FAA may be possible without a circadian oscillator that depends on BMAL1.

  16. Reduced cellular DNA repair capacity after environmentally relevant arsenic exposure. Influence of Ogg1 deficiency. (United States)

    Bach, Jordi; Peremartí, Jana; Annangi, Balasubramnayam; Marcos, Ricard; Hernández, Alba


    Inorganic arsenic (i-As) is a genotoxic and carcinogenic environmental contaminant known to affect millions of people worldwide. Our previous work demonstrated that chronic sub-toxic i-As concentrations were able to induce biologically significant levels of genotoxic and oxidative DNA damage that were strongly influenced by the Ogg1 genotype. In order to study the nature of the observed levels of damage and the observed differences between MEF Ogg1(+/+) and Ogg1(-/-) genetic backgrounds, the genotoxic and oxidative DNA repair kinetics of 18-weeks exposed MEF cells were evaluated by the comet assay. Results indicate that MEF Ogg1(+/+) and Ogg1(-/-) cells chronically exposed to i-As repair the DNA damage induced by arsenite, potassium bromide and UVC radiation less efficiently than control cells, being that observation clearly more pronounced in MEF Ogg1(-/-) cells. Consequently, exposed cells accumulate a higher percentage of unrepaired DNA damage at the end of the repair period. As an attempt to eliminate i-As associated toxicity, chronically exposed MEF Ogg1(-/-) cells overexpress the arsenic metabolizing enzyme As3mt. This adaptive response confers cells a significant resistance to i-As-induced cell death, but at expenses of accumulating high levels of DNA damage due to their repair impairment. Overall, the work presented here evidences that i-As chronic exposure disrupts the normal cellular repair function, and that oxidative DNA damage-and Ogg1 deficiency-exacerbates this phenomenon. The observed cell death resistance under a chronic scenario of genotoxic and oxidative stress may in turn contribute to the carcinogenic effects of i-As.

  17. DJ-1 deficiency impairs glutamate uptake into astrocytes via the regulation of flotillin-1 and caveolin-1 expression (United States)

    Kim, Jin-Mo; Cha, Seon-Heui; Choi, Yu Ree; Jou, Ilo; Joe, Eun-Hye; Park, Sang Myun


    Parkinson’s disease (PD) is a common chronic and progressive neurodegenerative disorder. Although the cause of PD is still poorly understood, mutations in many genes including SNCA, parkin, PINK1, LRRK2, and DJ-1 have been identified in the familial forms of PD. It was recently proposed that alterations in lipid rafts may cause the neurodegeneration shown in PD. Here, we observe that DJ-1 deficiency decreased the expression of flotillin-1 (flot-1) and caveolin-1 (cav-1), the main protein components of lipid rafts, in primary astrocytes and MEF cells. As a mechanism, DJ-1 regulated flot-1 stability by direct interaction, however, decreased cav-1 expression may not be a direct effect of DJ-1, but rather as a result of decreased flot-1 expression. Dysregulation of flot-1 and cav-1 by DJ-1 deficiency caused an alteration in the cellular cholesterol level, membrane fluidity, and alteration in lipid rafts-dependent endocytosis. Moreover, DJ-1 deficiency impaired glutamate uptake into astrocytes, a major function of astrocytes in the maintenance of CNS homeostasis, by altering EAAT2 expression. This study will be helpful to understand the role of DJ-1 in the pathogenesis of PD, and the modulation of lipid rafts through the regulation of flot-1 or cav-1 may be a novel therapeutic target for PD. PMID:27346864

  18. Syndecan-1 deficiency promotes tumor growth in a murine model of colitis-induced colon carcinoma (United States)

    Binder Gallimidi, Adi; Nussbaum, Gabriel; Hermano, Esther; Weizman, Barak; Meirovitz, Amichay; Vlodavsky, Israel; Götte, Martin; Elkin, Michael


    Syndecan-1 (Sdc1) is an important member of the cell surface heparan sulfate proteoglycan family, highly expressed by epithelial cells in adult organisms. Sdc1 is involved in the regulation of cell migration, cell-cell and cell-matrix interactions, growth-factor, chemokine and integrin activity, and implicated in inflammatory responses and tumorigenesis. Gastrointestinal tract represents an important anatomic site where loss of Sdc1 expression was reported both in inflammation and malignancy. However, the biological significance of Sdc1 in chronic colitis-associated tumorigenesis has not been elucidated. To the best of our knowledge, this study is the first to test the effects of Sdc1 loss on colorectal tumor development in inflammation-driven colon tumorigenesis. Utilizing a mouse model of colitis-related colon carcinoma induced by the carcinogen azoxymethane (AOM), followed by the inflammatory agent dextran sodium sulfate (DSS), we found that Sdc1 deficiency results in increased susceptibility to colitis-associated tumorigenesis. Importantly, colitis-associated tumors developed in Sdc1-defficient mice were characterized by increased local production of IL-6, activation of STAT3, as well as induction of several STAT3 target genes that act as important effectors of colonic tumorigenesis. Altogether, our results highlight a previously unknown effect of Sdc1 loss in progression of inflammation-associated cancer and suggest that decreased levels of Sdc1 may serve as an indicator of colon carcinoma progression in the setting of chronic inflammation. PMID:28350804

  19. Thrombospondin1 deficiency reduces obesity-associated inflammation and improves insulin sensitivity in a diet-induced obese mouse model.

    Directory of Open Access Journals (Sweden)

    Yanzhang Li

    Full Text Available BACKGROUND: Obesity is prevalent worldwide and is associated with insulin resistance. Advanced studies suggest that obesity-associated low-grade chronic inflammation contributes to the development of insulin resistance and other metabolic complications. Thrombospondin 1 (TSP1 is a multifunctional extracellular matrix protein that is up-regulated in inflamed adipose tissue. A recent study suggests a positive correlation of TSP1 with obesity, adipose inflammation, and insulin resistance. However, the direct effect of TSP1 on obesity and insulin resistance is not known. Therefore, we investigated the role of TSP1 in mediating obesity-associated inflammation and insulin resistance by using TSP1 knockout mice. METHODOLOGY/PRINCIPAL FINDINGS: Male TSP1-/- mice and wild type littermate controls were fed a low-fat (LF or a high-fat (HF diet for 16 weeks. Throughout the study, body weight and fat mass increased similarly between the TSP1-/- mice and WT mice under HF feeding conditions, suggesting that TSP1 deficiency does not affect the development of obesity. However, obese TSP1-/- mice had improved glucose tolerance and increased insulin sensitivity compared to the obese wild type mice. Macrophage accumulation and inflammatory cytokine expression in adipose tissue were reduced in obese TSP1-/- mice. Consistent with the local decrease in pro-inflammatory cytokine levels, systemic inflammation was also decreased in the obese TSP1-/- mice. Furthermore, in vitro data demonstrated that TSP1 deficient macrophages had decreased mobility and a reduced inflammatory phenotype. CONCLUSION: TSP1 deficiency did not affect the development of high-fat diet induced obesity. However, TSP1 deficiency reduced macrophage accumulation in adipose tissue and protected against obesity related inflammation and insulin resistance. Our data demonstrate that TSP1 may play an important role in regulating macrophage function and mediating obesity-induced inflammation and insulin

  20. Protein Stability, Folding and Misfolding in Human PGK1 Deficiency

    Directory of Open Access Journals (Sweden)

    Giovanna Valentini


    Full Text Available Conformational diseases are often caused by mutations, altering protein folding and stability in vivo. We review here our recent work on the effects of mutations on the human phosphoglycerate kinase 1 (hPGK1, with a particular focus on thermodynamics and kinetics of protein folding and misfolding. Expression analyses and in vitro biophysical studies indicate that disease-causing mutations enhance protein aggregation propensity. We found a strong correlation among protein aggregation propensity, thermodynamic stability, cooperativity and dynamics. Comparison of folding and unfolding properties with previous reports in PGKs from other species suggests that hPGK1 is very sensitive to mutations leading to enhance protein aggregation through changes in protein folding cooperativity and the structure of the relevant denaturation transition state for aggregation. Overall, we provide a mechanistic framework for protein misfolding of hPGK1, which is insightful to develop new therapeutic strategies aimed to target native state stability and foldability in hPGK1 deficient patients.

  1. ACAT1 deficiency increases cholesterol synthesis in mouse peritoneal macrophages. (United States)

    Dove, Dwayne E; Su, Yan Ru; Swift, Larry L; Linton, MacRae F; Fazio, Sergio


    Acyl-coenzyme A:cholesterol acyltransferase (ACAT) esterifies free cholesterol and stores cholesteryl esters in lipid droplets. Macrophage ACAT1 deficiency results in increased atherosclerotic lesion area in hyperlipidemic mice via disrupted cholesterol efflux, increased lipoprotein uptake, accumulation of intracellular vesicles, and accelerated apoptosis. The objective of this study was to determine whether lipid synthesis is affected by ACAT1. The synthesis, esterification, and efflux of new cholesterol were measured in peritoneal macrophages from ACAT1(-/-) mice. Cholesterol synthesis was increased by 134% (p=0.001) in ACAT1(-/-) macrophages compared to wildtype macrophages. Increased synthesis resulted in a proportional increase in the efflux of newly synthesized cholesterol. Although the esterification of new cholesterol was reduced by 93% (pSREBP1a mRNA was increased 6-fold in ACAT1(-/-) macrophages compared to wildtype macrophages, suggesting an up-regulation of cholesterol and fatty acid synthesis in ACAT1(-/-) macrophages. Increased cholesterol synthesis and up-regulation of SREBP in ACAT1(-/-) macrophages suggests that ACAT1 affects the regulation of lipid metabolism in macrophages. This change in cholesterol homeostasis may contribute to the atherogenic potential of ACAT1(-/-) macrophages.

  2. Dlic1 deficiency impairs ciliogenesis of photoreceptors by destabilizing dynein

    Institute of Scientific and Technical Information of China (English)

    Shanshan Kong; Xinrong Du; Chao Peng; Yiming Wu; Huirong Li; Xi Jin; Ling Hou


    Cytoplasmic dynein 1 is fundamentally important for transporting a variety of essential cargoes along microtubules within eukaryotic cells.However,in mammals,few mutants are available for studying the effects of defects in dynein-controlled processes in the context of the whole organism.Here,we deleted mouse Dlic1 gene encoding DLIC1,a subunit of the dynein complex.Dlic1-/-mice are viable,but display severe photoreceptor degeneration.Ablation of Dlic1 results in ectopic accumulation of outer segment (OS) proteins,and impairs OS growth and ciliogenesis of photoreceptors by interfering with Rabll-vesicle trafficking and blocking efficient OS protein transport from Golgi to the basal body.Our studies show that Dlic1 deficiency partially blocks vesicle export from endoplasmic reticulum (ER),but seems not to affect vesicle transport from the ER to Golgi.Further mechanistic study reveals that lack of Dlic1 destabilizes dynein subunits and alters the normal subcellular distribution of dynein in photoreceptors,probably due to the impaired transport function of dynein.Our results demonstrate that Dlic1 plays important roles in ciliogenesis and protein transport to the OS,and is required for photoreceptor development and survival.The Dlic1-/-mice also provide a new mouse model to study human retinal degeneration.

  3. Intestinal Irradiation and Fibrosis in a Th1-Deficient Environment

    Energy Technology Data Exchange (ETDEWEB)

    Linard, Christine, E-mail: [Institut de Radioprotection et de Surete Nucleaire, Fontenay-aux-Roses (France); Billiard, Fabienne; Benderitter, Marc [Institut de Radioprotection et de Surete Nucleaire, Fontenay-aux-Roses (France)


    Purpose: Changes in the Th1/Th2 immune balance may play a role in increasing the incidence of radiation-induced toxicity. This study evaluates the consequences of Th1 deficiency on intestinal response (fibrosis and T cell trafficking) to abdominal irradiation and examines in mucosa and mesenteric lymph nodes (MLN) the differential involvement of the two Th1 pathways, T-bet/STAT1 and IL-12/STAT4, in controlling this balance in mice. Methods and Materials: Using T-bet-deficient mice (T-bet{sup -/-}), we evaluated the mRNA and protein expression of the Th1 pathways (IFN-{gamma}, T-bet/STAT1, and IL-12/STAT4) and the CD4{sup +} and CD8{sup +} populations in ileal mucosa and MLN during the first 3 months after 10 Gy abdominal irradiation. Results: The T-bet-deficient mice showed an increased fibrotic response to radiation, characterized by higher TGF-{beta}1, col3a1 expression, and collagen deposition in mucosa compared with wild-type mice. This response was associated with drastically lower expression of IFN-{gamma}, the hallmark Th1 cytokine. Analysis of the Th1 expression pathways, T-bet/STAT1 and IL-12/STAT4, showed their equal involvement in the failure of Th1 polarization. A minimal IFN-{gamma} level depended on the IL-23-p19/STAT4 level. In addition, the radiation-induced deficiency in the priming of Th1 by IFN-{gamma} was related to the defective homing capacity of CD8{sup +} cells in the mucosa. Conclusion: Irradiation induces Th2 polarization, and the Th2 immune response may play a role in potentiating irradiation-induced intestinal collagen deposition.

  4. Evidence of adrenal failure in aging Dax1-deficient mice. (United States)

    Scheys, Joshua O; Heaton, Joanne H; Hammer, Gary D


    Dosage-sensitive sex reversal, adrenal hypoplasia congenita (AHC) critical region on the X chromosome, gene 1 (Dax1) is an orphan nuclear receptor essential for development and function of the mammalian adrenal cortex and gonads. DAX1 was cloned as the gene responsible for X-linked AHC, which is characterized by adrenocortical failure necessitating glucocorticoid replacement. Contrary to these human data, young mice with genetic Dax1 knockout (Dax1(-/Y)) exhibit adrenocortical hyperfunction, consistent with the historic description of Dax1 as a transcriptional repressor that inhibits steroidogenic factor 1-dependent steroidogenesis. This paradox of molecular function and two apparently opposite phenotypes associated with Dax1 deficiency in mice and humans is compounded by the recent observations that under certain circumstances, Dax1 can serve as a transcriptional activator of steroidogenic factor 1. The recently revealed role of Dax1 in embryonic stem cell pluripotency, together with the observation that its expression in the adult adrenal is restricted to the subcapsular cortex, where presumptive undifferentiated progenitor cells reside, has led us to reexamine the phenotype of Dax1(-/Y) mice in order to reconcile the conflicting mouse and human data. In this report, we demonstrate that although young Dax1(-/Y) mice have enhanced steroidogenesis and subcapsular adrenocortical proliferation, as these mice age, they exhibit declining adrenal growth, decreasing adrenal steroidogenic capacity, and a reversal of their initial enhanced hormonal sensitivity. Together with a marked adrenal dysplasia in aging mice, these data reveal that both Dax1(-/Y) mice and patients with X-linked AHC exhibit adrenal failure that is consistent with adrenocortical subcapsular progenitor cell depletion and argue for a significant role of Dax1 in maintenance of these cells.

  5. Autophagy resolves early retinal inflammation in Igf1-deficient mice

    Directory of Open Access Journals (Sweden)

    Ana I. Arroba


    provides new evidence in a mouse model of IGF-1 deficiency that autophagy is an adaptive response that might confer protection against persistent inflammation in the retina during ageing.

  6. Autophagy resolves early retinal inflammation in Igf1-deficient mice. (United States)

    Arroba, Ana I; Rodríguez-de la Rosa, Lourdes; Murillo-Cuesta, Silvia; Vaquero-Villanueva, Laura; Hurlé, Juan M; Varela-Nieto, Isabel; Valverde, Ángela M


    a mouse model of IGF-1 deficiency that autophagy is an adaptive response that might confer protection against persistent inflammation in the retina during ageing.

  7. Autophagy resolves early retinal inflammation in Igf1-deficient mice (United States)

    Rodríguez-de la Rosa, Lourdes; Murillo-Cuesta, Silvia; Vaquero-Villanueva, Laura; Hurlé, Juan M.; Varela-Nieto, Isabel; Valverde, Ángela M.


    provides new evidence in a mouse model of IGF-1 deficiency that autophagy is an adaptive response that might confer protection against persistent inflammation in the retina during ageing. PMID:27483352

  8. Reduced cellular DNA repair capacity after environmentally relevant arsenic exposure. Influence of Ogg1 deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Bach, Jordi; Peremartí, Jana; Annangi, Balasubramnayam [Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona (Spain); Marcos, Ricard, E-mail: [Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona (Spain); CIBER Epidemiología y Salud Pública, ISCIII, Madrid (Spain); Hernández, Alba, E-mail: [Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona (Spain); CIBER Epidemiología y Salud Pública, ISCIII, Madrid (Spain)


    Highlights: • Repair ability under long-term exposure to arsenic was tested using the comet assay. • Effects were measured under Ogg1 wild-type and deficient backgrounds. • Exposed cells repair less efficiency the DNA damage induced by SA, KBrO{sub 3}, MMA{sup III} or UVC radiation. • Oxidative damage and Ogg1 deficient background exacerbate repair deficiencies. • Overexpression of the arsenic metabolizing enzyme As3mt acts as adaptive mechanism. - Abstract: Inorganic arsenic (i-As) is a genotoxic and carcinogenic environmental contaminant known to affect millions of people worldwide. Our previous work demonstrated that chronic sub-toxic i-As concentrations were able to induce biologically significant levels of genotoxic and oxidative DNA damage that were strongly influenced by the Ogg1 genotype. In order to study the nature of the observed levels of damage and the observed differences between MEF Ogg1{sup +/+} and Ogg1{sup −/−} genetic backgrounds, the genotoxic and oxidative DNA repair kinetics of 18-weeks exposed MEF cells were evaluated by the comet assay. Results indicate that MEF Ogg1{sup +/+} and Ogg1{sup −/−} cells chronically exposed to i-As repair the DNA damage induced by arsenite, potassium bromide and UVC radiation less efficiently than control cells, being that observation clearly more pronounced in MEF Ogg1{sup −/−} cells. Consequently, exposed cells accumulate a higher percentage of unrepaired DNA damage at the end of the repair period. As an attempt to eliminate i-As associated toxicity, chronically exposed MEF Ogg1{sup −/−} cells overexpress the arsenic metabolizing enzyme As3mt. This adaptive response confers cells a significant resistance to i-As-induced cell death, but at expenses of accumulating high levels of DNA damage due to their repair impairment. Overall, the work presented here evidences that i-As chronic exposure disrupts the normal cellular repair function, and that oxidative DNA damage—and Ogg1 deficiency

  9. Arginine Deprivation Inhibits the Warburg Effect and Upregulates Glutamine Anaplerosis and Serine Biosynthesis in ASS1-Deficient Cancers

    Directory of Open Access Journals (Sweden)

    Jeff Charles Kremer


    Full Text Available Targeting defects in metabolism is an underutilized strategy for the treatment of cancer. Arginine auxotrophy resulting from the silencing of argininosuccinate synthetase 1 (ASS1 is a common metabolic alteration reported in a broad range of aggressive cancers. To assess the metabolic effects that arise from acute and chronic arginine starvation in ASS1-deficient cell lines, we performed metabolite profiling. We found that pharmacologically induced arginine depletion causes increased serine biosynthesis, glutamine anaplerosis, oxidative phosphorylation, and decreased aerobic glycolysis, effectively inhibiting the Warburg effect. The reduction of glycolysis in cells otherwise dependent on aerobic glycolysis is correlated with reduced PKM2 expression and phosphorylation and upregulation of PHGDH. Concurrent arginine deprivation and glutaminase inhibition was found to be synthetic lethal across a spectrum of ASS1-deficient tumor cell lines and is sufficient to cause in vivo tumor regression in mice. These results identify two synthetic lethal therapeutic strategies exploiting metabolic vulnerabilities of ASS1-negative cancers.

  10. The GH-IGF1 axis and longevity. The paradigm of IGF1 deficiency. (United States)

    Laron, Zvi


    Primary or secondary IGF1 deficiency has been implicated in shortening of lifespan. This paper reviews available data on the influence of IGF1 deficiency on lifespan and longevity in animals and man. It has been shown that inactivation of the IGF1 gene or of the GH receptor in both invertebrates (C-elegans, flies-Drosphila) and rodents (mice and rats), leading to IGF1 deficiency, prolong life, particularly in females. In man, evaluation of the 2 largest cohorts of patients with Laron syndrome (inactive GH receptor resulting in IGF1 deficiency) in Israel and Ecuador revealed that despite their dwarfism and marked obesity, patients are alive at the ages of 75-78 years, with some having reached even more advanced ages. It is assumed that a major contributing factor is their protection from cancer, a major cause of death in the general population.

  11. Effects of growth hormone and insulin-like growth factor 1 deficiency on ageing and longevity. (United States)

    Laron, Zvi


    Present knowledge on the effects of growth hormone (GH)/insulin-like growth hormone (IGF)1 deficiency on ageing and lifespan are reviewed. Evidence is presented that isolated GH deficiency (IGHD), multiple pituitary hormone deficiencies (MPHD) including GH, as well as primary IGE1 deficiency (GH resistance, Laron syndrome) present signs of early ageing such as thin and wrinkled skin, obesity, hyperglycemia and osteoporosis. These changes do not seem to affect the lifespan, as patients reach old age. Animal models of genetic MPHD (Ames and Snell mice) and GH receptor knockout mice (primary IGF1 deficiency) also have a statistically significant higher longevity compared to normal controls. On the contrary, mice transgenic for GH and acromegalic patients secreting large amounts of GH have premature death. In conclusion longstanding GH/IGF1 deficiency affects several parameters of the ageing process without impairing lifespan, and as shown in animal models prolongs longevity. In contrast high GH/IGF1 levels accelerate death.

  12. Caspase-1 deficiency in mice reduces intestinal triglyceride absorption and hepatic triglyceride secretion. (United States)

    van Diepen, Janna A; Stienstra, Rinke; Vroegrijk, Irene O C M; van den Berg, Sjoerd A A; Salvatori, Daniela; Hooiveld, Guido J; Kersten, Sander; Tack, Cees J; Netea, Mihai G; Smit, Johannes W A; Joosten, Leo A B; Havekes, Louis M; van Dijk, Ko Willems; Rensen, Patrick C N


    Caspase-1 is known to activate the proinflammatory cytokines IL-1β and IL-18. Additionally, it can cleave other substrates, including proteins involved in metabolism. Recently, we showed that caspase-1 deficiency in mice strongly reduces high-fat diet-induced weight gain, at least partly caused by an increased energy production. Increased feces secretion by caspase-1-deficient mice suggests that lipid malabsorption possibly further reduces adipose tissue mass. In this study we investigated whether caspase-1 plays a role in triglyceride-(TG)-rich lipoprotein metabolism using caspase-1-deficient and wild-type mice. Caspase-1 deficiency reduced the postprandial TG response to an oral lipid load, whereas TG-derived fatty acid (FA) uptake by peripheral tissues was not affected, demonstrated by unaltered kinetics of [(3)H]TG-labeled very low-density lipoprotein (VLDL)-like emulsion particles. An oral gavage of [(3)H]TG-containing olive oil revealed that caspase-1 deficiency reduced TG absorption and subsequent uptake of TG-derived FA in liver, muscle, and adipose tissue. Similarly, despite an elevated hepatic TG content, caspase-1 deficiency reduced hepatic VLDL-TG production. Intestinal and hepatic gene expression analysis revealed that caspase-1 deficiency did not affect FA oxidation or FA uptake but rather reduced intracellular FA transport, thereby limiting lipid availability for the assembly and secretion of TG-rich lipoproteins. The current study reveals a novel function for caspase-1, or caspase-1-cleaved substrates, in controlling intestinal TG absorption and hepatic TG secretion.

  13. Regulation of the viability of Nf1 deficient cells by PKC isoforms. (United States)

    Zhou, Xiaodong; Shen, Ling; Parris, Toshima; Huang, Junchi; Yi, Bo; Helou, Khalil; Chen, Changyan


    Suppression of protein kinase C (PKC) is known to be synthetically lethal with ras mutations in various types of cancer cells. The studies also showed that blockade of PKC affected the viability of Nf1 deficient cells. Since PKC family consists of more than 10 isoforms, our study aimed at identifying which isoform(s) played the crucial role in sensitizing Nf1 deficient cells to apoptosis. Using genetic and chemical PKC inhibitors, we demonstrated that the concurrent inhibition of PKC α and β induced Nf1 deficient ST or 96.2 cells, but not SNF02.2 cells with a normal Nf1 or ST cells ectopically expressing Nf1 effective domain gene, to apoptosis. In this process, PKC δ in Nf1 deficient cells, but not in ST/Nf1 cells, was upregulated and translocated to the nucleus. Furthermore, caspase 3 was cleaved and cytochrome c was released to the cytosol. Thus, it appeared that PKC δ and α/β are the crucial components for sustaining the aberrant Ras signaling and further viability of Nf1 deficient cells. The abrogation of these two isoforms activated their opponent PKC δ for switching on the caspase 3-governed apoptotic machinery.

  14. Induction of mitotic catastrophe by PKC inhibition in Nf1-deficient cells. (United States)

    Zhou, Xiaodong; Kim, Sung-Hoon; Shen, Ling; Lee, Hyo-Jung; Chen, Changyan


    Mutations of tumor suppressor Nf1 gene deregulate Ras-mediated signaling, which confers the predisposition for developing benign or malignant tumors. Inhibition of protein kinase C (PKC) was shown to be in synergy with aberrant Ras for the induction of apoptosis in various types of cancer cells. However, it has not been investigated whether loss of PKC is lethal for Nf1-deficient cells. In this study, using HMG (3-hydroxy-3-methylgutaryl, a PKC inhibitor), we demonstrate that the inhibition of PKC by HMG treatment triggered a persistently mitotic arrest, resulting in the occurrence of mitotic catastrophe in Nf1-deficient ST8814 cells. However, the introduction of the Nf1 effective domain gene into ST8814 cells abolished this mitotic crisis. In addition, HMG injection significantly attenuated the growth of the xenografted ST8814 tumors. Moreover, Chk1 was phosphorylated, accompanied with the persistent increase of cyclin B1 expression in HMG-treated ST8814 cells. The knockdown of Chk1 by the siRNA prevented the Nf1-deficient cells from undergoing HMG-mediated mitotic arrest as well as mitotic catastrophe. Thus, our data suggested that the suppression of PKC activates the Chk1-mediated mitotic exit checkpoint in Nf1-deficient cells, leading to the induction of apoptosis via mitotic catastrophe. Collectively, the study indicates that targeting PKC may be a potential option for developing new strategies to treat Nf1-deficiency-related diseases.

  15. Circadian rhythms and food anticipatory behavior in Wfs1-deficient mice. (United States)

    Luuk, Hendrik; Fahrenkrug, Jan; Hannibal, Jens


    The dorsomedial hypothalamic nucleus (DMH) has been proposed as a candidate for the neural substrate of a food-entrainable oscillator. The existence of a food-entrainable oscillator in the mammalian nervous system was inferred previously from restricted feeding-induced behavioral rhythmicity in rodents with suprachiasmatic nucleus lesions. In the present study, we have characterized the circadian rhythmicity of behavior in Wfs1-deficient mice during ad libitum and restricted feeding. Based on the expression of Wfs1 protein in the DMH it was hypothesized that Wfs1-deficient mice will display reduced or otherwise altered food anticipatory activity. Wfs1 immunoreactivity in DMH was found almost exclusively in the compact part. Restricted feeding induced c-Fos immunoreactivity primarily in the ventral and lateral aspects of DMH and it was similar in both genotypes. Wfs1-deficiency resulted in significantly lower body weight and reduced wheel-running activity. Circadian rhythmicity of behavior was normal in Wfs1-deficient mice under ad libitum feeding apart from elongated free-running period in constant light. The amount of food anticipatory activity induced by restricted feeding was not significantly different between the genotypes. Present results indicate that the effects of Wfs1-deficiency on behavioral rhythmicity are subtle suggesting that Wfs1 is not a major player in the neural networks responsible for circadian rhythmicity of behavior.

  16. ROCK1 deficiency enhances protective effects of antioxidants against apoptosis and cell detachment.

    Directory of Open Access Journals (Sweden)

    Michelle Surma

    Full Text Available We have recently reported that the homologous Rho kinases, ROCK1 and ROCK2, play different roles in regulating stress-induced stress fiber disassembly and cell detachment, and the ROCK1 deficiency in mouse embryonic fibroblasts (MEF has remarkable anti-apoptotic, anti-detachment and pro-survival effects against doxorubicin, a chemotherapeutic drug. This study investigated the roles of ROCK isoforms in doxorubicin-induced reactive oxygen species (ROS generation which is believed to be the major mechanism underlying its cytotoxicity to normal cells, and especially to cardiomyocytes. Different antioxidants have been shown to provide a protective role reported in numerous experimental studies, but clinical trials of antioxidant therapy showed insufficient benefit against the cardiac side effect. We found that both ROCK1-/- and ROCK2-/- MEFs exhibited reduced ROS production in response to doxorubicin treatment. Interestingly, only ROCK1 deficiency, but not ROCK2 deficiency, significantly enhanced the protective effects of antioxidants against doxorubicin-induced cytotoxicity. First, ROCK1 deficiency and N-acetylcysteine (an anti-oxidant treatment synergistically reduced ROS levels, caspase activation and cell detachment. In addition, the reduction of ROS generation in ROCK1-/- MEFs in response to doxorubicin treatment was in part through inhibiting NADPH oxidase activity. Furthermore, ROCK1 deficiency enhanced the inhibitory effects of diphenyleneiodonium (an inhibitor of NADPH oxidase on ROS generation and caspase 3 activation induced by doxorubicin. Finally, ROCK1 deficiency had greater protective effects than antioxidant treatment, especially on reducing actin cytoskeleton remodeling. ROCK1 deficiency not only reduced actomyosin contraction but also preserved central stress fiber stability, whereas antioxidant treatment only reduced actomyosin contraction without preserving central stress fibers. These results reveal a novel strategy to enhance

  17. Glucose transporter-1 (GLUT1) deficiency syndrome: diagnosis and treatment in late childhood.

    NARCIS (Netherlands)

    Gramer, G.; Wolf, N.I.; Vater, D.; Bast, T.; Santer, R.; Kamsteeg, E.J.; Wevers, R.A.; Ebinger, F.


    BACKGROUND: Typical cases of glucose transporter-1 deficiency syndrome (GLUT1-DS) present with early-onset epilepsy. We report symptoms, diagnostic results, and effects of therapy in two patients diagnosed with GLUT1-DS at the age of 10 and 15 years, respectively. PATIENTS: Patient 1: After four cer

  18. Paracaspase MALT1 deficiency protects mice from autoimmune-mediated demyelination. (United States)

    Mc Guire, Conor; Wieghofer, Peter; Elton, Lynn; Muylaert, David; Prinz, Marco; Beyaert, Rudi; van Loo, Geert


    The paracaspase MALT 1 is a major player in lymphocyte activation and proliferation. MALT1 mediates Ag-induced signaling to the transcription factor NF-κB by functioning both as a scaffold protein and cysteine protease. We studied the role of MALT1 in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. MALT1-knockout mice did not develop any clinical symptoms of EAE. In addition, lymphocyte and macrophage infiltration into the spinal cord was absent in MALT1-knockout mice, as were demyelination and proinflammatory gene expression. Adoptive transfer experiments showed that MALT1 deficiency in splenocytes is sufficient for EAE resistance. Moreover, autoreactive T cell activation was severely impaired in MALT1-deficient T cells, suggesting the inability of MALT1-deficient effector T cells to induce demyelinating inflammation in the CNS. Finally, the MALT1 substrates A20 and CYLD were completely processed in wild-type T cells during EAE, which was partially impaired in MALT1-deficient T cells, suggesting a contribution of MALT1 proteolytic activity in T cell activation and EAE development. Together, our data indicate that MALT1 may be an interesting therapeutic target in the treatment of multiple sclerosis.

  19. Movement disorders in GLUT1 deficiency syndrome respond to the modified Atkins diet

    NARCIS (Netherlands)

    Leen, W.G.; Mewasingh, L.; Verbeek, M.M.; Kamsteeg, E.J.; Warrenburg, B.P.C. van de; Willemsen, M.A.A.P.


    BACKGROUND: Movement disorders are a prominent feature of glucose transporter-1 (GLUT1) deficiency syndrome (GLUT1DS). First-choice treatment is a ketogenic diet, but compliance is poor. We have investigated the effect of the modified Atkins diet as an alternative treatment for movement disorders in

  20. Glucose Transporter Type 1 Deficiency Syndrome with Carbohydrate-Responsive Symptoms but without Epilepsy (United States)

    Koy, Anne; Assmann, Birgit; Klepper, Joerg; Mayatepek, Ertan


    Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is caused by a defect in glucose transport across the blood-brain barrier. The main symptoms are epilepsy, developmental delay, movement disorders, and deceleration of head circumference. A ketogenic diet has been shown to be effective in controlling epilepsy in GLUT1-DS. We report a female…

  1. Glucose transporter-1 deficiency syndrome: The expanding clinical and genetic spectrum of a treatable disorder

    NARCIS (Netherlands)

    W.G. Leen (Wilhelmina); J. Klepper (Joerg); M.M. Verbeek (Marcel); M. Leferink (Maike); T. Hofste (Tom); B.G.M. van Engelen (Baziel); R.A. Wevers (Ron); T. Arthur (Todd); N. Bahi-Buisson (Nadia); D. Ballhausen (Diana); J. Bekhof (Jolita); P. van Bogaert (Patrick); I. Carrilho (Inês); B. Chabrol (Brigitte); M.P. Champion (Michael); J. Coldwell (James); P. Clayton (Peter); E. Donner (Elizabeth); A. Evangeliou (Athanasios); F. Ebinger (Friedrich); K. Farrell (Kevin); R.J. Forsyth (Rob); C.G.E.L. de Goede (Christian); S. Gross (Stephanie); S. Grünewald (Sonja); H. Holthausen (Hans); S. Jayawant (Sandeep); K. Lachlan (Katherine); V. Laugel (Vincent); K. Leppig (Kathy); M.J. Lim (Ming); G.M.S. Mancini (Grazia); A.D. Marina; L. Martorell (Loreto); J. McMenamin (Joe); M.E.C. Meuwissen (Marije); H. Mundy (Helen); N.O. Nilsson (Nils); A. Panzer (Axel); B.T. Poll-The; C. Rauscher (Christian); C.M.R. Rouselle (Christophe); I. Sandvig (Inger); T. Scheffner (Thomas); E. Sheridan (Eamonn); N. Simpson (Neil); P. Sykora (Parol); R. Tomlinson (Richard); J. Trounce (John); D.W.M. Webb (David); B. Weschke (Bernhard); H. Scheffer (Hans); M.A. Willemsen (Michél)


    textabstractGlucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing an

  2. IDH1 deficiency attenuates gluconeogenesis in mouse liver by impairing amino acid utilization (United States)

    Ye, Jing; Gu, Yu; Zhang, Feng; Zhao, Yuanlin; Yuan, Yuan; Hao, Zhenyue; Sheng, Yi; Li, Wanda Y.; Wakeham, Andrew; Cairns, Rob A.; Mak, Tak W.


    Although the enzymatic activity of isocitrate dehydrogenase 1 (IDH1) was defined decades ago, its functions in vivo are not yet fully understood. Cytosolic IDH1 converts isocitrate to α-ketoglutarate (α-KG), a key metabolite regulating nitrogen homeostasis in catabolic pathways. It was thought that IDH1 might enhance lipid biosynthesis in liver or adipose tissue by generating NADPH, but we show here that lipid contents are relatively unchanged in both IDH1-null mouse liver and IDH1-deficient HepG2 cells generated using the CRISPR-Cas9 system. Instead, we found that IDH1 is critical for liver amino acid (AA) utilization. Body weights of IDH1-null mice fed a high-protein diet (HPD) were abnormally low. After prolonged fasting, IDH1-null mice exhibited decreased blood glucose but elevated blood alanine and glycine compared with wild-type (WT) controls. Similarly, in IDH1-deficient HepG2 cells, glucose consumption was increased, but alanine utilization and levels of intracellular α-KG and glutamate were reduced. In IDH1-deficient primary hepatocytes, gluconeogenesis as well as production of ammonia and urea were decreased. In IDH1-deficient whole livers, expression levels of genes involved in AA metabolism were reduced, whereas those involved in gluconeogenesis were up-regulated. Thus, IDH1 is critical for AA utilization in vivo and its deficiency attenuates gluconeogenesis primarily by impairing α-KG–dependent transamination of glucogenic AAs such as alanine. PMID:28011762

  3. Caspase-1 deficiency in mice reduces intestinal triglyceride absorption and hepatic triglyceride secretion

    NARCIS (Netherlands)

    Diepen, J.A. van; Stienstra, R.; Vroegrijk, I.O.C.M.; Berg, S.A.A. van den; Salvatori, D.; Hooiveld, G.J.; Kersten, S.; Tack, C.J.; Netea, M.G.; Smit, J.W.A.; Joosten, L.A.B.; Havekes, L.M.; Dijk, K.W. van; Rensen, P.C.N.


    Caspase-1 is known to activate the proinflammatory cytokines IL-1β and IL-18. Additionally, it can cleave other substrates, including proteins involved in metabolism. Recently, we showed that caspase-1 deficiency in mice strongly reduces high-fat diet-induced weight gain, at least partly caused by a

  4. Glucose transporter-1 deficiency syndrome : the expanding clinical and genetic spectrum of a treatable disorder

    NARCIS (Netherlands)

    Leen, Wilhelmina G.; Klepper, Joerg; Verbeek, Marcel M.; Leferink, Maike; Hofste, Tom; van Engelen, Baziel G.; Wevers, Ron A.; Arthur, Todd; Bahi-Buisson, Nadia; Ballhausen, Diana; Bekhof, Jolita; van Bogaert, Patrick; Carrilho, Ines; Chabrol, Brigitte; Champion, Michael P.; Coldwell, James; Clayton, Peter; Donner, Elizabeth; Evangeliou, Athanasios; Ebinger, Friedrich; Farrell, Kevin; Forsyth, Rob J.; de Goede, Christian G. E. L.; Gross, Stephanie; Grunewald, Stephanie; Holthausen, Hans; Jayawant, Sandeep; Lachlan, Katherine; Laugel, Vincent; Leppig, Kathy; Lim, Ming J.; Mancini, Grazia; Della Marina, Adela; Martorell, Loreto; McMenamin, Joe; Meuwissen, Marije E. C.; Mundy, Helen; Nilsson, Nils O.; Panzer, Axel; Poll-The, Bwee T.; Rauscher, Christian; Rouselle, Christophe M. R.; Sandvig, Inger; Scheffner, Thomas; Sheridan, Eamonn; Simpson, Neil; Sykora, Parol; Tomlinson, Richard; Trounce, John; Webb, David; Weschke, Bernhard; Scheffer, Hans; Willemsen, Michel A.


    Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex

  5. MLH1-deficient tumor cells are resistant to lipoplatin, but retain sensitivity to lipoxal. (United States)

    Fedier, André; Poyet, Cédric; Perucchini, Daniele; Boulikas, Teni; Fink, Daniel


    Lipoplatin, currently under phase III evaluation, is a novel liposomal cisplatin formulation highly effective against cancers. Lipoplatin has eliminated or reduced the systemic toxicity frequently seen for cisplatin. The objective of the present study was to determine whether the cytotoxic effect of lipoplatin is dependent on the functional integrity of DNA mismatch repair (MMR), a post-replicative DNA repair machinery implicated in cell cycle control and apoptosis. Clonogenic data revealed a significant (Plipoplatin of HCT116 human colorectal adenocarcinoma cells lacking MLH1, one of five proteins crucial to MMR function, as compared to MLH1-expressing HCT116 cells. In addition, MLH1-deficient cells were at least 3-fold less susceptible to apoptosis (DNA fragmentation) than MLH1-proficient cells. However, proteolytic processing of caspase-3, caspase-7 and poly(ADP-ribose)polymerase-1 following lipoplatin treatment was comparable in MLH1-deficient cells and -proficient cells. Furthermore, MLH1-deficient cells retained the ability to attenuate cell cycle progression past the G2/M checkpoint following lipoplatin treatment. In conclusion, our results indicate that the lipoplatin-sensitive phenotype of MLH1-proficient cells correlated with increased apoptosis which may occur via caspase-independent pathways. They also suggest that the integrity of MMR function is a relevant determinant accounting for the cytotoxicity of lipoplatin. However, this does not seem to apply to lipoxal, a novel liposomal formulation of oxaliplatin, because MLH1-deficient cells were as sensitive to lipoxal as MLH1-proficient cells.

  6. Wfs1-deficient mice display altered function of serotonergic system and increased behavioural response to antidepressants

    Directory of Open Access Journals (Sweden)

    Tanel eVisnapuu


    Full Text Available It has been shown that mutations in the WFS1 gene make humans more susceptible to mood disorders. Besides that, mood disorders are associated with alterations in the activity of serotonergic and noradrenergic systems. Therefore, in this study, the effects of imipramine, an inhibitor of serotonin (5-HT and noradrenaline (NA reuptake, and paroxetine, a selective inhibitor of 5-HT reuptake, were studied in tests of behavioural despair. The tail suspension test (TST and forced swimming test (FST were performed in Wfs1-deficient mice. Simultaneously, gene expression and monoamine metabolism studies were conducted to evaluate changes in 5-HT- and NA-ergic systems of Wfs1-deficient mice. The basal immobility time of Wfs1-deficient mice in TST and FST did not differ from that of their wild-type littermates. However, a significant reduction of immobility time in response to lower doses of imipramine and paroxetine was observed in homozygous Wfs1-deficient mice, but not in their wild-type littermates. In gene expression studies, the levels of 5-HT transporter (SERT were significantly reduced in the pons of homozygous animals. Monoamine metabolism was assayed separately in the dorsal and ventral striatum of naive mice and mice exposed for 30 minutes tobrightly lit motility boxes. We found that this aversive challenge caused a significant increase in the levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA, a metabolite of 5-HT, in the ventral and dorsal striatum of wild-type mice, but not in their homozygous littermates. Taken together, the blunted 5-HT metabolism and reduced levels of SERT are a likely reason for the elevated sensitivity of these mice to the action of imipramine and paroxetine. These changes in the pharmacological and neurochemical phenotype of Wfs1-deficient mice may help to explain the increased susceptibility of Wolfram syndrome patients to depressive states.

  7. Rereplication in emi1-deficient zebrafish embryos occurs through a Cdh1-mediated pathway.

    Directory of Open Access Journals (Sweden)

    Mara E Robu

    Full Text Available Disruption of early mitotic inhibitor 1 (Emi1 interferes with normal cell cycle progression and results in early embryonic lethality in vertebrates. During S and G2 phases the ubiquitin ligase complex APC/C is inhibited by Emi1 protein, thereby enabling the accumulation of Cyclins A and B so they can regulate replication and promote the transition from G2 phase to mitosis, respectively. Depletion of Emi1 prevents mitotic entry and causes rereplication and an increase in cell size. In this study, we show that the developmental and cell cycle defects caused by inactivation of zebrafish emi1 are due to inappropriate activation of APC/C through its cofactor Cdh1. Inhibiting/slowing progression into S-phase by depleting Cdt1, an essential replication licensing factor, partially rescued emi1 deficiency-induced rereplication and the increased cell size. The cell size effect was enhanced by co-depletion of cell survival regulator p53. These data suggest that the increased size of emi1-deficient cells is either directly or indirectly caused by the rereplication defects. Moreover, enforced expression of Cyclin A partially ablated the rereplicating population in emi1-deficient zebrafish embryos, consistent with the role of Cyclin A in origin licensing. Forced expression of Cyclin B partially restored the G1 population, in agreement with the established role of Cyclin B in mitotic progression and exit. However, expression of Cyclin B also partially inhibited rereplication in emi1-deficient embryos, suggesting a role for Cyclin B in regulating replication in this cellular context. As Cyclin A and B are substrates for APC/C-Cdh1 - mediated degradation, and Cdt1 is under control of Cyclin A, these data indicate that emi1 deficiency-induced defects in vivo are due to the dysregulation of an APC/C-Cdh1 molecular axis.

  8. Bleomycin-Treated Chimeric Thy1-Deficient Mice with Thy1-Deficient Myofibroblasts and Thy-Positive Lymphocytes Resolve Inflammation without Affecting the Fibrotic Response

    Directory of Open Access Journals (Sweden)

    Pazit Y. Cohen


    Full Text Available Lung fibrosis is characterized by abnormal accumulation of fibroblasts in the interstitium of the alveolar space. Two populations of myofibroblasts, distinguished by Thy1 expression, are detected in human and murine lungs. Accumulation of Thy1-negative (Thy1− myofibroblasts was shown in the lungs of humans with idiopathic pulmonary fibrosis (IPF and of bleomycin-treated mice. We aimed to identify genetic changes in lung myofibroblasts following Thy1 crosslinking and assess the impact of specific lung myofibroblast Thy1-deficiency, in vivo, in bleomycin-injured mouse lungs. Thy1 increased in mouse lung lymphocytes following bleomycin injury but decreased in myofibroblasts when fibrosis was at the highest point (14 days, as assessed by immunohistochemistry. Using gene chip analysis, we detected that myofibroblast Thy1 crosslinking mediates downregulation of genes promoting cell proliferation, survival, and differentiation, and reduces production of extracellular matrix (ECM components, while concurrently mediating the upregulation of genes known to foster inflammation and immunological functions. Chimeric Thy1-deficient mice with Thy1+ lymphocytes and Thy1− myofibroblasts showed fibrosis similar to wild-type mice and an increased number of CD4/CD25 regulatory T cells, with a concomitant decrease in inflammation. Lung myofibroblasts downregulate Thy1 expression to increase their proliferation but to diminish the in vivo inflammatory milieu. Inflammation is not essential for evolution of fibrosis as was previously stated.

  9. PICK1 deficiency impairs secretory vesicle biogenesis and leads to growth retardation and decreased glucose tolerance

    DEFF Research Database (Denmark)

    Holst, Birgitte; Madsen, Kenneth L; Jansen, Anna M


    , we identify the lipid binding BAR (Bin/amphiphysin/Rvs) domain protein PICK1 (protein interacting with C kinase 1) as a key component early in the biogenesis of secretory vesicles in GH-producing cells. Both PICK1-deficient Drosophila and mice displayed somatic growth retardation. Growth retardation...... was rescued in flies by reintroducing PICK1 in neurosecretory cells producing somatotropic peptides. PICK1-deficient mice were characterized by decreased body weight and length, increased fat accumulation, impaired GH secretion, and decreased storage of GH in the pituitary. Decreased GH storage was supported...... by electron microscopy showing prominent reduction in secretory vesicle number. Evidence was also obtained for impaired insulin secretion associated with decreased glucose tolerance. PICK1 localized in cells to immature secretory vesicles, and the PICK1 BAR domain was shown by live imaging to associate...

  10. MTO1-deficient mouse model mirrors the human phenotype showing complex I defect and cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Lore Becker

    Full Text Available Recently, mutations in the mitochondrial translation optimization factor 1 gene (MTO1 were identified as causative in children with hypertrophic cardiomyopathy, lactic acidosis and respiratory chain defect. Here, we describe an MTO1-deficient mouse model generated by gene trap mutagenesis that mirrors the human phenotype remarkably well. As in patients, the most prominent signs and symptoms were cardiovascular and included bradycardia and cardiomyopathy. In addition, the mutant mice showed a marked worsening of arrhythmias during induction and reversal of anaesthesia. The detailed morphological and biochemical workup of murine hearts indicated that the myocardial damage was due to complex I deficiency and mitochondrial dysfunction. In contrast, neurological examination was largely normal in Mto1-deficient mice. A translational consequence of this mouse model may be to caution against anaesthesia-related cardiac arrhythmias which may be fatal in patients.

  11. Creation of an isogenic P1-deficient mutant of Haemophilus influenzae biogroup aegyptius. (United States)

    Segada, L M; Lesse, A J


    Haemophilus influenzae biogroup aegyptius, the causative agent of Brazilian purpuric fever (BPF), expresses a heat-modifiable 48 kDa outer membrane protein, P1, which is conserved in most Brazilian case-clone isolates. To study the role of P1 in pathogenesis of BPF we constructed via homologous recombination an isogenic P1-deficient mutant of H. influenzae biogroup aegyptius. The procedure involved a modification of Hererot's method for development of competence. Modifications included variations in the growth conditions, use of cAMP, specific characteristics of the donor DNA, and antibiotic selection. P1-deficient mutants were confirmed by SDS-PAGE, loss of reactivity with a specific monoclonal antibody on Western blot, restriction analysis and Southern blot. Our results establish the first successful transformation of homologous DNA into H. influenzae biogroup aegyptius.

  12. Circadian rhythms and food anticipatory behavior in Wfs1-deficient mice

    DEFF Research Database (Denmark)

    Luuk, Hendrik; Fahrenkrug, Jan; Hannibal, Jens


    The dorsomedial hypothalamic nucleus (DMH) has been proposed as a candidate for the neural substrate of a food-entrainable oscillator. The existence of a food-entrainable oscillator in the mammalian nervous system was inferred previously from restricted feeding-induced behavioral rhythmicity...... reduced or otherwise altered food anticipatory activity. Wfs1 immunoreactivity in DMH was found almost exclusively in the compact part. Restricted feeding induced c-Fos immunoreactivity primarily in the ventral and lateral aspects of DMH and it was similar in both genotypes. Wfs1-deficiency resulted...... in significantly lower body weight and reduced wheel-running activity. Circadian rhythmicity of behavior was normal in Wfs1-deficient mice under ad libitum feeding apart from elongated free-running period in constant light. The amount of food anticipatory activity induced by restricted feeding...

  13. SOCS-1 deficiency does not prevent diet-induced insulin resistance

    DEFF Research Database (Denmark)

    Emanuelli, Brice; Macotela, Yazmin; Boucher, Jérémie


    Obesity is associated with inflammation and increased expression of suppressor of cytokine signaling (SOCS) proteins, which inhibit cytokine and insulin signaling. Thus, reducing SOCS expression could prevent the development of obesity-induced insulin resistance. Using SOCS-1 knockout mice, we...... investigated the contribution of SOCS-1 in the development of insulin resistance induced by a high-fat diet (HFD). SOCS-1 knockout mice on HFD gained 70% more weight, displayed a 2.3-fold increase in epididymal fat pads mass and increased hepatic lipid content. This was accompanied by increased mRNA expression...... of leptin and the macrophage marker CD68 in white adipose tissue and of SREBP1c and FAS in liver. HFD also induced hyperglycemia in SOCS-1 deficient mice with impairment of glucose and insulin tolerance tests. Thus, despite the role of SOCS proteins in obesity-related insulin resistance, SOCS-1 deficiency...

  14. Aberrant recombination and repair during immunoglobulin class switching in BRCA1-deficient human B cells

    DEFF Research Database (Denmark)

    Björkman, Andrea; Qvist, Per; Du, Likun


    machinery. A shift to the use of microhomology-based, alternative end-joining (A-EJ) and increased frequencies of intra-S region deletions as well as insertions of inverted S sequences were observed at the recombination junctions amplified from BRCA1-deficient human B cells. Furthermore, increased use...... underlying BRCA1’s function in maintaining genome stability and tumor suppression but may also point to a previously unrecognized role of BRCA1 in B-cell lymphomagenesis....... of long microhomologies was found at recombination junctions derived from E3 ubiquitin-protein ligase RNF168-deficient, Fanconi anemia group J protein (FACJ, BRIP1)-deficient, or DNA endonuclease RBBP8 (CtIP)-compromised cells, whereas an increased frequency of S-region inversions was observed in breast...

  15. Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction


    Thongthip, Supawat; Bellani, Marina; Gregg, Siobhan Q.; Sridhar, Sunandini; Conti, Brooke A.; Chen, Yanglu; Seidman, Michael M.; Smogorzewska, Agata


    Thongthip et al. describe a FANCD2/FANCI-associated nuclease 1 (Fan1)-deficient mouse and show that FAN1 is required for cellular and organismal resistance to DNA interstrand cross-links. Karyomegaly becomes prominent in the kidneys and livers of Fan1-deficient mice with age, and mice develop liver dysfunction.

  16. Novel Mechanisms of PARP Inhibitor Resistance in BRCA1-Deficient Breast Cancers (United States)


    independently of PARPi treatment. MEKi treatment prevents the emergence of PARPi resistant clones . Treatment with MEKi does not result in a decrease...Furthmore the combination of ATRi and PARPi prevents PARPi resistant clones from emerging. This suggests that the combination therapy of ATRi and...PARPi resistance to emerge, suggesting co-treatment with MEKi maybe a way to prevent resistance to PARPi from emerging in BRCA1-deficient cancer

  17. BRCA1 deficiency increases the sensitivity of ovarian cancer cells to auranofin

    Energy Technology Data Exchange (ETDEWEB)

    Oommen, Deepu [School of Biological Sciences, Plymouth University, Plymouth PL4 8AA (United Kingdom); Yiannakis, Dennis [Plymouth Oncology Centre, Derriford Hospital, Plymouth Hospitals NHS Trust, Plymouth PL6 8DH (United Kingdom); Jha, Awadhesh N., E-mail: [School of Biological Sciences, Plymouth University, Plymouth PL4 8AA (United Kingdom)


    Highlights: • BRCA1 deficient cancer cells exhibit increased DNA damage upon auranofin treatment. • Auranofin induces apoptosis in BRCA1 deficient cancer cells despite the activation of Nrf2. • Antioxidant protects BRCA1 deficient cancer cells from auranofin. - Abstract: Auranofin, a thioredoxin reductase inhibitor and an anti-rheumatic drug is currently undergoing phase 2 clinical studies for repurposing to treat recurrent epithelial ovarian cancer. Previous studies have established that auranofin exerts its cytotoxic activity by increasing the production of reactive oxygen species (ROS). Breast cancer 1, early onset (BRCA1) is a DNA repair protein whose functional status is critical in the prognosis of ovarian cancer. Apart from its key role in DNA repair, BRCA1 is also known to modulate cellular redox homeostasis by regulating the stability of anti-oxidant transcription factor, nuclear factor erythroid 2—related factor 2 (Nrf2) via direct protein–protein interaction. However, it is currently unknown whether BRCA1 modulates the sensitivity of ovarian cancer cells to auranofin. Here we report that BRCA1-depleted cells exhibited increased DNA double strand breaks (DSBs) and decreased clonogenic cell survival upon auranofin treatment. Interestingly, auranofin induced the expression of Nrf2 in BRCA1-depleted cells suggesting its regulation independent of BRCA1. Furthermore, anti-oxidant agent, N-acetyl cysteine (NAC) protected BRCA1-depleted cells from DNA damage and apoptosis induced by auranofin. Our study suggests that accumulated lethal DSBs resulting from the oxidative damage render BRCA1 deficient cells more sensitive to auranofin despite the activation of Nrf2.

  18. Association between coenzyme Q10 and glucose transporter (GLUT1) deficiency


    Yubero, Delia; O’Callaghan, Mar; Montero, Raquel; Ormazabal, Aida; Armstrong, Judith; Espinos, Carmina; Rodríguez, Maria A; Jou, Cristina; Castejon, Esperanza; Aracil, Maria A; Cascajo, Maria V; Gavilan, Angela; Briones, Paz; Jimenez-Mallebrera, Cecilia; Pineda, Mercedes


    Background It has been demonstrated that glucose transporter (GLUT1) deficiency in a mouse model causes a diminished cerebral lipid synthesis. This deficient lipid biosynthesis could contribute to secondary CoQ deficiency. We report here, for the first time an association between GLUT1 and coenzyme Q10 deficiency in a pediatric patient. Case presentation We report a 15 year-old girl with truncal ataxia, nystagmus, dysarthria and myoclonic epilepsy as the main clinical features. Blood lactate ...

  19. Runx1 deficiency permits granulocyte lineage commitment but impairs subsequent maturation


    Ng, K. P.; Hu, Z.; Ebrahem, Q; Negrotto, S; Lausen, J.; Saunthararajah, Y


    First-hits in the multi-hit process of leukemogenesis originate in germline or hematopoietic stem cells (HSCs), yet leukemia-initiating cells (LICs) usually have a lineage-committed phenotype. The molecular mechanisms underlying this compartment shift during leukemia evolution have not been a major focus of investigation and remain poorly understood. Here a mechanism underlying this shift was examined in the context of Runx1 deficiency, a frequent leukemia-initiating event. Lineage-negative c...

  20. BRCA1 deficient Mouse Models to Study Pathogenesis and Therapy of Triple Negative Breast Cancer


    Diaz-Cruz, Edgar S.; Cabrera, Marina C.; Nakles, Rebecca; Rutstein, Beth H.; Furth, Priscilla A


    Genetically engineered mice along with allograft and xenograft models can be used to effectively model triple negative breast cancer both for studies of pathophysiology as well as preclinical prevention and therapeutic drug studies. In this review eight distinct genetically engineered mouse models of BRCA1 deficiency are discussed in relationship to the generation of triple negative mammary cancer. Allograft models derived from some of these genetically engineered mice are considered and xeno...

  1. Inherited MST1 deficiency underlies susceptibility to EV-HPV infections.

    Directory of Open Access Journals (Sweden)

    Amandine Crequer

    Full Text Available Epidermodysplasia verruciformis (EV is characterized by persistent cutaneous lesions caused by a specific group of related human papillomavirus genotypes (EV-HPVs in otherwise healthy individuals. Autosomal recessive (AR EVER1 and EVER2 deficiencies account for two thirds of known cases of EV. AR RHOH deficiency has recently been described in two siblings with EV-HPV infections as well as other infectious and tumoral manifestations. We report here the whole-exome based discovery of AR MST1 deficiency in a 19-year-old patient with a T-cell deficiency associated with EV-HPV, bacterial and fungal infections. MST1 deficiency has recently been described in seven patients from three unrelated kindreds with profound T-cell deficiency and various viral and bacterial infections. The patient was also homozygous for a rare ERCC3 variation. Our findings broaden the clinical range of infections seen in MST1 deficiency and provide a new genetic etiology of susceptibility to EV-HPV infections. Together with the recent discovery of RHOH deficiency, they suggest that T cells are involved in the control of EV-HPVs, at least in some individuals.

  2. Mcph1-deficient mice reveal a role for MCPH1 in otitis media. (United States)

    Chen, Jing; Ingham, Neil; Clare, Simon; Raisen, Claire; Vancollie, Valerie E; Ismail, Ozama; McIntyre, Rebecca E; Tsang, Stephen H; Mahajan, Vinit B; Dougan, Gordon; Adams, David J; White, Jacqueline K; Steel, Karen P


    Otitis media is a common reason for hearing loss, especially in children. Otitis media is a multifactorial disease and environmental factors, anatomic dysmorphology and genetic predisposition can all contribute to its pathogenesis. However, the reasons for the variable susceptibility to otitis media are elusive. MCPH1 mutations cause primary microcephaly in humans. So far, no hearing impairment has been reported either in the MCPH1 patients or mouse models with Mcph1 deficiency. In this study, Mcph1-deficient (Mcph1(tm1a) (/tm1a) ) mice were produced using embryonic stem cells with a targeted mutation by the Sanger Institute's Mouse Genetics Project. Auditory brainstem response measurements revealed that Mcph1(tm1a) (/tm1a) mice had mild to moderate hearing impairment with around 70% penetrance. We found otitis media with effusion in the hearing-impaired Mcph1(tm1a) (/tm1a) mice by anatomic and histological examinations. Expression of Mcph1 in the epithelial cells of middle ear cavities supported its involvement in the development of otitis media. Other defects of Mcph1(tm1a) (/tm1a) mice included small skull sizes, increased micronuclei in red blood cells, increased B cells and ocular abnormalities. These findings not only recapitulated the defects found in other Mcph1-deficient mice or MCPH1 patients, but also revealed an unexpected phenotype, otitis media with hearing impairment, which suggests Mcph1 is a new gene underlying genetic predisposition to otitis media.

  3. A distinct response to endogenous DNA damage in the development of Nbs1-deficient cortical neurons

    Institute of Scientific and Technical Information of China (English)

    Rui Li; Yun-Gui Yang; Yunzhou Gao; Zhao-Qi Wang; Wei-Min Tong


    Microcephaly is a clinical characteristic for human nijmegen breakage syndrome (NBS,mutated in NBS1 gene),a chromosomal instability syndrome.However,the underlying molecular pathogenesis remains elusive.In the present study,we demonstrate that neuronal disruption ofNBS (Nbn in mice) causes microcephaly characterized by the reduction of cerebral cortex and corpus cailosum,recapitulating neuronal anomalies in human NBS.Nbs1-deficient neocortex shows accumulative endogenous DNA damage and defective activation ofAtaxia telangiectasia and Rad3-related (ATR)-Chk1 pathway upon DNA damage.Notably,in contrast to massive apoptotic cell death in Nbs1-deficient cerebella,activation of p53 leads to a defective neuroprogenitor proliferation in neocortex,likely via specific persistent induction of hematopoietic zinc finger (Hzf) that preferentially promotes p53-mediated cell cycle arrest whilst inhibiting apoptosis.Moreover,Trp53 mutations substantially rescue the microcephaly in Nbs1-deficient mice.Thus,the present results reveal the first clue that developing neurons at different regions of brain selectively respond to endogenous DNA damage,and underscore an important role for Nbs1 in neurogenesis.

  4. Clk1 deficiency promotes neuroinflammation and subsequent dopaminergic cell death through regulation of microglial metabolic reprogramming. (United States)

    Gu, Ruinan; Zhang, Fali; Chen, Gang; Han, Chaojun; Liu, Jay; Ren, Zhaoxiang; Zhu, Yi; Waddington, John L; Zheng, Long Tai; Zhen, Xuechu


    Clock (Clk)1/COQ7 is a mitochondrial hydroxylase that is necessary for the biosynthesis of ubiquinone (coenzyme Q or UQ). Here, we investigate the role of Clk1 in neuroinflammation and consequentially dopaminergic (DA) neuron survival. Reduced expression of Clk1 in microglia enhanced the LPS-induced proinflammatory response and promoted aerobic glycolysis. Inhibition of glycolysis abolished Clk1 deficiency-induced hypersensitivity to the inflammatory stimulation. Mechanistic studies demonstrated that mTOR/HIF-1α and ROS/HIF-1α signaling pathways were involved in Clk1 deficiency-induced aerobic glycolysis. The increase in neuronal cell death was observed following treatment with conditioned media from Clk1 deficient microglia. Increased DA neuron loss and microgliosis were observed in Clk1(+/-) mice after treatment with MPTP, a rodent model of Parkinson's disease (PD). This increase in DA neuron loss was due to an exacerbated microglial inflammatory response, rather than direct susceptibility of Clk1(+/-) DA cells to MPP(+), the active species of MPTP. Exaggerated expressions of proinflammatory genes and loss of DA neurons were also observed in Clk1(+/-) mice after stereotaxic injection of LPS. Our results suggest that Clk1 regulates microglial metabolic reprogramming that is, in turn, involved in the neuroinflammatory processes and PD.

  5. Metabolic Effects of CX3CR1 Deficiency in Diet-Induced Obese Mice.

    Directory of Open Access Journals (Sweden)

    Rachana Shah

    Full Text Available The fractalkine (CX3CL1-CX3CR1 chemokine system is associated with obesity-related inflammation and type 2 diabetes, but data on effects of Cx3cr1 deficiency on metabolic pathways is contradictory. We examined male C57BL/6 Cx3cr1-/- mice on chow and high-fat diet to determine the metabolic effects of Cx3cr1 deficiency. We found no difference in body weight and fat content or feeding and energy expenditure between Cx3cr1-/- and WT mice. Cx3cr1-/- mice had reduced glucose intolerance assessed by intraperitoneal glucose tolerance tests at chow and high-fat fed states, though there was no difference in glucose-stimulated insulin values. Cx3cr1-/- mice also had improved insulin sensitivity at hyperinsulinemic-euglycemic clamp, with higher glucose infusion rate, rate of disposal, and hepatic glucose production suppression compared to WT mice. Enhanced insulin signaling in response to acute intravenous insulin injection was demonstrated in Cx3cr1-/- by increased liver protein levels of phosphorylated AKT and GSK3β proteins. There were no differences in adipose tissue macrophage populations, circulating inflammatory monocytes, adipokines, lipids, or inflammatory markers. In conclusion, we demonstrate a moderate and reproducible protective effect of Cx3cr1 deficiency on glucose intolerance and insulin resistance.

  6. The ketogenic diet compensates for AGC1 deficiency and improves myelination. (United States)

    Dahlin, Maria; Martin, Daniel A; Hedlund, Zandra; Jonsson, Monica; von Döbeln, Ulrika; Wedell, Anna


    The brain aspartate-glutamate carrier (AGC1) is specifically expressed in neurons, where it transports aspartate from the mitochondria to the cytosol, and plays a role in transfer of nicotinamide adenine dinucleotide (NADH)-reducing equivalents into the mitochondria as a part of the malate-aspartate shuttle. Deficient function of AGC1 underlies an inborn error of metabolism that presents with severe hypotonia, arrested psychomotor development, and seizures from a few months of age. In AGC1 deficiency, there is secondary hypomyelination due to lack of N-acetylaspartate (NAA), which is normally generated by acetylation of aspartate in the neuron and required for fatty acid synthesis by the adjacent oligodendrocyte. Based on experiences from AGC2 deficiency, we predicted that reduced glycolysis should compensate for the metabolic defect and allow resumed myelination in AGC1 deficiency. Carbohydrate restriction was therefore initiated in a patient with AGC1 deficiency at 6 years of age by introducing a ketogenic diet. The response was dramatic, clinically as well as radiologically. Psychomotor development showed clear improvement, and magnetic resonance imaging (MRI) indicated resumed myelination. This is the first successful treatment of secondary hypomyelination reported. Because AGC1 is driven by the proton gradient generated by the neuronal mitochondrial respiratory chain, the results have potential relevance for secondary hypomyelination in general.

  7. MCPIP1 deficiency in mice results in severe anemia related to autoimmune mechanisms.

    Directory of Open Access Journals (Sweden)

    Zhou Zhou

    Full Text Available Autoimmune gastritis is an organ-specific autoimmune disease of the stomach associated with pernicious anemia. The previous work from us and other groups identified MCPIP1 as an essential factor controlling inflammation and immune homeostasis. MCPIP1(-/- developed severe anemia. However, the mechanisms underlying this phenotype remain unclear. In the present study, we found that MCPIP1 deficiency in mice resulted in severe anemia related to autoimmune mechanisms. Although MCPIP1 deficiency did not affect erythropoiesis per se, the erythropoiesis in MCPIP1(-/- bone marrow erythroblasts was significantly attenuated due to iron and vitamin B12 (VB12 deficiency, which was mainly resulted from autoimmunity-associated gastritis and parietal cell loss. Consistently, exogenous supplement of iron and VB12 greatly improved the anemia phenotype of MCPIP1(-/- mice. Finally, we have evidence suggesting that autoimmune hemolysis may also contribute to anemia phenotype of MCPIP1(-/- mice. Taken together, our study suggests that MCPIP1 deficiency in mice leads to the development of autoimmune gastritis and pernicious anemia. Thus, MCPIP1(-/- mice may be a good mouse model for investigating the pathogenesis of pernicious anemia and testing the efficacy of some potential drugs for treatment of this disease.

  8. Nat1 Deficiency Is Associated with Mitochondrial Dysfunction and Exercise Intolerance in Mice

    Directory of Open Access Journals (Sweden)

    Indumathi Chennamsetty


    Full Text Available We recently identified human N-acetyltransferase 2 (NAT2 as an insulin resistance (IR gene. Here, we examine the cellular mechanism linking NAT2 to IR and find that Nat1 (mouse ortholog of NAT2 is co-regulated with key mitochondrial genes. RNAi-mediated silencing of Nat1 led to mitochondrial dysfunction characterized by increased intracellular reactive oxygen species and mitochondrial fragmentation as well as decreased mitochondrial membrane potential, biogenesis, mass, cellular respiration, and ATP generation. These effects were consistent in 3T3-L1 adipocytes, C2C12 myoblasts, and in tissues from Nat1-deficient mice, including white adipose tissue, heart, and skeletal muscle. Nat1-deficient mice had changes in plasma metabolites and lipids consistent with a decreased ability to utilize fats for energy and a decrease in basal metabolic rate and exercise capacity without altered thermogenesis. Collectively, our results suggest that Nat1 deficiency results in mitochondrial dysfunction, which may constitute a mechanistic link between this gene and IR.

  9. RB1 deficiency in triple-negative breast cancer induces mitochondrial protein translation (United States)

    Jones, Robert A.; Robinson, Tyler J.; Liu, Jeff C.; Shrestha, Mariusz; Voisin, Veronique; Ju, YoungJun; Chung, Philip E.D.; Pellecchia, Giovanna; Fell, Victoria L.; Bae, SooIn; Muthuswamy, Lakshmi; Egan, Sean E.; Jiang, Zhe; Leone, Gustavo; Bader, Gary D.; Schimmer, Aaron


    Triple-negative breast cancer (TNBC) includes basal-like and claudin-low subtypes for which no specific treatment is currently available. Although the retinoblastoma tumor-suppressor gene (RB1) is frequently lost together with TP53 in TNBC, it is not directly targetable. There is thus great interest in identifying vulnerabilities downstream of RB1 that can be therapeutically exploited. Here, we determined that combined inactivation of murine Rb and p53 in diverse mammary epithelial cells induced claudin-low–like TNBC with Met, Birc2/3-Mmp13-Yap1, and Pvt1-Myc amplifications. Gene set enrichment analysis revealed that Rb/p53-deficient tumors showed elevated expression of the mitochondrial protein translation (MPT) gene pathway relative to tumors harboring p53 deletion alone. Accordingly, bioinformatic, functional, and biochemical analyses showed that RB1-E2F complexes bind to MPT gene promoters to regulate transcription and control MPT. Additionally, a screen of US Food and Drug Administration–approved (FDA-approved) drugs identified the MPT antagonist tigecycline (TIG) as a potent inhibitor of Rb/p53-deficient tumor cell proliferation. TIG preferentially suppressed RB1-deficient TNBC cell proliferation, targeted both the bulk and cancer stem cell fraction, and strongly attenuated xenograft growth. It also cooperated with sulfasalazine, an FDA-approved inhibitor of cystine xCT antiporter, in culture and xenograft assays. Our results suggest that RB1 deficiency promotes cancer cell proliferation in part by enhancing mitochondrial function and identify TIG as a clinically approved drug for RB1-deficient TNBC. PMID:27571409

  10. Arterial dysfunction but maintained systemic blood pressure in cavin-1-deficient mice.

    Directory of Open Access Journals (Sweden)

    Karl Swärd

    Full Text Available Caveolae are omega-shaped plasma membrane micro-domains that are abundant in cells of the vascular system. Formation of caveolae depends on caveolin-1 and cavin-1 and lack of either protein leads to loss of caveolae. Mice with caveolin-1 deficiency have dysfunctional blood vessels, but whether absence of cavin-1 similarly leads to vascular dysfunction is not known. Here we addressed this hypothesis using small mesenteric arteries from cavin-1-deficient mice. Cavin-1-reporter staining was intense in mesenteric arteries, brain arterioles and elsewhere in the vascular system, with positive staining of both endothelial and smooth muscle cells. Arterial expression of cavin-1, -2 and -3 was reduced in knockout (KO arteries as was expression of caveolin-1, -2 and -3. Caveolae were absent in the endothelial and smooth muscle layers of small mesenteric arteries as determined by electron microscopy. Arginase, a negative regulator of nitric oxide production, was elevated in cavin-1 deficient arteries as was contraction in response to the α1-adrenergic agonist cirazoline. Detailed assessment of vascular dimensions revealed increased media thickness and reduced distensibility, arguing that enhanced contraction was due to increased muscle mass. Contrasting with increased α1-adrenergic contraction, myogenic tone was essentially absent and this appeared to be due in part to increased nitric oxide production. Vasomotion was less frequent in the knock-out vessels. In keeping with the opposing influences on arterial resistance of increased agonist-induced contractility and reduced myogenic tone, arterial blood pressure was unchanged in vivo. We conclude that deficiency of cavin-1 affects the function of small arteries, but that opposing influences on arterial resistance balance each other such that systemic blood pressure in unstressed mice is well maintained.

  11. Glucose transporter type 1 deficiency syndrome effectively treated with modified Atkins diet. (United States)

    Haberlandt, Edda; Karall, Daniela; Jud, Veronika; Baumgartner, Sara Sigl; Zotter, Sibylle; Rostasy, Kevin; Baumann, Matthias; Scholl-Buergi, Sabine


    This is a report on the successful treatment of a 6-year-old girl with genetically proven glucose transporter type 1 deficiency syndrome (GLUT1-DS) with modified Atkins diet (MAD). GLUT1-DS is an inborn disorder of glucose transport across the blood-brain barrier, which leads to energy deficiency of the brain with a broad spectrum of neurological symptoms including therapy-resistant epilepsy. Usually classical ketogenic diet (KD) is the standard treatment for patients with GLUT1-DS. Treatment with MAD, a variant of KD, for an observation period of 17 months resulted in improvement of seizures, alertness, cognitive abilities, and electroencephalography in this patient.


    Directory of Open Access Journals (Sweden)

    Arsov Todor


    Full Text Available The classical GLUT-1 deficiency syndrome (GLUT-1 DS, De Vivo disease was described over 2 decades ago as a metabolic encephalopathy characterized by developmental delay, secondary microcephaly paroxysmal neurological symptoms (epilepsy and movement disorders. The biochemical parameters of this disease, used in diagnosis, are low levels of glucose in the cerebrospinal fluid, normal level of glucose in the blood and consequent low ratio of cerebrospinal fluid vs. blood glucose levels (<40-45%. So far, more than 200 cases of the classical GLUT-1 DS have been described in the literature. Genetic research demonstrated that this disease is caused by mutations in SLC2A1 gene coding for GLUT-1, a transporter of glucose across the blood brain barrier. Over the last few years the clinical spectrum of GLUT-1 deficiencywas expanded to include other rare diseases such as paroxysmal exertional dyskinesia and early-onset absence epilepsy, but also some more common diseases such as idiopathic generalised epilepsy (1-2%. GLUT-1 deficiency is an important pathophysiological basis of these diseases as early diagnosis (aided by DNA mutation testing and treatment (ketogenic diet could lead to improved disease outcomes.

  13. Partial absence of pleuropericardial membranes in Tbx18- and Wt1-deficient mice.

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    Julia Norden

    Full Text Available The pleuropericardial membranes are fibro-serous walls that separate the pericardial and pleural cavities and anchor the heart inside the mediastinum. Partial or complete absence of pleuropericardial membranes is a rare human disease, the etiology of which is poorly understood. As an attempt to better understand these defects, we wished to analyze the cellular and molecular mechanisms directing the separation of pericardial and pleural cavities by pleuropericardial membranes in the mouse. We found by histological analyses that both in Tbx18- and Wt1-deficient mice the pleural and pericardial cavities communicate due to a partial absence of the pleuropericardial membranes in the hilus region. We trace these defects to a persisting embryonic connection between these cavities, the pericardioperitoneal canals. Furthermore, we identify mesenchymal ridges in the sinus venosus region that tether the growing pleuropericardial membranes to the hilus of the lung, and thus, close the pericardioperitoneal canals. In Tbx18-deficient embryos these mesenchymal ridges are not established, whereas in Wt1-deficient embryos the final fusion process between these tissues and the body wall does not occur. We suggest that this fusion is an active rather than a passive process, and discuss the interrelation between closure of the pericardioperitoneal canals, lateral release of the pleuropericardial membranes from the lateral body wall, and sinus horn development.

  14. ATR pathway inhibition is synthetically lethal in cancer cells with ERCC1 deficiency (United States)

    Mohni, Kareem N.; Kavanaugh, Gina M.; Cortez, David


    The DNA damage response kinase ATR and its effector kinase CHEK1 are required for cancer cells to survive oncogene-induced replication stress. ATR inhibitors exhibit synthetic lethal interactions with deficiencies in the DNA damage response enzymes ATM and XRCC1 and with overexpression of the cell cycle kinase Cyclin E. Here we report a systematic screen to identify synthetic lethal interactions with ATR-pathway targeted drugs, rationalized by their predicted therapeutic utility in the oncology clinic. We found that reduced function in the ATR pathway itself provided the strongest synthetic lethal interaction. In addition, we found that loss of the structure specific-endonuclease ERCC1-XPF (ERCC4) is synthetic lethal with ATR pathway inhibitors. ERCC1-deficient cells exhibited elevated levels of DNA damage, which was increased further by ATR inhibition. When treated with ATR or CHEK1 inhibitors, ERCC1-deficient cells arrested in S phase and failed to complete cell cycle transit even after drug removal. Notably, triple-negative breast cancer cells and non-small cell lung cancer cells depleted of ERCC1 exhibited increased sensitivity to ATR-pathway targeted drugs. Overall, we concluded that ATR pathway-targeted drugs may offer particular utility in cancers with reduced ATR pathway function or reduced levels of ERCC4 activity. PMID:24662920

  15. T cells from Programmed Death-1 deficient mice respond poorly to Mycobacterium tuberculosis infection.

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    Sultan Tousif

    Full Text Available BACKGROUND: Programmed Death-1 (PD-1; CD279 receptor molecule is widely believed to be a negative regulator predominantly expressed by exhausted/activated mouse T cells. Upon interaction with its ligands, PD-L1 and PD-L2, PD-1 inhibits activation of T cells and cytokine production, which has been documented in various viral and fungal infections as well as in vitro studies. Therefore, inhibition of T cell responses by PD-1 resulted in disease resistance in a variety of mouse infection models studied heretofore. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report that PD-1 deficient (PD-1(-/- mice infected with Mycobacterium tuberculosis (M. tb H37Rv by the aerosol route have increased susceptibility as compared with their wild type littermates. Surprisingly, M. tb antigen-specific T cell proliferation was dramatically reduced in PD-1 deficient animals compared with wild-type littermates, and this was due to increased numbers of regulatory T cells (Tregs and recruitment of mesenchymal stem cells. Furthermore, PD-1(-/- mice exhibited decreases in the autophagy-induced LC3-B marker protein in macrophages. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that PD-1 does not play an inhibitory role during M. tb infection and instead promotes mycobacterial clearance in mice.

  16. Nogo-receptor 1 deficiency has no influence on immune cell repertoire or function during experimental autoimmune encephalomyelitis.

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    Sara A Litwak

    Full Text Available The potential role of Nogo-66 Receptor 1 (NgR1 on immune cell phenotypes and their activation during neuroinflammatory diseases such as multiple sclerosis (MS and its animal model, experimental autoimmune encephalomyelitis (EAE, is unclear. To further understand the function of this receptor on haematopoietically-derived cells, phenotypic and functional analyses were performed using NgR1-deficient (ngr1-/- animals. Flow cytometry-based phenotypic analyses performed on blood, spleen, thymus, lymph nodes, bone marrow and central nervous-system (CNS-infiltrating blood cells revealed no immunological defects in naïve ngr1-/- animals versus wild-type littermate (WTLM controls. EAE was induced by either recombinant myelin oligodendrocyte glycoprotein (rMOG, a model in which B cells are considered to contribute pathogenically, or by MOG35-55 peptide, a B cell-independent model. We have demonstrated that in ngr1-/- mice injected with MOG35-55, a significant reduction in the severity of EAE correlated with reduced axonal damage present in the spinal cord when compared to their WTLM controls. However, despite a reduction in axonal damage observed in the CNS of ngr1-/- mice at the chronic stage of disease, no clinical differences could be attributed to a specific genotype when rMOG was used as the encephalitogen. Following MOG35-55-induction of EAE, we could not derive any major changes to the immune cell populations analyzed between ngr1-/- and WTLM mice. Collectively, these data demonstrate that NgR1 has little if any effects on the repertoire of immune cells, their activation and trafficking to the CNS.

  17. Heme oxygenase-1 deficiency alters erythroblastic island formation, steady-state erythropoiesis and red blood cell lifespan in mice. (United States)

    Fraser, Stuart T; Midwinter, Robyn G; Coupland, Lucy A; Kong, Stephanie; Berger, Birgit S; Yeo, Jia Hao; Andrade, Osvaldo Cooley; Cromer, Deborah; Suarna, Cacang; Lam, Magda; Maghzal, Ghassan J; Chong, Beng H; Parish, Christopher R; Stocker, Roland


    Heme oxygenase-1 is critical for iron recycling during red blood cell turnover, whereas its impact on steady-state erythropoiesis and red blood cell lifespan is not known. We show here that in 8- to 14-week old mice, heme oxygenase-1 deficiency adversely affects steady-state erythropoiesis in the bone marrow. This is manifested by a decrease in Ter-119(+)-erythroid cells, abnormal adhesion molecule expression on macrophages and erythroid cells, and a greatly diminished ability to form erythroblastic islands. Compared with wild-type animals, red blood cell size and hemoglobin content are decreased, while the number of circulating red blood cells is increased in heme oxygenase-1 deficient mice, overall leading to microcytic anemia. Heme oxygenase-1 deficiency increases oxidative stress in circulating red blood cells and greatly decreases the frequency of macrophages expressing the phosphatidylserine receptor Tim4 in bone marrow, spleen and liver. Heme oxygenase-1 deficiency increases spleen weight and Ter119(+)-erythroid cells in the spleen, although α4β1-integrin expression by these cells and splenic macrophages positive for vascular cell adhesion molecule 1 are both decreased. Red blood cell lifespan is prolonged in heme oxygenase-1 deficient mice compared with wild-type mice. Our findings suggest that while macrophages and relevant receptors required for red blood cell formation and removal are substantially depleted in heme oxygenase-1 deficient mice, the extent of anemia in these mice may be ameliorated by the prolonged lifespan of their oxidatively stressed erythrocytes.

  18. Genetic KCa3.1-deficiency produces locomotor hyperactivity and alterations in cerebral monoamine levels.

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    Kate Lykke Lambertsen

    Full Text Available BACKGROUND: The calmodulin/calcium-activated K(+ channel KCa3.1 is expressed in red and white blood cells, epithelia and endothelia, and possibly central and peripheral neurons. However, our knowledge about its contribution to neurological functions and behavior is incomplete. Here, we investigated whether genetic deficiency or pharmacological activation of KCa3.1 change behavior and cerebral monoamine levels in mice. METHODOLOGY/PRINCIPAL FINDINGS: In the open field test, KCa3.1-deficiency increased horizontal activity, as KCa3.1(-/- mice travelled longer distances (≈145% of KCa3.1(+/+ and at higher speed (≈1.5-fold of KCa3.1(+/+. Working memory in the Y-maze was reduced by KCa3.1-deficiency. Motor coordination on the rotarod and neuromuscular functions were unchanged. In KCa3.1(-/- mice, HPLC analysis revealed that turn-over rates of serotonin were reduced in frontal cortex, striatum and brain stem, while noradrenalin turn-over rates were increased in the frontal cortex. Dopamine turn-over rates were unaltered. Plasma catecholamine and corticosterone levels were unaltered. Intraperitoneal injections of 10 mg/kg of the KCa3.1/KCa2-activator SKA-31 reduced rearing and turning behavior in KCa3.1(+/+ but not in KCa3.1(-/- mice, while 30 mg/kg SKA-31 caused strong sedation in 50% of the animals of either genotypes. KCa3.1(-/- mice were hyperactive (≈+60% in their home cage and SKA-31-administration reduced nocturnal physical activity in KCa3.1(+/+ but not in KCa3.1(-/- mice. CONCLUSIONS/SIGNIFICANCE: KCa3.1-deficiency causes locomotor hyperactivity and altered monoamine levels in selected brain regions, suggesting a so far unknown functional link of KCa3.1 channels to behavior and monoaminergic neurotransmission in mice. The tranquilizing effects of low-dose SKA-31 raise the possibility to use KCa3.1/KCa2 channels as novel pharmacological targets for the treatment of neuropsychiatric hyperactivity disorders.

  19. PICK1 deficiency impairs secretory vesicle biogenesis and leads to growth retardation and decreased glucose tolerance.

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    Birgitte Holst

    Full Text Available Secretory vesicles in endocrine cells store hormones such as growth hormone (GH and insulin before their release into the bloodstream. The molecular mechanisms governing budding of immature secretory vesicles from the trans-Golgi network (TGN and their subsequent maturation remain unclear. Here, we identify the lipid binding BAR (Bin/amphiphysin/Rvs domain protein PICK1 (protein interacting with C kinase 1 as a key component early in the biogenesis of secretory vesicles in GH-producing cells. Both PICK1-deficient Drosophila and mice displayed somatic growth retardation. Growth retardation was rescued in flies by reintroducing PICK1 in neurosecretory cells producing somatotropic peptides. PICK1-deficient mice were characterized by decreased body weight and length, increased fat accumulation, impaired GH secretion, and decreased storage of GH in the pituitary. Decreased GH storage was supported by electron microscopy showing prominent reduction in secretory vesicle number. Evidence was also obtained for impaired insulin secretion associated with decreased glucose tolerance. PICK1 localized in cells to immature secretory vesicles, and the PICK1 BAR domain was shown by live imaging to associate with vesicles budding from the TGN and to possess membrane-sculpting properties in vitro. In mouse pituitary, PICK1 co-localized with the BAR domain protein ICA69, and PICK1 deficiency abolished ICA69 protein expression. In the Drosophila brain, PICK1 and ICA69 co-immunoprecipitated and showed mutually dependent expression. Finally, both in a Drosophila model of type 2 diabetes and in high-fat-diet-induced obese mice, we observed up-regulation of PICK1 mRNA expression. Our findings suggest that PICK1, together with ICA69, is critical during budding of immature secretory vesicles from the TGN and thus for vesicular storage of GH and possibly other hormones. The data link two BAR domain proteins to membrane remodeling processes in the secretory pathway of

  20. Runx1 deficiency permits granulocyte lineage commitment but impairs subsequent maturation. (United States)

    Ng, K P; Hu, Z; Ebrahem, Q; Negrotto, S; Lausen, J; Saunthararajah, Y


    First-hits in the multi-hit process of leukemogenesis originate in germline or hematopoietic stem cells (HSCs), yet leukemia-initiating cells (LICs) usually have a lineage-committed phenotype. The molecular mechanisms underlying this compartment shift during leukemia evolution have not been a major focus of investigation and remain poorly understood. Here a mechanism underlying this shift was examined in the context of Runx1 deficiency, a frequent leukemia-initiating event. Lineage-negative cells isolated from the bone marrow of Runx1-haploinsufficient and wild-type control mice were cultured in granulocyte-colony-stimulating factor to force lineage commitment. Runx1-haploinsufficient cells demonstrated significantly greater and persistent exponential cell growth than wild-type controls. Not surprisingly, the Runx1-haploinsufficient cells were differentiation-impaired, by morphology and by flow-cytometric evaluation for granulocyte differentiation markers. Interestingly, however, this impaired differentiation was not because of decreased granulocyte lineage commitment, as RNA and protein upregulation of the master granulocyte lineage-commitment transcription factor Cebpa, and Hoxb4 repression, was similar in wild-type and Runx1-haploinsufficient cells. Instead, RNA and protein expression of Cebpe, a key driver of progressive maturation after lineage commitment, were significantly decreased in Runx1-haploinsufficient cells. Primary acute myeloid leukemia cells with normal cytogenetics and RUNX1 mutation also demonstrated this phenotype of very high CEBPA mRNA expression but paradoxically low expression of CEBPE, a CEBPA target gene. Chromatin-immunoprecipitation analyses suggested a molecular mechanism for this phenotype: in wild-type cells, Runx1 binding was substantially greater at the Cebpe than at the Cebpa enhancer. Furthermore, Runx1 deficiency substantially diminished high-level Runx1 binding at the Cebpe enhancer, but lower-level binding at the Cebpa

  1. PICK1 deficiency impairs secretory vesicle biogenesis and leads to growth retardation and decreased glucose tolerance

    DEFF Research Database (Denmark)

    Holst, Birgitte; Madsen, Kenneth L; Jansen, Anna M;


    Secretory vesicles in endocrine cells store hormones such as growth hormone (GH) and insulin before their release into the bloodstream. The molecular mechanisms governing budding of immature secretory vesicles from the trans-Golgi network (TGN) and their subsequent maturation remain unclear. Here...... was rescued in flies by reintroducing PICK1 in neurosecretory cells producing somatotropic peptides. PICK1-deficient mice were characterized by decreased body weight and length, increased fat accumulation, impaired GH secretion, and decreased storage of GH in the pituitary. Decreased GH storage was supported...... dependent expression. Finally, both in a Drosophila model of type 2 diabetes and in high-fat-diet-induced obese mice, we observed up-regulation of PICK1 mRNA expression. Our findings suggest that PICK1, together with ICA69, is critical during budding of immature secretory vesicles from the TGN and thus...

  2. TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner. (United States)

    Ablasser, Andrea; Hemmerling, Inga; Schmid-Burgk, Jonathan L; Behrendt, Rayk; Roers, Axel; Hornung, Veit


    Cytosolic detection of DNA is crucial for the initiation of antiviral immunity but can also cause autoimmunity in the context of endogenous nucleic acids being sensed. Mutations in the human 3' repair exonuclease 1 (TREX1) have been linked to the type I IFN-associated autoimmune disease Aicardi-Goutières syndrome. The exact mechanisms driving unabated type I IFN responses in the absence of TREX1 are only partly understood, but it appears likely that accumulation of endogenous DNA species triggers a cell-autonomous immune response by activating a cytosolic DNA receptor. In this article, we demonstrate that knocking out the DNA sensor cyclic GMP-AMP synthase completely abrogates spontaneous induction of IFN-stimulated genes in TREX1-deficient cells. These findings indicate a key role of cyclic GMP-AMP synthase for the initiation of self-DNA-induced autoimmune disorders, thus providing important implications for novel therapeutic approaches.

  3. RAD51AP1-deficiency in vertebrate cells impairs DNA replication. (United States)

    Parplys, Ann C; Kratz, Katja; Speed, Michael C; Leung, Stanley G; Schild, David; Wiese, Claudia


    RAD51-associated protein 1 (RAD51AP1) is critical for homologous recombination (HR) by interacting with and stimulating the activities of the RAD51 and DMC1 recombinases. In human somatic cells, knockdown of RAD51AP1 results in increased sensitivity to DNA damaging agents and to impaired HR, but the formation of DNA damage-induced RAD51 foci is unaffected. Here, we generated a genetic model system, based on chicken DT40 cells, to assess the phenotype of fully inactivated RAD51AP1 in vertebrate cells. Targeted inactivation of both RAD51AP1 alleles has no effect on either viability or doubling-time in undamaged cells, but leads to increased levels of cytotoxicity after exposure to cisplatin or to ionizing radiation. Interestingly, ectopic expression of GgRAD51AP1, but not of HsRAD51AP1 is able to fully complement in cell survival assays. Notably, in RAD51AP1-deficient DT40 cells the resolution of DNA damage-induced RAD51 foci is greatly slowed down, while their formation is not impaired. We also identify, for the first time, an important role for RAD51AP1 in counteracting both spontaneous and DNA damage-induced replication stress. In human and in chicken cells, RAD51AP1 is required to maintain wild type speed of replication fork progression, and both RAD51AP1-depleted human cells and RAD51AP1-deficient DT40 cells respond to replication stress by a slow-down of replication fork elongation rates. However, increased firing of replication origins occurs in RAD51AP1-/- DT40 cells, likely to ensure the timely duplication of the entire genome. Taken together, our results may explain why RAD51AP1 commonly is overexpressed in tumor cells and tissues, and we speculate that the disruption of RAD51AP1 function could be a promising approach in targeted tumor therapy.

  4. Delayed onset of experimental autoimmune encephalomyelitis in Olig1 deficient mice.

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    Xiaoli Guo

    Full Text Available BACKGROUND: Olig1 is a basic helix-loop-helix (bHLH transcription factor that is essential for oligodendrogenesis and efficient remyelination. However, its role in neurodegenerative disorders has not been well-elucidated. METHODOLOGY/PRINCIPAL FINDINGS: Here we investigated the effects of Olig1 deficiency on experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS. We show that the mean disease onset of myelin oligodendrocyte glycoprotein (MOG-induced EAE in Olig1(-/- mice is significantly slower than wide-type (WT mice (19.8 ± 2.2 in Olig1(-/- mice and 9.5 ± 0.3 days in WT mice. In addition, 10% of Olig1(-/- mice did not develop EAE by the end of the observation periods (60 days. The severity of EAE, the extent of demyelination, and the activation of microglial cells and astrocytes in spinal cords, were significantly milder in Olig1(-/- mice compared with WT mice in the early stage. Moreover, the visual function, as assessed by the second-kernel of multifocal electroretinograms, was better preserved, and the number of degenerating axons in the optic nerve was significantly reduced in Olig1(-/- mice. Interestingly, Olig1 deficiency had no effect on T cell response capability, however, it reduced the expression of myelin proteins such as MOG, myelin basic protein (MBP and myelin-associated glycoprotein (MAG. The expression of Olig2 remained unchanged in the optic nerve and brain, and it was reduced in the spinal cord of Olig1(-/- mice. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the Olig1 signaling pathways may be involved in the incidence rate and the severity of neurological symptoms in MS.

  5. Mitochondrial alterations in PINK1 deficient cells are influenced by calcineurin-dependent dephosphorylation of dynamin-related protein 1.

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    Anna Sandebring

    Full Text Available PTEN-induced novel kinase 1 (PINK1 mutations are associated with autosomal recessive parkinsonism. Previous studies have shown that PINK1 influences both mitochondrial function and morphology although it is not clearly established which of these are primary events and which are secondary. Here, we describe a novel mechanism linking mitochondrial dysfunction and alterations in mitochondrial morphology related to PINK1. Cell lines were generated by stably transducing human dopaminergic M17 cells with lentiviral constructs that increased or knocked down PINK1. As in previous studies, PINK1 deficient cells have lower mitochondrial membrane potential and are more sensitive to the toxic effects of mitochondrial complex I inhibitors. We also show that wild-type PINK1, but not recessive mutant or kinase dead versions, protects against rotenone-induced mitochondrial fragmentation whereas PINK1 deficient cells show lower mitochondrial connectivity. Expression of dynamin-related protein 1 (Drp1 exaggerates PINK1 deficiency phenotypes and Drp1 RNAi rescues them. We also show that Drp1 is dephosphorylated in PINK1 deficient cells due to activation of the calcium-dependent phosphatase calcineurin. Accordingly, the calcineurin inhibitor FK506 blocks both Drp1 dephosphorylation and loss of mitochondrial integrity in PINK1 deficient cells but does not fully rescue mitochondrial membrane potential. We propose that alterations in mitochondrial connectivity in this system are secondary to functional effects on mitochondrial membrane potential.

  6. IL-12Rβ1 deficiency in two of fifty children with severe tuberculosis from Iran, Morocco, and Turkey.

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    Stéphanie Boisson-Dupuis

    Full Text Available BACKGROUND AND OBJECTIVES: In the last decade, autosomal recessive IL-12Rβ1 deficiency has been diagnosed in four children with severe tuberculosis from three unrelated families from Morocco, Spain, and Turkey, providing proof-of-principle that tuberculosis in otherwise healthy children may result from single-gene inborn errors of immunity. We aimed to estimate the fraction of children developing severe tuberculosis due to IL-12Rβ1 deficiency in areas endemic for tuberculosis and where parental consanguinity is common. METHODS AND PRINCIPAL FINDINGS: We searched for IL12RB1 mutations in a series of 50 children from Iran, Morocco, and Turkey. All children had established severe pulmonary and/or disseminated tuberculosis requiring hospitalization and were otherwise normally resistant to weakly virulent BCG vaccines and environmental mycobacteria. In one child from Iran and another from Morocco, homozygosity for loss-of-function IL12RB1 alleles was documented, resulting in complete IL-12Rβ1 deficiency. Despite the small sample studied, our findings suggest that IL-12Rβ1 deficiency is not a very rare cause of pediatric tuberculosis in these countries, where it should be considered in selected children with severe disease. SIGNIFICANCE: This finding may have important medical implications, as recombinant IFN-γ is an effective treatment for mycobacterial infections in IL-12Rβ1-deficient patients. It also provides additional support for the view that severe tuberculosis in childhood may result from a collection of single-gene inborn errors of immunity.

  7. Skeletal Muscle-Specific CPT1 Deficiency Elevates Lipotoxic Intermediates but Preserves Insulin Sensitivity

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    Wanchun Shi


    Full Text Available Objective. By specific knockout of carnitine palmitoyl transferase 1b (CPT1b in skeletal muscles, we explored the effect of CPT1b deficiency on lipids and insulin sensitivity. Methods. Mice with specific knockout of CPT1b in skeletal muscles (CPT1b M−/− were used for the experiment group, with littermate C57BL/6 as controls (CPT1b. General and metabolic profiles were measured and compared between groups. mRNA expression and CPT1 activity were measured in skeletal muscle tissues and compared between groups. Mitochondrial fatty acid oxidation (FAO, triglycerides (TAGs, diglycerides (DAGs, and ceramides were examined in skeletal muscles in two groups. Phosphorylated AKT (pAkt and glucose transporter 4 (Glut4 were determined with real-time polymerase chain reaction (RT-PCR. Insulin tolerance test, glucose tolerance test, and pyruvate oxidation were performed in both groups. Results. CPT1b M−/− model was successfully established, with impaired muscle CPT1 activity. Compared with CPT1b mice, CPT1b M−/− mice had similar food intake but lower body weight or fat mass and higher lipids but similar glucose or insulin levels. Their mitochondrial FAO of skeletal muscles was impaired. There were lipids accumulations (TAGs, DAGs, and ceramides in skeletal muscle. However, pAkt and Glut4, insulin sensitivity, glucose tolerance, and pyruvate oxidation were preserved. Conclusion. Skeletal muscle-specific CPT1 deficiency elevates lipotoxic intermediates but preserves insulin sensitivity.

  8. Heat shock transcription factor 1-deficiency attenuates overloading-associated hypertrophy of mouse soleus muscle. (United States)

    Koya, Tomoyuki; Nishizawa, Sono; Ohno, Yoshitaka; Goto, Ayumi; Ikuta, Akihiro; Suzuki, Miho; Ohira, Tomotaka; Egawa, Tatsuro; Nakai, Akira; Sugiura, Takao; Ohira, Yoshinobu; Yoshioka, Toshitada; Beppu, Moroe; Goto, Katsumasa


    Hypertrophic stimuli, such as mechanical stress and overloading, induce stress response, which is mediated by heat shock transcription factor 1 (HSF1), and up-regulate heat shock proteins (HSPs) in mammalian skeletal muscles. Therefore, HSF1-associated stress response may play a key role in loading-associated skeletal muscle hypertrophy. The purpose of this study was to investigate the effects of HSF1-deficiency on skeletal muscle hypertrophy caused by overloading. Functional overloading on the left soleus was performed by cutting the distal tendons of gastrocnemius and plantaris muscles for 4 weeks. The right muscle served as the control. Soleus muscles from both hindlimbs were dissected 2 and 4 weeks after the operation. Hypertrophy of soleus muscle in HSF1-null mice was partially inhibited, compared with that in wild-type (C57BL/6J) mice. Absence of HSF1 partially attenuated the increase of muscle wet weight and fiber cross-sectional area of overloaded soleus muscle. Population of Pax7-positive muscle satellite cells in HSF1-null mice was significantly less than that in wild-type mice following 2 weeks of overloading (pmuscle hypertrophy might be attributed to the greater and prolonged enhancement of IL-6 expression. HSF1 and/or HSF1-mediated stress response may, in part, play a key role in loading-induced skeletal muscle hypertrophy.

  9. Soluble guanylate cyclase α1-deficient mice: a novel murine model for primary open angle glaucoma.

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    Emmanuel S Buys

    Full Text Available Primary open angle glaucoma (POAG is a leading cause of blindness worldwide. The molecular signaling involved in the pathogenesis of POAG remains unknown. Here, we report that mice lacking the α1 subunit of the nitric oxide receptor soluble guanylate cyclase represent a novel and translatable animal model of POAG, characterized by thinning of the retinal nerve fiber layer and loss of optic nerve axons in the context of an open iridocorneal angle. The optic neuropathy associated with soluble guanylate cyclase α1-deficiency was accompanied by modestly increased intraocular pressure and retinal vascular dysfunction. Moreover, data from a candidate gene association study suggests that a variant in the locus containing the genes encoding for the α1 and β1 subunits of soluble guanylate cyclase is associated with POAG in patients presenting with initial paracentral vision loss, a disease subtype thought to be associated with vascular dysregulation. These findings provide new insights into the pathogenesis and genetics of POAG and suggest new therapeutic strategies for POAG.

  10. Modified Atkins diet therapy for a case with glucose transporter type 1 deficiency syndrome. (United States)

    Ito, Susumu; Oguni, Hirokazu; Ito, Yasushi; Ishigaki, Keiko; Ohinata, Junko; Osawa, Makiko


    Glucose transporter type 1 deficiency syndrome (GLUT-1 DS), giving rise to impaired glucose transport across the blood-brain barrier, is characterized by infantile seizures, complex motor disorders, global developmental delay, acquired microcephaly, and hypoglycorrhachia. GLUT-1 DS can be treated effectively with a ketogenic diet because it can provide an alternative fuel for brain metabolism; however, the excessive restriction of food intake involved frequently makes it difficult for patients to initiate or continue the diet. Recently, the modified Atkins diet, which is much less restrictive in terms of the total calorie and protein intake than the classical ketogenic diet, has been shown to be effective and well tolerated in children with intractable epilepsy. We successfully introduced the modified Atkins diet to a 7-year-old boy with GLUT-1 DS, whose caregivers refused ketogenic diet treatment because of strong concerns over restricting the diet. The modified Atkins diet should be considered for patients with GLUT-1 DS as an alternative to the traditional ketogenic diet.

  11. Effects of PARP-1 Deficiency on Th1 and Th2 Cell Differentiation

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    M. Sambucci


    Full Text Available T cell differentiation to effector Th cells such as Th1 and Th2 requires the integration of multiple synergic and antagonist signals. Poly(ADP-ribosylation is a posttranslational modification of proteins catalyzed by Poly(ADP-ribose polymerases (PARPs. Recently, many reports showed that PARP-1, the prototypical member of the PARP family, plays a role in immune/inflammatory responses. Consistently, its enzymatic inhibition confers protection in several models of immune-mediated diseases, mainly through an inhibitory effect on NF-κB (and NFAT activation. PARP-1 regulates cell functions in many types of immune cells, including dendritic cells, macrophages, and T and B lymphocytes. Our results show that PARP-1KO cells displayed a reduced ability to differentiate in Th2 cells. Under both nonskewing and Th2-polarizing conditions, naïve CD4 cells from PARP-1KO mice generated a reduced frequency of IL-4+ cells, produced less IL-5, and expressed GATA-3 at lower levels compared with cells from wild type mice. Conversely, PARP-1 deficiency did not substantially affect differentiation to Th1 cells. Indeed, the frequency of IFN-γ+ cells as well as IFN-γ production, in nonskewing and Th1-polarizing conditions, was not affected by PARP-1 gene ablation. These findings demonstrate that PARP-1 plays a relevant role in Th2 cell differentiation and it might be a target to be exploited for the modulation of Th2-dependent immune-mediated diseases.

  12. Sod1 deficiency reduces incubation time in mouse models of prion disease.

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    Shaheen Akhtar

    Full Text Available Prion infections, causing neurodegenerative conditions such as Creutzfeldt-Jakob disease and kuru in humans, scrapie in sheep and BSE in cattle are characterised by prolonged and variable incubation periods that are faithfully reproduced in mouse models. Incubation time is partly determined by genetic factors including polymorphisms in the prion protein gene. Quantitative trait loci studies in mice and human genome-wide association studies have confirmed that multiple genes are involved. Candidate gene approaches have also been used and identified App, Il1-r1 and Sod1 as affecting incubation times. In this study we looked for an association between App, Il1-r1 and Sod1 representative SNPs and prion disease incubation time in the Northport heterogeneous stock of mice inoculated with the Chandler/RML prion strain. No association was seen with App, however, significant associations were seen with Il1-r1 (P = 0.02 and Sod1 (P<0.0001 suggesting that polymorphisms at these loci contribute to the natural variation observed in incubation time. Furthermore, following challenge with Chandler/RML, ME7 and MRC2 prion strains, Sod1 deficient mice showed highly significant reductions in incubation time of 20, 13 and 24%, respectively. No differences were detected in Sod1 expression or activity. Our data confirm the protective role of endogenous Sod1 in prion disease.

  13. Occurrence of GLUT1 deficiency syndrome in patients treated with ketogenic diet. (United States)

    Ramm-Pettersen, Anette; Nakken, Karl O; Haavardsholm, Kathrine Cammermeyer; Selmer, Kaja Kristine


    Glucose transporter 1 deficiency syndrome (GLUT1-DS) is a treatable metabolic encephalopathy caused by a mutation in the SLC2A1 gene. This mutation causes a compromised transport of glucose across the blood-brain barrier. The treatment of choice is ketogenic diet, with which most patients become seizure-free. At the National Centre for Epilepsy, we have, since 2005, offered treatment with ketogenic diet (KD) and modified Atkins diet (MAD) to children with difficult-to-treat epilepsy. As we believe many children with GLUT1-DS are unrecognized, the aim of this study was to search for patients with GLUT1-DS among those who had been responders (>50% reduction in seizure frequency) to KD or MAD. Of the 130 children included, 58 (44%) were defined as responders. Among these, 11 were already diagnosed with GLUT1-DS. No mutations in the SLC2A1 gene were detected in the remaining patients. However, the clinical features of these patients differed considerably from the patients diagnosed with GLUT1-DS. While 9 out of 10 patients with GLUT1-DS became seizure-free with dietary treatment, only 3 out of the 33 remaining patients were seizure-free with KD or MAD treatment. We therefore conclude that a seizure reduction of >50% following dietary treatment is not a suitable criterion for identifying patients with GLUT1-DS, as these patients generally achieve complete seizure freedom shortly after diet initiation.

  14. Analysis of metabolic effects of menthol on WFS1-deficient mice. (United States)

    Ehrlich, Marite; Ivask, Marilin; Raasmaja, Atso; Kõks, Sulev


    In this study, we investigated the physiological regulation of energy metabolism in wild-type (WT) and WFS1-deficient (Wfs1KO) mice by measuring the effects of menthol treatment on the O2 consumption, CO2 production, rectal body temperature, and heat production. The basal metabolism and behavior was different between these genotypes as well as TRP family gene expressions. Wfs1KO mice had a shorter life span and weighed less than WT mice. The food and water intake of Wfs1KO mice was lower as well as the body temperature when compared to their WT littermates. Furthermore, Wfs1KO mice had higher basal O2 consumption, and CO2 and heat production than WT mice. In addition, Wfs1KO mice showed a higher response to menthol administration in comparison to WT mice. The strongest menthol effect was seen on different physiological measures 12 h after oral administration. The highest metabolic response of Wfs1KO mice was seen at the menthol dose of 10 mg/kg. Menthol increased O2 consumption, and CO2 and heat production in Wfs1KO mice when compared to their WT littermates. In addition, the expression of Trpm8 gene was increased. In conclusion, our results show that the Wfs1KO mice develop a metabolic phenotype characterized with several physiological dysfunctions.

  15. Monocyte chemotactic protein-1 deficiency reduces spontaneous metastasis of Lewis lung carcinoma in mice fed a high-fat diet (United States)

    Obesity is a risk factor for cancer. Adipose tissue produces pro-inflammatory adipokines that contribute obesity-related malignant progression. This study investigated the effects of monocyte chemotactic protein-1 (MCP-1) deficiency on pulmonary metastasis of Lewis lung carcinoma (LLC) in male C57...

  16. Cholestasis and hypercholesterolemia in SCD1-deficient mice fed a low-fat, high-carbohydrate diet

    NARCIS (Netherlands)

    M.T. Flowers; A.K. Groen; A.T. Oler; M.P. Keller; Y. Choi; K.L. Schueler; O.C. Richards; H. Lan; M. Miyazaki; F. Kuipers; C.M. Kendziorski; J.M. Ntambi; A.D. Attie


    Stearoyl-coenzyme A desaturase 1-deficient (SCD1(-/-)) mice have impaired MUFA synthesis. When maintained on a very low-fat (VLF) diet, SCD1(-/-) mice developed severe hypercholesterolemia, characterized by an increase in apolipoprotein B (apoB)-containing lipoproteins and the appearance of lipoprot

  17. Successful clinical treatment and functional immunological normalization of human MALT1 deficiency following hematopoietic stem cell transplantation. (United States)

    Rozmus, Jacob; McDonald, Rachel; Fung, Shan-Yu; Del Bel, Kate L; Roden, Juliana; Senger, Christof; Schultz, Kirk R; McKinnon, Margaret L; Davis, Jeffrey; Turvey, Stuart E


    MALT1 mutations impair normal NF-κB activation and paracaspase activity to cause a novel combined immunodeficiency. The clinical and immunological phenotype of MALT1 deficiency can be successfully treated with hematopoietic stem cell transplantation following reduced intensity conditioning.

  18. LPIN1 deficiency with severe recurrent rhabdomyolysis and persistent elevation of creatine kinase levels due to chromosome 2 maternal isodisomy

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    I.A. Meijer


    Full Text Available Fatty acid oxidation disorders and lipin-1 deficiency are the commonest genetic causes of rhabdomyolysis in children. We describe a lipin-1-deficient boy with recurrent, severe rhabdomyolytic episodes from the age of 4 years. Analysis of the LPIN1 gene that encodes lipin-1 revealed a novel homozygous frameshift mutation in exon 9, c.1381delC (p.Leu461SerfsX47, and complete uniparental isodisomy of maternal chromosome 2. This mutation is predicted to cause complete lipin-1 deficiency. The patient had six rhabdomyolytic crises, with creatine kinase (CK levels up to 300,000 U/L (normal, 30 to 200. Plasma CK remained elevated between crises. A treatment protocol was instituted, with early aggressive monitoring, hydration, electrolyte replacement and high caloric, high carbohydrate intake. The patient received dexamethasone during two crises, which was well-tolerated and in these episodes, peak CK values were lower than in preceding episodes. Studies of anti-inflammatory therapy may be indicated in lipin-1 deficiency.

  19. Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer (United States)

    Henneman, Linda; van Miltenburg, Martine H.; Michalak, Ewa M.; Braumuller, Tanya M.; Jaspers, Janneke E.; Drenth, Anne Paulien; de Korte-Grimmerink, Renske; Gogola, Ewa; Szuhai, Karoly; Schlicker, Andreas; Bin Ali, Rahmen; Pritchard, Colin; Huijbers, Ivo J.; Berns, Anton; Rottenberg, Sven; Jonkers, Jos


    Metaplastic breast carcinoma (MBC) is a rare histological breast cancer subtype characterized by mesenchymal elements and poor clinical outcome. A large fraction of MBCs harbor defects in breast cancer 1 (BRCA1). As BRCA1 deficiency sensitizes tumors to DNA cross-linking agents and poly(ADP-ribose) polymerase (PARP) inhibitors, we sought to investigate the response of BRCA1-deficient MBCs to the PARP inhibitor olaparib. To this end, we established a genetically engineered mouse model (GEMM) for BRCA1-deficient MBC by introducing the MET proto-oncogene into a BRCA1-associated breast cancer model, using our novel female GEMM ES cell (ESC) pipeline. In contrast to carcinomas, BRCA1-deficient mouse carcinosarcomas resembling MBC show intrinsic resistance to olaparib caused by increased P-glycoprotein (Pgp) drug efflux transporter expression. Indeed, resistance could be circumvented by using another PARP inhibitor, AZD2461, which is a poor Pgp substrate. These preclinical findings suggest that patients with BRCA1-associated MBC may show poor response to olaparib and illustrate the value of GEMM-ESC models of human cancer for evaluation of novel therapeutics. PMID:26100884

  20. Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer. (United States)

    Henneman, Linda; van Miltenburg, Martine H; Michalak, Ewa M; Braumuller, Tanya M; Jaspers, Janneke E; Drenth, Anne Paulien; de Korte-Grimmerink, Renske; Gogola, Ewa; Szuhai, Karoly; Schlicker, Andreas; Bin Ali, Rahmen; Pritchard, Colin; Huijbers, Ivo J; Berns, Anton; Rottenberg, Sven; Jonkers, Jos


    Metaplastic breast carcinoma (MBC) is a rare histological breast cancer subtype characterized by mesenchymal elements and poor clinical outcome. A large fraction of MBCs harbor defects in breast cancer 1 (BRCA1). As BRCA1 deficiency sensitizes tumors to DNA cross-linking agents and poly(ADP-ribose) polymerase (PARP) inhibitors, we sought to investigate the response of BRCA1-deficient MBCs to the PARP inhibitor olaparib. To this end, we established a genetically engineered mouse model (GEMM) for BRCA1-deficient MBC by introducing the MET proto-oncogene into a BRCA1-associated breast cancer model, using our novel female GEMM ES cell (ESC) pipeline. In contrast to carcinomas, BRCA1-deficient mouse carcinosarcomas resembling MBC show intrinsic resistance to olaparib caused by increased P-glycoprotein (Pgp) drug efflux transporter expression. Indeed, resistance could be circumvented by using another PARP inhibitor, AZD2461, which is a poor Pgp substrate. These preclinical findings suggest that patients with BRCA1-associated MBC may show poor response to olaparib and illustrate the value of GEMM-ESC models of human cancer for evaluation of novel therapeutics.

  1. Defective small intestinal anion secretion, dipeptide absorption, and intestinal failure in suckling NBCe1-deficient mice. (United States)

    Yu, Qin; Liu, Xuemei; Liu, Yongjian; Riederer, Brigitte; Li, Taolang; Tian, De-An; Tuo, Biguang; Shull, Gary; Seidler, Ursula


    The electrogenic Na(+)HCO3 (-) cotransporter NBCe1 (Slc4a4) is strongly expressed in the basolateral enterocyte membrane in a villous/surface predominant fashion. In order to better understand its physiological function in the intestine, isolated mucosae in miniaturized Ussing chambers and microdissected intestinal villi or crypts loaded with the fluorescent pH-indicator BCECF were studied from the duodenum, jejunum, and colon of 14- to 17-days-old slc4a4-deficient (KO) and WT mice. NBCe1 was active in the basal state in all intestinal segments under study, most likely to compensate for acid loads imposed upon the enterocytes. Upregulation of other basolateral base uptake mechanism occurs, but in a segment-specific fashion. Loss of NBCe1 resulted in severely impaired Cl(-) and fluid secretory response, but not HCO3 (-) secretory response to agonist stimulation. In addition, NBCe1 was found to be active during transport processes that load the surface enterocytes with acid, such as Slc26a3 (DRA)-mediated luminal Cl(-)/HCO3 (-) exchange or PEPT1-mediated H(+)/dipeptide uptake. Possibly because of the high energy demand for hyperventilation in conjunction with the fluid secretory and nutrient absorptive defects and the relative scarcity of compensatory mechanisms, NBCe1-deficient mice developed progressive jejunal failure, worsening of metabolic acidosis, and death in the third week of life. Our data suggest that the electrogenic influx of base via NBCe1 maintains enterocyte anion homeostasis and pHi control. Its loss impairs small intestinal Cl(-) and fluid secretion as well as the neutralization of acid loads imposed on the enterocytes during nutrient and electrolyte absorption.

  2. PTRF/Cavin-1 Deficiency Causes Cardiac Dysfunction Accompanied by Cardiomyocyte Hypertrophy and Cardiac Fibrosis (United States)

    Ogata, Takehiro; Kasahara, Takeru; Nakanishi, Naohiko; Miyagawa, Kotaro; Naito, Daisuke; Hamaoka, Tetsuro; Nishi, Masahiro; Matoba, Satoaki; Ueyama, Tomomi


    Mutations in the PTRF/Cavin-1 gene cause congenital generalized lipodystrophy type 4 (CGL4) associated with myopathy. Additionally, long-QT syndrome and fatal cardiac arrhythmia are observed in patients with CGL4 who have homozygous PTRF/Cavin-1 mutations. PTRF/Cavin-1 deficiency shows reductions of caveolae and caveolin-3 (Cav3) protein expression in skeletal muscle, and Cav3 deficiency in the heart causes cardiac hypertrophy with loss of caveolae. However, it remains unknown how loss of PTRF/Cavin-1 affects cardiac morphology and function. Here, we present a characterization of the hearts of PTRF/Cavin-1-null (PTRF−/−) mice. Electron microscopy revealed the reduction of caveolae in cardiomyocytes of PTRF−/− mice. PTRF−/− mice at 16 weeks of age developed a progressive cardiomyopathic phenotype with wall thickening of left ventricles and reduced fractional shortening evaluated by echocardiography. Electrocardiography revealed that PTRF−/− mice at 24 weeks of age had low voltages and wide QRS complexes in limb leads. Histological analysis showed cardiomyocyte hypertrophy accompanied by progressive interstitial/perivascular fibrosis. Hypertrophy-related fetal gene expression was also induced in PTRF−/− hearts. Western blotting analysis and quantitative RT-PCR revealed that Cav3 expression was suppressed in PTRF−/− hearts compared with that in wild-type (WT) ones. ERK1/2 was activated in PTRF−/− hearts compared with that in WT ones. These results suggest that loss of PTRF/Cavin-1 protein expression is sufficient to induce a molecular program leading to cardiomyocyte hypertrophy and cardiomyopathy, which is partly attributable to Cav3 reduction in the heart. PMID:27612189

  3. Olfactomedin 1 Deficiency Leads to Defective Olfaction and Impaired Female Fertility. (United States)

    Li, Rong; Diao, Honglu; Zhao, Fei; Xiao, Shuo; El Zowalaty, Ahmed E; Dudley, Elizabeth A; Mattson, Mark P; Ye, Xiaoqin


    Olfactomedin 1 (OLFM1) is a glycoprotein highly expressed in the brain. Olfm1(-/-) female mice were previously reported to have reduced fertility. Previous microarray analysis revealed Olfm1 among the most highly upregulated genes in the uterine luminal epithelium upon embryo implantation, which was confirmed by in situ hybridization. We hypothesized that Olfm1 deficiency led to defective embryo implantation and thus impaired fertility. Indeed, Olfm1(-/-) females had defective embryo implantation. However, Olfm1(-/-) females rarely mated and those that mated rarely became pregnant. Ovarian histology indicated the absence of corpora lutea in Olfm1(-/-) females, indicating defective ovulation. Superovulation using equine chorionic gonadotropin-human chorionic gonadotropin rescued mating, ovulation, and pregnancy, and equine chorionic gonadotropin alone rescued ovulation in Olfm1(-/-) females. Olfm1(-/-) females had a 13% reduction of hypothalamic GnRH neurons but comparable basal serum LH levels and GnRH-induced LH levels compared with wild-type controls. These results indicated no obvious local defects in the female reproductive system and a functional hypothalamic-pituitary-gonadal axis. Olfm1(-/-) females were unresponsive to the effects of male bedding stimulation on pubertal development and estrous cycle. There were 41% fewer cFos-positive cells in the mitral cell layer of accessory olfactory bulb upon male urine stimulation for 90 minutes. OLFM1 was expressed in the main and accessory olfactory systems including main olfactory epithelium, vomeronasal organ, main olfactory bulb, and accessory olfactory bulb, with the highest expression detected in the axon bundles of olfactory sensory neurons. These data demonstrate that defective fertility in Olfm1(-/-) females is most likely a secondary effect of defective olfaction.

  4. Human TLR1 Deficiency Is Associated with Impaired Mycobacterial Signaling and Protection from Leprosy Reversal Reaction (United States)

    Misch, Elizabeth A.; Macdonald, Murdo; Ranjit, Chaman; Sapkota, Bishwa R.; Wells, Richard D.; Siddiqui, M. Ruby; Kaplan, Gilla; Hawn, Thomas R.


    Toll-like receptors (TLRs) are important regulators of the innate immune response to pathogens, including Mycobacterium leprae, which is recognized by TLR1/2 heterodimers. We previously identified a transmembrane domain polymorphism, TLR1_T1805G, that encodes an isoleucine to serine substitution and is associated with impaired signaling. We hypothesized that this TLR1 SNP regulates the innate immune response and susceptibility to leprosy. In HEK293 cells transfected with the 1805T or 1805G variant and stimulated with extracts of M. leprae, NF-κB activity was impaired in cells with the 1805G polymorphism. We next stimulated PBMCs from individuals with different genotypes for this SNP and found that 1805GG individuals had significantly reduced cytokine responses to both whole irradiated M. leprae and cell wall extracts. To investigate whether TLR1 variation is associated with clinical presentations of leprosy or leprosy immune reactions, we examined 933 Nepalese leprosy patients, including 238 with reversal reaction (RR), an immune reaction characterized by a Th1 T cell cytokine response. We found that the 1805G allele was associated with protection from RR with an odds ratio (OR) of 0.51 (95% CI 0.29–0.87, p = 0.01). Individuals with 1805 genotypes GG or TG also had a reduced risk of RR in comparison to genotype TT with an OR of 0.55 (95% CI 0.31–0.97, p = 0.04). To our knowledge, this is the first association of TLR1 with a Th1-mediated immune response. Our findings suggest that TLR1 deficiency influences adaptive immunity during leprosy infection to affect clinical manifestations such as nerve damage and disability. PMID:18461142

  5. Human TLR1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction.

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    Elizabeth A Misch

    Full Text Available Toll-like receptors (TLRs are important regulators of the innate immune response to pathogens, including Mycobacterium leprae, which is recognized by TLR1/2 heterodimers. We previously identified a transmembrane domain polymorphism, TLR1_T1805G, that encodes an isoleucine to serine substitution and is associated with impaired signaling. We hypothesized that this TLR1 SNP regulates the innate immune response and susceptibility to leprosy. In HEK293 cells transfected with the 1805T or 1805G variant and stimulated with extracts of M. leprae, NF-kappaB activity was impaired in cells with the 1805G polymorphism. We next stimulated PBMCs from individuals with different genotypes for this SNP and found that 1805GG individuals had significantly reduced cytokine responses to both whole irradiated M. leprae and cell wall extracts. To investigate whether TLR1 variation is associated with clinical presentations of leprosy or leprosy immune reactions, we examined 933 Nepalese leprosy patients, including 238 with reversal reaction (RR, an immune reaction characterized by a Th1 T cell cytokine response. We found that the 1805G allele was associated with protection from RR with an odds ratio (OR of 0.51 (95% CI 0.29-0.87, p = 0.01. Individuals with 1805 genotypes GG or TG also had a reduced risk of RR in comparison to genotype TT with an OR of 0.55 (95% CI 0.31-0.97, p = 0.04. To our knowledge, this is the first association of TLR1 with a Th1-mediated immune response. Our findings suggest that TLR1 deficiency influences adaptive immunity during leprosy infection to affect clinical manifestations such as nerve damage and disability.

  6. Marrow Adipose Tissue Expansion Coincides with Insulin Resistance in MAGP1-Deficient Mice. (United States)

    Walji, Tezin A; Turecamo, Sarah E; Sanchez, Alejandro Coca; Anthony, Bryan A; Abou-Ezzi, Grazia; Scheller, Erica L; Link, Daniel C; Mecham, Robert P; Craft, Clarissa S


    Marrow adipose tissue (MAT) is an endocrine organ with the potential to influence skeletal remodeling and hematopoiesis. Pathologic MAT expansion has been studied in the context of severe metabolic challenge, including caloric restriction, high fat diet feeding, and leptin deficiency. However, the rapid change in peripheral fat and glucose metabolism associated with these models impedes our ability to examine which metabolic parameters precede or coincide with MAT expansion. Microfibril-associated glycoprotein-1 (MAGP1) is a matricellular protein that influences cellular processes by tethering signaling molecules to extracellular matrix structures. MAGP1-deficient (Mfap2 (-/-)) mice display a progressive excess adiposity phenotype, which precedes insulin resistance and occurs without changes in caloric intake or ambulation. Mfap2 (-/-) mice were, therefore, used as a model to associate parameters of metabolic disease, bone remodeling, and hematopoiesis with MAT expansion. Marrow adiposity was normal in Mfap2 (-/-) mice until 6 months of age; however, by 10 months, marrow fat volume had increased fivefold relative to wild-type control at the same age. Increased gonadal fat pad mass and hyperglycemia were detectable in Mfap2 (-/-) mice by 2 months, but peaked by 6 months. The development of insulin resistance coincided with MAT expansion. Longitudinal characterization of bone mass demonstrated a disconnection in MAT volume and bone volume. Specifically, Mfap2 (-/-) mice had reduced trabecular bone volume by 2 months, but this phenotype did not progress with age or MAT expansion. Interestingly, MAT expansion in the 10-month-old Mfap2 (-/-) mice was associated with modest alterations in basal hematopoiesis, including a shift from granulopoiesis to B lymphopoiesis. Together, these findings indicate MAT expansion is coincident with insulin resistance, but not excess peripheral adiposity or hyperglycemia in Mfap2 (-/-) mice; and substantial MAT accumulation does

  7. Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis. (United States)

    Rabinovich, Shiran; Adler, Lital; Yizhak, Keren; Sarver, Alona; Silberman, Alon; Agron, Shani; Stettner, Noa; Sun, Qin; Brandis, Alexander; Helbling, Daniel; Korman, Stanley; Itzkovitz, Shalev; Dimmock, David; Ulitsky, Igor; Nagamani, Sandesh C S; Ruppin, Eytan; Erez, Ayelet


    Cancer cells hijack and remodel existing metabolic pathways for their benefit. Argininosuccinate synthase (ASS1) is a urea cycle enzyme that is essential in the conversion of nitrogen from ammonia and aspartate to urea. A decrease in nitrogen flux through ASS1 in the liver causes the urea cycle disorder citrullinaemia. In contrast to the well-studied consequences of loss of ASS1 activity on ureagenesis, the purpose of its somatic silencing in multiple cancers is largely unknown. Here we show that decreased activity of ASS1 in cancers supports proliferation by facilitating pyrimidine synthesis via CAD (carbamoyl-phosphate synthase 2, aspartate transcarbamylase, and dihydroorotase complex) activation. Our studies were initiated by delineating the consequences of loss of ASS1 activity in humans with two types of citrullinaemia. We find that in citrullinaemia type I (CTLN I), which is caused by deficiency of ASS1, there is increased pyrimidine synthesis and proliferation compared with citrullinaemia type II (CTLN II), in which there is decreased substrate availability for ASS1 caused by deficiency of the aspartate transporter citrin. Building on these results, we demonstrate that ASS1 deficiency in cancer increases cytosolic aspartate levels, which increases CAD activation by upregulating its substrate availability and by increasing its phosphorylation by S6K1 through the mammalian target of rapamycin (mTOR) pathway. Decreasing CAD activity by blocking citrin, the mTOR signalling, or pyrimidine synthesis decreases proliferation and thus may serve as a therapeutic strategy in multiple cancers where ASS1 is downregulated. Our results demonstrate that ASS1 downregulation is a novel mechanism supporting cancerous proliferation, and they provide a metabolic link between the urea cycle enzymes and pyrimidine synthesis.

  8. NKCC1-deficiency results in abnormal proliferation of neural progenitor cells of the lateral ganglionic eminence

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    Ana Cathia Magalhães


    Full Text Available The proliferative pool of neural progenitor cells is maintained by exquisitely controlled mechanisms for cell cycle regulation. The Na-K-Cl cotransporter NKCC1 is important for regulating cell volume and the proliferation of different cell types in vitro. NKCC1 is expressed in ventral telencephalon of embryonic brains suggesting a potential role in neural development of this region. The ventral telencephalon is a major source for both interneuron and oligodendrocyte precursor cells. Whether NKCC1 is involved in the proliferation of these cell populations remains unknown. In order to assess this question, we monitored several markers for neural, neuronal, and proliferating cells in wild-type and NKCC1 knockout mouse brains. We found that NKCC1 was expressed in neural progenitor cells from the lateral ganglionic eminence (LGE at E12.5. Mice lacking NKCC1 expression displayed reduced PH3-labeled mitotic cells in the ventricular zone and reduced cell cycle reentry. Accordingly, we found a significant reduction of Sp8-labeled immature interneurons migrating from the dorsal LGE in NKCC1-deficient mice at a later developmental stage. Interestingly, at E14.5, NKCC1 regulated also the formation of Olig2-labeled oligodendrocyte precursor cells. Collectively, these findings show that NKCC1 serves in vivo as a modulator of the cell cycle decision in the developing ventral telencephalon at the early stage of neurogenesis. These results present a novel mechanistic avenue to be considered in the recent proposed involvement of chloride transporters in a number of developmentally related diseases such as epilepsy, autism, and schizophrenia.

  9. Mendelian Susceptibility to Mycobacterial Disease due to IL-12Rβ1 Deficiency in Three Iranian Children

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    Shokouh azam SARRAFZADEH


    Full Text Available Mendelian susceptibility to mycobacterial diseases (MSMD is a rare inheritance syndrome, characterized by a disseminated infection with mycobacterium in children following BCG vaccination at birth. Regarding the vaccination program in Iran, it may consider as a public health problem. The pathogenesis of MSMD is dependent on either insufficient production of IFN-gamma (γ or inadequate response to it. Here, we want to introduce three cases including two siblings and one girl from two unrelated families with severe mycobacterial infections referred to Immunology, Asthma and Allergy Research Institute (IAARI, from 2013 to 2015; their MSMD was confirmed by both cytokine assessment and genetic analysis. Regarding the clinical features of the patients, cell proliferation against a mitogen and BCG antigen was ordered in a lymphocyte transformation test (LTT setting. ELISA was performed for the measurement of IL-12p70 and IFN- γ in whole blood samples activated by BCG + recombinant human IFN-γ and BCG + recombinant human IL-12, respectively. In contrast to mitogen, the antigen-dependent proliferation activity of the patients’ leukocytes was significantly lower than that in normal range. We identified a homozygous mutation in IL12RB1 gene for two kindred who had a homozygous mutation affecting an essential splice site. For the third patient, a novel frameshift deletion in IL12RB1 gene was found. The genetic study results confirmed the impaired function of stimulated lymphocytes to release IFN-γ following stimulation with BCG+IL-12 while the response to rhIFN-γ for IL-12p70 production was relatively intact. Our findings show that cellular and molecular assessments are needed for precise identification of immunodeficiency disorders especially those without clear-cut diagnostic criteria. Keywords: Mendelian, IL-12Rβ1 Deficiency, Interfron-gamma, Interleukin 12, Mycobacterium

  10. Trps1 deficiency inhibits the morphogenesis of secondary hair follicles via decreased Noggin expression

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    Sun, Yujing [Department of Pathology, School of Medicine, Shandong University, Jinan Wen Hua Xi Road 44, Jinan 250012 (China); Nakanishi, Masako; Sato, Fuyuki; Oikawa, Kosuke [First Department of Pathology, Wakayama Medical University School of Medicine, 811-1 Kimiidera, Wakayama 641-0012 (Japan); Muragaki, Yasuteru, E-mail: [First Department of Pathology, Wakayama Medical University School of Medicine, 811-1 Kimiidera, Wakayama 641-0012 (Japan); Zhou, Gengyin, E-mail: [Department of Pathology, School of Medicine, Shandong University, Jinan Wen Hua Xi Road 44, Jinan 250012 (China)


    Highlights: • The number of secondary hair follicles is reduced by half in Trps1 KO embryonic skin compared to wild-type skin. • Noggin expression is significantly decreased and BMP signaling is promoted in Trps1 KO embryonic skin. • Treatment with a Noggin or BMP inhibitor rescued the decreased number of hair follicles in Trps1 KO skin graft cultures. • Cell proliferation and apoptosis of the epidermis were normalized by Noggin treatment. - Abstract: A representative phenotype of patients with tricho-rhino-phalangeal syndrome (TRPS) is sparse hair. To understand the developmental defects of these patient’s hair follicles, we analyzed the development of hair follicles histologically and biochemically using Trps1 deficient (KO) mice. First, we compared the numbers of primary hair follicles in wild-type (WT) and KO embryos at different developmental stages. No differences were observed in the E14.5 skins of WT and KO mice. However, at later time points, KO fetal skin failed to properly develop secondary hair follicles, and the number of secondary hair follicles present in E18.5 KO skin was approximately half compared to that of WT skin. Sonic hedgehog expression was significantly decreased in E17.5 KO skin, whereas no changes were observed in Eda/Edar expression in E14.5 or E17.5 skins. In addition, Noggin expression was significantly decreased in E14.5 and E17.5 KO skin compared to WT skin. In parallel with the suppression of Noggin expression, BMP signaling was promoted in the epidermal cells of KO skins compared to WT skins as determined by immunohistochemistry for phosphorylated Smad1/5/8. The reduced number of secondary hair follicles was restored in skin graft cultures treated with a Noggin and BMP inhibitor. Furthermore, decreased cell proliferation, and increased apoptosis in KO skin was rescued by Noggin treatment. Taken together, we conclude that hair follicle development in Trps1 KO embryos is impaired directly or indirectly by decreased Noggin

  11. Fractalkine receptor (CX3CR1 deficiency sensitizes mice to the behavioral changes induced by lipopolysaccharide

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    Kelley Keith W


    Full Text Available Abstract Background Interactions between fractalkine (CX3CL1 and fractalkine receptor (CX3CR1 regulate microglial activation in the CNS. Recent findings indicate that age-associated impairments in CX3CL1 and CX3CR1 are directly associated with exaggerated microglial activation and an impaired recovery from sickness behavior after peripheral injection of lipopolysaccharide (LPS. Therefore, the purpose of this study was to determine the extent to which an acute LPS injection causes amplified and prolonged microglial activation and behavioral deficits in CX3CR1-deficient mice (CX3CR1-/-. Methods CX3CR1-/- mice or control heterozygote mice (CX3CR1+/- were injected with LPS (0.5 mg/kg i.p. or saline and behavior (i.e., sickness and depression-like behavior, microglial activation, and markers of tryptophan metabolism were determined. All data were analyzed using Statistical Analysis Systems General Linear Model procedures and were subjected to one-, two-, or three-way ANOVA to determine significant main effects and interactions. Results LPS injection caused a prolonged duration of social withdrawal in CX3CR1-/- mice compared to control mice. This extended social withdrawal was associated with enhanced mRNA expression of IL-1β, indolamine 2,3-dioxygenase (IDO and kynurenine monooxygenase (KMO in microglia 4 h after LPS. Moreover, elevated expression of IL-1β and CD14 was still detected in microglia of CX3CR1-/- mice 24 h after LPS. There was also increased turnover of tryptophan, serotonin, and dopamine in the brain 24 h after LPS, but these increases were independent of CX3CR1 expression. When submitted to the tail suspension test 48 and 72 h after LPS, an increased duration of immobility was evident only in CX3CR1-/- mice. This depression-like behavior in CX3CR1-/- mice was associated with a persistent activated microglial phenotype in the hippocampus and prefrontal cortex. Conclusions Taken together, these data indicate that a deficiency of CX3CR1

  12. Oxidative stress markers and phosphorus magnetic resonance spectroscopy in a patient with GLUT1 deficiency treated with modified Atkins diet. (United States)

    Kitamura, Yuri; Okumura, Akihisa; Hayashi, Masaharu; Mori, Harushi; Takahashi, Satoru; Yanagihara, Keiko; Miyata, Rie; Tanuma, Naoyuki; Mimaki, Takashi; Abe, Shinpei; Shimizu, Toshiaki


    Glucose transporter type 1 deficiency syndrome is an inborn error of glucose transport across blood-tissue barriers, and the modified Atkins diet is an effective and well-tolerated treatment. To investigate the effects of the modified Atkins diet, we examined the cerebrospinal fluid markers and performed phosphorus magnetic resonance spectroscopy in a patient with glucose transporter type 1 deficiency syndrome before and after the modified Atkins diet. Cerebrospinal fluid levels of the oxidative stress markers, 8-hydroxy-2'-deoxyguanosine and hexanoyl-lysine adduct, were markedly increased above the cutoff index and were normalized 18 months after the modified Atkins diet. Phosphorus magnetic resonance spectroscopy measurements showed 18% increase of PCr/γ-ATP ratio after the modified Atkins diet. These results suggest that the modified Atkins diet may reduce oxidative stress in the brain and improve energy reserve capacity, which is important in sustaining electrophysiological activities essential for performing brain functions.

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




    Similar to mammalian fetuses FOXN1 deficient (nude) mice are able to restore the structure and integrity of injured skin in a scarless healing process by mechanisms independent of the genetic background. Matrix metalloproteinases (MMPs) are required for regular skin wound healing and the distinctive pattern of their expression has been implicated to promote scarless healing. In this study, we analyzed the temporal and spatial expression patterns of these molecules during the incisional skin w...

  15. Characterization of P1-deficient isogenic mutant of Haemophilus influenzae biogroup aegyptius associated with Brazilian purpuric fever. (United States)

    Segada, L M; Carlone, G M; Gheesling, L L; Lesse, A J


    Haemophilus influenzae biogroup aegyptius (formerly H. aegyptius) is the etiologic agent of Brazilian purpuric fever (BPF). A surface-exposed epitope on the outer membrane protein P1 is present on most strains of H. influenzae biogroup aegyptius associated with BPF but is absent in almost all non-disease associated strains. The role of the outer membrane protein P1 in the pathogenesis of this disease was evaluated by utilizing an isogenic P1-deficient mutant. We compared the ability of the wild type and P1 isogenic mutant to grow under various conditions. The P1-deficient strain grew at a similar rate to the wild type in both complex and chemically defined medium. The P1-deficient mutant also had a similar growth rate to the wild type under anaerobic conditions. Anaerobic growth, however, resulted in up-regulation of the P1 protein in the wild type strain. Three assays were used to examine the pathophysiologic role of the P1 protein in BPF: 1) serum resistance; 2) sustained bacteremia in the infant rat model; and 3) the human microvascular endothelial cell (HMEC) cytotoxicity assay. Both the mutant and wild-type strains were resistant to killing in 95% normal human serum. The P1-deficient strain was also as virulent as the wild type in both the infant rat model of bacteremia and in the HMEC-1 tissue culture model. These results demonstrate that serum resistance, sustained bacteremia in the infant rat, and cytotoxicity of HMEC cells occur in the absence of P1. The P1 protein is not essential for the pathogenic potential identified by these assays. However, these results demonstrate that an anaerobic environment is a potent physiologic regulator of P1 protein expression. The impact of anaerobiosis on protein expression and pathogenesis will require further investigations.

  16. Hypercholesterolemia and changes in lipid and bile acid metabolism in male and female cyp7A1-deficient mice. (United States)

    Erickson, Sandra K; Lear, Steven R; Deane, Sean; Dubrac, Sandrine; Huling, Sandra L; Nguyen, Lien; Bollineni, Jaya S; Shefer, Sarah; Hyogo, Hideyuki; Cohen, David E; Shneider, Benjamin; Sehayek, Ephraim; Ananthanarayanan, Meena; Balasubramaniyan, Natarajan; Suchy, Fredrick J; Batta, Ashok K; Salen, Gerald


    Cholesterol 7alpha-hydroxylase, a rate-limiting enzyme for bile acid synthesis, has been implicated in genetic susceptibility to atherosclerosis. The gene, CYP7A1, encoding a protein with this activity, is expressed normally only in hepatocytes and is highly regulated. Our cyp7A1 gene knockout mouse colony, as young adults on a chow diet, is hypercholesterolemic. These mice were characterized extensively to understand how cyp7A1 affects lipid and bile acid homeostasis in different tissue compartments and whether gender plays a modifying role. Both male and female cyp7A1-deficient mice had decreased hepatic LDL receptors, unchanged hepatic cholesterol synthesis, increased intestinal cholesterol synthesis and bile acid transporters, and decreased fecal bile acids but increased fecal sterols. In females, cyp7A1 deficiency also caused changes in hepatic fatty acid metabolism, decreased hepatic canalicular bile acid transporter, Bsep, and gallbladder bile composition altered to a lithogenic profile. Taken together, the data suggest that cyp7A1 deficiency results in a proatherogenic phenotype in both genders and leads to a prolithogenic phenotype in females.

  17. A novel approach to analyze lysosomal dysfunctions through subcellular proteomics and lipidomics: the case of NPC1 deficiency (United States)

    Tharkeshwar, Arun Kumar; Trekker, Jesse; Vermeire, Wendy; Pauwels, Jarne; Sannerud, Ragna; Priestman, David A.; Te Vruchte, Danielle; Vints, Katlijn; Baatsen, Pieter; Decuypere, Jean-Paul; Lu, Huiqi; Martin, Shaun; Vangheluwe, Peter; Swinnen, Johannes V.; Lagae, Liesbet; Impens, Francis; Platt, Frances M.; Gevaert, Kris; Annaert, Wim


    Superparamagnetic iron oxide nanoparticles (SPIONs) have mainly been used as cellular carriers for genes and therapeutic products, while their use in subcellular organelle isolation remains underexploited. We engineered SPIONs targeting distinct subcellular compartments. Dimercaptosuccinic acid-coated SPIONs are internalized and accumulate in late endosomes/lysosomes, while aminolipid-SPIONs reside at the plasma membrane. These features allowed us to establish standardized magnetic isolation procedures for these membrane compartments with a yield and purity permitting proteomic and lipidomic profiling. We validated our approach by comparing the biomolecular compositions of lysosomes and plasma membranes isolated from wild-type and Niemann-Pick disease type C1 (NPC1) deficient cells. While the accumulation of cholesterol and glycosphingolipids is seen as a primary hallmark of NPC1 deficiency, our lipidomics analysis revealed the buildup of several species of glycerophospholipids and other storage lipids in selectively late endosomes/lysosomes of NPC1-KO cells. While the plasma membrane proteome remained largely invariable, we observed pronounced alterations in several proteins linked to autophagy and lysosomal catabolism reflecting vesicular transport obstruction and defective lysosomal turnover resulting from NPC1 deficiency. Thus the use of SPIONs provides a major advancement in fingerprinting subcellular compartments, with an increased potential to identify disease-related alterations in their biomolecular compositions.

  18. Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration.

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    Suzana Gispert

    Full Text Available BACKGROUND: Parkinson's disease (PD is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1 cause the recessive PARK6 variant of PD. METHODOLOGY/PRINCIPAL FINDINGS: Now we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements occurred at old age. As in PD, abnormal dopamine levels in the aged nigrostriatal projection accompanied the reduced movements. Possibly in line with the PARK6 syndrome but in contrast to sporadic PD, a reduced lifespan, dysfunction of brainstem and sympathetic nerves, visible aggregates of alpha-synuclein within Lewy bodies or nigrostriatal neurodegeneration were not present in aged PINK1-deficient mice. However, we demonstrate PINK1 mutant mice to exhibit a progressive reduction in mitochondrial preprotein import correlating with defects of core mitochondrial functions like ATP-generation and respiration. In contrast to the strong effect of PINK1 on mitochondrial dynamics in Drosophila melanogaster and in spite of reduced expression of fission factor Mtp18, we show reduced fission and increased aggregation of mitochondria only under stress in PINK1-deficient mouse neurons. CONCLUSION: Thus, aging Pink1(-/- mice show increasing mitochondrial dysfunction resulting in impaired neural activity similar to PD, in absence of overt neuronal death.

  19. A novel approach to analyze lysosomal dysfunctions through subcellular proteomics and lipidomics: the case of NPC1 deficiency (United States)

    Tharkeshwar, Arun Kumar; Trekker, Jesse; Vermeire, Wendy; Pauwels, Jarne; Sannerud, Ragna; Priestman, David A.; te Vruchte, Danielle; Vints, Katlijn; Baatsen, Pieter; Decuypere, Jean-Paul; Lu, Huiqi; Martin, Shaun; Vangheluwe, Peter; Swinnen, Johannes V.; Lagae, Liesbet; Impens, Francis; Platt, Frances M.; Gevaert, Kris; Annaert, Wim


    Superparamagnetic iron oxide nanoparticles (SPIONs) have mainly been used as cellular carriers for genes and therapeutic products, while their use in subcellular organelle isolation remains underexploited. We engineered SPIONs targeting distinct subcellular compartments. Dimercaptosuccinic acid-coated SPIONs are internalized and accumulate in late endosomes/lysosomes, while aminolipid-SPIONs reside at the plasma membrane. These features allowed us to establish standardized magnetic isolation procedures for these membrane compartments with a yield and purity permitting proteomic and lipidomic profiling. We validated our approach by comparing the biomolecular compositions of lysosomes and plasma membranes isolated from wild-type and Niemann-Pick disease type C1 (NPC1) deficient cells. While the accumulation of cholesterol and glycosphingolipids is seen as a primary hallmark of NPC1 deficiency, our lipidomics analysis revealed the buildup of several species of glycerophospholipids and other storage lipids in selectively late endosomes/lysosomes of NPC1-KO cells. While the plasma membrane proteome remained largely invariable, we observed pronounced alterations in several proteins linked to autophagy and lysosomal catabolism reflecting vesicular transport obstruction and defective lysosomal turnover resulting from NPC1 deficiency. Thus the use of SPIONs provides a major advancement in fingerprinting subcellular compartments, with an increased potential to identify disease-related alterations in their biomolecular compositions. PMID:28134274

  20. Pancreas-Specific Sirt1-Deficiency in Mice Compromises Beta-Cell Function without Development of Hyperglycemia.

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    Andreia V Pinho

    Full Text Available Sirtuin 1 (Sirt1 has been reported to be a critical positive regulator of glucose-stimulated insulin secretion in pancreatic beta-cells. The effects on islet cells and blood glucose levels when Sirt1 is deleted specifically in the pancreas are still unclear.This study examined islet glucose responsiveness, blood glucose levels, pancreatic islet histology and gene expression in Pdx1Cre; Sirt1ex4F/F mice that have loss of function and loss of expression of Sirt1 specifically in the pancreas.We found that in the Pdx1Cre; Sirt1ex4F/F mice, the relative insulin positive area and the islet size distribution were unchanged. However, beta-cells were functionally impaired, presenting with lower glucose-stimulated insulin secretion. This defect was not due to a reduced expression of insulin but was associated with a decreased expression of the glucose transporter Slc2a2/Glut2 and of the Glucagon like peptide-1 receptor (Glp1r as well as a marked down regulation of endoplasmic reticulum (ER chaperones that participate in the Unfolded Protein Response (UPR pathway. Counter intuitively, the Sirt1-deficient mice did not develop hyperglycemia. Pancreatic polypeptide (PP cells were the only other islet cells affected, with reduced numbers in the Sirt1-deficient pancreas.This study provides new mechanistic insights showing that beta-cell function in Sirt1-deficient pancreas is affected due to altered glucose sensing and deregulation of the UPR pathway. Interestingly, we uncovered a context in which impaired beta-cell function is not accompanied by increased glycemia. This points to a unique compensatory mechanism. Given the reduction in PP, investigation of its role in the control of blood glucose is warranted.

  1. Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency. (United States)

    Sachs, Zohar; Been, Raha A; DeCoursin, Krista J; Nguyen, Hanh T; Mohd Hassan, Nurul A; Noble-Orcutt, Klara E; Eckfeldt, Craig E; Pomeroy, Emily J; Diaz-Flores, Ernesto; Geurts, Jennifer L; Diers, Miechaleen D; Hasz, Diane E; Morgan, Kelly J; MacMillan, Margaret L; Shannon, Kevin M; Largaespada, David A; Wiesner, Stephen M


    Juvenile myelomonocytic leukemia is a rare myeloproliferative neoplasm characterized by hyperactive RAS signaling. Neurofibromin1 (encoded by the NF1 gene) is a negative regulator of RAS activation. Patients with neurofibromatosis type 1 harbor loss-of-function mutations in NF1 and have a 200- to 500-fold increased risk of juvenile myelomonocytic leukemia. Leukemia cells from patients with juvenile myelomonocytic leukemia display hypersensitivity to certain cytokines, such as granulocyte-macrophage colony-stimulating factor. The granulocyte-macrophage colony-stimulating factor receptor utilizes pre-associated JAK2 to initiate signals after ligand binding. JAK2 subsequently activates STAT5, among other downstream effectors. Although STAT5 is gaining recognition as an important mediator of growth factor signaling in myeloid leukemias, the contribution of STAT5 to the development of hyperactive RAS-initiated myeloproliferative disease has not been well described. In this study, we investigated the consequence of STAT5 attenuation via genetic and pharmacological approaches in Nf1-deficient murine models of juvenile myelomonocytic leukemia. We found that homozygous Stat5 deficiency extended the lifespan of Nf1-deficient mice and eliminated the development of myeloproliferative neoplasm associated with Nf1 gene loss. Likewise, we found that JAK inhibition with ruxolitinib attenuated myeloproliferative neoplasm in Nf1-deficient mice. Finally, we found that primary cells from a patient with KRAS-mutant juvenile myelomonocytic leukemia displayed reduced colony formation in response to JAK2 inhibition. Our findings establish a central role for STAT5 activation in the pathogenesis of juvenile myelomonocytic leukemia and suggest that targeting this pathway may be of clinical utility in these patients.

  2. Tsc1 deficiency impairs mammary development in mice by suppression of AKT, nuclear ERα, and cell-cycle-driving proteins


    Zhenqi Qin; Hang Zheng; Ling Zhou; Yanhua Ou; Bin Huang; Bo Yan; Zhenshu Qin; Cuilan Yang; Yongchun Su; Xiaochun Bai; Jiasong Guo; Jun Lin


    Loss of Tsc1/Tsc2 results in excess cell growth that eventually forms hamartoma in multiple organs. Our study using a mouse model with Tsc1 conditionally knockout in mammary epithelium showed that Tsc1 deficiency impaired mammary development. Phosphorylated S6 was up-regulated in Tsc1 −/− mammary epithelium, which could be reversed by rapamycin, suggesting that mTORC1 was hyperactivated in Tsc1 −/− mammary epithelium. The mTORC1 inhibitor rapamycin restored the development of Tsc1 −/− mammary...

  3. [Purulent pericarditis and colonic infiltrating to Salmonella enteritidis complicated by acute intussusception in a case of IL-12Rβ1 deficiency]. (United States)

    Ailal, F; Tazi, A; Bustamante, J; Picard, C; Najib, J; Casanova, J-L; Bousfiha, A A


    IL-12 receptor β1 deficiency (IL-12Rβ1) predisposes patients to mycobacteria and Salmonella infections. We report a case of IL-12Rβ1 deficiency with a fatal multi-resistant Salmonella enteritidis infection. This boy was born after from a consanguineous marriage, and diagnosed as having a IL-12Rβ1 deficiency since the age of 3 months. He presented with recurrent Salmonella enteritidis essentially digestive localization, complicated by purulent pericarditis at the same germ at the age of two and a half years. At the age of 3, a colonic infiltration due to a Salmonella enteritidis resistant to antibiotics, was complicated by acute intussusception, and the child died. The IL-12Rβ1 deficiency is considered as having a good prognosis, in contrast to what happened in our patient. We review therapeutic issues in these patients.

  4. Role of BH3-only molecules Bim and Puma in β-cell death in Pdx1 deficiency. (United States)

    Ren, Decheng; Sun, Juan; Wang, Changzheng; Ye, Honggang; Mao, Liqun; Cheng, Emily H; Bell, Graeme I; Polonsky, Kenneth S


    Mutations in pancreatic duodenal homeobox-1 (PDX1) are associated with diabetes in humans. Pdx1-haploinsufficient mice develop diabetes due to an increase in β-cell death leading to reduced β-cell mass. For definition of the molecular link between Pdx1 deficiency and β-cell death, Pdx1-haploinsufficient mice in which the genes for the BH3-only molecules Bim and Puma had been ablated were studied on a high-fat diet. Compared with Pdx1(+/-) mice, animals haploinsufficient for both Pdx1 and Bim or Puma genes showed improved glucose tolerance, enhanced β-cell mass, and reduction in the number of TUNEL-positive cells in islets. These results suggest that Bim and Puma ablation improves β-cell survival in Pdx1(+/-) mice. For exploration of the mechanisms responsible for these findings, Pdx1 gene expression was knocked down in mouse MIN6 insulinoma cells resulting in apoptotic cell death that was found to be associated with increased expression of BH3-only molecules Bim and Puma. If the upregulation of Bim and Puma that occurs during Pdx1 suppression was prevented, apoptotic β-cell death was reduced in vitro. These results suggest that Bim and Puma play an important role in β-cell apoptosis in Pdx1-deficient diabetes.

  5. Chronic pancreatitis (United States)

    Chronic pancreatitis - chronic; Pancreatitis - chronic - discharge; Pancreatic insufficiency - chronic; Acute pancreatitis - chronic ... alcohol abuse over many years. Repeated episodes of acute ... chronic pancreatitis. Genetics may be a factor in some cases. ...

  6. Calpain-2 compensation promotes angiotensin II-induced ascending and abdominal aortic aneurysms in calpain-1 deficient mice.

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    Venkateswaran Subramanian

    Full Text Available Recently, we demonstrated that angiotensin II (AngII-infusion profoundly increased both aortic protein and activity of calpains, calcium-activated cysteine proteases, in mice. In addition, pharmacological inhibition of calpain attenuated AngII-induced abdominal aortic aneurysm (AA in mice. Recent studies have shown that AngII infusion into mice leads to aneurysmal formation localized to the ascending aorta. However, the precise functional contribution of calpain isoforms (-1 or -2 in AngII-induced abdominal AA formation is not known. Similarly, a functional role of calpain in AngII-induced ascending AA remains to be defined. Using BDA-410, an inhibitor of calpains, and calpain-1 genetic deficient mice, we examined the relative contribution of calpain isoforms in AngII-induced ascending and abdominal AA development.To investigate the relative contribution of calpain-1 and -2 in development of AngII-induced AAs, male LDLr -/- mice that were either calpain-1 +/+ or -/- were fed a saturated fat-enriched diet and infused with AngII (1,000 ng/kg/min for 4 weeks. Calpain-1 deficiency had no significant effect on body weight or blood pressure during AngII infusion. Moreover, calpain-1 deficiency showed no discernible effects on AngII-induced ascending and abdominal AAs. Interestingly, AngII infusion induced increased expression of calpain-2 protein, thus compensating for total calpain activity in aortas of calpain-1 deficient mice. Oral administration of BDA-410, a calpain inhibitor, along with AngII-infusion significantly attenuated AngII-induced ascending and abdominal AA formation in both calpain-1 +/+ and -/- mice as compared to vehicle administered mice. Furthermore, BDA-410 administration attenuated AngII-induced aortic medial hypertrophy and macrophage accumulation. Western blot and immunostaining analyses revealed BDA-410 administration attenuated AngII-induced C-terminal fragmentation of filamin A, an actin binding cytoskeletal protein in aorta

  7. TRAF1 is a negative regulator of TNF signaling. enhanced TNF signaling in TRAF1-deficient mice. (United States)

    Tsitsikov, E N; Laouini, D; Dunn, I F; Sannikova, T Y; Davidson, L; Alt, F W; Geha, R S


    TNF receptor-associated factor 1 (TRAF1) is a unique TRAF protein because it lacks a RING finger domain and is predominantly expressed in activated lymphocytes. To elucidate the function of TRAF1, we generated TRAF1-deficient mice. TRAF1(-/-) mice are viable and have normal lymphocyte development. TRAF1(-/-) T cells exhibit stronger than wild-type (WT) T cell proliferation to anti-CD3 mAb, which persisted in the presence of IL-2 or anti-CD28 antibodies. Activated TRAF1(-/-) T cells, but not TRAF1(+/+) T cells, responded to TNF by proliferation and activation of the NF-kappa B and AP-1 signaling pathways. This TNF effect was mediated by TNFR2 (p75) but not by TNFR1 (p55). Furthermore, skin from TRAF1(-/-) mice was hypersensitive to TNF-induced necrosis. These findings suggest that TRAF1 is a negative regulator of TNF signaling.

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

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    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.

  9. Perilipin1 deficiency in whole body or bone marrow-derived cells attenuates lesions in atherosclerosis-prone mice.

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    Xiaojing Zhao

    Full Text Available The objective of this study is to determine the role of perilipin 1 (Plin1 in whole body or bone marrow-derived cells on atherogenesis.Accumulated evidence have indicated the role of Plin1 in atherosclerosis, however, these findings are controversial. In this study, we showed that Plin1 was assembled and colocalized with CD68 in macrophages in atherosclerotic plaques of ApoE-/- mice. We further found 39% reduction of plaque size in the aortic roots of Plin1 and ApoE double knockout (Plin1-/-ApoE-/- females compared with ApoE-/- female littermates. In order to verify whether this reduction was macrophage-specific, the bone marrow cells from wild-type or Plin1 deficient mice (Plin1-/- were transplanted into LDL receptor deficient mice (LDLR-/-. Mice receiving Plin1-/- bone marrow cells showed also 49% reduction in aortic atherosclerotic lesions compared with LDLR-/- mice received wild-type bone marrow cells. In vitro experiments showed that Plin1-/- macrophages had decreased protein expression of CD36 translocase and an enhanced cholesterol ester hydrolysis upon aggregated-LDL loading, with unaltered expression of many other regulators of cholesterol metabolism, such as cellular lipases, and Plin2 and 3. Given the fundamental role of Plin1 in protecting LD lipids from lipase hydrolysis, it is reasonably speculated that the assembly of Plin1 in microphages might function to reduce lipolysis and hence increase lipid retention in ApoE-/- plaques, but this pro-atherosclerotic property would be abrogated on inactivation of Plin1.Plin1 deficiency in bone marrow-derived cells may be responsible for reduced atherosclerotic lesions in the mice.

  10. Epiphyseal abnormalities, trabecular bone loss and articular chondrocyte hypertrophy develop in the long bones of postnatal Ext1-deficient mice. (United States)

    Sgariglia, Federica; Candela, Maria Elena; Huegel, Julianne; Jacenko, Olena; Koyama, Eiki; Yamaguchi, Yu; Pacifici, Maurizio; Enomoto-Iwamoto, Motomi


    Long bones are integral components of the limb skeleton. Recent studies have indicated that embryonic long bone development is altered by mutations in Ext genes and consequent heparan sulfate (HS) deficiency, possibly due to changes in activity and distribution of HS-binding/growth plate-associated signaling proteins. Here we asked whether Ext function is continuously required after birth to sustain growth plate function and long bone growth and organization. Compound transgenic Ext1(f/f);Col2CreERT mice were injected with tamoxifen at postnatal day 5 (P5) to ablate Ext1 in cartilage and monitored over time. The Ext1-deficient mice exhibited growth retardation already by 2weeks post-injection, as did their long bones. Mutant growth plates displayed a severe disorganization of chondrocyte columnar organization, a shortened hypertrophic zone with low expression of collagen X and MMP-13, and reduced primary spongiosa accompanied, however, by increased numbers of TRAP-positive osteoclasts at the chondro-osseous border. The mutant epiphyses were abnormal as well. Formation of a secondary ossification center was significantly delayed but interestingly, hypertrophic-like chondrocytes emerged within articular cartilage, similar to those often seen in osteoarthritic joints. Indeed, the cells displayed a large size and round shape, expressed collagen X and MMP-13 and were surrounded by an abundant Perlecan-rich pericellular matrix not seen in control articular chondrocytes. In addition, ectopic cartilaginous outgrowths developed on the lateral side of mutant growth plates over time that resembled exostotic characteristic of children with Hereditary Multiple Exostoses, a syndrome caused by Ext mutations and HS deficiency. In sum, the data do show that Ext1 is continuously required for postnatal growth and organization of long bones as well as their adjacent joints. Ext1 deficiency elicits defects that can occur in human skeletal conditions including trabecular bone loss

  11. Partial recessive IFN-γR1 deficiency: genetic, immunological and clinical features of 14 patients from 11 kindreds (United States)

    Sologuren, Ithaisa; Boisson-Dupuis, Stéphanie; Pestano, Jose; Vincent, Quentin Benoit; Fernández-Pérez, Leandro; Chapgier, Ariane; Cárdenes, María; Feinberg, Jacqueline; García-Laorden, M. Isabel; Picard, Capucine; Santiago, Esther; Kong, Xiaofei; Jannière, Lucile; Colino, Elena; Herrera-Ramos, Estefanía; Francés, Adela; Navarrete, Carmen; Blanche, Stéphane; Faria, Emilia; Remiszewski, Paweł; Cordeiro, Ana; Freeman, Alexandra; Holland, Steven; Abarca, Katia; Valerón-Lemaur, Mónica; Gonçalo-Marques, José; Silveira, Luisa; García-Castellano, José Manuel; Caminero, José; Pérez-Arellano, José Luis; Bustamante, Jacinta; Abel, Laurent; Casanova, Jean-Laurent; Rodríguez-Gallego, Carlos


    We report a series of 14 patients from 11 kindreds with recessive partial (RP)-interferon (IFN)-γR1 deficiency. The I87T mutation was found in nine homozygous patients from Chile, Portugal and Poland, and the V63G mutation was found in five homozygous patients from the Canary Islands. Founder effects accounted for the recurrence of both mutations. The most recent common ancestors of the patients with the I87T and V63G mutations probably lived 1600 (875–2950) and 500 (200–1275) years ago, respectively. The two alleles confer phenotypes that are similar but differ in terms of IFN-γR1 levels and residual response to IFN-γ. The patients suffered from bacillus Calmette-Guérin-osis (n= 6), environmental mycobacteriosis (n= 6) or tuberculosis (n= 1). One patient did not suffer from mycobacterial infections but had disseminated salmonellosis, which was also present in two other patients. Age at onset of the first environmental mycobacterial disease differed widely between patients, with a mean value of 11.25 ± 9.13 years. Thirteen patients survived until the age of 14.82 ± 11.2 years, and one patient died at the age of 7 years, 9 days after the diagnosis of long-term Mycobacterium avium infection and the initiation of antimycobacterial treatment. Up to 10 patients are currently free of infection with no prophylaxis. The clinical heterogeneity of the 14 patients was not clearly related to either IFNGR1 genotype or the resulting cellular phenotype. RP-IFN-γR1 deficiency is, thus, more common than initially thought and should be considered in both children and adults with mild or severe mycobacterial diseases. PMID:21266457

  12. Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Protein Kinase Inhibition Is Synthetically Lethal in XRCC1 Deficient Ovarian Cancer Cells (United States)

    Sultana, Rebeka; Abdel-Fatah, Tarek; Perry, Christina; Moseley, Paul; Albarakti, Nada; Mohan, Vivek; Seedhouse, Claire; Chan, Stephen; Madhusudan, Srinivasan


    Introduction Ataxia telangiectasia mutated and Rad3 Related (ATR) protein kinase is a key sensor of single-stranded DNA associated with stalled replication forks and repair intermediates generated during DNA repair. XRCC1 is a critical enzyme in single strand break repair and base excision repair. XRCC1-LIG3 complex is also an important contributor to the ligation step of the nucleotide excision repair response. Methods In the current study, we investigated synthetic lethality in XRCC1 deficient and XRCC1 proficient Chinese Hamster ovary (CHO) and human ovarian cancer cells using ATR inhibitors (NU6027). In addition, we also investigated the ability of ATR inhibitors to potentiate cisplatin cytotoxicity in XRCC1 deficient and XRCC1 proficient CHO and human cancer cells. Clonogenic assays, alkaline COMET assays, γH2AX immunocytochemistry, FACS for cell cycle as well as FITC-annexin V flow cytometric analysis were performed. Results ATR inhibition is synthetically lethal in XRCC1 deficient cells as evidenced by increased cytotoxicity, accumulation of double strand DNA breaks, G2/M cell cycle arrest and increased apoptosis. Compared to cisplatin alone, combination of cisplatin and ATR inhibitor results in enhanced cytotoxicity in XRCC1 deficient cells compared to XRCC1 proficient cells. Conclusions Our data provides evidence that ATR inhibition is suitable for synthetic lethality application and cisplatin chemopotentiation in XRCC1 deficient ovarian cancer cells. PMID:23451157

  13. Ataxia telangiectasia mutated and Rad3 related (ATR protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells.

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    Rebeka Sultana

    Full Text Available INTRODUCTION: Ataxia telangiectasia mutated and Rad3 Related (ATR protein kinase is a key sensor of single-stranded DNA associated with stalled replication forks and repair intermediates generated during DNA repair. XRCC1 is a critical enzyme in single strand break repair and base excision repair. XRCC1-LIG3 complex is also an important contributor to the ligation step of the nucleotide excision repair response. METHODS: In the current study, we investigated synthetic lethality in XRCC1 deficient and XRCC1 proficient Chinese Hamster ovary (CHO and human ovarian cancer cells using ATR inhibitors (NU6027. In addition, we also investigated the ability of ATR inhibitors to potentiate cisplatin cytotoxicity in XRCC1 deficient and XRCC1 proficient CHO and human cancer cells. Clonogenic assays, alkaline COMET assays, γH2AX immunocytochemistry, FACS for cell cycle as well as FITC-annexin V flow cytometric analysis were performed. RESULTS: ATR inhibition is synthetically lethal in XRCC1 deficient cells as evidenced by increased cytotoxicity, accumulation of double strand DNA breaks, G2/M cell cycle arrest and increased apoptosis. Compared to cisplatin alone, combination of cisplatin and ATR inhibitor results in enhanced cytotoxicity in XRCC1 deficient cells compared to XRCC1 proficient cells. CONCLUSIONS: Our data provides evidence that ATR inhibition is suitable for synthetic lethality application and cisplatin chemopotentiation in XRCC1 deficient ovarian cancer cells.

  14. In a model of Batten disease, palmitoyl protein thioesterase-1 deficiency is associated with brown adipose tissue and thermoregulation abnormalities.

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    Alfia Khaibullina

    Full Text Available Infantile neuronal ceroid lipofuscinosis (INCL is a fatal neurodegenerative disorder caused by a deficiency of palmitoyl-protein thioesterase-1 (PPT1. We have previously shown that children with INCL have increased risk of hypothermia during anesthesia and that PPT1-deficiency in mice is associated with disruption of adaptive energy metabolism, downregulation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α, and mitochondrial dysfunction. Here we hypothesized that Ppt1-knockout mice, a well-studied model of INCL that shows many of the neurologic manifestations of the disease, would recapitulate the thermoregulation impairment observed in children with INCL. We also hypothesized that when exposed to cold, Ppt1-knockout mice would be unable to maintain body temperature as in mice thermogenesis requires upregulation of Pgc-1α and uncoupling protein 1 (Ucp-1 in brown adipose tissue. We found that the Ppt1-KO mice had lower basal body temperature as they aged and developed hypothermia during cold exposure. Surprisingly, this inability to maintain body temperature during cold exposure in Ppt1-KO mice was associated with an adequate upregulation of Pgc-1α and Ucp-1 but with lower levels of sympathetic neurotransmitters in brown adipose tissue. In addition, during baseline conditions, brown adipose tissue of Ppt1-KO mice had less vacuolization (lipid droplets compared to wild-type animals. After cold stress, wild-type animals had significant decreases whereas Ppt1-KO had insignificant changes in lipid droplets compared with baseline measurements, thus suggesting that Ppt1-KO had less lipolysis in response to cold stress. These results uncover a previously unknown phenotype associated with PPT1 deficiency, that of altered thermoregulation, which is associated with impaired lipolysis and neurotransmitter release to brown adipose tissue during cold exposure. These findings suggest that INCL should be added to the list of

  15. CX3CR1 deficiency alters hippocampal-dependent plasticity phenomena blunting the effects of enriched environment

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    Laura eMaggi


    Full Text Available In recent years several evidence demonstrated that some features of hippocampal biology, like neurogenesis, synaptic transmission, learning and memory performances are deeply modulated by social, motor and sensorial experiences. Fractalkine/CX3CL1 is a transmembrane chemokine abundantly expressed in the brain by neurons, where it modulates glutamatergic transmission and long-term plasticity processes regulating the intercellular communication between glia and neurons, being its specific receptor CX3CR1 expressed by microglia. In this paper we investigated the role of CX3CL1/CX3CR1 signaling on experience-dependent hippocampal plasticity processes. At this aim wt and CX3CR1GFP/GFP mice were exposed to long-lasting-enriched environment (EE and the effects on hippocampal functions were studied by electrophysiological recordings of long-term potentiation (LTP of synaptic activity, behavioral tests of learning and memory in the Morris water maze paradigm and analysis of neurogenesis in the subgranular zone of the dentate gyrus (DG.We found that CX3CR1 deficiency increases hippocampal plasticity and spatial memory blunting the potentiating effects of EE. In contrast, exposure to EE increased the number and migration of neural progenitors in the DG of both wt and CX3CR1GFP/GFP mice. These data indicate that CX3CL1/CX3CR1-mediated signaling is crucial for a normal experience-dependent modulation of hippocampal functions.

  16. Amino acid substitution in NPC1 that abolishes cholesterol binding reproduces phenotype of complete NPC1 deficiency in mice (United States)

    Xie, Xuefen; Brown, Michael S.; Shelton, John M.; Richardson, James A.; Goldstein, Joseph L.; Liang, Guosheng


    Substitution mutations in adjacent amino acids of the N-terminal domain of NPC1, a lysosomal membrane protein, abolish its cholesterol binding activity and impair its ability to export cholesterol from lysosomes of cultured cells lacking npc1 [Kwon HJ, et al. (2009) Cell 137:1213–1224]. Here, we show that the same two mutations (proline-202 and phenylalanine-203, both changed to alanine) reproduce the phenotype of complete NPC1 deficiency when knocked into the mouse npc1 gene by homologous recombination. Homozygous npc1pf/pf mice exhibited neurodegeneration beginning at day 49 and died at a median age of 84 d, as previously reported for mice that lack npc1. Liver and other organs of the npc1pf/pf mice accumulated excess cholesterol in lysosomes. In liver, mRNAs encoding several lysosomal proteins were elevated, including NPC1 and NPC2 and several digestive enzymes (acid lipase, β-glucuronidase, and cathepsins B and D). Weekly treatment with hydroxypropyl-β-cyclodextrin (HPCD) beginning at 7 wk reduced hepatic cholesterol accumulation and diminished the lysosomal mRNAs. We conclude that the cholesterol binding site in the N-terminal domain of NPC1 is essential for cholesterol export from lysosomes in living animals as it is in cultured cells. The HPCD-mediated reduction of excess lysosomal enzymes may contribute to the ability of this drug to delay the progression of NPC disease in mice. PMID:21896731

  17. A Protein Kinase C Phosphorylation Motif in GLUT1 Affects Glucose Transport and is Mutated in GLUT1 Deficiency Syndrome. (United States)

    Lee, Eunice E; Ma, Jing; Sacharidou, Anastasia; Mi, Wentao; Salato, Valerie K; Nguyen, Nam; Jiang, Youxing; Pascual, Juan M; North, Paula E; Shaul, Philip W; Mettlen, Marcel; Wang, Richard C


    Protein kinase C has been implicated in the phosphorylation of the erythrocyte/brain glucose transporter, GLUT1, without a clear understanding of the site(s) of phosphorylation and the possible effects on glucose transport. Through in vitro kinase assays, mass spectrometry, and phosphospecific antibodies, we identify serine 226 in GLUT1 as a PKC phosphorylation site. Phosphorylation of S226 is required for the rapid increase in glucose uptake and enhanced cell surface localization of GLUT1 induced by the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Endogenous GLUT1 is phosphorylated on S226 in primary endothelial cells in response to TPA or VEGF. Several naturally occurring, pathogenic mutations that cause GLUT1 deficiency syndrome disrupt this PKC phosphomotif, impair the phosphorylation of S226 in vitro, and block TPA-mediated increases in glucose uptake. We demonstrate that the phosphorylation of GLUT1 on S226 regulates glucose transport and propose that this modification is important in the physiological regulation of glucose transport.

  18. Dysfunction of the heme recycling system in heme oxygenase 1-deficient mice: effects on macrophage viability and tissue iron distribution. (United States)

    Kovtunovych, Gennadiy; Eckhaus, Michael A; Ghosh, Manik C; Ollivierre-Wilson, Hayden; Rouault, Tracey A


    To better understand the tissue iron overload and anemia previously reported in a human patient and mice that lack heme oxygenase-1 (HO-1), we studied iron distribution and pathology in HO-1(Hmox1)(-/-) mice. We found that resident splenic and liver macrophages were mostly absent in HO-1(-/-) mice. Erythrophagocytosis caused the death of HO-1(-/-) macrophages in in vitro experiments, supporting the hypothesis that HO-1(-/-) macrophages died of exposure to heme released on erythrophagocytosis. Rupture of HO-1(-/-) macrophages in vivo and release of nonmetabolized heme probably caused tissue inflammation. In the spleen, initial splenic enlargement progressed to red pulp fibrosis, atrophy, and functional hyposplenism in older mice, recapitulating the asplenia of an HO-1-deficient patient. We postulate that the failure of tissue macrophages to remove senescent erythrocytes led to intravascular hemolysis and increased expression of the heme and hemoglobin scavenger proteins, hemopexin and haptoglobin. Lack of macrophages expressing the haptoglobin receptor, CD163, diminished the ability of haptoglobin to neutralize circulating hemoglobin, and iron overload occurred in kidney proximal tubules, which were able to catabolize heme with HO-2. Thus, in HO-1(-/-) mammals, the reduced function and viability of erythrophagocytosing macrophages are the main causes of tissue damage and iron redistribution.

  19. Collagen peptide and vitamin C additively attenuate age-related skin atrophy in Sod1-deficient mice. (United States)

    Shibuya, Shuichi; Ozawa, Yusuke; Toda, Toshihiko; Watanabe, Kenji; Tometsuka, Chisa; Ogura, Takayuki; Koyama, Yoh-ichi; Shimizu, Takahiko


    Age-related skin thinning is correlated with a decrease in the content of collagen in the skin. Accumulating evidence suggests that collagen peptide (CP) and vitamin C (VC) transcriptionally upregulate type I collagen in vivo. However, the additive effects of CP and VC on age-related skin changes remain unclear. We herein demonstrate that CP and a VC derivative additively corrected age-related skin thinning via reduced oxidative damage in superoxide dismutase 1 (Sod1)-deficient mice. Co-treatment with these compounds significantly normalized the altered gene expression of Col1a1, Has2, and Ci1, a proton-coupled oligopeptide transporter, in Sod1(-/-) skin. The in vitro analyses further revealed that collagen oligopeptide, a digestive product of ingested CP, significantly promoted the bioactivity of the VC derivative with respect to the migration and proliferation of Sod1(-/-) fibroblasts. These findings suggest that combined treatment with CP and VC is effective in cases of age-related skin pathology.

  20. Successful Gene Therapy in the RPGRIP1-deficient Dog: a Large Model of Cone–Rod Dystrophy (United States)

    Lhériteau, Elsa; Petit, Lolita; Weber, Michel; Le Meur, Guylène; Deschamps, Jack-Yves; Libeau, Lyse; Mendes-Madeira, Alexandra; Guihal, Caroline; François, Achille; Guyon, Richard; Provost, Nathalie; Lemoine, Françoise; Papal, Samantha; El-Amraoui, Aziz; Colle, Marie-Anne; Moullier, Philippe; Rolling, Fabienne


    For the development of new therapies, proof-of-concept studies in large animal models that share clinical features with their human counterparts represent a pivotal step. For inherited retinal dystrophies primarily involving photoreceptor cells, the efficacy of gene therapy has been demonstrated in canine models of stationary cone dystrophies and progressive rod–cone dystrophies but not in large models of progressive cone–rod dystrophies, another important cause of blindness. To address the last issue, we evaluated gene therapy in the retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1)-deficient dog, a model exhibiting a severe cone–rod dystrophy similar to that seen in humans. Subretinal injection of AAV5 (n = 5) or AAV8 (n = 2) encoding the canine Rpgrip1 improved photoreceptor survival in transduced areas of treated retinas. Cone function was significantly and stably rescued in all treated eyes (18–72% of those recorded in normal eyes) up to 24 months postinjection. Rod function was also preserved (22–29% of baseline function) in four of the five treated dogs up to 24 months postinjection. No detectable rod function remained in untreated contralateral eyes. More importantly, treatment preserved bright- and dim-light vision. Efficacy of gene therapy in this large animal model of cone–rod dystrophy provides great promise for human treatment. PMID:24091916

  1. Melatonin-receptor-1-deficiency affects neurogenic differentiation factor immunoreaction in pancreatic islets and enteroendocrine cells of mice. (United States)

    Shalabi, Andree; Fischer, Claudia; Korf, Horst-Werner; von Gall, Charlotte


    Neurogenic differentiation factor (NeuroD) is a transcription factor involved in the differentiation of neurons and in the control of energy balance and metabolism. It plays a key role in type 1 and type 2 diabetes. Melatonin is an important rhythmic endocrine signal within the circadian system of mammals and modulates insulin secretion and glucose metabolism. In the mouse pars tuberalis, NeuroD mRNA levels show day/night variation, which is independent of the molecular clock gene mPER1 but depends on the functional melatonin receptor 1 (MT1). So far, little is known about the effect of melatonin on NeuroD synthesis in the gastrointestinal tract. Thus, NeuroD protein levels and cellular localization were analyzed by immunohistochemistry in pancreatic islets and duodenal enteroendocrine cells of MT1- and mPER1-deficienct mice. In addition, the localization of NeuroD-positive cells was analyzed by double-immunofluorescence and confocal laser microscopy. In duodenal enteroendocrine cells and pancreatic islets of WT and PER1-deficient mice, NeuroD immunoreaction showed a peak during the early subjective night. In contrast, this peak was absent in MT1-deficent mice. These data suggest that melatonin, by acting on MT1 receptors, affects NeuroD expression in the gastrointestinal tract and thus might contribute to circadian regulation in metabolic functions.

  2. Pannexin-1 Deficient Mice Have an Increased Susceptibility for Atrial Fibrillation and Show a QT-Prolongation Phenotype

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    Stella Petric


    Full Text Available Background/Aims: Pannexin-1 (Panx1 is an ATP release channel that is ubiquitously expressed and coupled to several ligand-gated receptors. In isolated cardiac myocytes, Panx1 forms large conductance channels that can be activated by Ca2+ release from the sarcoplasmic reticulum. Here we characterized the electrophysiological function of these channels in the heart in vivo, taking recourse to mice with Panx1 ablation. Methods: Cardiac phenotyping of Panx1 knock-out mice (Panx1-/- was performed by employing a molecular, cellular and functional approach, including echocardiography, surface and telemetric ECG recordings with QT analysis, physical stress testing and quantification of heart rate variability. In addition, an in vivo electrophysiological study entailed programmed electrical stimulation using an intracardiac octapolar catheter. Results: Panx1 deficiency results in a higher incidence of AV-block, delayed ventricular depolarisation, significant prolongation of QT- and rate corrected QT-interval and a higher incidence of atrial fibrillation after intraatrial burst stimulation. Conclusion: Panx1 seems to play an important role in murine cardiac electrophysiology and warrants further consideration in the context of hereditary forms of atrial fibrillation.

  3. Cholestasis and hypercholesterolemia in SCD1-deficient mice fed a low-fat, high-carbohydrate diet. (United States)

    Flowers, Matthew T; Groen, Albert K; Oler, Angie Tebon; Keller, Mark P; Choi, Younjeong; Schueler, Kathryn L; Richards, Oliver C; Lan, Hong; Miyazaki, Makoto; Kuipers, Folkert; Kendziorski, Christina M; Ntambi, James M; Attie, Alan D


    Stearoyl-coenzyme A desaturase 1-deficient (SCD1(-/-)) mice have impaired MUFA synthesis. When maintained on a very low-fat (VLF) diet, SCD1(-/-) mice developed severe hypercholesterolemia, characterized by an increase in apolipoprotein B (apoB)-containing lipoproteins and the appearance of lipoprotein X. The rate of LDL clearance was decreased in VLF SCD1(-/-) mice relative to VLF SCD1(+/+) mice, indicating that reduced apoB-containing lipoprotein clearance contributed to the hypercholesterolemia. Additionally, HDL-cholesterol was dramatically reduced in these mice. The presence of increased plasma bile acids, bilirubin, and aminotransferases in the VLF SCD1(-/-) mice is indicative of cholestasis. Supplementation of the VLF diet with MUFA- and PUFA-rich canola oil, but not saturated fat-rich hydrogenated coconut oil, prevented these plasma phenotypes. However, dietary oleate was not as effective as canola oil in reducing LDL-cholesterol, signifying a role for dietary PUFA deficiency in the development of this phenotype. These results indicate that the lack of SCD1 results in an increased requirement for dietary unsaturated fat to compensate for impaired MUFA synthesis and to prevent hypercholesterolemia and hepatic dysfunction. Therefore, endogenous MUFA synthesis is essential during dietary unsaturated fat insufficiency and influences the dietary requirement of PUFA.

  4. Cardiomyopathy as presenting sign of glycogenin-1 deficiency-report of three cases and review of the literature. (United States)

    Hedberg-Oldfors, Carola; Glamuzina, Emma; Ruygrok, Peter; Anderson, Lisa J; Elliott, Perry; Watkinson, Oliver; Occleshaw, Chris; Abernathy, Malcolm; Turner, Clinton; Kingston, Nicola; Murphy, Elaine; Oldfors, Anders


    We describe a new type of cardiomyopathy caused by a mutation in the glycogenin-1 gene (GYG1). Three unrelated male patients aged 34 to 52 years with cardiomyopathy and abnormal glycogen storage on endomyocardial biopsy were homozygous for the missense mutation p.Asp102His in GYG1. The mutated glycogenin-1 protein was expressed in cardiac tissue but had lost its ability to autoglucosylate as demonstrated by an in vitro assay and western blot analysis. It was therefore unable to form the primer for normal glycogen synthesis. Two of the patients showed similar patterns of heart dilatation, reduced ejection fraction and extensive late gadolinium enhancement on cardiac magnetic resonance imaging. These two patients were severely affected, necessitating cardiac transplantation. The cardiomyocyte storage material was characterized by large inclusions of periodic acid and Schiff positive material that was partly resistant to alpha-amylase treatment consistent with polyglucosan. The storage material had, unlike normal glycogen, a partly fibrillar structure by electron microscopy. None of the patients showed signs or symptoms of muscle weakness but a skeletal muscle biopsy in one case revealed muscle fibres with abnormal glycogen storage. Glycogenin-1 deficiency is known as a rare cause of skeletal muscle glycogen storage disease, usually without cardiomyopathy. We demonstrate that it may also be the cause of severe cardiomyopathy and cardiac failure without skeletal muscle weakness. GYG1 should be included in cardiomyopathy gene panels.

  5. Seizure control and acceptance of the ketogenic diet in GLUT1 deficiency syndrome: a 2- to 5-year follow-up of 15 children enrolled prospectively.

    NARCIS (Netherlands)

    Klepper, J.; Scheffer, H.; Leiendecker, B.; Gertsen, E.; Binder, S.; Leferink, M.; Hertzberg, C.; Nake, A.; Voit, T.; Willemsen, M.A.A.P.


    BACKGROUND: GLUT1 deficiency syndrome is caused by impaired glucose transport into the brain resulting in an epileptic encephalopathy, developmental delay, and a complex motor disorder. A ketogenic diet provides an alternative fuel to the brain and effectively restores brain energy metabolism. METHO

  6. Monocyte chemoattractant protein-1-deficiency impairs the expression of IL-6, IL-1β and G-CSF after transient focal ischemia in mice.

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    Jan-Kolja Strecker

    Full Text Available Monocyte chemoattractant protein-1 (MCP-1, a chemokine secreted by neurons and astrocytes following stroke is known to aggravate ischemia-related damage. Previous studies revealed that MCP-1-deficient mice develop smaller infarcts and have an improved neurological outcome, whereas mice overexpressing MCP-1 show worsened brain damage and impaired neurological function. The aim of the present study was to elucidate the molecular background of the enhanced recovery in MCP-1-deficient mice after stroke. For this purpose, we (1 performed expression analyses on crucial post-stroke related inflammatory genes in MCP-1-deficient mice compared to wildtype controls, (2 analyzed a possible impact of MCP-1 on astrocyte activation (3 investigated the cellular origin of respective inflammatory cytokines and (4 analyzed the impact of MCP-1 secretion on the migration of both neutrophil granulocytes and T-cells. Here we report that MCP-1-deficiency leads to a shift towards a less inflammatory state following experimental occlusion of the middle cerebral artery including an impaired induction of interleukin-6, interleukin-1β and granulocyte-colony stimulating factor expression as well as a subsequent diminished influx of hematogenous cells. Additionally, MCP-1-deficient mice developed smaller infarcts 36 hours after experimental stroke. Investigations revealed no differences in transcription of tumor necrosis factor-α and astrogliosis 12 and 36 hours after onset of ischemia. These novel results help to understand post ischemic, inflammatory mechanisms and might give further arguments towards therapeutical interventions by modulation of MCP-1 expression in post stroke inflammation.

  7. Resistance to diet-induced adiposity in cannabinoid receptor-1 deficient mice is not due to impaired adipocyte function

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    Oosterveer Maaike H


    Full Text Available Abstract Background Overactivity and/or dysregulation of the endocannabinoid system (ECS contribute to development of obesity. In vitro studies indicate a regulatory role for the cannabinoid receptor 1 (CB1 in adipocyte function and CB1-receptor deficient (CB1-/- mice are resistant to high fat diet-induced obesity. Whether this phenotype of CB1-/- mice is related to altered fat metabolism in adipose tissue is unknown. Methods We evaluated adipose tissue differentiation/proliferation markers and quantified lipogenic and lipolytic activities in fat tissues of CB1-/- and CB1+/+ mice fed a high-fat (HF or a high-fat/fish oil (HF/FO diet as compared to animals receiving a low-fat chow diet. Comparison between HF diet and HF/FO diet allowed to investigate the influence of dietary fat quality on adipose tissue biology in relation to CB1 functioning. Results The adiposity-resistant phenotype of the CB1-/- mice was characterized by reduced fat mass and adipocyte size in HF and HF/FO-fed CB1-/- mice in parallel to a significant increase in energy expenditure as compared to CB1+/+ mice. The expression levels of adipocyte differentiation and proliferation markers were however maintained in these animals. Consistent with unaltered lipogenic gene expression, the fatty acid synthesis rates in adipose tissues from CB1-/- and CB1+/+ mice were unchanged. Whole-body and adipose-specific lipoprotein lipase (LPL activities were also not altered in CB1-/- mice. Conclusions These findings indicate that protection against diet-induced adiposity in CB1-deficient mice is not related to changes in adipocyte function per se, but rather results from increased energy dissipation by oxidative and non-oxidative pathways.

  8. SF-1 deficiency causes lipid accumulation in Leydig cells via suppression of STAR and CYP11A1. (United States)

    Hatano, Megumi; Migita, Toshiro; Ohishi, Tomokazu; Shima, Yuichi; Ogawa, Yoshihiro; Morohashi, Ken-Ichirou; Hasegawa, Yukihiro; Shibasaki, Futoshi


    Genetic mutations of steroidogenic factor 1 (also known as Ad4BP or Nr5a1) have increasingly been reported in patients with 46,XY disorders of sex development (46,XY disorders of sex development). However, because the phenotype of 46,XY disorders of sex development with a steroidogenic factor 1 mutation is wide-ranging, its precise diagnosis remains a clinical problem. We previously reported the frequent occurrence of lipid accumulation in Leydig cells among patients with 46,XY disorders of sex development with a steroidogenic factor 1 mutation, an observation also reported by other authors. To address the mechanism of lipid accumulation in this disease, we examined the effects of steroidogenic factor 1 deficiency on downstream targets of steroidogenic factor 1 in in vitro and in vivo. We found that lipid accumulation in Leydig cells was enhanced after puberty in heterozygous steroidogenic factor 1 knockout mice compared with wild-type mice, and was accompanied by a significant decrease in steroidogenic acute regulatory protein and CYP11A1 expression. In mouse Leydig cell lines, steroidogenic factor 1 knockdown induced a remarkable accumulation of neutral lipids and cholesterol with reduced androgen levels. Steroidogenic factor 1 knockdown reduced the expression of steroidogenic acute regulatory protein and CYP11A1, both of which are transcriptional targets of steroidogenic factor 1 and key molecules for steroidogenesis from cholesterol in the mitochondria. Knockdown of either steroidogenic acute regulatory protein or CYP11A1 also induced lipid accumulation, and knockdown of both had an additive effect. Our data suggested that lipid accumulation in the Leydig cells of the 46,XY disorders of sex development phenotype with a steroidogenic factor 1 mutation is due, at least in part, to the suppression of steroidogenic acute regulatory protein and CYP11A1, and a resulting increase in unmetabolized cholesterol.

  9. Protective effects of selenium on oxidative damage and oxidative stress related gene expression in rat liver under chronic poisoning of arsenic. (United States)

    Xu, Zhao; Wang, Zhou; Li, Jian-jun; Chen, Chen; Zhang, Ping-chuan; Dong, Lu; Chen, Jing-hong; Chen, Qun; Zhang, Xiao-tian; Wang, Zhi-lun


    Arsenic (As) is a toxic metalloid existing widely in the environment, and chronic exposure to it through contaminated drinking water has become a global problem of public health. The present study focused on the protective effects of selenium on oxidative damage of chronic arsenic poisoning in rat liver. Rats were divided into four groups at random and given designed treatments for 20 weeks. The oxidative damage of liver tissue was evaluated by lipid peroxidation and antioxidant enzymes. Oxidative stress related genes were detected to reflect the liver stress state at the molecular level. Compared to the control and Na2SeO3 groups, the MDA content in liver tissue was decreased and the activities of antioxidant enzymes were increased in the Na2SeO3 intervention group. The mRNA levels of SOD1, CAT, GPx and Txnrd1 were increased significantly (Ptreatment group. The expressions of HSP70 and HO-1 were significantly (Ptreatment group. The results indicate that long-term intake of NaAsO2 causes oxidative damage in the rat liver, and Na2SeO3 protects liver cells by adjusting the expression of oxidative stress related genes to improve the activities of antioxidant enzymes.

  10. SMARCB1/INI1-deficient sinonasal carcinoma shows methylation of RASSF1 gene: A clinicopathological, immunohistochemical and molecular genetic study of a recently described entity. (United States)

    Laco, Jan; Chmelařová, Marcela; Vošmiková, Hana; Sieglová, Kateřina; Bubancová, Ivana; Dundr, Pavel; Němejcová, Kristýna; Michálek, Jaroslav; Čelakovský, Petr; Mottl, Radovan; Sirák, Igor; Vošmik, Milan; Ryška, Aleš


    The aim of the study was detailed clinicopathological investigation of SMARCB1/INI1-deficient sinonasal carcinomas, including molecular genetic analysis of mutational status and DNA methylation of selected protooncogenes and tumor suppressor genes by means of next generation sequencing (NGS) and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). A total of 4/56 (7%) cases of SMARCB1/INI1-deficient carcinomas were detected among 56 sinonasal carcinomas diagnosed over a 19year period using immunohistochemical screening. The series comprised 3 males and 1 female, aged 27-76 years (median 64 years). All tumors arose in the nasal cavity. Three neoplasms were diagnosed in advanced stage pT4. During the follow-up period (range 14-111 months (median 72 months)), three tumors recurred locally, but none of the patients developed regional or distant metastases. Ultimately, two patients died due to the tumor. Microscopically, all tumors consisted of infiltrating nests of polygonal basaloid cells with a variable component of rhabdoid cells with eosinophilic cytoplasm. Immunohistochemically, there was almost diffuse expression of cytokeratins (CK), p16, p40 and p63 in all cases, while expression of CK5/6, CK7 and vimentin was only focal or absent. The detection of NUT gave negative results. In three cases, the absence of SMARCB1/INI1 expression was due to deletion of SMARCB1/INI1 gene. Methylation of SMARCB1/INI1 gene was not found. One tumor harbored HPV18 E6/E7 mRNA. All 12 genes (BRAF, BRCA1, BRCA2, KIT, EGFR, KRAS, NRAS, PDGFRA, PIK3CA, PTEN, RET, and ROS1) tested for mutations using NGS were wild-type. Regarding DNA methylation, all four SMARCB1/INI1-deficient tumors showed methylation of RASSF1 gene by means of MS-MLPA. There was a statistically significant difference in RASSF1 gene methylation between SMARCB1/INI1-deficient and SMARCB1/INI1-positive tumors (p=0.0095). All other examined genes (ATM, BRCA1, BRCA2, CADM1, CASP8, CD44, CDKN1B

  11. Cellular model of neuronal atrophy induced by DYNC1I1 deficiency reveals protective roles of RAS-RAF-MEK signaling

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    Zhi-Dong Liu


    Full Text Available Abstract Neuronal atrophy is a common pathological feature occurred in aging and neurodegenerative diseases. A variety of abnormalities including motor protein malfunction and mitochondrial dysfunction contribute to the loss of neuronal architecture; however, less is known about the intracellular signaling pathways that can protect against or delay this pathogenic process. Here, we show that the DYNC1I1 deficiency, a neuron-specific dynein intermediate chain, causes neuronal atrophy in primary hippocampal neurons. With this cellular model, we are able to find that activation of RAS-RAF-MEK signaling protects against neuronal atrophy induced by DYNC1I1 deficiency, which relies on MEK-dependent autophagy in neuron. Moreover, we further reveal that BRAF also protects against neuronal atrophy induced by mitochondrial impairment. These findings demonstrate protective roles of the RAS-RAF-MEK axis against neuronal atrophy, and imply a new therapeutic target for clinical intervention.

  12. Thrombospondin-1 deficiency causes a shift from fibroproliferative to inflammatory kidney disease and delays onset of renal failure. (United States)

    Zeisberg, Michael; Tampe, Björn; LeBleu, Valerie; Tampe, Desiree; Zeisberg, Elisabeth M; Kalluri, Raghu


    Thrombospondin-1 (TSP1) is a multifunctional matricellular protein known to promote progression of chronic kidney disease. To gain insight into the underlying mechanisms through which TSP1 accelerates chronic kidney disease, we compared disease progression in Col4a3 knockout (KO) mice, which develop spontaneous kidney failure, with that of Col4a3;Tsp1 double-knockout (DKO) mice. Decline of excretory renal function was significantly delayed in the absence of TSP1. Although Col4a3;Tsp1 DKO mice did progress toward end-stage renal failure, their kidneys exhibited distinct histopathological lesions, compared with creatinine level-matched Col4a3 KO mice. Although kidneys of both Col4a3 KO and Col4a3;Tsp1 DKO mice exhibited a widened tubulointerstitium, predominant lesions in Col4a3 KO kidneys were collagen deposition and fibroblast accumulation, whereas in Col4a3;Tsp1 DKO kidney inflammation was predominant, with less collagen deposition. Altered disease progression correlated with impaired activation of transforming growth factor-β1 (TGF-β1) in vivo and in vitro in the absence of TSP1. In summary, our findings suggest that TSP1 contributes to progression of chronic kidney disease by catalyzing activation of latent TGF-β1, resulting in promotion of a fibroproliferative response over an inflammatory response. Furthermore, the findings suggest that fibroproliferative and inflammatory lesions are independent entities, both of which contribute to decline of renal function.

  13. Wfs1-deficient animals have brain-region-specific changes of Na+, K+-ATPase activity and mRNA expression of α1 and β1 subunits. (United States)

    Sütt, S; Altpere, A; Reimets, R; Visnapuu, T; Loomets, M; Raud, S; Salum, T; Mahlapuu, R; Kairane, C; Zilmer, M; Vasar, E


    Mutations in the WFS1 gene, which encodes the endoplasmic reticulum (ER) glycoprotein, cause Wolfram syndrome, a disease characterized by juvenile-onset diabetes mellitus, optic atrophy, deafness, and different psychiatric abnormalities. Loss of neuronal cells and pancreatic β-cells in Wolfram syndrome patients is probably related to the dysfunction of ER stress regulation, which leads to cell apoptosis. The present study shows that Wfs1-deficient mice have brain-region-specific changes in Na(+),K(+)-ATPase activity and in the expression of the α1 and β1 subunits. We found a significant (1.6-fold) increase of Na-pump activity and β1 subunit mRNA expression in mice lacking the Wfs1 gene in the temporal lobe compared with their wild-type littermates. By contrast, exposure of mice to the elevated plus maze (EPM) model of anxiety decreased Na-pump activity 1.3-fold in the midbrain and dorsal striatum and 2.0-fold in the ventral striatum of homozygous animals compared with the nonexposed group. Na-pump α1 -subunit mRNA was significantly decreased in the dorsal striatum and midbrain of Wfs1-deficient homozygous animals compared with wild-type littermates. In the temporal lobe, an increase in the activity of the Na-pump is probably related to increased anxiety established in Wfs1-deficient mice, whereas the blunted dopamine function in the forebrain of Wfs1-deficient mice may be associated with a decrease of Na-pump activity in the dorsal and ventral striatum and in the midbrain after exposure to the EPM.

  14. 4PS/insulin receptor substrate (IRS)-2 is the alternative substrate of the insulin receptor in IRS-1-deficient mice. (United States)

    Patti, M E; Sun, X J; Bruening, J C; Araki, E; Lipes, M A; White, M F; Kahn, C R


    Insulin receptor substrate-1 (IRS-1) is the major cytoplasmic substrate of the insulin and insulin-like growth factor (IGF)-1 receptors. Transgenic mice lacking IRS-1 are resistant to insulin and IGF-1, but exhibit significant residual insulin action which corresponds to the presence of an alternative high molecular weight substrate in liver and muscle. Recently, Sun et al. (Sun, X.-J., Wang, L.-M., Zhang, Y., Yenush, L. P., Myers, M. G., Jr., Glasheen, E., Lane, W.S., Pierce, J. H., and White, M. F. (1995) Nature 377, 173-177) purified and cloned 4PS, the major substrate of the IL-4 receptor-associated tyrosine kinase in myeloid cells, which has significant structural similarity to IRS-1. To determine if 4PS is the alternative substrate of the insulin receptor in IRS-1-deficient mice, we performed immunoprecipitation, immunoblotting, and phosphatidylinositol (PI) 3-kinase assays using specific antibodies to 4PS. Following insulin stimulation, 4PS is rapidly phosphorylated in liver and muscle, binds to the p85 subunit of PI 3-kinase, and activates the enzyme. Insulin stimulation also results in the association of 4PS with Grb 2 in both liver and muscle. In IRS-1-deficient mice, both the phosphorylation of 4PS and associated PI 3-kinase activity are enhanced, without an increase in protein expression. Immunodepletion of 4PS from liver and muscle homogenates removes most of the phosphotyrosine-associated PI 3-kinase activity in IRS-1-deficient mice. Thus, 4PS is the primary alternative substrate, i.e. IRS-2, which plays a major role in physiologic insulin signal transduction via both PI 3-kinase activation and Grb 2/Sos association. In IRS-1-deficient mice, 4PS/IRS-2 provides signal transduction to these two major pathways of insulin signaling.

  15. NT-3 protein levels are enhanced in the hippocampus of PRG1-deficient mice but remain unchanged in PRG1/LPA2 double mutants. (United States)

    Petzold, Sandra; Sommer, Babette; Kröber, Andrea; Nitsch, Robert; Schwegler, Herbert; Vogt, Johannes; Roskoden, Thomas


    The plasticity-related gene 1 (PRG1) modulates bioactive lipids at the postsynaptic density and is a novel player in neuronal plasticity and regulation of glutamatergic transmission at principal neurons. PRG1, a neuronal molecule, is highly expressed during development and regeneration processes at the postsynaptic density, modulates synaptic lysophosphatidic acid (LPA) levels and is related to epilepsy and brain injury. In the present study, we analyzed the interaction between the synaptic molecules PRG1 and LPA2R with other plasticity-related molecules the neurotrophins. The protein levels of NGF, BDNF and NT-3 were measured using ELISA in hippocampal tissue of homozygous (PRG(-/-)) and heterozygous (PRG(+/-)) PRG1 deficient mice and compared to their wild type (PRG(+/+)/WT) littermates. In the hippocampus, protein levels of NT-3 were significantly increased in PRG(-/-) mice (compared to WT-litters) while protein levels of NGF and BDNF were not affected. Since PRG1 deficiency leads to increased neuronal excitability and higher hippocampal network activity, which may well influence neurotrophin levels, we further assessed PRG1 deficient mice on an LPA2-receptor (LPA2R) deficient background, reported to normalize hippocampal over-excitability in PRG1(-/-) mice. However, on an LPA2R deficient background, protein levels of NT-3 in PRG1(-/-) mice (PRG1(-/-)/LPA2R(-/-)) were not significantly different when compared to WT animals. Since PRG1 deficient mice showed over-excitability in glutamatergic neurons. This was normalized by additional LPA2R deletion, and we conclude the increased NT3-levels were directly or indirectly attributable to increased hippocampal network activity, possibly exerting a protective effect against over-excitability.

  16. ILDR1 deficiency causes degeneration of cochlear outer hair cells and disrupts the structure of the organ of Corti: a mouse model for human DFNB42

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    Qing Sang


    Full Text Available Immunoglobulin-like domain containing receptor 1 (ILDR1 is a poorly characterized gene that was first identified in lymphoma cells. Mutations in ILDR1 are responsible for DFNB42, but the pathogenesis of hearing loss caused by ILDR1 mutations remains to be elucidated. To explore the role of ILDR1 in hearing, we created Ildr1 knockout mice. In heterozygous mice, ILDR1 expression was found in outer hair cells (OHCs and inner hair cells (IHCs of the organ of Corti. ILDR1-deficient mice are profoundly deaf by postnatal day 21 (P21. No significant difference was observed in the supporting cells and IHCs of ILDR1-deficient mice, but progressive degeneration of OHCs occurred at P15 and disruption of the tunnel running through the organ of Corti was noticeable at P21. By P28, there were no OHCs visible in any of the turns of the organ of Corti, and the tunnel of the organ of Corti was entirely destroyed. ILDR1 deficiency affects expression of tricellulin in vivo, and this provides a possible explanation to hearing loss. To further elucidate the mechanism of deafness related to ILDR1 deficiency, we pursued a differential proteomic approach to comprehensively assess differential protein expression in the cochleae of Ildr1+/− and Ildr1−/− mice at P21. Altogether, 708 proteins were up-regulated (fold change >1.5 and 114 proteins were down-regulated (fold change <0.5 in the Ildr1−/− mice compared with Ildr1+/− mice. Gene ontology classification indicated that a number of differentially expressed proteins are involved in cell adhesion, protein and vesicle-mediated transport, cell death, membrane organization, and cellular homeostasis. A few of these proteins are closely related to hearing development. Taken together, our data suggest that ILDR1 is important for the survival of OHCs and provide novel insights into the pathogenesis of human deafness DFNB42 deafness.

  17. Signaling from Mus81-Eme2-Dependent DNA Damage Elicited by Chk1 Deficiency Modulates Replication Fork Speed and Origin Usage

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    Hervé Técher


    Full Text Available Mammalian cells deficient in ATR or Chk1 display moderate replication fork slowing and increased initiation density, but the underlying mechanisms have remained unclear. We show that exogenous deoxyribonucleosides suppress both replication phenotypes in Chk1-deficient, but not ATR-deficient, cells. Thus, in the absence of exogenous stress, depletion of either protein impacts the replication dynamics through different mechanisms. In addition, Chk1 deficiency, but not ATR deficiency, triggers nuclease-dependent DNA damage. Avoiding damage formation through invalidation of Mus81-Eme2 and Mre11, or preventing damage signaling by turning off the ATM pathway, suppresses the replication phenotypes of Chk1-deficient cells. Damage and resulting DDR activation are therefore the cause, not the consequence, of replication dynamics modulation in these cells. Together, we identify moderate reduction of precursors available for replication as an additional outcome of DDR activation. We propose that resulting fork slowing, and subsequent firing of backup origins, helps replication to proceed along damaged templates.

  18. Chronic myelogenous leukemia (CML) (United States)

    CML; Chronic myeloid leukemia; Chronic granulocytic leukemia; Leukemia - chronic granulocytic ... Chronic myelogenous leukemia is grouped into phases: Chronic Accelerated Blast crisis The chronic phase can last for ...

  19. Dietary-Induced Chronic Hypothyroidism Negatively Affects Rat Follicular Development and Ovulation Rate and Is Associated with Oxidative Stress. (United States)

    Meng, Li; Rijntjes, Eddy; Swarts, Hans; Bunschoten, Annelies; van der Stelt, Inge; Keijer, Jaap; Teerds, Katja


    The long-term effects of chronic hypothyroidism on ovarian follicular development in adulthood are not well known. Using a rat model of chronic diet-induced hypothyroidism initiated in the fetal period, we investigated the effects of prolonged reduced plasma thyroid hormone concentrations on the ovarian follicular reserve and ovulation rate in prepubertal (12-day-old) and adult (64-day-old and 120-day-old) rats. Besides, antioxidant gene expression, mitochondrial density and the occurrence of oxidative stress were analyzed. Our results show that continuous hypothyroidism results in lower preantral and antral follicle numbers in adulthood, accompanied by a higher percentage of atretic follicles, when compared to euthyroid age-matched controls. Not surprisingly, ovulation rate was lower in the hypothyroid rats. At the age of 120 days, the mRNA and protein content of superoxide dismutase 1 (SOD1) were significantly increased while catalase (CAT) mRNA and protein content was significantly decreased, suggesting a disturbed antioxidant defense capacity of ovarian cells in the hypothyroid animals. This was supported by a significant reduction in the expression of peroxiredoxin 3 ( ITALIC! Prdx3), thioredoxin reductase 1 ( ITALIC! Txnrd1), and uncoupling protein 2 ( ITALIC! Ucp2) and a downward trend in glutathione peroxidase 3 ( ITALIC! Gpx3) and glutathione S-transferase mu 2 ( ITALIC! Gstm2) expression. These changes in gene expression were likely responsible for the increased immunostaining of the oxidative stress marker 4-hydroxynonenal. Together these results suggest that chronic hypothyroidism initiated in the fetal/neonatal period results in a decreased ovulation rate associated with a disturbance of the antioxidant defense system in the ovary.

  20. Chemokine-like receptor 1 deficiency does not affect the development of insulin resistance and nonalcoholic fatty liver disease in mice.

    Directory of Open Access Journals (Sweden)

    Nanda Gruben

    Full Text Available The adipokine chemerin and its receptor, chemokine-like receptor 1 (Cmklr1, are associated with insulin resistance and nonalcoholic fatty liver disease (NAFLD, which covers a broad spectrum of liver diseases, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH. It is possible that chemerin and/or Cmklr1 exert their effects on these disorders through inflammation, but so far the data have been controversial. To gain further insight into this matter, we studied the effect of whole-body Cmklr1 deficiency on insulin resistance and NAFLD. In view of the primary role of macrophages in hepatic inflammation, we also transplanted bone marrow from Cmklr1 knock-out (Cmklr1-/- mice and wild type (WT mice into low-density lipoprotein receptor knock-out (Ldlr-/- mice, a mouse model for NASH. All mice were fed a high fat, high cholesterol diet containing 21% fat from milk butter and 0.2% cholesterol for 12 weeks. Insulin resistance was assessed by an oral glucose tolerance test, an insulin tolerance test, and by measurement of plasma glucose and insulin levels. Liver pathology was determined by measuring hepatic inflammation, fibrosis, lipid accumulation and the NAFLD activity score (NAS. Whole-body Cmklr1 deficiency did not affect body weight gain or food intake. In addition, we observed no differences between WT and Cmklr1-/- mice for hepatic inflammatory and fibrotic gene expression, immune cell infiltration, lipid accumulation or NAS. In line with this, we detected no differences in insulin resistance. In concordance with whole-body Cmklr1 deficiency, the absence of Cmklr1 in bone marrow-derived cells in Ldlr-/- mice did not affect their insulin resistance or liver pathology. Our results indicate that Cmklr1 is not involved in the pathogenesis of insulin resistance or NAFLD. Thus, we recommend that the associations reported between Cmklr1 and insulin resistance or NAFLD should be interpreted with caution.

  1. Inflammatory mediator TAK1 regulates hair follicle morphogenesis and anagen induction shown by using keratinocyte-specific TAK1-deficient mice.

    Directory of Open Access Journals (Sweden)

    Koji Sayama

    Full Text Available Transforming growth factor-beta-activated kinase 1 (TAK1 is a member of the NF-kappaB pathway and regulates inflammatory responses. We previously showed that TAK1 also regulates keratinocyte growth, differentiation, and apoptosis. However, it is unknown whether TAK1 has any role in epithelial-mesenchymal interactions. To examine this possibility, we studied the role of TAK1 in mouse hair follicle development and cycling as an instructive model system. By comparing keratinocyte-specific TAK1-deficient mice (Map3k7(fl/flK5-Cre with control mice, we found that the number of hair germs (hair follicles precursors in Map3k7(fl/flK5-Cre mice was significantly reduced at E15.5, and that subsequent hair follicle morphogenesis was retarded. Next, we analyzed the role of TAK1 in the cyclic remodeling in follicles by analyzing hair cycle progression in mice with a tamoxifen-inducible keratinocyte-specific TAK1 deficiency (Map3k7(fl/flK14-Cre-ER(T2. After active hair growth (anagen was induced by depilation, TAK1 was deleted by topical tamoxifen application. This resulted in significantly retarded anagen development in TAK1-deficient mice. Deletion of TAK1 in hair follicles that were already in anagen induced premature, apoptosis-driven hair follicle regression, along with hair follicle damage. These studies provide the first evidence that the inflammatory mediator TAK1 regulates hair follicle induction and morphogenesis, and is required for anagen induction and anagen maintenance.

  2. Gamma-H2AX upregulation caused by Wip1 deficiency increases depression-related cellular senescence in hippocampus (United States)

    He, Zhi-Yong; Wang, Wen-Yue; Hu, Wei-Yan; Yang, Lu; Li, Yan; Zhang, Wei-Yuan; Yang, Ya-Shu; Liu, Si-Cheng; Zhang, Feng-Lan; Mei, Rong; Xing, Da; Xiao, Zhi-Cheng; Zhang, Ming


    The PP2C family member Wild-type p53-induced phosphatase 1 (Wip1) critically regulates DNA damage response (DDR) under stressful situations. In the present study, we investigated whether Wip1 expression was involved in the regulation of DDR-induced and depression-related cellular senescence in mouse hippocampus. We found that Wip1 gene knockout (KO) mice showed aberrant elevation of hippocampal cellular senescence and of γ-H2AX activity, which is known as a biomarker of DDR and cellular senescence, indicating that the lack of Wip1-mediated γ-H2AX dephosphorylation facilitates cellular senescence in hippocampus. Administration of the antidepressant fluoxetine had no significant effects on the increased depression-like behaviors, enriched cellular senescence, and aberrantly upregulated hippocampal γ-H2AX activity in Wip1 KO mice. After wildtype C57BL/6 mice were exposed to the procedure of chronic unpredictable mild stress (CUMS), cellular senescence and γ-H2AX activity in hippocampus were also elevated, accompanied by the suppression of Wip1 expression in hippocampus when compared to the control group without CUMS experience. These CUMS-induced symptoms were effectively prevented following fluoxetine administration in wildtype C57BL/6 mice, with the normalization of depression-like behaviors. Our data demonstrate that Wip1-mediated γ-H2AX dephosphorylation may play an important role in the occurrence of depression-related cellular senescence. PMID:27686532

  3. Mice with DNA repair gene Ercc1 deficiency in a neural crest lineage are a model for late-onset Hirschsprung disease. (United States)

    Selfridge, Jim; Song, Liang; Brownstein, David G; Melton, David W


    The Ercc1 gene is essential for nucleotide excision repair and is also important in recombination repair and the repair of interstrand crosslinks. We have previously used a floxed Ercc1 allele with a keratinocyte-specific Cre recombinase transgene to inactivate Ercc1 in the epidermal layer of the skin and so generate a mouse model for UV-induced non-melanoma skin cancer. Now, in an attempt to generate a model for UV-induced melanoma, we have used the floxed Ercc1 allele in combination with a Cre transgene under the control of the tyrosinase gene promoter to produce mice with Ercc1-deficient melanocytes that are hypersensitive to UV irradiation. These animals developed normally, but died when 4-6 months old with severe colonic obstruction. Melanocytes are derived from the neural crest and the tyrosinase promoter is also expressed in additional neural crest-derived lineages, including the progenitors of the parasympathetic nervous system that innervates the gastrointestinal tract and controls gut peristalsis. A functional enteric nervous system developed in floxed Ercc1 mice with the tyrosinase Cre transgene, but was found to have degenerated in the colons of affected mice. We suggest that accumulating unrepaired endogenous DNA damage in the Ercc1-deficient colonic parasympathetic ganglia leads to the degeneration of this network and results in a colonic obstructive disorder that resembles late-onset Hirschsprung disease in man.

  4. Meiotic failure in cyclin A1-deficient mouse spermatocytes triggers apoptosis through intrinsic and extrinsic signaling pathways and 14-3-3 proteins (United States)

    Panigrahi, Sunil K.; Manterola, Marcia; Wolgemuth, Debra J.


    Cyclin A1 (Ccna1), a member of the mammalian A type cyclins, is most abundantly expressed in spermatocytes and is essential for spermatogenesis in the mouse. Ccna1- deficient spermatocytes arrest at late meiotic prophase and undergo apoptosis. To further delineate the mechanisms and key factors involved in this process, we have examined changes in expression of genes involved in both intrinsic and extrinsic signaling pathways that trigger apoptosis in the mutant spermatocytes. Our results show that both pathways are involved, and that the factors involved in the intrinsic pathway were expressed earlier than those involved in the extrinsic pathway. We have also begun to identify in vivo Ccna1-interacting proteins, using an unbiased biochemical approach, and identified 14-3-3, a key regulator of apoptosis, as a Ccna1-interacting protein. Expression levels of 14-3-3 proteins remain unchanged between wild type and mutant testes but there were differences in the subcellular distribution. In wild type control, 14-3-3 is detected in both cytosolic and nuclear fractions whereas it is restricted to the cytoplasm in mutant testes. This differential distribution of 14-3-3 may contribute to the induction of apoptosis in Ccna1-deficient spermatocytes. These results provide insight into the apoptotic mechanisms and pathways that are triggered when progression through the meiotic cell cycle is defective in male gametogenesis. PMID:28301569

  5. Lipid absorption defects in intestine-specific microsomal triglyceride transfer protein and ATP-binding cassette transporter A1-deficient mice. (United States)

    Iqbal, Jahangir; Parks, John S; Hussain, M Mahmood


    We have previously described apolipoprotein B (apoB)-dependent and -independent cholesterol absorption pathways and the role of microsomal triglyceride transfer protein (MTP) and ATP-binding cassette transporter A1 (ABCA1) in these pathways. To assess the contribution of these pathways to cholesterol absorption and to determine whether there are other pathways, we generated mice that lack MTP and ABCA1, individually and in combination, in the intestine. Intestinal deletions of Mttp and Abca1 decreased plasma cholesterol concentrations by 45 and 24%, respectively, whereas their combined deletion reduced it by 59%. Acute cholesterol absorption was reduced by 28% in the absence of ABCA1, and it was reduced by 92-95% when MTP was deleted in the intestine alone or together with ABCA1. MTP deficiency significantly reduced triglyceride absorption, although ABCA1 deficiency had no effect. ABCA1 deficiency did not affect cellular lipids, but Mttp deficiency significantly increased intestinal levels of triglycerides and free fatty acids. Accumulation of intestinal free fatty acids, but not triglycerides, in Mttp-deficient intestines was prevented when mice were also deficient in intestinal ABCA1. Combined deficiency of these genes increased intestinal fatty acid oxidation as a consequence of increased expression of peroxisome proliferator-activated receptor-γ (PPARγ) and carnitine palmitoyltransferase 1α (CPT1α). These studies show that intestinal MTP and ABCA1 are critical for lipid absorption and are the main determinants of plasma and intestinal lipid levels. Reducing their activities might lower plasma lipid concentrations.

  6. Chronic cholecystitis (United States)

    Cholecystitis - chronic ... Most of the time, chronic cholecystitis is caused by repeated attacks of acute (sudden) cholecystitis. Most of these attacks are caused by gallstones in the gallbladder. These ...

  7. Chronic Pain (United States)

    ... pain. Psychotherapy, relaxation and medication therapies, biofeedback, and behavior modification may also be employed to treat chronic pain. × ... pain. Psychotherapy, relaxation and medication therapies, biofeedback, and behavior modification may also be employed to treat chronic pain. ...

  8. Chronic Pain (United States)

    ... a problem you need to take care of. Chronic pain is different. The pain signals go on ... there is no clear cause. Problems that cause chronic pain include Headache Low back strain Cancer Arthritis ...

  9. Chronic prostatitis


    Le, Brian; Schaeffer, Anthony J.


    Chronic prostatitis can cause pain and urinary symptoms, and usually occurs without positive bacterial cultures from prostatic secretions (known as chronic abacterial prostatitis or chronic pelvic pain syndrome [CP/CPPS]). Bacterial infection can result from urinary tract instrumentation, but the cause and natural history of CP/CPPS are unknown.

  10. Chronic prostatitis


    Erickson, Bradley A.; Schaeffer, Anthony J.; Le, Brian


    Chronic prostatitis can cause pain and urinary symptoms, and usually occurs without positive bacterial cultures from prostatic secretions (known as chronic abacterial prostatitis or chronic pelvic pain syndrome, CP/CPPS). Bacterial infection can result from urinary tract instrumentation, but the cause and natural history of CP/CPPS are unknown.

  11. Dermatan Sulfate Epimerase 1-Deficient Mice Have Reduced Content and Changed Distribution of Iduronic Acids in Dermatan Sulfate and an Altered Collagen Structure in Skin

    DEFF Research Database (Denmark)

    Maccarana, M.; Kalamajski, S.; Kongsgaard, M.;


    Dermatan sulfate epimerase 1 (DS-epi1) and DS-epi2 convert glucuronic acid to iduronic acid in chondroitin/dermatan sulfate biosynthesis. Here we report on the generation of DS-epi1-null mice and the resulting alterations in the chondroitin/dermatan polysaccharide chains. The numbers of long blocks...... of adjacent iduronic acids are greatly decreased in skin decorin and biglycan chondroitin/dermatan sulfate, along with a parallel decrease in iduronic-2-O-sulfated-galactosamine-4-O-sulfated structures. Both iduronic acid blocks and iduronic acids surrounded by glucuronic acids are also decreased in versican......-derived chains. DS-epi1-deficient mice are smaller than their wild-type littermates but otherwise have no gross macroscopic alterations. The lack of DS-epi1 affects the chondroitin/dermatan sulfate in many proteoglycans, and the consequences for skin collagen structure were initially analyzed. We found...

  12. Aberrant autolysosomal regulation is linked to the induction of embryonic senescence: differential roles of Beclin 1 and p53 in vertebrate Spns1 deficiency.

    Directory of Open Access Journals (Sweden)

    Tomoyuki Sasaki


    Full Text Available Spinster (Spin in Drosophila or Spinster homolog 1 (Spns1 in vertebrates is a putative lysosomal H+-carbohydrate transporter, which functions at a late stage of autophagy. The Spin/Spns1 defect induces aberrant autolysosome formation that leads to embryonic senescence and accelerated aging symptoms, but little is known about the mechanisms leading to the pathogenesis in vivo. Beclin 1 and p53 are two pivotal tumor suppressors that are critically involved in the autophagic process and its regulation. Using zebrafish as a genetic model, we show that Beclin 1 suppression ameliorates Spns1 loss-mediated senescence as well as autophagic impairment, whereas unexpectedly p53 deficit exacerbates both of these characteristics. We demonstrate that 'basal p53' activity plays a certain protective role(s against the Spns1 defect-induced senescence via suppressing autophagy, lysosomal biogenesis, and subsequent autolysosomal formation and maturation, and that p53 loss can counteract the effect of Beclin 1 suppression to rescue the Spns1 defect. By contrast, in response to DNA damage, 'activated p53' showed an apparent enhancement of the Spns1-deficient phenotype, by inducing both autophagy and apoptosis. Moreover, we found that a chemical and genetic blockage of lysosomal acidification and biogenesis mediated by the vacuolar-type H+-ATPase, as well as of subsequent autophagosome-lysosome fusion, prevents the appearance of the hallmarks caused by the Spns1 deficiency, irrespective of the basal p53 state. Thus, these results provide evidence that Spns1 operates during autophagy and senescence differentially with Beclin 1 and p53.

  13. ALDH1A1 Deficiency in Gorlin Syndrome Suggests a Central Role for Retinoic Acid and ATM Deficits in Radiation Carcinogenesis. (United States)

    Weber, Thomas J; Magnaldo, Thierry; Xiong, Yijia


    We hypothesize that aldehyde dehydrogenase 1A1 (ALDH1A1) deficiency will result in impaired ataxia-telangiectasia mutated (ATM) activation in a retinoic acid-sensitive fashion. Data supporting this hypothesis include (1) reduced ATM activation in irradiated primary dermal fibroblasts from ALDH1A1-deficient Gorlin syndrome patients (GDFs), relative to ALDH1A1-positive normal human dermal fibroblasts (NHDFs) and (2) increased ATM activation by X-radiation in GDFs pretreated with retinoic acid, however, the impact of donor variability on ATM activation in fibroblasts was not assessed and is a prudent consideration in future studies. Clonogenic survival of irradiated cells showed differential responses to retinoic acid as a function of treatment time. Long-term (5 Day) retinoic acid treatment functioned as a radiosensitizer and was associated with downregulation of ATM protein levels. Short-term (7 h) retinoic acid treatment showed a trend toward increased survival of irradiated cells and did not downregulate ATM protein levels. Using a newly developed IncubATR technology, which defines changes in bulk chemical bond patterns in live cells, we can discriminate between the NHDF and GDF phenotypes, but treatment of GDFs with retinoic acid does not induce reversion of bulk chemical bond patterns associated with GDFs toward the NHDF phenotype. Collectively, our preliminary investigation of the Gorlin phenotype has identified deficient ALDH1A1 expression associated with deficient ATM activation as a possible susceptibility factor that is consistent with the high incidence of spontaneous and radiation-induced carcinogenesis in these patients. The IncubATR technology exhibits sufficient sensitivity to detect phenotypic differences in live cells that may be relevant to radiation health effects.

  14. [Chronicity, chronicization, systematization of delusions]. (United States)

    Trapet, P; Fernandez, C; Galtier, M C; Gisselmann, A


    Chronicity in psychopathology is indicative of a term, a decay. Chronicization only leads the way to this term. Here, chronicization is taken literally as an inscription in the time course of delusions. The mechanism of systematization seems to be a central mark in the approach to chronic delusions. It is not an alienation or an irreversible closing but an attempted accommodation with reality in the life of psychotic subjects, irrespective of the delusional structure. The role of therapy and drug treatment as a follow-up may in that case assume another meaning.

  15. Chronic pancreatitis


    Kocher, Hemant M.; Froeling, Fieke EM


    Chronic pancreatitis is characterised by long-standing inflammation of the pancreas owing to a wide variety of causes, including recurrent acute attacks of pancreatitis. Chronic pancreatitis affects 3–9 people in 100,000; 70% of cases are alcohol-induced.

  16. Chronic pancreatitis


    Kocher, Hemant M.; Kadaba, Raghu


    Chronic pancreatitis is characterised by long-standing inflammation of the pancreas due to a wide variety of causes, including recurrent acute attacks of pancreatitis. Chronic pancreatitis affects between 3 and 9 people in 100,000; 70% of cases are alcohol-induced.

  17. NF1 deficiency causes Bcl-xL upregulation in Schwann cells derived from neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors. (United States)

    Park, Ho-Jin; Lee, Su-Jin; Sohn, Young Bae; Jin, Hyun-Seok; Han, Jae-Ho; Kim, Young-Bae; Yim, Hyunee; Jeong, Seon-Yong


    Since the bi-allelic inactivation of both neurofibromin 1 (NF1) gene alleles (NF1(-/-)) in Schwann cells (SCs) is common in both benign plexiform neurofibromas (PNs) and malignant peripheral nerve sheath tumors (MPNSTs) in patients with neurofibromatosis type 1 (NF1), other genetic alterations in SCs may be required for tumor progression of PNs to MPNSTs. We found that the anti-apoptotic Bcl-xL protein is upregulated in MPNST tissues compared to PN tissues from patients with NF1 by immunohistological staining. In addition, we investigated whether Bcl-xL is upregulated in SCs derived from MPNSTs and found a significantly higher Bcl-xL expression level in sNF96.2 MPNST-derived SCs compared to normal human SCs (HSCs). We also discovered that the increased Bcl-xL expression caused an increase in drug resistance to doxorubicin in MPNST-derived SCs. Manipulation of NF1 gene expression levels by treatment with small interfering RNA (siRNA) and overexpression of the neurofibromin GAP-related domain (NF1-GRD) demonstrated that upregulated Bcl-xL expression in MPNST-derived SCs was caused by NF1 deficiency. Treatment with the Erk1/2 inhibitor, PD98059, resulted in a slight increase in Bcl-xL levels in neurofibromin-depleted normal HSCs, indicating that Bcl-xL upregulation in MPNST-derived SCs is mediated by activated Erk1/2, which is a Ras downstream protein regulated by neurofibromin. As the reduction of Bcl-xL expression restored sensitivity to doxorubicin-induced apoptosis in sNF96.2 cells, we examined the effect of the small molecule Bcl-xL inhibitor ABT-737 on sNF96.2 cells. A very low dose of ABT-737 combined with doxorubicin synergistically enhanced sensitivity to doxorubicin-induced apoptosis in sNF96.2 cells, suggesting that ABT-737 and doxorubicin may be a good combination to effectively treat NF1-associated MPNSTs with minimal side-effects. Collectively, our results suggest that upregulation of Bcl-xL in MPNST-derived SCs may be caused by the NF1 deficiency

  18. STIM1 controls T cell-mediated immune regulation and inflammation in chronic infection. (United States)

    Desvignes, Ludovic; Weidinger, Carl; Shaw, Patrick; Vaeth, Martin; Ribierre, Theo; Liu, Menghan; Fergus, Tawania; Kozhaya, Lina; McVoy, Lauren; Unutmaz, Derya; Ernst, Joel D; Feske, Stefan


    Chronic infections induce a complex immune response that controls pathogen replication, but also causes pathology due to sustained inflammation. Ca2+ influx mediates T cell function and immunity to infection, and patients with inherited mutations in the gene encoding the Ca2+ channel ORAI1 or its activator stromal interaction molecule 1 (STIM1) are immunodeficient and prone to chronic infection by various pathogens, including Mycobacterium tuberculosis (Mtb). Here, we demonstrate that STIM1 is required for T cell-mediated immune regulation during chronic Mtb infection. Compared with WT animals, mice with T cell-specific Stim1 deletion died prematurely during the chronic phase of infection and had increased bacterial burdens and severe pulmonary inflammation, with increased myeloid and lymphoid cell infiltration. Although STIM1-deficient T cells exhibited markedly reduced IFN-γ production during the early phase of Mtb infection, bacterial growth was not immediately exacerbated. During the chronic phase, however, STIM1-deficient T cells displayed enhanced IFN-γ production in response to elevated levels of IL-12 and IL-18. The lack of STIM1 in T cells was associated with impaired activation-induced cell death upon repeated TCR engagement and pulmonary lymphocytosis and hyperinflammation in Mtb-infected mice. Chronically Mtb-infected, STIM1-deficient mice had reduced levels of inducible regulatory T cells (iTregs) due to a T cell-intrinsic requirement for STIM1 in iTreg differentiation and excessive production of IFN-γ and IL-12, which suppress iTreg differentiation and maintenance. Thus, STIM1 controls multiple aspects of T cell-mediated immune regulation to limit injurious inflammation during chronic infection.

  19. MD-1 deficiency attenuates dextran sodium sulfate (DSS)-induced colitis through modulating the function of colonic lamina propria dendritic cells. (United States)

    Pan, Huaqin; Zhang, Guqin; Zhang, Lin; Wang, Wei; Shang, Jian; Wang, Xiaobing; Zhao, Qiu; Li, Jin


    Available evidence suggests that both dysregulated innate and adaptive immune pathways contribute to the aberrant intestinal inflammatory response in patients with inflammatory bowel disease (IBD). Myeloid Differentiation 1 (MD-1), also known as Lymphocyte Antigen 86 (Ly86), a secreted protein interacting with radioprotective 105 (RP105), plays an important role in Toll-like receptor 4 (TLR4) signaling pathway. Previous studies showed that MD-1 may be involved in the (patho) physiological regulation of the innate immune system and inflammation. In this study, we reported for the first time that MD-1 mRNA expression was up-regulated in both human IBD patients and DSS-treated WT mice. We showed that MD-1(-/-) mice were less susceptible to the development of colitis than WT controls as demonstrated by significantly reduced weight loss, disease activity index, colon histological scores, cellular infiltration and expression of inflammatory mediators. In addition, mucosal barrier function seemed to be intact in response to the loss of MD-1. Finally, lamina propria dendritic cells (LPDCs) from the colon of MD-1(-/-) mice after DSS exposure not only decreased in number but also significantly down-regulated the expression of surface maturation co-stimulatory molecules MHC-II, CD40 and CD86 compared with those from WT mice. Taken together, our results reveal that MD-1 deficiency is of critical importance in down-regulating induction and progression of DSS colitis, thereby suggesting that MD-1 might be a target for future interventional therapies of IBD.

  20. Different molecular mechanisms involved in spontaneous and oxidative stress-induced mitochondrial fragmentation in tripeptidyl peptidase-1 (TPP-1)-deficient fibroblasts (United States)

    Van Beersel, Guillaume; Tihon, Eliane; Demine, Stéphane; Hamer, Isabelle; Jadot, Michel; Arnould, Thierry


    NCLs (neuronal ceroid lipofuscinoses) form a group of eight inherited autosomal recessive diseases characterized by the intralysosomal accumulation of autofluorescent pigments, called ceroids. Recent data suggest that the pathogenesis of NCL is associated with the appearance of fragmented mitochondria with altered functions. However, even if an impairement in the autophagic pathway has often been evoked, the molecular mechanisms leading to mitochondrial fragmentation in response to a lysosomal dysfunction are still poorly understood. In this study, we show that fibroblasts that are deficient for the TPP-1 (tripeptidyl peptidase-1), a lysosomal hydrolase encoded by the gene mutated in the LINCL (late infantile NCL, CLN2 form) also exhibit a fragmented mitochondrial network. This morphological alteration is accompanied by an increase in the expression of the protein BNIP3 (Bcl2/adenovirus E1B 19 kDa interacting protein 3) as well as a decrease in the abundance of mitofusins 1 and 2, two proteins involved in mitochondrial fusion. Using RNAi (RNA interference) and quantitative analysis of the mitochondrial morphology, we show that the inhibition of BNIP3 expression does not result in an increase in the reticulation of the mitochondrial population in LINCL cells. However, this protein seems to play a key role in cell response to mitochondrial oxidative stress as it sensitizes mitochondria to antimycin A-induced fragmentation. To our knowledge, our results bring the first evidence of a mechanism that links TPP-1 deficiency and oxidative stress-induced changes in mitochondrial morphology. PMID:23249249

  1. Restoration of human B-cell differentiation into NOD-SCID mice engrafted with gene-corrected CD34+ cells isolated from Artemis or RAG1-deficient patients. (United States)

    Lagresle-Peyrou, Chantal; Benjelloun, Fatine; Hue, Christophe; Andre-Schmutz, Isabelle; Bonhomme, Delphine; Forveille, Monique; Beldjord, Kheira; Hacein-Bey-Abina, Salima; De Villartay, Jean-Pierre; Charneau, Pierre; Durandy, Anne; Fischer, Alain; Cavazzana-Calvo, Marina


    Severe combined immunodeficiency (SCID) caused by mutation of the recombination-activating gene 1 (RAG1) or Artemis gene lead to the absence of B- and T-cell differentiation. The only curative treatment is allogeneic bone marrow (BM) transplantation, which displays a high survival rate when an HLA compatible donor is available but has a poorer prognosis when the donor is partially compatible. Consequently, gene therapy may be a promising alternative strategy for these diseases. Here, we report that lentiviral gene-corrected BM CD34(+) cells (isolated from Artemis- or RAG1-deficient patients) sustain human B-cell differentiation following injection into non-obese diabetic/SCID (NOD-SCID) mice previously infused with anti-interleukin-2 receptor beta chain monoclonal antibody. In most of the mice BM, engrafted with Artemis-transduced cells, human B-cell differentiation occurred until the mature stage. The B cells were functional as human immunoglobulin M (IgM) was present in the serum. Following injection with RAG1-transduced cells, human engraftment occurred in vivo but B-cell differentiation until the mature stage was less frequent. However, when it occurred, it was always associated with human IgM production. This overall approach represents a useful tool for evaluating gene transfer efficiency in human SCID forms affecting B-cell development (such as Artemis deficiency) and for testing new vectors for improving in vivo RAG1 complementation.

  2. Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency. (United States)

    Herreman, A; Hartmann, D; Annaert, W; Saftig, P; Craessaerts, K; Serneels, L; Umans, L; Schrijvers, V; Checler, F; Vanderstichele, H; Baekelandt, V; Dressel, R; Cupers, P; Huylebroeck, D; Zwijsen, A; Van Leuven, F; De Strooper, B


    Mutations in the homologous presenilin 1 (PS1) and presenilin 2 (PS2) genes cause the most common and aggressive form of familial Alzheimer's disease. Although PS1 function and dysfunction have been extensively studied, little is known about the function of PS2 in vivo. To delineate the relationships of PS2 and PS1 activities and whether PS2 mutations involve gain or loss of function, we generated PS2 homozygous deficient (-/-) and PS1/PS2 double homozygous deficient mice. In contrast to PS1(-/-) mice, PS2(-/-) mice are viable and fertile and develop only mild pulmonary fibrosis and hemorrhage with age. Absence of PS2 does not detectably alter processing of amyloid precursor protein and has little or no effect on physiologically important apoptotic processes, indicating that Alzheimer's disease-causing mutations in PS2, as in PS1, result in gain of function. Although PS1(+/-) PS2( -/-) mice survive in relatively good health, complete deletion of both PS2 and PS1 genes causes a phenotype closely resembling full Notch-1 deficiency. These results demonstrate in vivo that PS1 and PS2 have partially overlapping functions and that PS1 is essential and PS2 is redundant for normal Notch signaling during mammalian embryological development.

  3. CCR2(+) monocytes infiltrate atrophic lesions in age-related macular disease and mediate photoreceptor degeneration in experimental subretinal inflammation in Cx3cr1 deficient mice. (United States)

    Sennlaub, Florian; Auvynet, Constance; Calippe, Bertrand; Lavalette, Sophie; Poupel, Lucie; Hu, Shulong J; Dominguez, Elisa; Camelo, Serge; Levy, Olivier; Guyon, Elodie; Saederup, Noah; Charo, Israel F; Rooijen, Nico Van; Nandrot, Emeline; Bourges, Jean-Louis; Behar-Cohen, Francine; Sahel, José-Alain; Guillonneau, Xavier; Raoul, William; Combadiere, Christophe


    Atrophic age-related macular degeneration (AMD) is associated with the subretinal accumulation of mononuclear phagocytes (MPs). Their role in promoting or inhibiting retinal degeneration is unknown. We here show that atrophic AMD is associated with increased intraocular CCL2 levels and subretinal CCR2(+) inflammatory monocyte infiltration in patients. Using age- and light-induced subretinal inflammation and photoreceptor degeneration in Cx3cr1 knockout mice, we show that subretinal Cx3cr1 deficient MPs overexpress CCL2 and that both the genetic deletion of CCL2 or CCR2 and the pharmacological inhibition of CCR2 prevent inflammatory monocyte recruitment, MP accumulation and photoreceptor degeneration in vivo. Our study shows that contrary to CCR2 and CCL2, CX3CR1 is constitutively expressed in the retina where it represses the expression of CCL2 and the recruitment of neurotoxic inflammatory CCR2(+) monocytes. CCL2/CCR2 inhibition might represent a powerful tool for controlling inflammation and neurodegeneration in AMD.

  4. CCR2+ monocytes infiltrate atrophic lesions in age-related macular disease and mediate photoreceptor degeneration in experimental subretinal inflammation in Cx3cr1 deficient mice (United States)

    Sennlaub, Florian; Auvynet, Constance; Calippe, Bertrand; Lavalette, Sophie; Poupel, Lucie; Hu, Shulong J; Dominguez, Elisa; Camelo, Serge; Levy, Olivier; Guyon, Elodie; Saederup, Noah; Charo, Israel F; Van Rooijen, Nico; Nandrot, Emeline; Bourges, Jean-Louis; Behar-Cohen, Francine; Sahel, José-Alain; Guillonneau, Xavier; Raoul, William; Combadiere, Christophe


    Atrophic age-related macular degeneration (AMD) is associated with the subretinal accumulation of mononuclear phagocytes (MPs). Their role in promoting or inhibiting retinal degeneration is unknown. We here show that atrophic AMD is associated with increased intraocular CCL2 levels and subretinal CCR2+ inflammatory monocyte infiltration in patients. Using age- and light-induced subretinal inflammation and photoreceptor degeneration in Cx3cr1 knockout mice, we show that subretinal Cx3cr1 deficient MPs overexpress CCL2 and that both the genetic deletion of CCL2 or CCR2 and the pharmacological inhibition of CCR2 prevent inflammatory monocyte recruitment, MP accumulation and photoreceptor degeneration in vivo. Our study shows that contrary to CCR2 and CCL2, CX3CR1 is constitutively expressed in the retina where it represses the expression of CCL2 and the recruitment of neurotoxic inflammatory CCR2+ monocytes. CCL2/CCR2 inhibition might represent a powerful tool for controlling inflammation and neurodegeneration in AMD. PMID:24142887

  5. Maximizing bone formation in posterior spine fusion using rhBMP-2 and zoledronic acid in wild type and NF1 deficient mice. (United States)

    Bobyn, Justin; Rasch, Anton; Kathy, Mikulec; Little, David G; Schindeler, Aaron


    Spinal pseudarthrosis is a well described complication of spine fusion surgery in NF1 patients. Reduced bone formation and excessive resorption have been described in NF1 and anti-resorptive agents may be advantageous in these individuals. In this study, 16 wild type and 16 Nf1(+/-) mice were subjected to posterolateral fusion using collagen sponges containing 5 µg rhBMP-2 introduced bilaterally. Mice were dosed twice weekly with 0.02 mg/kg zoledronic acid (ZA) or sterile saline. The fusion mass was assessed for bone volume (BV) and bone mineral density (BMD) by microCT. Co-treatment using rhBMP-2 and ZA produced a significant increase (p Nf1(+/-) mice (+174%). Co-treatment also produced a significantly higher total BMD of the fusion mass compared to rhBMP-2 alone in both groups (p Nf1(+/-) deficient mice still generated less bone than wild type controls. TRAP staining on histological sections indicated an increased osteoclast surface/bone surface (Oc.S/BS) in Nf1(+/-) mice relative to wild type mice, and this was reduced with ZA treatment.

  6. PINK1 Deficiency Decreases Expression Levels of mir-326, mir-330, and mir-3099 during Brain Development and Neural Stem Cell Differentiation (United States)

    Choi, Insup; Woo, Joo Hong; Jou, Ilo


    PTEN-induced putative kinase 1 (PINK1) is a Parkinson's disease (PD) gene. We examined miRNAs regulated by PINK1 during brain development and neural stem cell (NSC) differentiation, and found that lvels of miRNAs related to tumors and inflammation were different between 1-day-old-wild type (WT) and PINK1-knockout (KO) mouse brains. Notably, levels of miR-326, miR-330 and miR-3099, which are related to astroglioma, increased during brain development and NSC differentiation, and were significantly reduced in the absence of PINK1. Interestingly, in the presence of ciliary neurotrophic factor (CNTF), which pushes differentiation of NSCs into astrocytes, miR-326, miR-330, and miR-3099 levels in KO NSCs were also lower than those in WT NSCs. Furthermore, mimics of all three miRNAs increased expression of the astrocytic marker glial fibrillary acidic protein (GFAP) during differentiation of KO NSCs, but inhibitors of these miRNAs decreased GFAP expression in WT NSCs. Moreover, these miRNAs increased the translational efficacy of GFAP through the 3'-UTR of GFAP mRNA. Taken together, these results suggest that PINK1 deficiency reduce expression levels of miR-326, miR-330 and miR-3099, which may regulate GFAP expression during NSC differentiation and brain development. PMID:26924929

  7. Profile of mecasermin for the long-term treatment of growth failure in children and adolescents with severe primary IGF-1 deficiency

    Directory of Open Access Journals (Sweden)

    Danilo Fintini


    Full Text Available Danilo Fintini, Claudia Brufani, Marco CappaEndocrinology Unit, “Bambino Gesù” Children’s Hospital-IRCCS, Rome, ItalyAbstract: Growth hormone insensitivity syndrome (GHI or insulin-like growth factor-1 (IGF-1 deficiency (IGFD is characterized by deficit of IGF-1 production due to alteration of response of growth hormone (GH receptor to GH. This syndrome is due to mutation of GH receptor or IGF-1 gene and patients affected showed no response to GH therapy. The only treatment is recombinant IGF-1 (mecasermin, which has been available since 1986, but approved in the United States by the US Food and Drug Administration only in 2005 and in Europe by the European Medicines Agency in 2007. To date, few studies are available on long-term treatment with mecasermin in IGFD patients and some of them have a very small number of subjects. In this review we discuss briefly clinical features of severe primary IGFD, laboratory findings, and indications for treatment. Results of long-term therapy with rhIGF1 (mecasermin in patients affected by severe primary IGFD and possible side effects are explained.Keywords: mecasermin, therapy, Laron syndrome, IGF-1

  8. [Bacillus Calmette-Guérin (BCG) disease and interleukin 12 receptor β1 deficiency: clinical experience of two familial and one sporadic case]. (United States)

    Strickler, Alexis; Pérez, Amir; Risco, Migdy; Gallo, Silvanna


    BCG disease has been reported in primary and secondary immunodeficiency and as Mendelian Susceptibility to Mycobacterial Diseases (MSMD). Investigation of this syndrome has led to the identifications of a series of genetic, inherited defects in the IL-12/IFN-γ axis. MSMD-causing mutations have been found in seven autosomal and two X-linked genes. In these patients, local or disseminated vaccine BCG infections are common. We report a clinical series including two infants with left axillary adenitis ipsilateral to the site of neonatal BCG immunization; one of them member of a family with two previously reported cases and a single sporadic case. All of them were diagnosed sequentially in Puerto Montt, Chile. The aim of this report is to notify the first Chilean disseminated BCG patients without previous immunodeficiency, in whom it was possible to identify an underlying immunodeficiency, although specific tests for IL-12/IFN-γ axis was no performed in our country. Clinical suspicion and international collaboration permitted to confirm IL12-Rβ1 deficiency in 2 of 3 familial cases and a sporadic case.

  9. Phenotypic complementation of genetic immunodeficiency by chronic herpesvirus infection (United States)

    MacDuff, Donna A; Reese, Tiffany A; Kimmey, Jacqueline M; Weiss, Leslie A; Song, Christina; Zhang, Xin; Kambal, Amal; Duan, Erning; Carrero, Javier A; Boisson, Bertrand; Laplantine, Emmanuel; Israel, Alain; Picard, Capucine; Colonna, Marco; Edelson, Brian T; Sibley, L David; Stallings, Christina L; Casanova, Jean-Laurent; Iwai, Kazuhiro; Virgin, Herbert W


    Variation in the presentation of hereditary immunodeficiencies may be explained by genetic or environmental factors. Patients with mutations in HOIL1 (RBCK1) present with amylopectinosis-associated myopathy with or without hyper-inflammation and immunodeficiency. We report that barrier-raised HOIL-1-deficient mice exhibit amylopectin-like deposits in the myocardium but show minimal signs of hyper-inflammation. However, they show immunodeficiency upon acute infection with Listeria monocytogenes, Toxoplasma gondii or Citrobacter rodentium. Increased susceptibility to Listeria was due to HOIL-1 function in hematopoietic cells and macrophages in production of protective cytokines. In contrast, HOIL-1-deficient mice showed enhanced control of chronic Mycobacterium tuberculosis or murine γ-herpesvirus 68 (MHV68), and these infections conferred a hyper-inflammatory phenotype. Surprisingly, chronic infection with MHV68 complemented the immunodeficiency of HOIL-1, IL-6, Caspase-1 and Caspase-1;Caspase-11-deficient mice following Listeria infection. Thus chronic herpesvirus infection generates signs of auto-inflammation and complements genetic immunodeficiency in mutant mice, highlighting the importance of accounting for the virome in genotype-phenotype studies. DOI: PMID:25599590

  10. Ear infection - chronic (United States)

    Middle ear infection - chronic; Otitis media - chronic; Chronic otitis media; Chronic ear infection ... up. When this happens, infection can occur. A chronic ear infection develops when fluid or an infection ...

  11. Impact of physiological levels of chenodeoxycholic acid supplementation on intestinal and hepatic bile acid and cholesterol metabolism in Cyp7a1-deficient mice. (United States)

    Jones, Ryan D; Lopez, Adam M; Tong, Ernest Y; Posey, Kenneth S; Chuang, Jen-Chieh; Repa, Joyce J; Turley, Stephen D


    Mice deficient in cholesterol 7α-hydroxylase (Cyp7a1) have a diminished bile acid pool (BAP) and therefore represent a useful model for investigating the metabolic effects of restoring the pool with a specific BA. Previously we carried out such studies in Cyp7a1(-/-) mice fed physiological levels of cholic acid (CA) and achieved BAP restoration, along with an increased CA enrichment, at a dietary level of just 0.03% (w/w). Here we demonstrate that in Cyp7a1(-/-) mice fed chenodeoxycholic acid (CDCA) at a level of 0.06% (w/w), the BAP was restored to normal size and became substantially enriched with muricholic acid (MCA) (>70%), leaving the combined contribution of CA and CDCA to be Cyp7a1 deficiency such as an elevated rate of intestinal sterol synthesis, an enhanced level of mRNA for Cyp8b1 in the liver, and depressed mRNA levels for Ibabp, Shp and Fgf15 in the distal small intestine. When Cyp7a1(-/-) and matching Cyp7a1(+/+) mice were fed a diet with added cholesterol (0.2%) (w/w), either alone, or also containing CDCA (0.06%) (w/w) or CA (0.03%) (w/w) for 18days, the hepatic total cholesterol concentrations (mg/g) in the Cyp7a1(-/-) mice were 26.9±3.7, 16.4±0.9 and 47.6±1.9, respectively, vs. 4.9±0.4, 5.0±0.7 and 6.4±1.9, respectively in the corresponding Cyp7a1(+/+) controls. These data affirm the importance of using moderate levels of dietary BA supplementation to elicit changes in hepatic cholesterol metabolism through shifts in BAP size and composition.

  12. Differential effects of IGF-1 deficiency during the life span on structural and biomechanical properties in the tibia of aged mice. (United States)

    Ashpole, Nicole M; Herron, Jacquelyn C; Estep, Patrick N; Logan, Sreemathi; Hodges, Erik L; Yabluchanskiy, Andriy; Humphrey, Mary Beth; Sonntag, William E


    Advanced aging is associated with the loss of structural and biomechanical properties in bones, which increases the risk for bone fracture. Aging is also associated with reductions in circulating levels of the anabolic signaling hormone, insulin-like growth factor (IGF)-1. While the role of IGF-1 in bone development has been well characterized, the impact of the age-related loss of IGF-1 on bone aging remains controversial. Here, we describe the effects of reducing IGF-1 at multiple time points in the mouse life span--early in postnatal development, early adulthood, or late adulthood on tibia bone aging in both male and female igf (f/f) mice. Bone structure was analyzed at 27 months of age using microCT. We find that age-related reductions in cortical bone fraction, cortical thickness, and tissue mineral density were more pronounced when IGF-1 was reduced early in life and not in late adulthood. Three-point bone bending assays revealed that IGF-1 deficiency early in life resulted in reduced maximum force, maximum bending moment, and bone stiffness in aged males and females. The effects of IGF-1 on bone aging are microenvironment specific, as early-life loss of IGF-1 resulted in decreased cortical bone structure and strength along the diaphysis while significantly increasing trabecular bone fraction and trabecular number at the proximal metaphysis. The increases in trabecular bone were limited to males, as early-life loss of IGF-1 did not alter bone fraction or number in females. Together, our data suggest that the age-related loss of IGF-1 influences tibia bone aging in a sex-specific, microenvironment-specific, and time-dependent manner.

  13. ALMS1-deficient fibroblasts over-express extra-cellular matrix components, display cell cycle delay and are resistant to apoptosis.

    Directory of Open Access Journals (Sweden)

    Elisabetta Zulato

    Full Text Available Alström Syndrome (ALMS is a rare genetic disorder (483 living cases, characterized by many clinical manifestations, including blindness, obesity, type 2 diabetes and cardiomyopathy. ALMS is caused by mutations in the ALMS1 gene, encoding for a large protein with implicated roles in ciliary function, cellular quiescence and intracellular transport. Patients with ALMS have extensive fibrosis in nearly all tissues resulting in a progressive organ failure which is often the ultimate cause of death. To focus on the role of ALMS1 mutations in the generation and maintenance of this pathological fibrosis, we performed gene expression analysis, ultrastructural characterization and functional assays in 4 dermal fibroblast cultures from ALMS patients. Using a genome-wide gene expression analysis we found alterations in genes belonging to specific categories (cell cycle, extracellular matrix (ECM and fibrosis, cellular architecture/motility and apoptosis. ALMS fibroblasts display cytoskeleton abnormalities and migration impairment, up-regulate the expression and production of collagens and despite the increase in the cell cycle length are more resistant to apoptosis. Therefore ALMS1-deficient fibroblasts showed a constitutively activated myofibroblast phenotype even if they do not derive from a fibrotic lesion. Our results support a genetic basis for the fibrosis observed in ALMS and show that both an excessive ECM production and a failure to eliminate myofibroblasts are key mechanisms. Furthermore, our findings suggest new roles for ALMS1 in both intra- and extra-cellular events which are essential not only for the normal cellular function but also for cell-cell and ECM-cell interactions.

  14. [Chronic hepatitis]. (United States)

    Figueroa Barrios, R


    Medical literature about chronic hepatitis is reviewed. This unresolving disease caused by viruses, drugs or unknown factors may progress to in cirrhosis and hepatocarcinoma. A classification based on liver biopsy histology into chronic persistent and chronic active types has been largely abandoned and emphasis is placed on recognizing the etiology of the various types. One is associated with continuing hepatitis B virus infection; another is related to chronic hepatitis C virus infection and the third is termed autoinmune, because of the association with positive serum autoantibodies. A fourth type with similar clinical functional and morphologic features is found with some drug reactions. Long term corticoesteroid therapy is usually successful in autoinmune type. Associations between antibodies to liver-kidney microsomes and the hepatitis C virus can cause diagnostic difficulties. Antiviral treatment of chronic hepatitis B and C with interpheron alfa is employed, controlling symptoms and abnormal biochemistry and the progression to cirrhosis and liver cancer in 30 to 40% patients. Alternative therapies or combinations with interpheron are being evaluated waiting for final results.

  15. CXC-chemokine regulation and neutrophil trafficking in hepatic ischemia-reperfusion injury in P-selectin/ICAM-1 deficient mice

    Directory of Open Access Journals (Sweden)

    Crockett Elahé T


    Full Text Available Abstract Background Neutrophil adhesion and migration are critical in hepatic ischemia and reperfusion injury (I/R. P-selectin and the intercellular adhesion molecule (ICAM-1 can mediate neutrophil-endothelial cell interactions, neutrophil migration, and the interactions of neutrophils with hepatocytes in the liver. Despite very strong preclinical data, recent clinical trials failed to show a protective effect of anti-adhesion therapy in reperfusion injury, indicating that the length of injury might be a critical factor in neutrophil infiltration. Therefore, the aim of this study was to assess the role of P-selectin and ICAM-1 in neutrophil infiltration and liver injury during early and late phases of liver I/R. Methods Adult male wild-type and P-selectin/ICAM-1-deficient (P/I null mice underwent 90 minutes of partial liver ischemia followed by various periods of reperfusion (6, 15 h, and a survival study. Liver injury was assessed by plasma level of alanine aminotransferase (ALT and histopathology. The plasma cytokines, TNF-α, IL-6, MIP-2 and KC, were measured by ELISA. Results Reperfusion caused significant hepatocellular injury in both wild-type and P/I null mice as was determined by plasma ALT levels and liver histopathology. The injury was associated with a marked neutrophil infiltration into the ischemic livers of both wild-type and P/I null mice. Although the levels of ALT and neutrophil infiltration were slightly lower in the P/I null mice compared with the wild-type mice the differences were not statistically significant. The plasma cytokine data of TNF-α and IL-6 followed a similar pattern to ALT data, and no significant difference was found between the wild-type and P/I null groups. In contrast, a significant difference in KC and MIP-2 chemokine levels was observed between the wild-type and P/I null mice. Additionally, the survival study showed a trend towards increased survival in the P/I null group. Conclusion While ICAM-1 and P

  16. Chronic gastritis. (United States)

    Sipponen, Pentti; Maaroos, Heidi-Ingrid


    Prevalence of chronic gastritis has markedly declined in developed populations during the past decades. However, chronic gastritis is still one of the most common serious pandemic infections with such severe killing sequelae as peptic ulcer or gastric cancer. Globally, on average, even more than half of people may have a chronic gastritis at present. Helicobacter pylori infection in childhood is the main cause of chronic gastritis, which microbial origin is the key for the understanding of the bizarre epidemiology and course of the disease. A life-long and aggressive inflammation in gastritis results in destruction (atrophic gastritis) of stomach mucosa with time (years and decades). The progressive worsening of atrophic gastritis results subsequently in dysfunctions of stomach mucosa. Atrophic gastritis will finally end up in a permanently acid-free stomach in the most extreme cases. Severe atrophic gastritis and acid-free stomach are the highest independent risk conditions for gastric cancer known so far. In addition to the risks of malignancy and peptic ulcer, acid-free stomach and severe forms of atrophic gastritis may associate with failures in absorption of essential vitamins, like vitamin B12, micronutrients (like iron, calcium, magnesium and zinc), diet and medicines.

  17. Chronic Bronchitis (United States)

    ... breathing. You may also have other tests. Chronic bronchitis is a long-term condition that keeps coming back or never goes away completely. If you smoke, it is important to quit. Treatment can help with your symptoms. It often includes ...

  18. Chronic Pancreatitis in Children (United States)

    ... Information > Children/Pediatric > Chronic Pancreatitis in Children test Chronic Pancreatitis in Children What symptoms would my child ... pancreatitis will develop diabetes in adolescence. Who gets chronic pancreatitis? Those at risk for chronic pancreatitis are ...

  19. Chronic Beryllium Disease (United States)

    ... Science Education & Training Home Conditions Chronic Beryllium Disease Chronic Beryllium Disease Make an Appointment Find a Doctor ... MD, MSPH, FCCP (February 01, 2016) What is chronic beryllium disease (CBD)? Chronic beryllium disease (CBD) is ...

  20. Chronic motor tic disorder (United States)

    Chronic vocal tic disorder; Tic - chronic motor tic disorder ... Chronic motor tic disorder is more common than Tourette syndrome . Chronic tics may be forms of Tourette syndrome. Tics usually start ...

  1. Chronic Pelvic Pain (United States)

    ... Education & Events Advocacy For Patients About ACOG Chronic Pelvic Pain Home For Patients Search FAQs Chronic Pelvic Pain ... Pelvic Pain FAQ099, August 2011 PDF Format Chronic Pelvic Pain Gynecologic Problems What is chronic pelvic pain? What ...

  2. BRCA1 deficient embryonic stem cells display a decreased homologous recombination frequency and an increased frequency of non-homologous recombination that is corrected by expression of a brca1 transgene. (United States)

    Snouwaert, J N; Gowen, L C; Latour, A M; Mohn, A R; Xiao, A; DiBiase, L; Koller, B H


    BRCA1 is a nuclear phosphoprotein that has been classified as a tumor suppressor based on the fact that women carrying a mutated copy of the BRCA1 gene are at increased risk of developing breast and ovarian cancer. The association of BRCA1 with RAD51 has led to the hypothesis that BRCA1 is involved in DNA repair. We describe here the generation and analysis of murine embryonic stem (ES) cell lines in which both copies of the murine homologue of the human BRCA1 gene have been disrupted by gene targeting. We show that exogenous DNA introduced into these BRCA1 deficient cells by electroporation is randomly integrated into the genome at a significantly higher rate than in wild type ES cells. In contrast, integration of exogenous DNA by homologous recombination occurs in BRCA1 deficient cells at a significantly lower rate than in wild type controls. When BRCA1 expression is re-established at 5-10% of normal levels by introduction of a Brca1 transgene into BRCA1 deficient ES cells, the frequency of random integration is reduced to wild type levels, although the frequency of homologous recombination is not significantly improved. These results suggest that BRCA1 plays a role in determining the response of cells to double stranded DNA breaks.

  3. Chronic thyroiditis (Hashimoto disease) (United States)

    Hashimoto thyroiditis; Chronic lymphocytic thyroiditis; Autoimmune thyroiditis; Chronic autoimmune thyroiditis; Lymphadenoid goiter - Hashimoto; Hypothyroidism - Hashimoto; Type 2 polyglandular autoimmune ...

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

    KAUST Repository

    Meylan, Elsa M.


    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.

  5. Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration

    Directory of Open Access Journals (Sweden)

    Bradley A. Carlson


    Full Text Available The selenoenzyme glutathione peroxidase 4 (Gpx4 is an essential mammalian glutathione peroxidase, which protects cells against detrimental lipid peroxidation and governs a novel form of regulated necrotic cell death, called ferroptosis. To study the relevance of Gpx4 and of another vitally important selenoprotein, cytosolic thioredoxin reductase (Txnrd1, for liver function, mice with conditional deletion of Gpx4 in hepatocytes were studied, along with those lacking Txnrd1 and selenocysteine (Sec tRNA (Trsp in hepatocytes. Unlike Txnrd1- and Trsp-deficient mice, Gpx4−/− mice died shortly after birth and presented extensive hepatocyte degeneration. Similar to Txnrd1-deficient livers, Gpx4−/− livers manifested upregulation of nuclear factor (erythroid-derived-like 2 (Nrf2 response genes. Remarkably, Gpx4−/− pups born from mothers fed a vitamin E-enriched diet survived, yet this protection was reversible as subsequent vitamin E deprivation caused death of Gpx4-deficient mice ~4 weeks thereafter. Abrogation of selenoprotein expression in Gpx4−/− mice did not result in viable mice, indicating that the combined deficiency aggravated the loss of Gpx4 in liver. By contrast, combined Trsp/Txnrd1-deficient mice were born, but had significantly shorter lifespans than either single knockout, suggesting that Txnrd1 plays an important role in supporting liver function of mice lacking Trsp. In sum our study demonstrates that the ferroptosis regulator Gpx4 is critical for hepatocyte survival and proper liver function, and that vitamin E can compensate for its loss by protecting cells against deleterious lipid peroxidation.

  6. Chronic inflammatory demyelinating polyneuropathy (United States)

    Polyneuropathy - chronic inflammatory; CIDP; Chronic inflammatory polyneuropathy; Guillain-Barré - CIDP ... Health care providers also consider CIDP as the chronic form of Guillain-Barré syndrome. The specific triggers ...

  7. Dealing with chronic cancer (United States)

    ... Dealing with chronic cancer To use the sharing features on this ... be controlled for a period of time. Controlling Chronic Cancer When you have a chronic cancer, the ...

  8. Chronic mucus hypersecretion

    DEFF Research Database (Denmark)

    Harmsen, L; Thomsen, S F; Sylvan Ingebrigtsen, Truls;


    Chronic mucus hypersecretion (CMH) is a common condition in patients with chronic respiratory diseases. Little is known about the incidence, prevalence and determinants of CMH in younger individuals....

  9. Growth hormone (GH)-transgenic insulin-like growth factor 1 (IGF1)-deficient mice allow dissociation of excess GH and IGF1 effects on glomerular and tubular growth. (United States)

    Blutke, Andreas; Schneider, Marlon R; Wolf, Eckhard; Wanke, Rüdiger


    Growth hormone (GH)-transgenic mice with permanently elevated systemic levels of GH and insulin-like growth factor 1 (IGF1) reproducibly develop renal and glomerular hypertrophy and subsequent progressive glomerulosclerosis, finally leading to terminal renal failure. To dissociate IGF1-dependent and -independent effects of GH excess on renal growth and lesion development in vivo, the kidneys of 75 days old IGF1-deficient (I(-/-)) and of IGF1-deficient GH-transgenic mice (I(-/-)/G), as well as of GH-transgenic (G) and nontransgenic wild-type control mice (I(+/+)) were examined by quantitative stereological and functional analyses. Both G and I(-/-)/G mice developed glomerular hypertrophy, hyperplasia of glomerular mesangial and endothelial cells, podocyte hypertrophy and foot process effacement, albuminuria, and glomerulosclerosis. However, I(-/-)/G mice exhibited less severe glomerular alterations, as compared to G mice. Compared to I(+/+) mice, G mice exhibited renal hypertrophy with a significant increase in the number without a change in the size of proximal tubular epithelial (PTE) cells. In contrast, I(-/-)/G mice did not display significant PTE cell hyperplasia, as compared to I(-/-) mice. These findings indicate that GH excess stimulates glomerular growth and induces lesions progressing to glomerulosclerosis in the absence of IGF1. In contrast, IGF1 represents an important mediator of GH-dependent proximal tubular growth in GH-transgenic mice.

  10. Chronic urticaria

    Directory of Open Access Journals (Sweden)

    Sandeep Sachdeva


    Full Text Available Chronic urticaria (CU is a disturbing allergic condition of the skin. Although frequently benign, it may sometimes be a red flag sign of a serious internal disease. A multitude of etiologies have been implicated in the causation of CU, including physical, infective, vasculitic, psychological and idiopathic. An autoimmune basis of most of the ′idiopathic′ forms is now hypothesized. Histamine released from mast cells is the major effector in pathogenesis and it is clinically characterized by wheals that have a tendency to recur. Laboratory investigations aimed at a specific etiology are not always conclusive, though may be suggestive of an underlying condition. A clinical search for associated systemic disease is strongly advocated under appropriate circumstances. The mainstay of treatment remains H1 antihistaminics. These may be combined with complementary pharmacopeia in the form of H2 blockers, doxepin, nifedipine and leukotriene inhibitors. More radical therapy in the form of immunoglobulins, plasmapheresis and cyclophosphamide may be required for recalcitrant cases. Autologous transfusion and alternative remedies like acupuncture have prospects for future. A stepwise management results in favorable outcomes. An update on CU based on our experience with patients at a tertiary care centre is presented.

  11. Chronic pain after hysterectomy

    DEFF Research Database (Denmark)

    Brandsborg, B.; Nikolajsen, L.; Kehlet, H.;


    BACKGROUND: Chronic pain is a well-known adverse effect of surgery, but the risk of chronic pain after gynaecological surgery is less established. METHOD: This review summarizes studies on chronic pain following hysterectomy. The underlying mechanisms and risk factors for the development of chronic...... post-hysterectomy pain are discussed. RESULTS AND CONCLUSION: Chronic pain is reported by 5-32% of women after hysterectomy. A guideline is proposed for future prospective studies Udgivelsesdato: 2008/3...

  12. Chronic pain after hysterectomy

    DEFF Research Database (Denmark)

    Brandsborg, B; Nikolajsen, L; Kehlet, Henrik;


    BACKGROUND: Chronic pain is a well-known adverse effect of surgery, but the risk of chronic pain after gynaecological surgery is less established. METHOD: This review summarizes studies on chronic pain following hysterectomy. The underlying mechanisms and risk factors for the development of chronic...... post-hysterectomy pain are discussed. RESULTS AND CONCLUSION: Chronic pain is reported by 5-32% of women after hysterectomy. A guideline is proposed for future prospective studies. Udgivelsesdato: 2008-Mar...

  13. [Chronic otitis mediaChronic Otitis Media]. (United States)

    Kohles, N; Schulz, T; Eßer, D


    There are 2 different kinds of chronic otitis media: Otitis media chronica mesotympanalis and otitis media chronica epitympanalis (cholesteatoma). The incidence of chronic otitis media as reported in literature differs in a wide range. The incidence rates vary between 0.45 and 46%. Both, otitis media chronica mesotympanalis and cholesteatoma, lead to eardrum perforation due to lengthy and recurring inflammations. Furthermore, chronic otitis media is characterized by frequently recurring otorrhea and conductive hearing loss.

  14. Predicting the Response to Intravenous Immunoglobulins in an Animal Model of Chronic Neuritis (United States)

    Pfaff, Johannes; Mathys, Christian; Mausberg, Anne K.; Bendszus, Martin; Pham, Mirko; Hartung, Hans-Peter; Kieseier, Bernd C.


    Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a disabling autoimmune disorder of the peripheral nervous system (PNS). Intravenous immunoglobulins (IVIg) are effective in CIDP, but the treatment response varies greatly between individual patients. Understanding this interindividual variability and predicting the response to IVIg constitute major clinical challenges in CIDP. We previously established intercellular adhesion molecule (ICAM)-1 deficient non-obese diabetic (NOD) mice as a novel animal model of CIDP. Here, we demonstrate that similar to human CIDP patients, ICAM-1 deficient NOD mice respond to IVIg treatment by clinical and histological measures. Nerve magnetic resonance imaging and histology demonstrated that IVIg ameliorates abnormalities preferentially in distal parts of the sciatic nerve branches. The IVIg treatment response also featured great heterogeneity allowing us to identify IVIg responders and non-responders. An increased production of interleukin (IL)-17 positively predicted IVIg treatment responses. In human sural nerve biopsy sections, high numbers of IL-17 producing cells were associated with younger age and shorter disease duration. Thus, our novel animal model can be utilized to identify prognostic markers of treatment responses in chronic inflammatory neuropathies and we identify IL-17 production as one potential such prognostic marker. PMID:27711247

  15. Chronic Kidney Diseases (United States)

    ... Room? What Happens in the Operating Room? Chronic Kidney Diseases KidsHealth > For Kids > Chronic Kidney Diseases Print ... re talking about your kidneys. What Are the Kidneys? Your kidneys are tucked under your lower ribs ...

  16. Diet - chronic kidney disease (United States)

    ... page: // Diet - chronic kidney disease To use the sharing features on this page, ... make changes to your diet when you have chronic kidney disease. These changes may include limiting fluids, eating a ...

  17. Chronic granulomatous disease (United States)

    CGD; Fatal granulomatosis of childhood; Chronic granulomatous disease of childhood; Progressive septic granulomatosis ... In chronic granulomatous disease (CGD), immune system cells called phagocytes are unable to kill some types of bacteria and ...

  18. Chronic mucus hypersecretion

    DEFF Research Database (Denmark)

    Ulrik, Charlotte Suppli; von Linstow, Marie-Louise; Nepper-Christensen, Steen;


    To investigate if chronic mucus hypersecretion (CMH) can be used as a marker of asthma in young adults.......To investigate if chronic mucus hypersecretion (CMH) can be used as a marker of asthma in young adults....

  19. Chronic tophaceous gout

    Directory of Open Access Journals (Sweden)

    Thappa D


    Full Text Available A rare case of chronic tophaceous gout, in a 27-year-old female on diuretics for chronic congestive cardiac failure with characteristic histopathological and radiological changes is reported.

  20. Chronic Pancreatitis in Children (United States)

    ... maintaining good health. Can chronic pancreatitis give my child cancer? If your child has chronic pancreatitis, he or she will be at an increased risk of developing pancreatic cancer compared to the general population. The degree of ...

  1. People Experiencing Chronic Homelessness (United States)

    ... Goals Ending Chronic Homelessness Share This: Ending Chronic Homelessness Last updated on January 19, 2017 We can ... the USICH newsletter. We know how to end homelessness. Let's do it, together. Sign up for our ...

  2. Approaching chronic sinusitis. (United States)

    Sarber, Kathleen M; Dion, Gregory Robert; Weitzel, Erik K; McMains, Kevin C


    Chronic sinusitis is a common disease that encompasses a number of syndromes that are characterized by sinonasal mucosal inflammation. Chronic sinusitis can be defined as two or more of the following symptoms lasting for more than 12 consecutive weeks: discolored rhinorrhea, postnasal drip, nasal obstruction, facial pressure or pain, or decreased sense of smell. Chronic sinusitis is further classified as chronic sinusitis with polyposis, chronic sinusitis without polyposis, or allergic fungal sinusitis using physical examination, and histologic and radiographic findings. Treatment methods for chronic sinusitis are based upon categorization of the disease and include oral and inhaled corticosteroids, nasal saline irrigations, and antibiotics in selected patients. Understanding the various forms of chronic sinusitis and managing and ruling out comorbidities are key to successful management of this common disorder.

  3. FOXN1 deficient nude severe combined immunodeficiency


    Rota, Ioanna A.; Dhalla, Fatima


    Nude severe combined immunodeficiency is a rare inherited disease caused by autosomal recessive loss-of-function mutations in FOXN1. This gene encodes a transcription factor essential for the development of the thymus, the primary lymphoid organ that supports T-cell development and selection. To date nine cases have been reported presenting with the clinical triad of absent thymus resulting in severe T-cell immunodeficiency, congenital alopecia universalis and nail dystrophy. Diagnosis relies...

  4. Identification of BRCA1-deficient ovarian cancers

    DEFF Research Database (Denmark)

    Skytte, Anne-Bine; Waldstrøm, Marianne; Rasmussen, Anders Aamann;


    Objective. It is believed that 24 - 40% of ovarian cancers have dysfunction in the BRCA1 or BRCA2 (BRCAness) genes, either due to inherited or somatic mutations or due to epigenetic inactivation. Demonstration of ovarian cancers with BRCAness is becoming important both due to the possibility...... of offering genetic counseling and due to beneficial effects of PARP inhibitor treatment in this group. Since DNA sequencing is expensive and time-consuming efforts have been devoted to develop more indirect methods for BRCA screening that can improve the selection of patients for sequence-based BRCA testing....... Design. BRCA1-immunohistochemistry (IHC), fluorescence in-situ hybridization (FISH) and methylation analyses were performed on formalin-fixed, paraffin-embedded ovarian cancer tissue. Sample: 54 ovarian cancers; 15 BRCA1 cancers, 4 BRCA2 cancers, 10 cancers from patients with a family history...

  5. Biofilms in chronic wounds. (United States)

    James, Garth A; Swogger, Ellen; Wolcott, Randall; Pulcini, Elinor deLancey; Secor, Patrick; Sestrich, Jennifer; Costerton, John W; Stewart, Philip S


    Chronic wounds including diabetic foot ulcers, pressure ulcers, and venous leg ulcers are a worldwide health problem. It has been speculated that bacteria colonizing chronic wounds exist as highly persistent biofilm communities. This research examined chronic and acute wounds for biofilms and characterized microorganisms inhabiting these wounds. Chronic wound specimens were obtained from 77 subjects and acute wound specimens were obtained from 16 subjects. Culture data were collected using standard clinical techniques. Light and scanning electron microscopy techniques were used to analyze 50 of the chronic wound specimens and the 16 acute wound specimens. Molecular analyses were performed on the remaining 27 chronic wound specimens using denaturing gradient gel electrophoresis and sequence analysis. Of the 50 chronic wound specimens evaluated by microscopy, 30 were characterized as containing biofilm (60%), whereas only one of the 16 acute wound specimens was characterized as containing biofilm (6%). This was a statistically significant difference (p<0.001). Molecular analyses of chronic wound specimens revealed diverse polymicrobial communities and the presence of bacteria, including strictly anaerobic bacteria, not revealed by culture. Bacterial biofilm prevalence in specimens from chronic wounds relative to acute wounds observed in this study provides evidence that biofilms may be abundant in chronic wounds.

  6. Severity of DSS-induced colitis is reduced in Ido1-deficient mice with down-regulation of TLR-MyD88-NF-kB transcriptional networks. (United States)

    Shon, Woo-Jeong; Lee, Young-Kwan; Shin, Ji Hee; Choi, Eun Young; Shin, Dong-Mi


    Indoleamine 2,3 -dioxygenase 1 (IDO1) catalyzes L-tryptophan to kynurenine in the first and rate-limiting step of tryptophan metabolism. IDO1 is expressed widely throughout the body, with especially high expression in colonic intestinal tissues. To examine the role of IDO1 in the colon, transcriptome analysis was performed in both Ido1(-/-) and Ido1(+/+) mice. Gene set enrichment analysis identified the Inflammatory Response as the most significant category modulated by the absence of IDO1. This observation prompted us to further investigate the function of IDO1 in the development of tissue inflammation. By using DSS-induced experimental colitis mice models, we found that the disease in Ido1(-/-) mice was less severe than in Ido1(+/+) mice. Pharmacological inhibition of IDO1 by L-1MT attenuated the severity of DSS-colitis as well. Transcriptome analyses revealed that pathways involving TLR and NF-kB signaling were significantly down-regulated by the absence of IDO1. Furthermore, dramatic changes in TLR and NF-kB signaling resulted in substantial changes in the expression of many inflammatory cytokines and chemokines. Numbers of inflammatory cells in colon and peripheral blood were reduced in IDO1 deficiency. These findings suggest that IDO1 plays important roles in producing inflammatory responses and modulating transcriptional networks during the development of colitis.

  7. Chronic Inflammatory Polyneuropathy

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap


    Full Text Available Thirteen children with chronic inflammatory demyelinating polyneuropathy monitored between 1975 and 2005 are reported from Centre hospitalier universitaire Sainte-Justine, Montreal, Canada.

  8. Coping with Chronic Illness (United States)

    Having a long-term, or chronic, illness can disrupt your life in many ways. You may often be tired and in pain. Your illness might affect your ... able to work, causing financial problems. For children, chronic illnesses can be frightening, because they may not ...

  9. Chronic Postoperative Roseomonas Endophthalmitis▿


    Chen, Kuan-Jen; Lai, Chi-Chun; Kuo, Ya-Hui; WU, WEI-CHI; CHEN, TUN-LU


    We report one case with chronic postoperative endophthalmitis caused by Roseomonas species. Roseomonas spp. induced chronic endophthalmitis, which might result in misdiagnosis and delayed treatment and causes ocular damage and severe visual loss. This report is the first one related to a case with postoperative endophthalmitis secondary to Roseomonas infection.

  10. Chronic postoperative Roseomonas endophthalmitis. (United States)

    Chen, Kuan-Jen; Lai, Chi-Chun; Kuo, Ya-Hui; Wu, Wei-Chi; Chen, Tun-Lu


    We report one case with chronic postoperative endophthalmitis caused by Roseomonas species. Roseomonas spp. induced chronic endophthalmitis, which might result in misdiagnosis and delayed treatment and causes ocular damage and severe visual loss. This report is the first one related to a case with postoperative endophthalmitis secondary to Roseomonas infection.

  11. Arabidopsis thaliana phytochelatin synthase 2 is constitutively active in vivo and can rescue the growth defect of the PCS1-deficient cad1-3 mutant on Cd-contaminated soil. (United States)

    Kühnlenz, Tanja; Schmidt, Holger; Uraguchi, Shimpei; Clemens, Stephan


    Phytochelatins play a key role in the detoxification of metals in plants and many other eukaryotes. Their formation is catalysed by phytochelatin synthases (PCS) in the presence of metal excess. It appears to be common among higher plants to possess two PCS genes, even though in Arabidopsis thaliana only AtPCS1 has been demonstrated to confer metal tolerance. Employing a highly sensitive quantification method based on ultraperformance electrospray ionization quadrupole time-of-flight mass spectrometry, we detected AtPCS2-dependent phytochelatin formation. Overexpression of AtPCS2 resulted in constitutive phytochelatin accumulation, i.e. in the absence of metal excess, both in planta and in a heterologous system. This indicates distinct enzymatic differences between AtPCS1 and AtPCS2. Furthermore, AtPCS2 was able to partially rescue the Cd hypersensitivity of the AtPCS1-deficient cad1-3 mutant in a liquid seedling assay, and, more importantly, when plants were grown on soil spiked with Cd to a level that is close to what can be found in agricultural soils. No rescue was found in vertical-plate assays, the most commonly used method to assess metal tolerance. Constitutive AtPCS2-dependent phytochelatin synthesis suggests a physiological role of AtPCS2 other than metal detoxification. The differences observed between wild-type plants and cad1-3 on Cd soil demonstrated: (i) the essentiality of phytochelatin synthesis for tolerating levels of Cd contamination that can naturally be encountered by plants outside of metal-rich habitats, and (ii) a contribution to Cd accumulation under these conditions.

  12. [Chronic pancreatitis, acute pancreatitis]. (United States)

    Mabuchi, T; Katada, N; Nishimura, D; Hoshino, H; Shimizu, F; Suzuki, R; Sano, H; Kato, K


    MRCP has been recognized as a safe and noninvasive diagnostic method. In the present study we evaluated the usefulness of MRCP in diagnosis of chronic and acute pancreatitis. Two-dimensional fast asymmetric spin-echo (FASE) MRCP was performed in 40 patients with chronic pancreatitis and 13 with acute pancreatitis. In 29 patients (72.5%) with chronic pancreatitis and 9 (66.7%) with acute pancreatitis, main pancreatic duct (MPD) was visualized entirely. MRCP could demonstrate the characteristic findings of chronic pancreatitis such as dilatation and irregularity of MPD in most cases. In acute pancreatitis, MRCP indicated that MPD was normal in diameter, but irregular in configuration compared with that of the control group. MRCP may facilitate the diagnosis of chronic and acute pancreatitis.

  13. The Chronic Responsibility

    DEFF Research Database (Denmark)

    Ravn, Iben M; Frederiksen, Kirsten; Beedholm, Kirsten


    This article reports on the results of a Fairclough-inspired critical discourse analysis aiming to clarify how chronically ill patients are presented in contemporary Danish chronic care policies. Drawing on Fairclough’s three-dimensional framework for analyzing discourse, and using Dean’s concepts...... of governmentality as an interpretative lens, we analyzed and explained six policies published by the Danish Health and Medicines Authority between 2005 and 2013. The analysis revealed that discourses within the policy vision of chronic care consider chronically ill patients’ active role, lifestyle, and health...... behavior to be the main factors influencing susceptibility to chronic diseases. We argue that this discursive construction naturalizes a division between people who can actively manage responsible self-care and those who cannot. Such discourses may serve the interests of those patients who are already...

  14. Chronic gastritis - an update. (United States)

    Varbanova, Mariya; Frauenschläger, Katrin; Malfertheiner, Peter


    Helicobacter pylori is the main aetiologic factor for chronic gastritis worldwide. The degree of inflammation and the evolution of this form of chronic gastritis can vary largely depending on bacterial virulence factors, host susceptibility factors and environmental conditions. Autoimmune gastritis is another cause of chronic inflammation in the stomach, which can occur in all age groups. This disease presents typically with vitamin B12 deficiency and pernicious anaemia. The presence of anti-parietal cell antibodies is highly specific for the diagnosis. The role of H. pylori as a trigger for autoimmune gastritis remains uncertain. Other rare conditions for chronic gastritis are chronic inflammatory conditions such as Crohn's disease or on the background of lymphocytic or collagenous gastroenteropathies.

  15. Chronic granulomatous disease associated with chronic glomerulonephritis

    DEFF Research Database (Denmark)

    Frifelt, J J; Schønheyder, Henrik Carl; Valerius, Niels Henrik


    A boy with chronic granulomatous disease (CGD) developed glomerulonephritis at the age of 12 years. The glomerulonephritis progressed to terminal uraemia at age 15 when maintenance haemodialysis was started. The clinical course was complicated by pulmonary aspergillosis and Pseudomonas septicaemia...... from which he eventually died. The glomerulonephritis was of unknown origin, and a possible relationship between CGD and glomerulonephritis is discussed....

  16. What Is Chronic Myeloid Leukemia? (United States)

    ... Chronic Myeloid Leukemia (CML) About Chronic Myeloid Leukemia What Is Chronic Myeloid Leukemia? Cancer starts when cells ... their treatment is the same as for adults. What is leukemia? Leukemia is a cancer that starts ...

  17. What Is Chronic Lymphocytic Leukemia? (United States)

    ... Chronic Lymphocytic Leukemia (CLL) About Chronic Lymphocytic Leukemia What Is Chronic Lymphocytic Leukemia? Cancer starts when cells ... body, including the lymph nodes, liver, and spleen. What is leukemia? Leukemia is a cancer that starts ...

  18. Changing glucocorticoid action: 11β-hydroxysteroid dehydrogenase type 1 in acute and chronic inflammation. (United States)

    Chapman, Karen E; Coutinho, Agnes E; Zhang, Zhenguang; Kipari, Tiina; Savill, John S; Seckl, Jonathan R


    Since the discovery of cortisone in the 1940s and its early success in treatment of rheumatoid arthritis, glucocorticoids have remained the mainstay of anti-inflammatory therapies. However, cortisone itself is intrinsically inert. To be effective, it requires conversion to cortisol, the active glucocorticoid, by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Despite the identification of 11β-HSD in liver in 1953 (which we now know to be 11β-HSD1), its physiological role has been little explored until recently. Over the past decade, however, it has become apparent that 11β-HSD1 plays an important role in shaping endogenous glucocorticoid action. Acute inflammation is more severe with 11β-HSD1-deficiency or inhibition, yet in some inflammatory settings such as obesity or diabetes, 11β-HSD1-deficiency/inhibition is beneficial, reducing inflammation. Current evidence suggests both beneficial and detrimental effects may result from 11β-HSD1 inhibition in chronic inflammatory disease. Here we review recent evidence pertaining to the role of 11β-HSD1 in inflammation. This article is part of a Special Issue entitled 'CSR 2013'.

  19. Chronic hypersensitivity pneumonitis (United States)

    Pereira, Carlos AC; Gimenez, Andréa; Kuranishi, Lilian; Storrer, Karin


    Hypersensitivity pneumonitis (HSP) is a common interstitial lung disease resulting from inhalation of a large variety of antigens by susceptible individuals. The disease is best classified as acute and chronic. Chronic HSP can be fibrosing or not. Fibrotic HSP has a large differential diagnosis and has a worse prognosis. The most common etiologies for HSP are reviewed. Diagnostic criteria are proposed for both chronic forms based on exposure, lung auscultation, lung function tests, HRCT findings, bronchoalveolar lavage, and biopsies. Treatment options are limited, but lung transplantation results in greater survival in comparison to idiopathic pulmonary fibrosis. Randomized trials with new antifibrotic agents are necessary. PMID:27703382

  20. 1型葡萄糖转运体缺陷综合征一例报告及文献复习%To report one case of glucose transporter type 1 deficiency syndrome and literature review

    Institute of Scientific and Technical Information of China (English)

    叶小飞; 赵忠礼; 杨斌


    目的 总结1型葡萄糖转运体缺陷综合征的临床特点、实验室检查、分子遗传学诊断及生酮饮食治疗疗效.方法 报告1例以痫样发作为首发的1型葡萄糖转运体缺陷综合征病例.检索国内外相关文献,共检索出明确诊断的1型葡萄糖转运体缺陷综合征32例,进行文献复习.结果 包括作者报告1例患者,共33例,男19例,女14例.临床特点:27/33例有痫样发作,发作年龄2个月至35岁之间.大多发作年龄在6个月以内.25/33例有共济失调,大多数轻中度共济失调,少部分患者共济失调影响行走及日常生活.24/33例肌张力障碍.14/33例有小头畸形.实验室检查:30/33例患者进行了脑脊液糖检查,23 - 56mg/dl之间,平均34.2±4.7mg/dl.脑脊液糖/血糖0.24 -0.57之间,平均0.38±0.07.21/33例患者进行了红细胞摄取3-0-甲基-D-葡萄糖的能力检查,结果显示红细胞摄取3-O-甲基-D-葡萄糖的能力较正常对照下降约50%左右.29/33例进行了脑电图检查,发现痫样放电25例,表现为多灶性棘波、棘慢波.32/33例患者进行了GLUT1 - DS基因SLC2A1筛查,发现12例错义突变,2例无义突变,2例插入突变,16例缺失或剪切住点突变.治疗:所有癫痫患者均进行了抗癫痫药物治疗,痫样发作均难以控制.28/33例患者(25例癫痫患者和3例发作性运动障碍)进行了生酮饮食治疗.24例癫痫患者的痫样发作完全控制,1例痫样发作明显缓解.3例发作性运动障碍明显改善.结论 1型葡萄糖转运体缺陷综合征临床以难治性痫样发作、语言智能发育落后、脑脊液糖/血糖明显降低为特点,常规抗癫痫药物难以控制痫样发作,生酮饮食能够控制痫样发作,并对语言、认知、运动障碍均有改善作用.%Objective: To summary the clinical characteristics, laboratory examination, molecular genetics diagnose and effects of ketogenic diet in glucose transporter type 1 deficiency syndrome (GLUT1 -DS

  1. E2f1-deficient NOD/SCID mice have dry mouth due to a change of acinar/duct structure and the down-regulation of AQP5 in the salivary gland. (United States)

    Satoh, Keitaro; Narita, Takanori; Matsuki-Fukushima, Miwako; Okabayashi, Ken; Ito, Tatsuro; Senpuku, Hidenobu; Sugiya, Hiroshi


    Non-obese diabetic (NOD) mice have been used as a model for dry mouth. NOD mice lacking the gene encoding E2f1, a transcription factor, develop hyposalivation more rapidly progressively than control NOD mice. However, the model mice are associated with an underlying disease such as diabetes. We have now established E2f1-deficient NOD/severe combined immunodeficiency disease (NOD/SCID.E2f1(-/-)) mice to avoid the development of diabetes (Matsui-Inohara et al., Exp Biol Med (Maywood) 234(12):1525-1536, 2009). In this study, we investigated the pathophysiological features of dry mouth using NOD/SCID.E2f1(-/-) mice. In NOD/SCID.E2f1(-/-) mice, the volume of secreted saliva stimulated with pilocarpine is about one third that of control NOD/SCID mice. In behavioral analysis, NOD/SCID.E2f1(-/-) mice drank plenty of water when they ate dry food, and the frequency and time of water intake were almost double compared with control NOD/SCID mice. Histological analysis of submandibular glands with hematoxylin-eosin stain revealed that NOD/SCID.E2f1(-/-) mice have more ducts than NOD/SCID mice. In western blot analysis, the expression of aquaporin 5 (AQP5), a marker of acinar cells, in parotid and in submandibular glands of NOD/SCID.E2f1(-/-) mice was lower than in NOD/SCID mice. Immunohistochemical analysis of parotid and submandibular acini revealed that the localization of AQP5 in NOD/SCID.E2f1(-/-) mice differs from that in NOD/SCID mice; AQP5 was leaky and diffusively localized from the apical membrane to the cytosol in NOD/SCID.E2f1(-/-) mice. The ubiquitination of AQP5 was detected in submandibular glands of NOD/SCID.E2f1(-/-) mice. These findings suggest that the change of acinar/duct structure and the down-regulation of AQP5 in the salivary gland cause the pathogenesis of hyposalivation in NOD/SCID.E2f1(-/-) mice.

  2. Chronic Fatigue Syndrome (United States)

    Chronic fatigue syndrome (CFS) is a disorder that causes extreme fatigue. This fatigue is not the kind of tired feeling that ... activities. The main symptom of CFS is severe fatigue that lasts for 6 months or more. You ...

  3. Chronic Kidney Disease (United States)

    You have two kidneys, each about the size of your fist. Their main job is to filter wastes and excess water out of ... help control blood pressure, and make hormones. Chronic kidney disease (CKD) means that your kidneys are damaged ...

  4. Chronic sinusitis (image) (United States)

    ... and cartilage and lined with a mucous membrane. Sinusitis occurs when the membranes becomes inflamed and painful, ... a result of a blocked sinus opening. Chronic sinusitis is often caused by inflammation and blockage due ...

  5. Chronic Condition Data Warehouse (United States)

    U.S. Department of Health & Human Services — The CMS Chronic Condition Data Warehouse (CCW) provides researchers with Medicare and Medicaid beneficiary, claims, and assessment data linked by beneficiary across...

  6. Zabofloxacin for chronic bronchitis. (United States)

    Kocsis, B; Szabo, D


    Treatment of lower respiratory tract infection poses as an ongoing challenge among respiratory tract diseases. Bacterial infections are causes of acute exacerbations in chronic bronchitis and indications for antibacterial therapy. Several antibiotics were applied to treat bacterial infections in chronic bronchitis, among them fluoroquinolones are considered potent, broad-spectrum agents with excellent tissue penetration. This monograph focuses on zabofloxacin, a novel fluoroquinolone agent recently approved and launched in South Korea, and summarizes the drug's antibacterial efficacy, pharmacokinetic properties and toxicity. Recent advances concerning fluoroquinolones in chronic bronchitis will be discussed, along with a comparison between zabofloxacin and moxifloxacin. Zabofloxacin has proved to be noninferior to moxifloxacin against major community-acquired Gram-positive and Gram-negative respiratory tract pathogens and found to be well tolerated in both oral and parenteral administrations. These features can make it a potential antimicrobial agent in therapy of chronic bronchitis and other lower respiratory tract infections.

  7. Living with Chronic Bronchitis (United States)

    ... Health Topics » Bronchitis » Living With Chronic Bronchitis Explore Bronchitis What Is... Other Names Causes Who Is at Risk Signs & Symptoms Diagnosis Treatments Prevention Living With Clinical Trials Links Related Topics ...

  8. Chronic Critical Illness (United States)

    ... the patient’s situation and on the hospital and city. Do Chronically Critically Ill Patients Regain the Ability ... as the patient. You may feel stress, worry, sadness, or fatigue. Some families worry about financial burdens. ...

  9. Chronic Conditions Dashboard (United States)

    U.S. Department of Health & Human Services — The CMS Chronic Conditions Dashboard presents statistical views of information on the prevalence, utilization and Medicare spending for Medicare beneficiaries with...

  10. Chronic Myeloproliferative Neoplasms Treatment (United States)

    ... way to treat some chronic myeloproliferative neoplasms. Platelet apheresis Platelet apheresis is a treatment that uses a special machine ... using interferon alfa or pegylated interferon alpha . Platelet apheresis . A clinical trial of a new treatment. Check ...

  11. Chronic penile strangulation

    Directory of Open Access Journals (Sweden)

    Lopes Roberto I


    Full Text Available Chronic penile strangulation is exceedingly rare with only 5 cases previously reported. We report an additional case of progressive penile lymphedema due to chronic intermittent strangulation caused by a rubber band applied to the penile base for 6 years. A 49-year-old man presented incapacity to exteriorize the glans penis. For erotic purposes, he had been using a rubber-enlarging band placed in the penile base for 6 years. With chronic use, he noticed that his penis swelled. Physical examination revealed lymphedema of the penis, phimosis and a stricture in the penile base. The patient was submitted to circumcision and the lymphedema remained stable 10 months postoperatively. Chronic penile incarceration usually causes penile lymphedema and urinary disturbance. Treatment consists of removal of foreign devices and surgical treatment of lymphedema.

  12. Chronic Illness & Mental Health (United States)

    ... is present. For More Information Share Chronic Illness & Mental Health Download PDF Download ePub Order a free hardcopy ... For more information, see the National Institute of Mental Health (NIMH) booklet on Depression at http://www.nimh. ...

  13. Chronic obstructive pulmonary disease (United States)

    ... and oxygen therapy Right-sided heart failure or cor pulmonale (heart swelling and heart failure due to chronic ... PA: Elsevier Saunders; 2016:chap 44. Read More Cor pulmonale Dilated cardiomyopathy Heart failure - overview Lung disease Patient ...

  14. Chronic Kidney Disease (CKD) (United States)

    ... CKD treated? Kidney-friendly diet for CKD What causes chronic kidney disease (CKD)? Anyone can get CKD. Some people are ... and high blood pressure are the most common causes of CKD. If you have diabetes or high blood pressure, ...

  15. Sleep and Chronic Disease (United States)

    ... message, please visit this page: About . Sleep About Us About Sleep Key Sleep Disorders Sleep ... Sheets Data & Statistics Projects and Partners Resources Events Sleep and Chronic Disease Recommend on Facebook Tweet Share ...

  16. Chronic Conditions PUF (United States)

    U.S. Department of Health & Human Services — The Chronic Conditions PUFs are aggregated files in which each record is a profile or cell defined by the characteristics of Medicare beneficiaries. A profile is...

  17. Chronic inflammatory demyelinative polyneuropathy

    DEFF Research Database (Denmark)

    Said, Gérard; Krarup, Christian


    Chronic inflammatory demyelinative polyneuropathy (CIDP) is an acquired polyneuropathy presumably of immunological origin. It is characterized by a progressive or a relapsing course with predominant motor deficit. The diagnosis rests on the association of non-length-dependent predominantly motor ...

  18. Chronic dysimmune neuropathies: Beyond chronic demyelinating polyradiculoneuropathy

    Directory of Open Access Journals (Sweden)

    Khadilkar Satish


    Full Text Available The spectrum of chronic dysimmune neuropathies has widened well beyond chronic demyelinating polyradiculoneuropathy (CIDP. Pure motor (multifocal motor neuropathy, sensorimotor with asymmetrical involvement (multifocal acquired demylinating sensory and motor neuropathy, exclusively distal sensory (distal acquired demyelinating sensory neuropathy and very proximal sensory (chronic immune sensory polyradiculopathy constitute the variants of CIDP. Correct diagnosis of these entities is of importance in terms of initiation of appropriate therapy as well as prognostication of these patients. The rates of detection of immune-mediated neuropathies with monoclonal cell proliferation (monoclonal gammopathy of unknown significance, multiple myeloma, etc. have been facilitated as better diagnostic tools such as serum immunofixation electrophoresis are being used more often. Immune neuropathies associated with malignancies and systemic vasculitic disorders are being defined further and treated early with better understanding of the disease processes. As this field of dysimmune neuropathies will evolve in the future, some of the curious aspects of the clinical presentations and response patterns to different immunosuppressants or immunomodulators will be further elucidated. This review also discusses representative case studies.

  19. Tolerance and chronic rejection.


    Womer, K. L.; Lee, R S; Madsen, J. C.; Sayegh, M H


    The most common cause of chronic allograft loss is an incompletely understood clinicopathological entity called chronic rejection (CR). Recent reports suggest an improvement in long-term renal allograft survival, although it is not clear from these data whether a true reduction of biopsy-proven CR has occurred. Although newer immunosuppressive medications have greatly reduced the incidence of acute rejection (AR) in the early post-transplantation period, the ideal therapy for both AR and CR w...

  20. Chronic obstructive pulmonary disease

    Institute of Scientific and Technical Information of China (English)


    2008430 Effect of gas exchange at maximal intensity on exercise capacity in patients with chronic obstructive pulmonary disease. WANG Haoyan(王浩彦), et al. Dept Respir Dis, Beijing Friendship Hosp, Capital Med Sci Univ, Beijing 100050. Chin J Tuberc Respir Dis 2008;31(6):414-416. Objective To investigate the effect of gas exchange at maximal intensity on exercise capacity in patients with chronic obstructive pulmonary disease (COPD).

  1. Experimental chronic periodontitis morphogenesis


    Schneider S.A.


    Morphogenesis of periodontium tissue in a model of chronic periodontitis was studied. Adult Wistar rats wereused in a model; chronic periodontitis was developed through mastication-related loading decrease. Histological assessmentof periodontium tissue was conducted at Days 7, 14, 21 and 30. It was demonstrated that dystrophic tissue changes prevailover the inflammatory one in this particular experimental model. The structural elements of periodontium were involved intothe pathologic process ...

  2. Understanding chronic heart failure


    Fenton, Matthew; Burch, Michael


    The key principles of chronic heart failure and the development of clinical management strategies are described. The physiological changes in chronic heart failure and the clinical management of children with heart failure are considered, but the treatment of heart failure related to congenital heart disease or the intensive care management of heart failure are not mentioned as both topics require consideration in their own right. A greater understanding of the maladaptive responses to chroni...

  3. Treatment of Chronic Cough. (United States)

    Soni, Resha S; Ebersole, Barbara; Jamal, Nausheen


    Objective Chronic cough remains a challenging condition, especially in cases where it persists despite comprehensive medical management. For these particular patients, there appears to be an emerging role for behavior modification therapy. We report a series of patients with refractory chronic cough to assess if there is any benefit of adding behavioral therapy to their treatment regimen. Study Design A case series with planned chart review of patients treated for chronic cough. Setting The review was performed with an outpatient electronic health record system at a tertiary care center. Subjects and Methods The charts of all patients treated for chronic cough by a single laryngologist over a 30-month period were analyzed. Patients' response to treatment and rate of cough improvement were assessed for those with refractory chronic cough who underwent behavior modification therapy. Results Thirty-eight patients with chronic cough were initially treated empirically for the most common causes of cough, of which 32% experienced improvement. Nineteen patients who did not significantly improve with medical management underwent behavior modification therapy with a speech-language pathologist. Of these patients, 84% experienced resolution or marked improvement of their symptoms. Conclusion Behavioral therapy may be underutilized in practice and could lead to improvement of otherwise recalcitrant cough.

  4. Chronic prostatitis: Current concepts

    Directory of Open Access Journals (Sweden)

    Ram Vaidyanathan


    Full Text Available Purpose: Chronic prostatitis (CP is a common condition. It causes significant suffering to the patients and constitutes a sizeable workload for the urologists. The purpose of this review is to describe the currently accepted concepts regarding the aspects of CP. Materials and Methods: Relevant papers on the epidemiology, etiology, diagnosis, evaluation and management of CP were identified through a search of MEDLINE using text terms "prostatitis", "chronic prostatitis" and "chronic pelvic pain syndrome". The list of articles thus obtained was supplemented by manual search of bibliographies of the identified articles and also by exploring the MEDLINE option "Related Articles". Results: The salient points of the relevant articles on each aspect of CP have been summarized in the form of a non-systematic narrative review. Conclusion: Chronic prostatitis is caused by a variety of infective and non-infective factors and is characterized by a rather long remitting and relapsing clinical course. The diagnosis is based on symptoms comprising pain and nonspecific urinary and/or ejaculatory disturbances and microbiological tests to localize bacteria and/or leucocytes in segmented urinary tract specimens. The contemporary classification was proposed by the National Institutes of Health/National Institute of Diabetes Digestive Kidney Diseases (NIH/NIDDK. National Institutes of Health - Chronic Prostatitis Symptom Index (NIH-CPSI is the patient evaluation tool used extensively in clinical practice and research. Management should be individualized, multimodal and of an appropriate duration.

  5. Autoantibodies in chronic pancreatitis

    DEFF Research Database (Denmark)

    Rumessen, J J; Marner, B; Pedersen, N T


    In 60 consecutive patients clinically suspected of having chronic pancreatitis the serum concentration of the immunoglobulins (IgA, IgG, IgM), the IgG- and IgA-type non-organ-specific autoantibodies against nuclear material (ANA), smooth and striated muscle, mitochondria, basal membrane, and reti......In 60 consecutive patients clinically suspected of having chronic pancreatitis the serum concentration of the immunoglobulins (IgA, IgG, IgM), the IgG- and IgA-type non-organ-specific autoantibodies against nuclear material (ANA), smooth and striated muscle, mitochondria, basal membrane......, and reticulin, and the IgG- and IgA-type pancreas-specific antibodies against islet cells, acinus cells, and ductal cells (DA) were estimated blindly. In 23 of the patients chronic pancreatitis was verified, whereas chronic pancreatitis was rejected in 37 patients (control group). IgG and IgA were found...... in significantly higher concentrations in the patients with chronic pancreatitis than in the control group but within the normal range. ANA and DA occurred very frequently in both groups but with no statistical difference. Other autoantibodies only occurred sporadically. The findings of this study do not support...

  6. Management of chronic paronychia

    Directory of Open Access Journals (Sweden)

    Vineet Relhan


    Full Text Available Chronic paronychia is an inflammatory disorder of the nail folds of a toe or finger presenting as redness, tenderness, and swelling. It is recalcitrant dermatoses seen commonly in housewives and housemaids. It is a multifactorial inflammatory reaction of the proximal nail fold to irritants and allergens. Repeated bouts of inflammation lead to fibrosis of proximal nail fold with poor generation of cuticle, which in turn exposes the nail further to irritants and allergens. Thus, general preventive measures form cornerstone of the therapy. Though previously anti-fungals were the mainstay of therapy, topical steroid creams have been found to be more effective in the treatment of chronic paronychia. In recalcitrant cases, surgical treatment may be resorted to, which includes en bloc excision of the proximal nail fold or an eponychial marsupialization, with or without nail plate removal. Newer therapies and surgical modalities are being employed in the management of chronic paronychia. In this overview, we review recent epidemiological studies, present current thinking on the pathophysiology leading to chronic paronychia, discuss the challenges chronic paronychia presents, and recommend a commonsense approach to management.

  7. Chronic daily headaches

    Directory of Open Access Journals (Sweden)

    Fayyaz Ahmed


    Full Text Available Chronic Daily Headache is a descriptive term that includes disorders with headaches on more days than not and affects 4% of the general population. The condition has a debilitating effect on individuals and society through direct cost to healthcare and indirectly to the economy in general. To successfully manage chronic daily headache syndromes it is important to exclude secondary causes with comprehensive history and relevant investigations; identify risk factors that predict its development and recognise its sub-types to appropriately manage the condition. Chronic migraine, chronic tension-type headache, new daily persistent headache and medication overuse headache accounts for the vast majority of chronic daily headaches. The scope of this article is to review the primary headache disorders. Secondary headaches are not discussed except medication overuse headache that often accompanies primary headache disorders. The article critically reviews the literature on the current understanding of daily headache disorders focusing in particular on recent developments in the treatment of frequent headaches.

  8. Sepse por Salmonella associada à deficiência do receptor da Interleucina-12 (IL-12Rbeta1 Samonella septicemia associated with interleukin 12 receptor b1 (IL-12Rbeta1 deficiency

    Directory of Open Access Journals (Sweden)

    Beatriz Tavares Costa Carvalho


    absence of IL-12 and the IFN-gamma post stimulation using BCG. COMMENTS: a severe infection by Salmonella enteritidis is strongly suggestive of an immune system dysfunction. Laboratory tests for humoral, cellular and innate immunity were performed. Interleukin 12 receptor beta1 (IL-12 Rbeta1 deficiency was confirmed after specific laboratory evaluation. The use of INF-gamma is recommended in severe cases.

  9. Clinical and genetic characteristics of glucose transporter type 1 deficiency syndrome%葡萄糖转运子1缺乏综合征的临床特点与基因突变分析

    Institute of Scientific and Technical Information of China (English)

    刘燕燕; 包新华; 王爽; 符娜; 刘晓燕; 宋福英; 杨艳玲; 吴晔; 张月华


    Objective To analyze the clinical and SLC2A1 gene mutation characteristics of glucose transporter type 1 deficiency syndrome.Method The detailed clinical manifestations of six cases were recorded.The laboratory tests including EEG,MRI,blood chemistry,and lumbar puncture were performed.SLC2A1 gene mutations were analyzed by PCR,DNA sequencing and multiplex ligation-dependent probe amplification (MLPA).Result Patient 1,2 and 3 had classical clinical symptoms including infantile onset seizures,development delay.Patient 4,5 and 6 had non-classical clinical symptoms including paroxysmal behavior disturbance,weakness,ataxia,lethargy,especially after fasting or exercise,without severe seizures.The plasma glucose levels were normal.The CSF glucose levels decreased in all the six cases,ranged from 1.10 mmol/L to 2.45 mmol/L,the mean level was 1.68 mmol/L.The CSF glucose/plasma glucose ratios decreased,ranged from 0.16 to 0.51,the mean ratio was 0.34.Four patients had normal EEG.Two patients had focal and diffuse epileptiform discharge,and one of them also had paroxysmal occipital or generalized high-amplitude slow waves during awake and sleep time.MRI abnormalities were found in three patients,patient 1 with mild brain atrophy,patient 3 with bilateral ventricle plump,and patient 4 with high signals in T2 in the frontal and occipital white matter,interpreted as hypomyelination.SLC2A1 gene mutations were found in six cases.Patient 1 has large scale deletion in exon 2.In patient 2 to 6,the mutations were c.741 G>A (E247K),599delA,761delA,c.1148 C >A (P383H),c.1198 C >T (R400C) respectively.Two patients were treated with ketogenic diet.The seizures disappeared and development became normal.Three patients responded to frequent meals with snacks.One patient refused any treatments,the symptoms continued to exist.Conclusion The clinical manifestations of glucose transporter type 1 deficiency syndrome are varied.The common symptoms included infantile onset seizures and various

  10. Chronic hypersensitivity pneumonitis

    Directory of Open Access Journals (Sweden)

    Pereira CA


    Full Text Available Carlos AC Pereira,1 Andréa Gimenez,2 Lilian Kuranishi,2 Karin Storrer 2 1Interstitial Lung Diseases Program, 2Pulmonology Postgraduate, Federal University of São Paulo, São Paulo, Brazil Abstract: Hypersensitivity pneumonitis (HSP is a common interstitial lung disease resulting from inhalation of a large variety of antigens by susceptible individuals. The disease is best classified as acute and chronic. Chronic HSP can be fibrosing or not. Fibrotic HSP has a large differential diagnosis and has a worse prognosis. The most common etiologies for HSP are reviewed. Diagnostic criteria are proposed for both chronic forms based on exposure, lung auscultation, lung function tests, HRCT findings, bronchoalveolar lavage, and biopsies. Treatment options are limited, but lung transplantation results in greater survival in comparison to idiopathic pulmonary fibrosis. Randomized trials with new antifibrotic agents are necessary. Keywords: interstitial lung diseases, extrinsic allergic alveolitis, diffuse lung disease, lung immune response, HRCT, farmers lung

  11. Chronic pelvic floor dysfunction. (United States)

    Hartmann, Dee; Sarton, Julie


    The successful treatment of women with vestibulodynia and its associated chronic pelvic floor dysfunctions requires interventions that address a broad field of possible pain contributors. Pelvic floor muscle hypertonicity was implicated in the mid-1990s as a trigger of major chronic vulvar pain. Painful bladder syndrome, irritable bowel syndrome, fibromyalgia, and temporomandibular jaw disorder are known common comorbidities that can cause a host of associated muscular, visceral, bony, and fascial dysfunctions. It appears that normalizing all of those disorders plays a pivotal role in reducing complaints of chronic vulvar pain and sexual dysfunction. Though the studies have yet to prove a specific protocol, physical therapists trained in pelvic dysfunction are reporting success with restoring tissue normalcy and reducing vulvar and sexual pain. A review of pelvic anatomy and common findings are presented along with suggested physical therapy management.

  12. Omalizumab for chronic urticaria

    DEFF Research Database (Denmark)

    Ivyanskiy, Ilya; Sand, Carsten; Thomsen, Simon Francis


    urticaria. We present a case series of 19 patients with chronic urticaria treated in a university department with omalizumab and give an overview of the existing literature comprising an additional 59 cases as well as a total of 139 patients enrolled in two randomized controlled trials comparing omalizumab...... with placebo. The collective evidence points to omalizumab as a safe and effective treatment option for patients with chronic urticaria who do not sufficiently respond to standard therapy as recommended by existing guidelines.......Omalizumab is a recombinant humanized monoclonal antibody that blocks the high-affinity Fc receptor of IgE. Omalizumab has been approved for the treatment of moderate to severe asthma; however, there is currently more and more data showing promising results in the management also of chronic...

  13. Altered microvascular hemodynamics during the induction and perpetuation of chronic gut inflammation. (United States)

    Harris, Norman R; Whatley, Joseph R; Carter, Patsy R; Morgan, Georgia A; Grisham, Matthew B


    Adoptive transfer of naïve CD4+ T cells into lymphopenic mice induces chronic small and large bowel inflammation similar to Crohn's disease. Although much is now known regarding the immunopathology in this model of inflammatory bowel disease, virtually nothing is known about the microvascular hemodynamic changes during the induction and perpetuation of chronic gut inflammation. In this study, CD4+CD45RBhigh T cells obtained from healthy C57BL/6 donor mice were transferred into lymphopenic recombinase-activating gene-1-deficient (RAG knockout) mice, which induced small and large bowel inflammation. At various time points following reconstitution (3 days-9 wk), intravital microscopy was used to examine the microvessels in the submucosa of the ileum and proximal colon following infusion of fluorescently labeled platelets and injection of rhodamine 6G (to label leukocytes). Hemodynamic measurements and the extent of blood cell adhesion to the venular wall were compared with measurements in unreconstituted RAG knockout controls. In 50% compared with controls, with this decrease also observed at 4-5 and 7-9 wk postreconstitution. At 7-9 wk, arteriolar diameters were found to be approximately 15% larger than in controls, but, despite this dilation, flow rates in the individual vessels were decreased by approximately 30%. Venular platelet and leukocyte adherence were not significantly elevated above controls; however, an association was found between platelet adherence and venular shear rate. In summary, significant decreases in arteriolar velocity and shear rates are observed in this model of chronic gut inflammation.

  14. [Histaminergic angioedema and chronic urticaria]. (United States)

    Hacard, Florence; Nosbaum, Audrey; Bensaid, Benoit; Nicolas, Jean-François; Augey, Frédéric; Goujon, Catherine; Bérard, Frédéric


    Most angioedemas are histaminergic and correspond to deep urticarial swelling. Recurrent histaminergic angioedema led to the diagnosis of chronic urticaria, even when there are no superficial associated hives. Chronic urticaria is a benign disease, and autoimmune in 40 % of cases. The occurrence of angioedema in chronic urticaria is not a sign of severity. The occurrence of angioedema in chronic urticaria is associated with a longer duration of urticarial disease. NSAIDs and/or systemic corticotherapy are classic triggers of angioedema in chronic urticaria. In the absence of clinical endpoints, there is no need to make further assessment in chronic urticaria good responders to antihistamines.

  15. Chronic obstructive pulmonary disease - adults - discharge (United States)

    COPD - adults - discharge; Chronic obstructive airways disease - adults - discharge; Chronic obstructive lung disease - adults - discharge; Chronic bronchitis - adults - discharge; Emphysema - adults - discharge; Bronchitis - ...

  16. Chronic pancreatitis in dogs. (United States)

    Watson, Penny


    Chronic pancreatitis used to be considered uncommon in dogs, but recent pathological and clinical studies have confirmed that it is in fact a common and clinically significant disease. Clinical signs can vary from low-grade recurrent gastrointestinal signs to acute exacerbations that are indistinguishable from classical acute pancreatitis. Chronic pancreatitis is a significant cause of chronic pain in dogs, which must not be underestimated. It also results in progressive impairment of endocrine and exocrine function and the eventual development of diabetes mellitus or exocrine pancreatic insufficiency or both in some affected dogs at end stage. The etiology is unknown in most cases. Chronic pancreatitis shows an increased prevalence in certain breeds, and recent work in English Cocker Spaniels suggests it is part of a polysystemic immune-mediated disease in this breed. The histological and clinical appearance is different in different breeds, suggesting that etiologies may also be different. Diagnosis is challenging because the sensitivities of the available noninvasive tests are relatively low. However, with an increased index of suspicion, clinicians will recognize more cases that will allow them to institute supportive treatment to improve the quality of life of the patient.

  17. Acetaminophen for Chronic Pain

    DEFF Research Database (Denmark)

    Ennis, Zandra Nymand; Dideriksen, Dorthe; Vaegter, Henrik Bjarke;


    strategies for acetaminophen use in chronic pain in both Embase and PubMed, 1,551 hits were obtained. Following cross-reference searches of both trials and 38 reviews, seven studies comparing acetaminophen in continuous dosing regimens of more than two weeks with placebo were included. The review...

  18. Refractory chronic migraine

    DEFF Research Database (Denmark)

    Martelletti, Paolo; Katsarava, Zaza; Lampl, Christian


    The debate on the clinical definition of refractory Chronic Migraine (rCM) is still far to be concluded. The importance to create a clinical framing of these rCM patients resides in the complete disability they show, in the high risk of serious adverse events from acute and preventative drugs...

  19. Diagnosing chronic rhinosinusitis

    DEFF Research Database (Denmark)

    Lange, B; Thilsing, T; Baelum, J;


    The European Position Paper on Rhinosinusitis and Nasal Polyps (EP3OS) incorporates symptomatic and endo- scopic criteria in the clinical diagnosis of chronic rhinosinusitis (CRS), while in epidemiological studies the definition is based on symptoms only. The aim of this study was to evaluate the...

  20. Chronic recurrent multifocal osteomyelitis

    NARCIS (Netherlands)

    Wedman, Jan; van Weissenbruch, Ranny


    We report what is, to our best knowledge, the first case of chronic recurrent multifocal osteomyelitis (CRMO) in which the frontal and sphenoid bones were involved. Characterized by a prolonged and fluctuating course of osteomyelitis at different sites, CRMO is self-limited, although sequelae can oc




  2. Chronic blood pressure control. (United States)

    Brands, Michael W


    Chronic blood pressure is maintained within very narrow limits around an average value. However, the multitude of physiologic processes that participate in blood pressure control present a bewildering array of possibilities to explain how such tight control of arterial pressure is achieved. Guyton and Coleman and colleagues addressed this challenge by creating a mathematical model that integrated the short- and long-term control systems for overall regulation of the circulation. The hub is the renal-body fluid feedback control system, which links cardiac function and vascular resistance and capacitance with fluid volume homeostasis as the foundation for chronic blood pressure control. The cornerstone of that system is renal sodium excretory capability, which is defined by the direct effect of blood pressure on urinary sodium excretion, that is, "pressure natriuresis." Steady-state blood pressure is the pressure at which pressure natriuresis balances sodium intake over time; therefore, renal sodium excretory capability is the set point for chronic blood pressure. However, this often is misinterpreted as dismissing, or minimizing, the importance of nonrenal mechanisms in chronic blood pressure control. This article explains the renal basis for the blood pressure set point by focusing on the absolute dependence of our survival on the maintenance of sodium balance. Two principal threats to sodium balance are discussed: (1) a change in sodium intake or renal excretory capability and (2) a change in blood pressure. In both instances, circulatory homeostasis is maintained because the sodium balance blood pressure set point is reached.

  3. Chronic Kidney Disease (United States)

    ... of the feet and ankles Causes & Risk FactorsWhat causes CKD?The most common causes of CKD are high blood pressure, diabetes and heart disease. ... caused by CKD.How else is CKD treated?Chronic kidney disease can cause other problems. Talk with your doctor about how ...


    Directory of Open Access Journals (Sweden)

    Eligio Pizzigallo


    Full Text Available The infection from Epstein-Barr virus (EBV or virus of infectious mononucleosis, together with other herpesviruses’ infections, represents a prototype of persistent viral infections characterized by the property of the latency. Although the reactivations of the latent infection are associated with the resumption of the viral replication and eventually with the “shedding”, it is still not clear if this virus can determine chronic infectious diseases, more or less evolutive. These diseases could include some pathological conditions actually defined as “idiopathic”and characterized by the “viral persistence” as the more credible pathogenetic factor. Among the so-called idiopathic syndromes, the “chronic fatigue syndrome” (CFS aroused a great interest around the eighties of the last century when, just for its relationship with EBV, it was called “chronic mononucleosis” or “chronic EBV infection”. Today CFS, as defined in 1994 by the CDC of Atlanta (USA, really represents a multifactorial syndrome characterized by a chronic course, where reactivation and remission phases alternate, and by a good prognosis. The etiopathogenetic role of EBV is demonstrated only in a well-examined subgroup of patients, while in most of the remaining cases this role should be played by other infectious agents - able to remain in a latent or persistent way in the host – or even by not infectious agents (toxic, neuroendocrine, methabolic, etc.. However, the pathogenetic substrate of the different etiologic forms seems to be the same, much probably represented by the oxidative damage due to the release of pro-inflammatory cytokines as a response to the triggering event (infectious or not infectious. Anyway, recently the scientists turned their’s attention to the genetic predisposition of the subjects affected by the syndrome, so that in the last years the genetic studies, together with those of molecular biology, received a great impulse

  5. Screening for Chronic Kidney Disease (United States)

    Understanding Task Force Recommendations Screening for Chronic Kidney Disease The U.S. Preventive Services Task Force (Task Force) has issued a final recommendation on Screening for Chronic Kidney Disease (CKD) . This recommendation ...

  6. Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) (United States)

    ... and abnormal sensations. CIDP is closely related to Guillain-Barre syndrome and it is considered the chronic counterpart ... and abnormal sensations. CIDP is closely related to Guillain-Barre syndrome and it is considered the chronic counterpart ...

  7. Chronic Fatigue Syndrome (CFS): Symptoms (United States)

    ... . Chronic Fatigue Syndrome (CFS) Share Compartir Symptoms On this Page Primary Symptoms Other Symptoms What's ... a doctor distinguish CFS from other illnesses. Primary Symptoms As the name chronic fatigue syndrome suggests , fatigue ...

  8. Chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    V K Vijayan


    Full Text Available The global prevalence of physiologically defined chronic obstructive pulmonary disease (COPD in adults aged >40 yr is approximately 9-10 per cent. Recently, the Indian Study on Epidemiology of Asthma, Respiratory Symptoms and Chronic Bronchitis in Adults had shown that the overall prevalence of chronic bronchitis in adults >35 yr is 3.49 per cent. The development of COPD is multifactorial and the risk factors of COPD include genetic and environmental factors. Pathological changes in COPD are observed in central airways, small airways and alveolar space. The proposed pathogenesis of COPD includes proteinase-antiproteinase hypothesis, immunological mechanisms, oxidant-antioxidant balance, systemic inflammation, apoptosis and ineffective repair. Airflow limitation in COPD is defined as a postbronchodilator FEV1 (forced expiratory volume in 1 sec to FVC (forced vital capacity ratio <0.70. COPD is characterized by an accelerated decline in FEV1. Co morbidities associated with COPD are cardiovascular disorders (coronary artery disease and chronic heart failure, hypertension, metabolic diseases (diabetes mellitus, metabolic syndrome and obesity, bone disease (osteoporosis and osteopenia, stroke, lung cancer, cachexia, skeletal muscle weakness, anaemia, depression and cognitive decline. The assessment of COPD is required to determine the severity of the disease, its impact on the health status and the risk of future events (e.g., exacerbations, hospital admissions or death and this is essential to guide therapy. COPD is treated with inhaled bronchodilators, inhaled corticosteroids, oral theophylline and oral phosphodiesterase-4 inhibitor. Non pharmacological treatment of COPD includes smoking cessation, pulmonary rehabilitation and nutritional support. Lung volume reduction surgery and lung transplantation are advised in selected severe patients. Global strategy for the diagnosis, management and prevention of Chronic Obstructive Pulmonary Disease

  9. Defining and Measuring Chronic Conditions

    Centers for Disease Control (CDC) Podcasts


    This podcast is an interview with Dr. Anand Parekh, U.S. Department of Health and Human Services Deputy Assistant Secretary for Health, and Dr. Samuel Posner, Preventing Chronic Disease Editor in Chief, about the definition and burden of multiple chronic conditions in the United States.  Created: 5/20/2013 by Preventing Chronic Disease (PCD), National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP).   Date Released: 5/20/2013.

  10. Treating Chronic Myeloid Leukemia by Phase (United States)

    ... Myeloid Leukemia (CML) Treating Chronic Myeloid Leukemia Treating Chronic Myeloid Leukemia by Phase Treatment options for people ... a stem cell donor with matching tissue type. Chronic phase The standard treatment for chronic phase CML ...

  11. [Chronic inflammatory demyelinating polyradiculoneuropathy]. (United States)

    Franques, J; Azulay, J-P; Pouget, J; Attarian, S


    Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a demyelinating chronic neuropathy of immune origin whose diagnosis is based upon clinical, biological and electrophysiological data; previously critical to the diagnosis the nerve biopsy is now restricted to the rare situations where accurate diagnosis cannot be reached using these data alone. CIDP are mainly idiopathic, but a few associated diseases must be sought for as they require specific attention. Such associated diseases must particularly be discussed when the manifestations are severe or resistant to immunomodulating or immunosuppressive agents. Indeed, idiopathic CIDP are usually responsive to these treatments. The effectiveness of these treatments is limited by the importance of the secondary axonal loss. The dependence or the resistance may sometimes justify the association of several immunomodulating treatments. A single randomized controlled trial support the use of cytotoxic drugs and none with rituximab.

  12. Chronic intestinal pseudoobstruction syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Yeon, Kyung Mo; Seo, Jeong Kee; Lee, Yong Seok [Seoul National University Children' s Hospital, Seoul (Korea, Republic of)


    Chronic intestinal pseudoobstruction syndrome is a rare clinical condition in which impaired intestinal peristalsis causes recurrent symptoms of bowel obstruction in the absence of a mechanical occlusion. This syndrome may involve variable segments of small or large bowel, and may be associated with urinary bladder retention. This study included 6 children(3 boys and 3 girls) of chronic intestinal obstruction. Four were symptomatic at birth and two were of the ages of one month and one year. All had abdominal distension and deflection difficulty. Five had urinary bladder distension. Despite parenteral nutrition and surgical intervention(ileostomy or colostomy), bowel obstruction persisted and four patients expired from sepses within one year. All had gaseous distension of small and large bowel on abdominal films. In small bowel series, consistent findings were variable degree of dilatation, decreased peristalsis(prolonged transit time) and microcolon or microrectum. This disease entity must be differentiated from congenital megacolon, ileal atresia and megacystis syndrome.

  13. Bilateral chronic subdural hematoma

    DEFF Research Database (Denmark)

    Andersen-Ranberg, Nina Christine; Poulsen, Frantz Rom; Bergholt, Bo


    OBJECTIVE Bilateral chronic subdural hematoma (bCSDH) is a common neurosurgical condition frequently associated with the need for retreatment. The reason for the high rate of retreatment has not been thoroughly investigated. Thus, the authors focused on determining which independent predictors...... are associated with the retreatment of bCSDH with a focus on surgical laterality. METHODS In a national database of CSDHs (Danish Chronic Subdural Hematoma Study) the authors retrospectively identified all bCSDHs treated in the 4 Danish neurosurgical departments over the 3-year period from 2010 to 2012....... Univariate and multivariate analyses were performed to determine the relationship between retreatment of bCSDH and clinical, radiological, and surgical variables. RESULTS Two hundred ninety-one patients with bCSDH were identified, and 264 of them underwent unilateral (136 patients) or bilateral (128 patients...

  14. Chronic pneumonitis of infancy

    Energy Technology Data Exchange (ETDEWEB)

    Abe, Katsumi; Kamata, Noriko; Okazaki, Eiwa [Department of Radiology, Tokyo Metropolitan Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677 (Japan); Moriyama, Sachiko; Funata, Nobuaki [Department of Pathology, Tokyo Metropolitan Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677 (Japan); Takita, Junko; Yamada, Hideo; Takayama, Naohide [Department of Pediatrics, Tokyo Metropolitan Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677 (Japan)


    Chronic pneumonitis of infancy (CPI) is a very rare lung disease in infants and young children. We report a 33-day-old infant with CPI, focusing on the radiologic aspects of the disease. Chest radiographs showed variable and non-specific appearances including ground-glass shadowing, consolidation, volume loss, and hyperinflation. Dense alveolar opacities progressed as CPI advanced. The radiologic features of our case reflected pathologic changes. (orig.)

  15. Renal failure (chronic)


    Clase, Catherine


    Chronic renal failure is characterised by a gradual and sustained decline in renal clearance or glomerular filtration rate (GFR). Continued progression of renal failure will lead to renal function too low to sustain healthy life. In developed countries, such people will be offered renal replacement therapy in the form of dialysis or renal transplantation. Requirement for dialysis or transplantation is termed end-stage renal disease (ESRD).Diabetes, glomerulonephritis, hypertension, pyelone...

  16. Chronic Stress and Performance (United States)


    to the cannabinoid CB(1) receptor agonist HU-210 following chronic stress. European Journal of Pharmacology, 499(3), 291-295. Holscher, C. (1999...learning and memory, has the highest concentration of GC receptors in the brain and is involved in the stress response. Extensive research has... receptor levels than stressed male rodents (Konkle, 2003; Figueiredo, 2002; Handa, 1994). Males and females react to stress differently, so two models


    Directory of Open Access Journals (Sweden)

    Delia Racciatti


    Full Text Available

    The infection from Epstein-Barr virus (EBV or virus of infectious mononucleosis, together with other herpesviruses’ infections, represents a prototype of persistent viral infections characterized by the property of the latency. Although the reactivations of the latent infection are associated with the resumption of the viral replication and eventually with the “shedding”, it is still not clear if this virus can determine chronic infectious diseases, more or less evolutive. These diseases could include some pathological conditions actually defined as “idiopathic”and characterized by the “viral persistence” as the more credible pathogenetic factor. Among the so-called idiopathic syndromes, the “chronic fatigue syndrome” (CFS aroused a great interest around the eighties of the last century when, just for its relationship with EBV, it was called “chronic mononucleosis” or “chronic EBV infection”.

    Today CFS, as defined in 1994 by the CDC of Atlanta (USA, really represents a multifactorial syndrome characterized by a chronic course, where reactivation and remission phases alternate, and by a good prognosis

  18. Chronic arsenic poisoning. (United States)

    Hall, Alan H


    Symptomatic arsenic poisoning is not often seen in occupational exposure settings. Attempted homicide and deliberate long-term poisoning have resulted in chronic toxicity. Skin pigmentation changes, palmar and plantar hyperkeratoses, gastrointestinal symptoms, anemia, and liver disease are common. Noncirrhotic portal hypertension with bleeding esophageal varices, splenomegaly, and hypersplenism may occur. A metallic taste, gastrointestinal disturbances, and Mee's lines may be seen. Bone marrow depression is common. 'Blackfoot disease' has been associated with arsenic-contaminated drinking water in Taiwan; Raynaud's phenomenon and acrocyanosis also may occur. Large numbers of persons in areas of India, Pakistan, and several other countries have been chronically poisoned from naturally occurring arsenic in ground water. Toxic delirium and encephalopathy can be present. CCA-treated wood (chromated copper arsenate) is not a health risk unless burned in fireplaces or woodstoves. Peripheral neuropathy may also occur. Workplace exposure or chronic ingestion of arsenic-contaminated water or arsenical medications is associated with development of skin, lung, and other cancers. Treatment may incklude the use of chelating agents such as dimercaprol (BAL), dimercaptosuccinic acid (DMSA), and dimercaptopanesulfonic acid (DMPS).

  19. Chronic Prostatitis/Chronic Pelvic Pain Syndrome Diagnosis and Treatment

    Directory of Open Access Journals (Sweden)

    Cem Nedim Yuceturk


    Full Text Available Chronic prostatitis is a chronic syndrome that effects men with a wide range of age. The etiology, natural history and appropriate therapy models are still unclear. According to the classification of National Institutes of Health; 4 types of prostatitis were defined; acute bacterial prostatitis (category I, chronic bacterial prostatitis (category II, chronic nonbacterial prostatitis/chronic pelvic pain syndrome (category III and asymptomatic prostatitis (category IV.Since microorganisms can only be isolated from a small percent of patients, empiric treatment is given to the most of the men. Multidisciplinary approach to the patients with suspected chronic prostatitis will help clinicians to play an active role in the treatment and prevent unnecessary medical therapies. [Archives Medical Review Journal 2014; 23(4.000: 691-702

  20. Chronic radiation syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Akleyev, Alexander V. [Urals Research Centre for Radiation Medicine, Chelyabinsk (Russian Federation). Clinical Dept.


    Comprehensive analysis of chronic radiation syndrome, covering epidemiology, pathogenesis, pathoanatomy, diagnosis and treatment. Based on observations in a unique sample of exposed residents of the Techa riverside villages in the Urals. Casts new light on the condition. Of value for all practitioners and researchers with an interest in chronic radiation syndrome. This book covers all aspects of chronic radiation syndrome (CRS) based on observations in a unique sample of residents of the Techa riverside villages in the southern Urals who were exposed to radioactive contamination in the 1950s owing to releases of liquid radioactive wastes from Mayak Production Association, which produced plutonium for weapons. In total, 940 cases of CRS were diagnosed in this population and these patients were subjected to detailed analysis. The opening chapters address the definition and classification of CRS, epidemiology and pathogenesis, covering molecular and cellular mechanisms, radioadaptation, and the role of tissue reactions. The pathoanatomy of CRS during the development and recovery stages is discussed for all organ systems. Clinical manifestations of CRS at the different stages are then described in detail and the dynamics of hematopoietic changes are thoroughly examined. In the following chapters, principles of diagnosis (including assessment of the exposure doses to critical organs) and differential diagnosis from a wide range of other conditions are discussed and current and potential treatment options, described. The medical and social rehabilitation of persons with CRS is also covered. This book, which casts new light on the condition, will be of value for all practitioners and researchers with an interest in CRS.

  1. Approaching chronic cough. (United States)

    Poulose, Vijo; Tiew, Pei Yee; How, Choon How


    Chronic cough is one of the most common reasons for referral to a respiratory physician. Although fatal complications are rare, it may cause considerable distress in the patient's daily life. Western and local data shows that in patients with a normal chest radiograph, the most common causes are postnasal drip syndrome, postinfectious cough, gastro-oesophageal reflux disease and cough variant asthma. Less common causes are the use of angiotensin-converting enzyme inhibitors, smoker's cough and nonasthmatic eosinophilic bronchitis. A detailed history-taking and physical examination will provide a diagnosis in most patients, even at the primary care level. Some cases may need further investigations or specialist referral for diagnosis.

  2. Chronic cough in children. (United States)

    Acosta, Rigoberto; Bahna, Sami L


    Cough is probably the most common cause of seeking medical care in pediatric practice. Most acute cough is caused by infection and usually resolves within less than 4 weeks. If it lasts longer, it is considered chronic and deserves investigation to identify the underlying cause, which can be almost any of a wide variety of illnesses of the respiratory tract and certain extrathoracic conditions. This review provides an optimal approach for diagnosis through a skillful history taking, physical examination, and selection of appropriate tests.

  3. The Chronic Poverty Report 2005


    The Chronic Poverty Research Centre, CPRC


    The report examines what chronic poverty is and why it matters, who the chronically poor are, where they live, what causes poverty to be persistent and what should be done about it. It argues that approaches to development policy must acknowledge the agency of the chronically poor themselves in overcoming their poverty. But they also need real commitment, matched by actions and resources, to support their efforts to attain their rights and overcome the obstacles that trap them in poverty.

  4. Treatment Strategies for Chronic Cases

    Directory of Open Access Journals (Sweden)

    Susan M Lord


    Full Text Available The treatment of chronic somatic pain, including pain referred to the head, neck, shoulder girdle and upper limb from somatic structures, is addressed. Levels of evidence for the various treatments that have been prescribed for chronic whiplash associated disorders are considered. The challenge to find a treatment strategy for chronic pain after whiplash that completely relieves the condition and prevents its sequelae is reviewed.

  5. Late and chronic Lyme disease. (United States)

    Donta, Sam T


    This article reviews the late and chronic manifestations of Lyme disease. Special attention is given to the chronic manifestations of the disease, detailing its pathogenesis, clinical spectrum, and laboratory criteria for the diagnosis. Based on experimental evidence and experience, approaches to the successful treatment of the late and chronic disease are outlined. Much additional work is needed to improve the understanding of the underlying pathophysiology of the disease, its diagnosis and treatment.

  6. Chronic avulsive injuries of childhood

    Energy Technology Data Exchange (ETDEWEB)

    Donnelly, L.F.; Helms, C.A. [Dept. of Radiology, Duke Univ. Medical Center, Durham, NC (United States); Bisset, G.S. III [Dept. of Radiology, Duke Univ. Medical Center, Durham, NC (United States)]|[Department of Pediatrics, Duke University Medical Center, Durham, NC (United States); Squire, D.L. [Department of Pediatrics, Duke University Medical Center, Durham, NC (United States)


    Children and adolescents are prone to avulsive injuries related to a combination of their propensity for great strength, ability to sustain extreme levels of activity, and immature growing apophyses. Appropriate interpretation of imaging studies showing chronic avulsive injuries is essential so that the irregularity and periostitis that can be associated with chronic avulsions is not misinterpreted as probable malignancy. This article reviews the chronic avulsive injuries of childhood. (orig.) With 12 figs., 8 refs.

  7. Understanding Biofilms in Chronic Sinusitis. (United States)

    Tajudeen, Bobby A; Schwartz, Joseph S; Palmer, James N


    Chronic sinusitis is a burdensome disease that has substantial individual and societal impact. Although great advances in medical and surgical therapies have been made, some patients continue to have recalcitrant infections. Microbial biofilms have been implicated as a cause of recalcitrant chronic sinusitis, and recent studies have tried to better understand the pathogenesis of chronic sinusitis as it relates to microbial biofilms. Here, we provide an overview of biofilms in chronic sinusitis with emphasis on pathogenesis, treatment, and future directions. In addition, recent evidence is presented, elucidating the role of bitter taste receptors as a possible key factor leading to biofilm formation.

  8. Diagnostic dilemmas in chronic urticaria. (United States)

    Toubi, E; Grattan, C; Zuberbier, T


    The European Academy of Allergy and Clinical Immunology (EAACI)/Global Allergy and Asthma European Network (GA(2) LEN)/European Dermatology Forum (EDF)/World Allergy Organization (WAO) recently published updated recommendations for the classification, diagnosis and management of chronic urticaria (CU). This article discusses several cases of CU that provide examples of how the recommendations in the guidelines can be implemented in the diagnosis of chronic spontaneous urticaria (CSU) (also called chronic idiopathic urticaria [CIU]), chronic inducible urticaria (CINDU) or CU with comorbidities.

  9. Chronic diseases and mental disorder.

    NARCIS (Netherlands)

    Verhaak, P.F.M.; Heijmans, M.J.W.M.; Peters, L.; Rijken, M.


    The aim of this study was to achieve a better understanding of the relationship between chronic medical illness and mental distress. Therefore, the association between chronic medical illness and mental distress was analysed, taking into account the modifying effects of generic disease characteristi

  10. Anemia in Chronic Kidney Disease (United States)

    ... High Blood Pressure Heart Disease Mineral & Bone Disorder Anemia in Chronic Kidney Disease What is anemia? Anemia is a condition in which the body ... function as well as they should. How is anemia related to chronic kidney disease? Anemia commonly occurs ...

  11. Chronic Kidney Disease and Medicines (United States)

    ... from our online catalog. Alternate Language URL Español Chronic Kidney Disease and Medicines: What You Need to Know Page ... What you need to know Because you have chronic kidney disease, you should take steps to protect your kidneys. ...

  12. Obinutuzumab in chronic lymphocytic leukemia. (United States)

    Dupuis, Jehan


    Obinutuzumab is the second next-generation monoclonal anti-CD20 antibody (after ofatumumab) to enter clinical practice in chronic lymphocytic leukemia. Its superiority in association with chlorambucil as compared with chlorambucil alone has led to its approval as a first-line treatment for chronic lymphocytic leukemia, for patients who are not candidates for a more intensive treatment.

  13. [Histopathologic study of chronic sinusitis]. (United States)

    Wayoff, M; Parache, R M; Bodelet, B; Gazel, P


    The conventional histopathology of the sinus is a criterium for the therapeutic indication, since it is possible to distinguish between granulomatous chronic sinusitis, chronic sinusitis with oedema and nasal polyposis. Each one of these clinical pictures has his own etiology and requires a specific therapeutic approach.

  14. [Chronic pyelonephritis in polycystic kidney]. (United States)

    Todorov, V; Penkova, S; Monov, A


    The characteristics of chronic pyelonephritis are studied in 37 patients out of a total of 53 patients with proved renal polycystosis. A group of 71 patients with chronic pyelonephritis selected at random are used as a control group. The frequency of chronic pyelonephritis among the patients with renal polycystosis is 69.8%. The difference between the mean age of the patients with renal polycystosis and chronic pyelonephritis and the patients with renal polycystosis without chronic pyelonephritis is 8.6 years. A significant difference is established between these two groups of patients concerning the frequency of symptomatic hypertension--89.2% for the patients with renal polycystosis and chronic pyelonephritis and 45% for the patients with uncomplicated renal polycystosis. A similar difference is established also for the renal failure--respectively 64.9% and 37.5%. The frequency of hypertension and chronic renal failure is lower in the control group of patients. 59% of the patients with renal polycystosis and chronic pyelonephritis have significant bacteriuria, E. coli and Proteus being the most frequently isolated bacteria but Pseudomonas shows the highest drug resistance. The isolated bacteria are most sensitive to nitroxoline and aminoglycoside antibiotics.

  15. Chronic Obstructive Pulmonary Disease (COPD) (United States)

    ... term that is used to include chronic bronchitis, emphysema, or a combination of both conditions. Asthma is also a disease where it is difficult ... with COPD to also have some degree of asthma. What is chronic ... back to their original size. In emphysema, the walls of some of the alveoli have ...

  16. Pharmacologic Agents for Chronic Diarrhea


    Lee, Kwang Jae


    Chronic diarrhea is usually associated with a number of non-infectious causes. When definitive treatment is unavailable, symptomatic drug therapy is indicated. Pharmacologic agents for chronic diarrhea include loperamide, 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, diosmectite, cholestyramine, probiotics, antispasmodics, rifaximin, and anti-inflammatory agents. Loperamide, a synthetic opiate agonist, decreases peristaltic activity and inhibits secretion, resulting in the reductio...

  17. Refractory chronic cluster headache

    DEFF Research Database (Denmark)

    Mitsikostas, Dimos D; Edvinsson, Lars; Jensen, Rigmor H


    Chronic cluster headache (CCH) often resists to prophylactic pharmaceutical treatments resulting in patients' life damage. In this rare but pragmatic situation escalation to invasive management is needed but framing criteria are lacking. We aimed to reach a consensus for refractory CCH definition...... for clinical and research use. The preparation of the final consensus followed three stages. Internal between authors, a larger between all European Headache Federation members and finally an international one among all investigators that have published clinical studies on cluster headache the last five years....... Eighty-five investigators reached by email. Proposed criteria were in the format of the International Classification of Headache Disorders III-beta (description, criteria, notes, comments and references). Following this evaluation eight drafts were prepared before the final. Twenty-four (28...

  18. [Chronic occupational metallic mercurialism]. (United States)

    Faria, Marcília de Araújo Medrado


    This is a review on current knowledge of chronic occupational mercurialism syndrome. Major scientific studies and reviews on clinical manifestation and physiopathology of mercury poisoning were evaluated. The search was complemented using Medline and Lilacs data. Erethism or neuropsychological syndrome, characterized by irritability, personality change, loss of self-confidence, depression, delirium, insomnia, apathy, loss of memory, headaches, general pain, and tremors, is seen after exposure to metallic mercury. Hypertension, renal disturbances, allergies and immunological conditions are also common. Mercury is found in many different work processes: industries, gold mining, and dentistry. As prevention measures are not often adopted there is an increasing risk of mercury poisoning. The disease has been under diagnosed even though 16 clinical forms of mercury poisoning are described by Brazilian regulations. Clinical diagnosis is important, especially because abnormalities in the central nervous, renal and immunological systems can be detected using current medical technology, helping to develop the knowledge and control measures for mercurialism.

  19. Chronic hypophosphatemic osteopathy

    Energy Technology Data Exchange (ETDEWEB)

    Koppers, B.; Schmid, L.; Hofmann, E.; Sauer, E.


    The process of chronic hypophosphatemic vitamine D-resistant rickets is described by observation of two cases. With the male patient - our first case - the disease was sporadic and had not been recognized for a long time. In his early adulthood it manifested itself as Umbauzonen (pseudofractures) in the larger context of active osteomalacia. It was possible to observe the pseudofractures before and while the patient was medicamentously treated. High doses of vitamine D 3 and dosage of phosphate mitigated the complaints although with respect to the radiological, scintigraphical, humoral and histological findings there was only slow improvement or no improvement at all. The patient's daughter is affected by the disease as well. In her case the pathological signs of her bones became better when treated with vitamine D 3.

  20. Chronic endometritis and infertility (United States)

    Park, Hyun Jong; Kim, You Shin; Yoon, Tae Ki


    Chronic endometritis (CE) is a condition involving the breakdown of the peaceful co-existence between microorganisms and the host immune system in the endometrium. A majority of CE cases produce no noticeable signs or mild symptoms, and the prevalence rate of CE has been found to be approximately 10%. Gynecologists and pathologists often do not focus much clinical attention on CE due to the time-consuming microscopic examinations necessary to diagnose CE, its mild clinical manifestations, and the benign nature of the disease. However, the relationship between CE and infertility-related conditions such as repeated implantation failure and recurrent miscarriage has recently emerged as an area of inquiry. In this study, we reviewed the literature on the pathophysiology of CE and how it may be associated with infertility, as well as the literature regarding the diagnosis and treatment of CE. In addition, we discuss the value of hysteroscopic procedures in the diagnosis and treatment of CE. PMID:28090456

  1. Mozart's chronic subdural hematoma. (United States)

    Drake, M E


    No commemoration of the bicentennial of Mozart's death would be complete without some consideration of that premature yet predictable demise. Mozart's premonitions of death are well known and apparently played a role in the composition of the K.626 Requiem and perhaps other works. His death has traditionally been ascribed to infectious causes, chiefly rheumatic fever or post-streptococcal glomerulonephritis, exacerbated by intemperance and chronic penury. Pathology has been difficult because of his supposed burial in a pauper's grave, the location and contents of which were later supposedly lost. Mozart's burial place in St. Mark's Cemetery in Vienna was known and, in the parlance of the day, "reorganized" a decade later, as the occupants of plots were disinterred to make room for the more recently decreased. A skull believed to the Mozart's was saved by the successor of the gravedigger who had supervised Mozart's burial, and then passed into the collections of the anatomist Josef Hyrtl, the municipality of Salzburg, and the Mozarteum museum (Salzburg). Forensic reconstruction of soft tissues related to this skull reveals substantial concordance with Mozart's portraits. The skull suggests premature closure of the metopic suture, which has been suggested on the basis of his physiognomy. A left temporal fracture and concomitant erosions raise the question of chronic subdural hematoma, which would be consistent with several falls in 1789 and 1790 and could have caused the weakness, headaches, and fainting he experienced in 1790 and 1791. Aggressive bloodletting to treat suspected rheumatic fever could have decompensated such a lesion to produce his death on December 5, 1791.

  2. [Conservative therapy of chronic sinusitis]. (United States)

    Reiss, Michael; Reiss, Gilfe


    The chronic rhinosinusitis is defined as chronic inflammation of the nose and nasal sinuses, with or without nasal polyps. Patients suffering from chronic rhinosinusitis report about nasal obstruction and secretion, olfactory impairment, head and facial pain. These symptoms cause also considerable impact on quality of life. Therefore, an adequate rhinological diagnostics as well as therapies are essential. This paper reviews the pharmacologic and non-pharmacologic therapy of chronic rhinosinusitis. First choice of therapy should be topical glucocorticoids. The application of glucocorticoids causes anti-inflammatory and certain curative effects. Hypertonic salt solutions improve nasal symptoms. Long-term therapy with oral macrolides might improve median to severe symptoms of chronic rhinosinusitis without nasal polyps. An additional therapy with antihistamines is possible in patients with an allergy. Adaptive desensitization in patients suffering from analgesic-intolerance associating among other with nasal polyps is currently the single causal therapy. Therefore, frequency of endonasal revision surgery is reduced after desensitization.

  3. Understanding anemia of chronic disease. (United States)

    Fraenkel, Paula G


    The anemia of chronic disease is an old disease concept, but contemporary research in the role of proinflammatory cytokines and iron biology has shed new light on the pathophysiology of the condition. Recent epidemiologic studies have connected the anemia of chronic disease with critical illness, obesity, aging, and kidney failure, as well as with the well-established associations of cancer, chronic infection, and autoimmune disease. Functional iron deficiency, mediated principally by the interaction of interleukin-6, the iron regulatory hormone hepcidin, and the iron exporter ferroportin, is a major contributor to the anemia of chronic disease. Although anemia is associated with adverse outcomes, experimental models suggest that iron sequestration is desirable in the setting of severe infection. Experimental therapeutic approaches targeting interleukin-6 or the ferroportin-hepcidin axis have shown efficacy in reversing anemia in either animal models or human patients, although these agents have not yet been approved for the treatment of the anemia of chronic disease.

  4. Microbial Biofilms and Chronic Wounds (United States)

    Omar, Amin; Wright, J. Barry; Schultz, Gregory; Burrell, Robert; Nadworny, Patricia


    Background is provided on biofilms, including their formation, tolerance mechanisms, structure, and morphology within the context of chronic wounds. The features of biofilms in chronic wounds are discussed in detail, as is the impact of biofilm on wound chronicity. Difficulties associated with the use of standard susceptibility tests (minimum inhibitory concentrations or MICs) to determine appropriate treatment regimens for, or develop new treatments for use in, chronic wounds are discussed, with alternate test methods specific to biofilms being recommended. Animal models appropriate for evaluating biofilm treatments are also described. Current and potential future therapies for treatment of biofilm-containing chronic wounds, including probiotic therapy, virulence attenuation, biofilm phenotype expression attenuation, immune response suppression, and aggressive debridement combined with antimicrobial dressings, are described. PMID:28272369

  5. Adjusting to Chronic Health Conditions. (United States)

    Helgeson, Vicki S; Zajdel, Melissa


    Research on adjustment to chronic disease is critical in today's world, in which people are living longer lives, but lives are increasingly likely to be characterized by one or more chronic illnesses. Chronic illnesses may deteriorate, enter remission, or fluctuate, but their defining characteristic is that they persist. In this review, we first examine the effects of chronic disease on one's sense of self. Then we review categories of factors that influence how one adjusts to chronic illness, with particular emphasis on the impact of these factors on functional status and psychosocial adjustment. We begin with contextual factors, including demographic variables such as sex and race, as well as illness dimensions such as stigma and illness identity. We then examine a set of dispositional factors that influence chronic illness adjustment, organizing these into resilience and vulnerability factors. Resilience factors include cognitive adaptation indicators, personality variables, and benefit-finding. Vulnerability factors include a pessimistic attributional style, negative gender-related traits, and rumination. We then turn to social environmental variables, including both supportive and unsupportive interactions. Finally, we review chronic illness adjustment within the context of dyadic coping. We conclude by examining potential interactions among these classes of variables and outlining a set of directions for future research.

  6. Common Questions About Chronic Prostatitis. (United States)

    Holt, James D; Garrett, W Allan; McCurry, Tyler K; Teichman, Joel M H


    Chronic prostatitis is relatively common, with a lifetime prevalence of 1.8% to 8.2%. Risk factors include conditions that facilitate introduction of bacteria into the urethra and prostate (which also predispose the patient to urinary tract infections) and conditions that can lead to chronic neuropathic pain. Chronic prostatitis must be differentiated from other causes of chronic pelvic pain, such as interstitial cystitis/bladder pain syndrome and pelvic floor dysfunction; prostate and bladder cancers; benign prostatic hyperplasia; urolithiasis; and other causes of dysuria, urinary frequency, and nocturia. The National Institutes of Health divides prostatitis into four syndromes: acute bacterial prostatitis, chronic bacterial prostatitis (CBP), chronic nonbacterial prostatitis (CNP)/chronic pelvic pain syndrome (CPPS), and asymptomatic inflammatory prostatitis. CBP and CNP/CPPS both lead to pelvic pain and lower urinary tract symptoms. CBP presents as recurrent urinary tract infections with the same organism identified on repeated cultures; it responds to a prolonged course of an antibiotic that adequately penetrates the prostate, if the urine culture suggests sensitivity. If four to six weeks of antibiotic therapy is effective but symptoms recur, another course may be prescribed, perhaps in combination with alpha blockers or nonopioid analgesics. CNP/CPPS, accounting for more than 90% of chronic prostatitis cases, presents as prostatic pain lasting at least three months without consistent culture results. Weak evidence supports the use of alpha blockers, pain medications, and a four- to six-week course of antibiotics for the treatment of CNP/CPPS. Patients may also be referred to a psychologist experienced in managing chronic pain. Experts on this condition recommend a combination of treatments tailored to the patient's phenotypic presentation. Urology referral should be considered when appropriate treatment is ineffective. Additional treatments include pelvic

  7. Laryngeal hypersensitivity in chronic cough. (United States)

    Hull, J H; Menon, A


    Patients with chronic cough often report symptoms arising in the throat, in response to non-specific stimuli. Accordingly, the concept of a 'hypersensitivity' of the larynx in chronic cough has evolved over the past ten years. Patients with cough and laryngeal hypersensitivity frequently report features that overlap other laryngeal dysfunction syndromes, including a tendency for the vocal cords to inappropriately adduct. The mechanisms underlying laryngeal hypersensitivity in chronic cough are currently unclear, however recent studies provide new clinical and physiological techniques to aid detection and monitoring of laryngeal hypersensitivity. This review provides an overview of the current state of knowledge in this field.

  8. Multimodal Treatment of Chronic Pain. (United States)

    Dale, Rebecca; Stacey, Brett


    Most patients with chronic pain receive multimodal treatment. There is scant literature to guide us, but when approaching combination pharmacotherapy, the practitioner and patient must weigh the benefits with the side effects; many medications have modest effect yet carry significant side effects that can be additive. Chronic pain often leads to depression, anxiety, and deconditioning, which are targets for treatment. Structured interdisciplinary programs are beneficial but costly. Interventions have their place in the treatment of chronic pain and should be a part of a multidisciplinary treatment plan. Further research is needed to validate many common combination treatments.

  9. [Chronic ataxia in childhood]. (United States)

    Erazo Torricelli, Ricardo


    Chronic ataxias are an heterogeneous group of disorders that affect the child at different ages. Thus, the congenital forms, generally non progressive are observed from first months of life and are expressed by hypotonia and motor delay long before the ataxia became evident. The cerebral magnetic resonance images (MRI) may be diagnostic in some pictures like Joubert syndrome. The group of progressive hereditary ataxias, usually begin after the infant period. The clinical signs are gait instability and ocular apraxia that can be associated with oculocutaneous telangiectasias (ataxia-telangiesctasia) or with sensory neuropathy (Friedreich ataxia). In this review are briefly described congenital ataxias and in more detailed form the progressive hereditary ataxias autosomal recessive, autosomal dominants and mitochondrials. The importance of genetic study is emphasized, because it is the key to obtain the diagnosis in the majority of these diseases. Although now there are no treatments for the majority of progressive hereditary ataxias, some they have like Refsum disease, vitamine E deficiency, Coenzyme Q10 deficiency and others, thus the diagnosis in these cases is even more important. At present the diagnosis of childhood hereditary ataxia not yet treatable is fundamental to obtain suitable handling, determine a precise outcome and to give to the family an opportune genetic counseling.

  10. [Chronic pain in geriatrics]. (United States)

    Kennes, B


    Pain is frequent in communicative or no-communicative, ambulatory, institutionalized or hospitalized veterans. It is associated with severe comorbidity so much more than chronic pain could be neglected and expressed of atypical manner or masked by the absence of classical symptoms in particular in case of dementia or of sensory disorders. Pain detection by clinic examination or by pain assessment's methods and adequate approach by pharmacological and non pharmacological therapies are essential for correct pain management. On pharmacological plan, the strategy of the O.M.S. landings is applicable owing to a more particular attention to secondary effects and drugs interactions. AINS must be manipulated with prudence. There are no reasons to exclude opioides from the therapeutic arsenal but with a reduction of the starting doses, a regular adaptation and a very attentive survey. In drugs of landing 2, tramadol reveals itself as efficient and better tolerated as the codeine and dextropropoxyphene has to be to avoid. The obtaining of a satisfactory result depends on a regular assessment of the pain in a context of polydisciplinar approach (physicians, nurses, paramedicals, other care givers).

  11. [Chronic recurrent multifocal osteomyelitis]. (United States)

    Schilling, F; Eckardt, A; Kessler, S


    The aim of this paper is to give a detailed description of the so-called "chronic recurrent multifocal osteomyelitis" (CRMO). The clinical, radiological and histopathological results of an analysis of 29 cases (15 children/adolescents and 14 adults) are presented and correlated to current data from the literature. We could delinate the following points: 1. CRMO is a systemic aseptic inflammation of the bone marrow (Osteitis), it can occur polytopically and association with pustulous dermatologic symptoms is possible. 2. It is not a rare disease 3. Osteomyelitis is probably "reactive" and a plasma-cell sclerotic process with ist own characteristic histologic three-phase course. 4. We could observe 5 specific types of localization which can be documented by X-ray or bone scan. 5. Accompanying arthritis os often present, especially "sympathetic coxitis". 6. The use of drugs in treatment of CRMO (i.e. azithromycin, calcitonin, and bisphosphonates) is discussed. In conclusion we want to point out, that 1. 99mTC bone scan should always be performed when there is suspicion for CRMO to reveal the pattern of affection, 2. the rheumatologist and dermatologist should be contacted, 3. operation is normally not necessary for treatment of the mostly self-limitin disease, and 4. the term "SAPHO syndrome" should be avoided, further differentiation of the diagnosis is necessary.

  12. Chronic recurrent multifocal osteomyelitis. (United States)

    Roderick, Marion R; Ramanan, Athimalaipet V


    Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disease occurring primarily in children and adolescents. Episodes of systemic inflammation occur due to immune dysregulation without autoantibodies, pathogens or antigen-specific T cells. CRMO is characterised by the insidious onset of pain with swelling and tenderness over the affected bones. Clavicular involvement was the classical description; however, the metaphyses and epiphyses of long bones are frequently affected. Lesions may occur in any bone, including vertebrae. Characteristic imaging includes bone oedema, lytic areas, periosteal reaction and soft tissue reaction. Biopsies from affected areas display polymorphonuclear leucocytes with osteoclasts and necrosis in the early stages. Subsequently, lymphocytes and plasma cells predominate followed by fibrosis and signs of reactive new bone forming around the inflammation. Diagnosis is facilitated by the use of STIR MRI scanning, potentially obviating the need for biopsy and unnecessary long-term antibiotics due to incorrect diagnosis. Treatment options include non-steroidal anti-inflammatory drugs and bisphosphonates. Biologics have been tried in resistant cases with promising initial results. Gene identification has not proved easy although research in this area continues. Early descriptions of the disease suggested a benign course; however, longer-term follow up shows that it can cause significant morbidity and longer-term disability. Although it has always been thought of as very rare, the prevalence is likely to be vastly underestimated due to poor recognition of the disease.

  13. Chronic lymphocytic leukaemia (United States)

    Kipps, Thomas J.; Stevenson, Freda K.; Wu, Catherine J.; Croce, Carlo M.; Packham, Graham; Wierda, William G.; O’Brien, Susan; Gribben, John; Rai, Kanti


    Chronic lymphocytic leukaemia (CLL) is a malignancy of CD5+ B cells that is characterized by the accumulation of small, mature-appearing lymphocytes in the blood, marrow and lymphoid tissues. Signalling via surface immunoglobulin, which constitutes the major part of the B cell receptor, and several genetic alterations play a part in CLL pathogenesis, in addition to interactions between CLL cells and other cell types, such as stromal cells, T cells and nurse-like cells in the lymph nodes. The clinical progression of CLL is heterogeneous and ranges from patients who require treatment soon after diagnosis to others who do not require therapy for many years, if at all. Several factors, including the immunoglobulin heavy-chain variable region gene (IGHV) mutational status, genomic changes, patient age and the presence of comorbidities, should be considered when defining the optimal management strategies, which include chemotherapy, chemoimmunotherapy and/or drugs targeting B cell receptor signalling or inhibitors of apoptosis, such as BCL-2. Research on the biology of CLL has profoundly enhanced our ability to identify patients who are at higher risk for disease progression and our capacity to treat patients with drugs that selectively target distinctive phenotypic or physiological features of CLL. How these and other advances have shaped our current understanding and treatment of patients with CLL is the subject of this Primer. PMID:28102226

  14. Pregnancy and chronic kidney disease. (United States)

    Davison, John M; Lindheimer, Marshall D


    This article reviews the association of chronic renal disease and pregnancy. Included are discussions of guidelines for counseling pregnant women with underlying chronic renal disease who are considering conceiving as well as management of those already pregnant. Specifically highlighted are recent studies that question the validity of using estimated glomerular filtration rate and other formulae and questions of whether we should strive to replace the classic counseling approaches based primarily on serum creatinine levels with guidelines based on chronic kidney disease classification. The article concludes with a review as well as a critique of recent research on the prevalence of preeclampsia in women with underlying chronic renal disease, as well as if women with preeclampsia and underlying kidney disease have accelerated courses toward end-stage renal disease.

  15. Nitazoxanide for chronic hepatitis C

    DEFF Research Database (Denmark)

    Nikolova, Kristiana; Gluud, Christian; Grevstad, Berit


    BACKGROUND: Hepatitis C infection is a disease of the liver caused by the hepatitis C virus. The estimated number of chronically infected people with hepatitis C virus worldwide is about 150 million people. Every year, another three to four million people acquire the infection. Chronic hepatitis C......) and ribavirin was the approved standard treatment for chronic hepatitis C. In 2011, first-generation direct-acting antivirals (DAAs) have been licensed, for use in combination with peginterferon and ribavirin for treating hepatitis C virus genotype 1 infection. Nitazoxanide is another antiviral drug with broad...... antiviral activity and may have potential as an effective alternative, or an addition to standard treatment for the treatment of the hepatitis C virus. OBJECTIVES: To assess the benefits and harms of nitazoxanide in people with chronic hepatitis C virus infection. SEARCH METHODS: We searched The Cochrane...

  16. Chronic Conditions among Medicare Beneficiaries (United States)

    U.S. Department of Health & Human Services — The data used in the chronic condition reports are based upon CMS administrative enrollment and claims data for Medicare beneficiaries enrolled in the...

  17. Treatment of chronic inflammatory neuropathies

    NARCIS (Netherlands)

    F. Eftimov


    This thesis focuses on the efficacy of existing and alternative treatments in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) and explores predictors of treatment response in patients with CIDP treated with corticosteroids. The efficacy of intra

  18. Chronic diseases in elderly men

    DEFF Research Database (Denmark)

    Nielsen, Morten Frost Munk; Wraae, Kristian; Gudex, Claire


    OBJECTIVE: prevalence estimates for chronic diseases and associated risk factors are needed for priority setting and disease prevention strategies. The aim of this cross-sectional study was to estimate the self-reported and clinical prevalence of common chronic disorders in elderly men. STUDY......-reported data on risk factors and disease prevalence were compared with data from hospital medical records. RESULTS: physical inactivity, smoking and excessive alcohol intake were reported by 27, 22 and 17% of the study population, respectively. Except for diabetes, all the chronic diseases investigated......: the study showed a high prevalence of detrimental life style factors including smoking, excessive alcohol consumption and physical inactivity in elderly Danish men. Except for diabetes and respiratory disease, chronic diseases were underreported and in particular erectile dysfunction and osteoporosis were...

  19. Tai chi and chronic pain. (United States)

    Peng, Philip W H


    In the last 2 decades, a growing body of research aimed at investigating the health benefits of Tai Chi in various chronic health conditions has been recognized in the literature. This article reviewed the history, the philosophy, and the evidence for the role of Tai Chi in a few selected chronic pain conditions. The ancient health art of Tai Chi contributes to chronic pain management in 3 major areas: adaptive exercise, mind-body interaction, and meditation. Trials examining the health benefit of Tai Chi in chronic pain conditions are mostly low quality. Only 5 pain conditions were reviewed: osteoarthritis, fibromyalgia, rheumatoid arthritis, low back pain, and headache. Of these, Tai Chi seems to be an effective intervention in osteoarthritis, low back pain, and fibromyalgia. The limitations of the Tai Chi study design and suggestions for the direction of future research are also discussed.

  20. Trulance Approved for Chronic Constipation (United States)

    ... news/fullstory_163171.html Trulance Approved for Chronic Constipation Drug designed to stimulate upper gastrointestinal tract To ... U.S. Food and Drug Administration to treat persistent constipation of unknown (idiopathic) cause in adults. Some 42 ...

  1. The Ubiquity of Chronic Illness. (United States)

    Fonseca, Claudia; Fleischer, Soraya; Rui, Taniele


    This is a review of five different books dealing with some aspect of what might be termed a "chronic illness" - Alzheimer's disease, lupus, addiction, erectile dysfunction, and leprosy. The array of different subjects examined in these books points to the negotiable limits of this hugely open category. What exactly constitutes an "illness"? Why not use a less biomedical term instead: "disturbance", "problem", or simply "condition"? And how are we to understand "chronic" - simply as the flipside of "acute" or "curable"?

  2. Occupational chronic obstructive pulmonary disease

    DEFF Research Database (Denmark)

    Omland, Oyvind; Würtz, Else Toft; Aasen, Tor Børvig


    Occupational-attributable chronic obstructive pulmonary disease (COPD) presents a substantial health challenge. Focusing on spirometric criteria for airflow obstruction, this review of occupational COPD includes both population-wide and industry-specific exposures.......Occupational-attributable chronic obstructive pulmonary disease (COPD) presents a substantial health challenge. Focusing on spirometric criteria for airflow obstruction, this review of occupational COPD includes both population-wide and industry-specific exposures....

  3. Neurovascular Unit in Chronic Pain (United States)

    Radu, Beatrice Mihaela; Bramanti, Placido; Osculati, Francesco; Flonta, Maria-Luisa; Radu, Mihai; Bertini, Giuseppe; Fabene, Paolo Francesco


    Chronic pain is a debilitating condition with major socioeconomic impact, whose neurobiological basis is still not clear. An involvement of the neurovascular unit (NVU) has been recently proposed. In particular, the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB), two NVU key players, may be affected during the development of chronic pain; in particular, transient permeabilization of the barrier is suggested by several inflammatory- and nerve-injury-based pain models, and we argue that the clarification of molecular BBB/BSCB permeabilization events will shed new light in understanding chronic pain mechanisms. Possible biases in experiments supporting this theory and its translational potentials are discussed. Moving beyond an exclusive focus on the role of the endothelium, we propose that our understanding of the mechanisms subserving chronic pain will benefit from the extension of research efforts to the NVU as a whole. In this view, the available evidence on the interaction between analgesic drugs and the NVU is here reviewed. Chronic pain comorbidities, such as neuroinflammatory and neurodegenerative diseases, are also discussed in view of NVU changes, together with innovative pharmacological solutions targeting NVU components in chronic pain treatment. PMID:23840097

  4. Chronic Constipation: Current Treatment Options

    Directory of Open Access Journals (Sweden)

    Louis Wing Cheong Liu


    Full Text Available Chronic constipation is a common functional gastrointestinal disorder that affects patients of all ages. In 2007, a consensus group of 10 Canadian gastroenterologists developed a set of recommendations pertaining to the management of chronic constipation and constipation-dominant irritable bowel syndrome. Since then, tegaserod has been withdrawn from the Canadian market. A new, highly selective serotonin receptor subtype 4 agonist, prucalopride, has been examined in several large, randomized, placebo-controlled trials demonstrating its efficacy and safety in the management of patients with chronic constipation. Additional studies evaluating the use of stimulant laxatives, polyethylene glycol and probiotics in the management of chronic constipation have also been published. The present review summarizes the previous recommendations and new evidence supporting different treatment modalities – namely, diet and lifestyle, bulking agents, stool softeners, osmotic and stimulant laxatives, prucalopride and probiotics in the management of chronic constipation. A brief summary of lubiprostone and linaclotide is also presented. The quality of evidence is presented by adopting the Grading of Recommendations, Assessment, Development and Evaluation system. Finally, a management pyramid for patients with chronic constipation is proposed based on the quality of evidence, impact of each modality on constipation and on general health, and their availabilities in Canada.

  5. Chronic Cough in Otorhinolaryngologic Routine

    Directory of Open Access Journals (Sweden)

    Palheta Neto, Francisco Xavier


    Full Text Available Introduction: The chronic cough is sometimes manifested as an imprecise symptom, but of great importance for both the diagnosis and the prognosis. In an otorhinolaryngologic approach, several illnesses that can occur with it can be numbered, including 2 of the 3 main causes of chronic cough. Objective: To identify the main otorhinolaryngologic diseases showing the chronic cough as one of their manifestations. Method: A literature's revision was performed in several scientific articles, specialized books and consultation in Birene and Scielo databases. Literature's revision: cough production in the upper airways is usually associated with an inflammatory reaction by stimulating sensitive receptors of these areas or by mechanic stimulus. The main cause of the chronic cough in the otorhinolaryngology day-to-day is the post-nasal drip, gathering together by itself 02 of the most common diseases: rhinitis and sinusitis. Laryngitis as a result of gastroesophageal reflux (GER stands out in the index of chronic cough etiology, but it is not as severe as GER . Neoplasias are also somewhat frequent causes of cough, and the difficulty in diagnosing the cough cause is common in this disease group. Motility disorder, laryngeal irritation persistence, parasitic disease and injuries by inhalation of toxic products were also found as a cause of cough for longer than 03 months. Conclusion:Chronic cough is a frequent and important finding in otorhinolaryngology and cannot be underestimated, and a careful anamnesis is the best way to determine the etiology and perform a correct treatment for the patient's disease.

  6. Guideline of Chronic Urticaria Beyond. (United States)

    Fine, Lauren M; Bernstein, Jonathan A


    Urticaria is a relatively common condition that if chronic can persist for weeks, months or years and affect quality of life significantly. The etiology is often difficult to determine, especially as it becomes chronic. Many cases of chronic urticaria are thought to be autoimmune, although there is no consensus that testing for autoimmunity alters the diagnostic or management strategies or outcomes. Many times, urticaria is easily managed with antihistamines and/or short courses of oral corticosteroids, but too often control is insufficient and additional therapies must be added. For years, immune modulating medications, such as cyclosporine and Mycophenolate Mofetil, have been used in cases refractory to antihistamines and oral corticosteroids, although the evidence supporting their efficacy and safety has been limited. Omalizumab was recently approved for the treatment of chronic urticaria unresponsive to H1-antagonists. This IgG anti-IgE monoclonal antibody has been well demonstrated to safely and effectively control chronic urticaria at least partially in approximately 2/3 of cases. However, the mechanism of action and duration of treatment for omalizumab is still unclear. It is hoped that as the pathobiology of chronic urticaria becomes better defined, future therapies that target specific mechanistic pathways will be developed that continue to improve the management of these often challenging patients.

  7. Neurovascular Unit in Chronic Pain

    Directory of Open Access Journals (Sweden)

    Beatrice Mihaela Radu


    Full Text Available Chronic pain is a debilitating condition with major socioeconomic impact, whose neurobiological basis is still not clear. An involvement of the neurovascular unit (NVU has been recently proposed. In particular, the blood-brain barrier (BBB and blood-spinal cord barrier (BSCB, two NVU key players, may be affected during the development of chronic pain; in particular, transient permeabilization of the barrier is suggested by several inflammatory- and nerve-injury-based pain models, and we argue that the clarification of molecular BBB/BSCB permeabilization events will shed new light in understanding chronic pain mechanisms. Possible biases in experiments supporting this theory and its translational potentials are discussed. Moving beyond an exclusive focus on the role of the endothelium, we propose that our understanding of the mechanisms subserving chronic pain will benefit from the extension of research efforts to the NVU as a whole. In this view, the available evidence on the interaction between analgesic drugs and the NVU is here reviewed. Chronic pain comorbidities, such as neuroinflammatory and neurodegenerative diseases, are also discussed in view of NVU changes, together with innovative pharmacological solutions targeting NVU components in chronic pain treatment.

  8. Chronic inflammatory demyelinating polyradiculoneuropathy. (United States)

    Van den Bergh, Peter Y K; Rajabally, Yusuf A


    Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is the most common autoimmune neuropathy. The diagnosis depends on the clinical presentation with a progressive or relapsing course over at least 2 months and electrophysiological evidence of primary demyelination. Whereas typical CIDP is quite easily recognizable because virtually no other neuropathies present with both distal and proximal motor and sensory deficit, atypical CIDP, focal and multifocal variants in particular, may represent a difficult diagnostic challenge. CIDP very likely is an underdiagnosed condition as suggested also by a positive correlation between prevalence rates and sensitivity of electrophysiological criteria. Since no 'gold standard' diagnostic marker exists, electrophysiological criteria have been optimized to be at the same time as sensitive and as specific as possible. Additional supportive laboratory features, such as increased spinal fluid protein, MRI abnormalities of nerve segments, and in selected cases nerve biopsy lead to the correct diagnosis in the large majority of the cases. Objective clinical improvement following immune therapy is also a useful parameter to confirm the diagnosis. The pathogenesis and pathophysiology of CIDP remain poorly understood, but the available evidence for an inflammatory origin is quite convincing. Steroids, intravenous immunoglobulin (IVIG), and plasma exchange (PE) have been proven to be effective treatments. IVIG usually leads to rapid improvement, which is useful in severely disabled patients. Repeat treatment over regular time intervals for many years is often necessary. The effect of steroids is slower and the side-effect profile may be problematic, but they may induce disease remission more frequently than IVIG. An important and as of yet uncompletely resolved issue is the evaluation of long-term outcome to determine whether the disease is still active and responsive to treatment.

  9. Chronic fatigue and chronic fatigue syndrome: shifting boundaries and attributions. (United States)

    Lloyd, A R


    The subjective symptom of "fatigue" is one of the most widespread in the general population and is a major source of healthcare utilization. Prolonged fatigue is often associated with neuropsychological and musculoskeletal symptoms that form the basis of several syndromal diagnoses including chronic fatigue syndrome, fibromyalgia, and neurasthenia, and is clearly not simply the result of a lack of force generation from the muscle. Current epidemiologic research in this area relies predominantly on self-report data to document the prevalence and associations of chronic fatigue. Of necessity, this subjective data source gives rise to uncertain diagnostic boundaries and consequent divergent epidemiologic, clinical, and pathophysiologic research findings. This review will highlight the impact of the case definition and ascertainment methods on the varying prevalence estimates of chronic fatigue syndrome and patterns of reported psychological comorbidty. It will also evaluate the evidence for a true postinfective fatigue syndrome.

  10. Observation on the Effect of Early Puncture Drainage in the Treatment of Patients with Intracranial Hemorrhage Caused by Delayed Vitamin K1 Deficiency%早期穿刺引流在迟发维生素K1缺乏致颅内出血中的疗效观察

    Institute of Scientific and Technical Information of China (English)

    栾劲; 杨皎莹


    目的:观察早期穿刺引流在迟发维生素K1缺乏致颅内出血中的疗效。方法:选取2010年1月-2013年4月于本院进行常规治疗的27例迟发维生素K1缺乏致颅内出血患儿为对照组,27例进行早期穿刺引流治疗的患儿为观察组,然后将两组患儿的治疗总有效率、出血停止时间、住院时间、并发症发生率及不同时间的NABA评分进行比较。结果:观察组患儿的治疗总有效率高于对照组,出血停止时间及住院时间均短于对照组,并发症发生率低于对照组,不同时间的NABA评分均优于对照组,差异均有统计学意义( P<0.05)。结论:早期穿刺引流在迟发维生素K1缺乏致颅内出血中的疗效较好,可有效改善患儿的预后。%Objective:To observe the effect of early puncture drainage in the treatment of patients with intracranial hemorrhage caused by delayed vitamin K1 deficiency.Method:27 newborns with intracranial hemorrhage caused by delayed vitamin K1 deficiency who were treated with routine treatment in our hospital from January 2010 to April 2013 were the control group,27 cases who were treated with early puncture drainage were the observation group,then the total effective rate,stopping time of bleeding,hospitalization time,rate of complications and NABA score at different time of two groups were compared.Result:The total effective rate of observation group was higher than that of control group,stopping time of bleeding and hospitalization time were shorter than those of control group,rate of complications was lower than that of control group,ABA score at different time were better than those of control group,there were all significant differences(P<0.05).Conclusion:The effect of early puncture drainage in the treatment of patients with intracranial hemorrhage caused by delayed vitamin K1 deficiency is better,and it can effectively improve the prognosis of newborns.

  11. Management of chronic refractory cough. (United States)

    Gibson, Peter G; Vertigan, Anne E


    Chronic refractory cough (CRC) is defined as a cough that persists despite guideline based treatment. It is seen in 20-46% of patients presenting to specialist cough clinics and it has a substantial impact on quality of life and healthcare utilization. Several terms have been used to describe this condition, including the recently introduced term cough hypersensitivity syndrome. Key symptoms include a dry irritated cough localized around the laryngeal region. Symptoms are not restricted to cough and can include globus, dyspnea, and dysphonia. Chronic refractory cough has factors in common with laryngeal hypersensitivity syndromes and chronic pain syndromes, and these similarities help to shed light on the pathophysiology of the condition. Its pathophysiology is complex and includes cough reflex sensitivity, central sensitization, peripheral sensitization, and paradoxical vocal fold movement. Chronic refractory cough often occurs after a viral infection. The diagnosis is made once the main diseases that cause chronic cough have been excluded (or treated) and cough remains refractory to medical treatment. Several treatments have been developed over the past decade. These include speech pathology interventions using techniques adapted from the treatment of hyperfunctional voice disorders, as well as the use of centrally acting neuromodulators such as gabapentin and pregabalin. Potential new treatments in development also show promise.

  12. Periodontitis in Chronic Heart Failure. (United States)

    Fröhlich, Hanna; Herrmann, Kristina; Franke, Jennifer; Karimi, Alamara; Täger, Tobias; Cebola, Rita; Katus, Hugo A; Zugck, Christian; Frankenstein, Lutz


    Periodontal disease has been associated with an increased risk of cardiovascular events. The purpose of our study was to investigate whether a correlation between periodontitis and chronic heart failure exists, as well as the nature of the underlying cause. We enrolled 71 patients (mean age, 54 ± 13 yr; 56 men) who had stable chronic heart failure; all underwent complete cardiologic and dental evaluations. The periodontal screening index was used to quantify the degree of periodontal disease. We compared the findings to those in the general population with use of data from the 4th German Dental Health Survey. Gingivitis, moderate periodontitis, and severe periodontitis were present in 17 (24%), 17 (24%), and 37 (52%) patients, respectively. Severe periodontitis was more prevalent among chronic heart failure patients than in the general population. In contrast, moderate periodontitis was more prevalent in the general population (P <0.00001). The severity of periodontal disease was not associated with the cause of chronic heart failure or the severity of heart failure symptoms. Six-minute walking distance was the only independent predictor of severe periodontitis. Periodontal disease is highly prevalent in chronic heart failure patients regardless of the cause of heart failure. Prospective trials are warranted to clarify the causal relationship between both diseases.

  13. [Chronic polyradiculoneuritis and its frontiers]. (United States)

    Vallat, J M; Tabaraud, F; Magy, L; Macian, F


    The Chronic Inflammatory Demyelinating Polyradiculoneuropathies (CIDP) constitute a syndrome whose incidence is difficult to evaluate, and is probably underestimated. In the course of this presentation, we deliberately restricted discussion to issues raised in recent years concerning the extent of this syndrome. We discuss diagnostic criteria, especially electrophysiological ones. As the criteria proposed by the ad hoc committee of the American Academy of Neurology in 1991 have been questioned due to lack of sensitivity, new ones have been proposed recently. We briefly discuss the different types of chronic dysimmune demyelinating neuropathy: not only the CIDP, but also the Lewis and Sumner syndrome or multifocal inflammatory demyelinating neuropathy and the multiple conduction block neuropathies. At last, we point out the consistent finding of axonal involvement in the course of a chronic demyelinating neuropathy; over time, it can become pre-dominant, which may make diagnosis difficult by suggesting a chronic axonal neuropathy that may be assumed to be primary. Consideration of these points may help clinicians recognize more chronic dysimmune neuropathies, for which immunosuppressive therapy has been found to be effective.

  14. Reduced hepatic tumor incidence in cyclin G1-deficient mice

    DEFF Research Database (Denmark)

    Jensen, Michael Rugaard; Factor, Valentina M; Fantozzi, Anna


    Cyclin G1 is a transcriptional target of the tumor suppressor p53, and its expression is increased after DNA damage. Recent data show that cyclin G1 can regulate the levels of p53 by a mechanism that involves dephosphorylation of Mdm2 by protein phosphatase 2A. To understand the biologic role......, together with Mdm2, constitute a part of a negative feedback system that attenuates the activity of p53. In conclusion, our data suggest that the decreased tumor susceptibility after loss of cyclin G1 function is caused by the increased tumor suppressor action of p53....

  15. Targeting Redox Homeostasis in LKB1-deficient NSCLC (United States)


    4 1 INTRODUCTION The overall objective of the current application is to apply metabolic flux analysis and quantitative metabolic ...erlotinib treatment alters cellular metabolism through analysis of glucose, lactate, and oxygen exchange rates. Knockdown of LKB1 in Calu-6 cells caused...NSCLC) patient tumors. Because wild-type LKB1 functions as a sensor of energetic stress, the response to metabolic inhibition or nutrient depletion

  16. CEACAM1 deficiency delays important wound healing processes. (United States)

    LeBlanc, Sarah; Arabzadeh, Azadeh; Benlolo, Samantha; Breton, Valérie; Turbide, Claire; Beauchemin, Nicole; Nouvion, Anne-Laure


    Cutaneous wound healing is a complex process that requires the coordination of many cell types to achieve proper tissue repair. Four major overlapping processes have been identified in wound healing: hemostasis, inflammation, reepithelialization and granulation tissue formation, and tissue remodeling. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a glycoprotein expressed in epithelial, endothelial, lymphoid, and myeloid cells. Given its known roles in angiogenesis, cell migration, and immune functions, we hypothesized that CEACAM1 might also be involved in cutaneous wound healing and that a number of relevant CEACAM1-positive cell types might contribute to wound healing. To evaluate the role of CEACAM1 in these processes, 6-mm-diameter skin wounds were inflicted on Ceacam1(-/-) and wild-type mice. Herein, we demonstrate that CEACAM1 deletion indeed affects wound healing in three key ways. Infiltration of F4/80(+) macrophages was decreased in Ceacam1(-/-) wounds, altering inflammatory processes. Reepithelialization in Ceacam1(-/-) wounds was delayed. Furthermore, the vascular density of the granulation tissue in Ceacam1(-/-) wounds was significantly diminished. These results confirm CEACAM1's role as an important regulator of key processes in cutaneous wound healing, although whether this works via a specific cell type or alterations in the functioning of multiple processes remains to be determined.

  17. PINK1 deficiency enhances autophagy and mitophagy induction

    NARCIS (Netherlands)

    Gómez-Sánchez, Rubén; Yakhine-Diop, Sokhna M S; Bravo-San Pedro, José M; Pizarro-Estrella, Elisa; Rodríguez-Arribas, Mario; Climent, Vicente; Martin-Cano, Francisco E; González-Soltero, María E; Tandon, Anurag; Fuentes, José M; González-Polo, Rosa A


    Parkinson's disease (PD) is a neurodegenerative disorder with poorly understood etiology. Increasing evidence suggests that age-dependent compromise of the maintenance of mitochondrial function is a key risk factor. Several proteins encoded by PD-related genes are associated with mitochondria includ

  18. Attenuation of Cerebral Ischemic Injury in Smad1 Deficient Mice.

    Directory of Open Access Journals (Sweden)

    Jamie K Wong

    Full Text Available Stroke results in brain tissue damage from ischemia and oxidative stress. Molecular regulators of the protective versus deleterious cellular responses after cerebral ischemia remain to be identified. Here, we show that deletion of Smad1, a conserved transcription factor that mediates canonical bone morphogenetic protein (BMP signaling, results in neuroprotection in an ischemia-reperfusion (I/R stroke model. Uninjured mice with conditional deletion of Smad1 in the CNS (Smad1 cKO displayed upregulation of the reactive astrocyte marker GFAP and hypertrophic morphological changes in astrocytes compared to littermate controls. Additionally, cultured Smad1(-/- astrocytes exhibited an enhanced antioxidant capacity. When subjected to I/R injury by transient middle cerebral artery occlusion (tMCAO, Smad1 cKO mice showed enhanced neuronal survival and improved neurological recovery at 7 days post-stroke. This neuroprotective phenotype is associated with attenuated reactive astrocytosis and neuroinflammation, along with reductions in oxidative stress, p53 induction, and apoptosis. Our data suggest that Smad1-mediated signaling pathway is involved in stroke pathophysiology and may present a new potential target for stroke therapy.

  19. Consequences of SOS1 deficiency: Intracellular physiology and transcription

    KAUST Repository

    Ha, OhDong


    As much as there is known about the function of the sodium/proton antiporter SOS1 in plants, recent studies point towards a more general role for this protein. The crucial involvement in salt stress protection is clearly one of its functions –confined to the N-terminus, but the modular structure of the protein includes a segment with several domains that are functionally not studied but comprise more than half of the protein’s length. Additional functions of the protein appear to be an influence on vesicle trafficking, vacuolar pH and general ion homeostasis during salt stress. Eliminating SOS1 leads to the expression of genes that are not strictly salinity stress related. Functions that are regulated in sos1 mutants included pathogen responses, and effects on circadian rhythm.

  20. Arap1 Deficiency Causes Photoreceptor Degeneration in Mice (United States)

    Moshiri, Ala; Humpal, Devin; Leonard, Brian C.; Imai, Denise M.; Tham, Addy; Bower, Lynette; Clary, Dave; Glaser, Thomas M.; Lloyd, K. C. Kent; Murphy, Christopher J.


    Purpose Small guanosine triphosphatase (GTPase) ADP-ribosylation factors (Arfs) regulate membrane traffic and actin reorganization under the control of GTPase-activating proteins (GAPs). Arap1 is an Arf-directed GAP that inhibits the trafficking of epidermal growth factor receptor (EGFR) to the early endosome, but the diversity of its functions is incompletely understood. The aim of this study was to determine the role of Arap1 in the mammalian retina. Methods Genetically engineered Arap1 knockout mice were screened for ocular abnormalities in the National Institutes of Health Knockout Mouse Production and Phenotyping (KOMP2) Project. Arap1 knockout and wild-type eyes were imaged using optical coherence tomography and fundus photography, and analyzed by immunohistochemistry. Results Arap1−/− mice develop a normal appearing retina, but undergo photoreceptor degeneration starting at 4 weeks postnatal age. The fundus appearance of mutants is notable for pigmentary changes, optic nerve pallor, vascular attenuation, and outer retinal thinning, reminiscent of retinitis pigmentosa in humans. Immunohistochemical studies suggest the cell death is predominantly in the outer nuclear layer. Functional evaluation of the retina by electroretinography reveals amplitudes are reduced. Arap1 is detected most notably in Müller glia, and not in photoreceptors, implicating a role for Müller glia in photoreceptor survival. Conclusions Arap1 is necessary for normal photoreceptor survival in mice, and may be a novel gene relevant to human retinal degenerative processes, although its mechanism is unknown. Further studies in this mouse model of retinal degeneration will give insights into the cellular functions and signaling pathways in which Arap1 participates. PMID:28324111

  1. Altered pupillary light reflex in PACAP receptor 1-deficient mice. (United States)

    Engelund, Anna; Fahrenkrug, Jan; Harrison, Adrian; Luuk, Hendrik; Hannibal, Jens


    The pupillary light reflex (PLR) is regulated by the classical photoreceptors, rods and cones, and by intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing the photopigment melanopsin. IpRGCs receive input from rods and cones and project to the olivary pretectal nucleus (OPN), which is the primary visual center involved in PLR. Mice lacking either the classical photoreceptors or melanopsin exhibit some changes in PLR, whereas the reflex is completely lost in mice deficient of all three photoreceptors. The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is co-stored with melanopsin in ipRGCs and mediates light signaling to the brain via the specific PACAP receptor 1 (PAC1R). Here, we examined the occurrence of PACAP and PAC1R in the mouse OPN, and studied if lack of PAC1R affected the PLR. PACAP-immunoreactive nerve fibers were shown in the mouse OPN, and by in situ hybridization histochemistry, we demonstrated the presence of PAC1R mRNA. Mice lacking PAC1R exhibited a significantly attenuated PLR compared to wild type mice upon light stimulation, and the difference became more pronounced as light intensity was increased. Our findings accord well with observations of the PLR in the melanopsin-deficient mouse. We conclude that PACAP/PAC1R signaling is involved in the sustained phase of the PLR at high irradiances.

  2. Increased adiposity in annexin A1-deficient mice.

    Directory of Open Access Journals (Sweden)

    Rand T Akasheh

    Full Text Available Production of Annexin A1 (ANXA1, a protein that mediates the anti-inflammatory action of glucocorticoids, is altered in obesity, but its role in modulation of adiposity has not yet been investigated. The objective of this study was to investigate modulation of ANXA1 in adipose tissue in murine models of obesity and to study the involvement of ANXA1 in diet-induced obesity in mice. Significant induction of ANXA1 mRNA was observed in adipose tissue of both C57BL6 and Balb/c mice with high fat diet (HFD-induced obesity versus mice on chow diet. Upregulation of ANXA1 mRNA was independent of leptin or IL-6, as demonstrated by use of leptin-deficient ob/ob mice and IL-6 KO mice. Compared to WT mice, female Balb/c ANXA1 KO mice on HFD had increased adiposity, as indicated by significantly elevated body weight, fat mass, leptin levels, and adipocyte size. Whereas Balb/c WT mice upregulated expression of enzymes involved in the lipolytic pathway in response to HFD, this response was absent in ANXA1 KO mice. A significant increase in fasting glucose and insulin levels as well as development of insulin resistance was observed in ANXA1 KO mice on HFD compared to WT mice. Elevated plasma corticosterone levels and blunted downregulation of 11-beta hydroxysteroid dehydrogenase type 1 in adipose tissue was observed in ANXA1 KO mice compared to diet-matched WT mice. However, no differences between WT and KO mice on either chow or HFD were observed in expression of markers of adipose tissue inflammation. These data indicate that ANXA1 is an important modulator of adiposity in mice, with female ANXA1 KO mice on Balb/c background being more susceptible to weight gain and diet-induced insulin resistance compared to WT mice, without significant changes in inflammation.

  3. MAN1B1 deficiency: an unexpected CDG-II.

    Directory of Open Access Journals (Sweden)

    Daisy Rymen

    Full Text Available Congenital disorders of glycosylation (CDG are a group of rare metabolic diseases, due to impaired protein and lipid glycosylation. In the present study, exome sequencing was used to identify MAN1B1 as the culprit gene in an unsolved CDG-II patient. Subsequently, 6 additional cases with MAN1B1-CDG were found. All individuals presented slight facial dysmorphism, psychomotor retardation and truncal obesity. Generally, MAN1B1 is believed to be an ER resident alpha-1,2-mannosidase acting as a key factor in glycoprotein quality control by targeting misfolded proteins for ER-associated degradation (ERAD. However, recent studies indicated a Golgi localization of the endogenous MAN1B1, suggesting a more complex role for MAN1B1 in quality control. We were able to confirm that MAN1B1 is indeed localized to the Golgi complex instead of the ER. Furthermore, we observed an altered Golgi morphology in all patients' cells, with marked dilatation and fragmentation. We hypothesize that part of the phenotype is associated to this Golgi disruption. In conclusion, we linked mutations in MAN1B1 to a Golgi glycosylation disorder. Additionally, our results support the recent findings on MAN1B1 localization. However, more work is needed to pinpoint the exact function of MAN1B1 in glycoprotein quality control, and to understand the pathophysiology of its deficiency.

  4. Rescue of cyclin D1 deficiency by knockin cyclin E

    NARCIS (Netherlands)

    Geng, Y.; Whoriskey, W.; Park, M.Y.; Bronson, R.T.; Medema, R.H.; Li, T.; Weinberg, R.A.; Sicinski, P.


    D-type cyclins and cyclin E represent two very distinct classes of mammalian G1 cyclins. We have generated a mouse strain in which the coding sequences of the cyclin D1 gene (Ccnd1) have been deleted and replaced by those of human cyclin E (CCNE). In the tissues and cells of these mice, the expressi

  5. BACE1 deficiency causes altered neuronal activity and neurodegeneration


    Hu, Xiangyou; Zhou, Xiangdong; He, Wanxia; Yang, Jun; Xiong, Wenchen; Wong, Philip; Wilson, Christopher G.; Yan, Riqiang


    BACE1 is required for the release of β–amyloid (Aβ) in vivo, and inhibition of BACE1 activity is targeted for reducing Aβ generation in Alzheimer's patients. In order to further our understanding of the safe use of BACE1 inhibitors in human patients, we aimed to study the physiological functions of BACE1 by characterizing BACE1–null mice. Here we report the finding of spontaneous behavioral seizures in BACE1–null mice. Electroencephalographic recordings revealed abnormal spike-wave discharges...

  6. Aminoadamantanes for chronic hepatitis C

    DEFF Research Database (Denmark)

    Lamers, Mieke H; Broekman, Mark; Drenth, Joost Ph


    BACKGROUND: Around 3% of the world's population (approximately 160 million people) are chronically infected with hepatitis C virus. The proportion of infected people who develop clinical symptoms varies between 5% and 40%. Combination therapy with pegylated interferon-alpha plus ribavirin...... response in genotype 1 infected patients to at least 70%. There is therefore an unmet need for drugs that can achieve a higher proportion of sustained virological response. Aminoadamantanes are antiviral drugs used for treatment of patients with chronic hepatitis C. OBJECTIVES: To assess the beneficial...... and harmful effects of aminoadamantanes for patients with chronic hepatitis C infection by conducting a systematic review with meta-analyses of randomised clinical trials, as well as trial sequential analyses. SEARCH METHODS: We conducted electronic searches of the Cochrane Hepato-Biliary Group Controlled...

  7. [Neurosurgical treatment of chronic pain]. (United States)

    Fontaine, D; Blond, S; Mertens, P; Lanteri-Minet, M


    Neurosurgical treatment of pain used two kind of techniques: 1) Lesional techniques interrupt the transmission of nociceptive neural input by lesionning the nociceptive pathways (drezotomy, cordotomy, tractotomy…). They are indicated to treat morphine-resistant cancer pain and few cases of selected neuropathic pain. 2) Neuromodulation techniques try to decrease pain by reinforcing inhibitory and/or to limit activatory mechanisms. Chronic electrical stimulation of the nervous system (peripheral nerve stimulation, spinal cord stimulation, motor cortex stimulation…) is used to treat chronic neuropathic pain. Intrathecal infusion of analgesics (morphine, ziconotide…), using implantable pumps, allows to increase their efficacy and to reduce their side effects. These techniques can improve, sometimes dramatically, selected patients with severe and chronic pain, refractory to all other treatments. The quality of the analgesic outcome depends on the relevance of the indications.

  8. Peripheral neuromodulation in chronic migraine. (United States)

    Perini, F; De Boni, A


    Patients with chronic migraines are often refractory to medical treatment. Therefore, they might need other strategies to modulate their pain, according to their level of disability. Neuromodulation can be achieved with several tools: meditation, biofeedback, physical therapy, drugs and electric neurostimulation (ENS). ENS can be applied to the central nervous system (brain and spinal cord), either invasively (cortical or deep brain) or non-invasively [cranial electrotherapy stimulation, transcranial direct current stimulation and transcranial magnetic stimulation]. Among chronic primary headaches, cluster headaches are most often treated either through deep brain stimulation or occipital nerve stimulation because there is a high level of disability related to this condition. ENS, employed through several modalities such as transcutaneous electrical nerve stimulation, interferential currents and pulsed radiofrequency, has been applied to the peripheral nervous system at several sites. We briefly review the indications for the use of peripheral ENS at the site of the occipital nerves for the treatment of chronic migraine.

  9. Pharmacological challenges in chronic pancreatitis

    DEFF Research Database (Denmark)

    Olesen, Anne Estrup; Brokjaer, Anne; Fischer, Iben Wendelboe Deleuran


    Drug absorption in patients with chronic pancreatitis might be affected by the pathophysiology of the disease. The exocrine pancreatic insufficiency is associated with changes in gastrointestinal intraluminal pH, motility disorder, bacterial overgrowth and changed pancreatic gland secretion....... Together these factors can result in malabsorption and may also affect the efficacy of pharmacological intervention. The lifestyle of chronic pancreatitis patients may also contribute to gastrointestinal changes. Many patients limit their food intake because of the pain caused by eating and in some cases...... food intake is more or less substituted with alcohol, tobacco and coffee. Alcohol and drug interaction are known to influence the pharmacokinetics by altering either drug absorption or by affecting liver metabolism. Since patients suffering from chronic pancreatitis experience severe pain, opioids...

  10. Chronic renal disease in pregnancy. (United States)

    Ramin, Susan M; Vidaeff, Alex C; Yeomans, Edward R; Gilstrap, Larry C


    The purpose of this review was to examine the impact of varying degrees of renal insufficiency on pregnancy outcome in women with chronic renal disease. Our search of the literature did not reveal any randomized clinical trials or meta-analyses. The available information is derived from opinion, reviews, retrospective series, and limited observational series. It appears that chronic renal disease in pregnancy is uncommon, occurring in 0.03-0.12% of all pregnancies from two U.S. population-based and registry studies. Maternal complications associated with chronic renal disease include preeclampsia, worsening renal function, preterm delivery, anemia, chronic hypertension, and cesarean delivery. The live birth rate in women with chronic renal disease ranges between 64% and 98% depending on the severity of renal insufficiency and presence of hypertension. Significant proteinuria may be an indicator of underlying renal insufficiency. Management of pregnant women with underlying renal disease should ideally entail a multidisciplinary approach at a tertiary center and include a maternal-fetal medicine specialist and a nephrologist. Such women should receive counseling regarding the pregnancy outcomes in association with maternal chronic renal disease and the effect of pregnancy on renal function, especially within the ensuing 5 years postpartum. These women will require frequent visits and monitoring of renal function during pregnancy. Women whose renal disease is further complicated by hypertension should be counseled regarding the increased risk of adverse outcome and need for blood pressure control. Some antihypertensives, especially angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, should be avoided during pregnancy, if possible, because of the potential for both teratogenic (hypocalvaria) and fetal effects (renal failure, oliguria, and demise).

  11. Prevention Of Chronic Renal Diseases

    Directory of Open Access Journals (Sweden)

    Fejzi Alushi


    Full Text Available It is easier to prevent a disease than to cure it. This postulate is a foundation stone of the contemporary medicine, furthermore its mission. The Chronic Kidney Diseases (CKD, amongst them the Chronic Pyelonephrites (CP and the mass kidney reduction  take an important  place in human pathologies in general, and in particular in renal ones. The Chronic Pyelonephrites  are chronic renal pathologies, which on one side are of various causes and on the other side are multi systemic. At the same time they tend, earlier or later, depending on their course, to bring the patient towards the Chronic Kidney Insufficiency  in stage of uremia, consequently in need of substitution therapies e.g. dialysis, peritoneum dialysis or transplant. It is worthy to emphasize that from the prevention and correct cure of CP make profit the patients, the family, the state and in the last analyses  the entire society, because in that way the budget expense destined for the fore going substitution cures, dialysis, peritoneum dialysis or transplant, is considerably  reduced. The same should be mentioned  in relation to the CP and the mass kidney reduction, speaking about our country, which are still at the first place as the very cause of Chronic Kidney  Insufficiencies (CRI, later on advancing toward uremia and terminal uremia along with its grave consequences. In general  the very foundation of the CP is on  the  infections of urinary roads, in particular on the complicated ones, among them it should be mentioned-congenital kidney anomalies, renal calculosis  so much present in our country, and pathologies of segment or vesical-ureteral reflux, and rarely the pathologies of prostate.

  12. Management of chronic visceral pain

    DEFF Research Database (Denmark)

    Olesen, Anne E; Farmer, Adam D; Olesen, Søren S


    ' symptoms, adopting an empathic approach and taking time to educate patients. To optimize treatment and outcomes in chronic visceral pain we need to move away from approaches exclusively based on dealing with peripheral nociceptive input toward more holistic strategies, taking into account alterations......Despite marked differences in underlying pathophysiology, the current management of visceral pain largely follows the guidelines derived from the somatic pain literature. The effective management of patients with chronic visceral pain should be multifaceted, including both pharmacological...... in central pain processing....

  13. Oxidized Phospholipid OxPAPC Activates TRPA1 and Contributes to Chronic Inflammatory Pain in Mice (United States)

    Liu, Boyi; Tai, Yan; Caceres, Ana I.; Achanta, Satyanarayana; Balakrishna, Shrilatha; Shao, Xiaomei; Fang, Junfan


    Oxidation products of the naturally occurring phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycerol-3-phosphatidylcholine (PAPC), which are known as OxPAPC, accumulate in atherosclerotic lesions and at other sites of inflammation in conditions such as septic inflammation and acute lung injury to exert pro- or anti-inflammatory effects. It is currently unknown whether OxPAPC also contributes to inflammatory pain and peripheral neuronal excitability in these conditions. Here, we observed that OxPAPC dose-dependently and selectively activated human TRPA1 nociceptive ion channels expressed in HEK293 cells in vitro, without any effect on other TRP channels, including TRPV1, TRPV4 and TRPM8. OxPAPC agonist activity was dependent on essential cysteine and lysine residues within the N-terminus of the TRPA1 channel protein. OxPAPC activated calcium influx into a subset of mouse sensory neurons which were also sensitive to the TRPA1 agonist mustard oil. Neuronal OxPAPC responses were largely abolished in neurons isolated from TRPA1-deficient mice. Intraplantar injection of OxPAPC into the mouse hind paw induced acute pain and persistent mechanical hyperalgesia and this effect was attenuated by the TRPA1 inhibitor, HC-030031. More importantly, we found levels of OxPAPC to be significantly increased in inflamed tissue in a mouse model of chronic inflammatory pain, identified by the binding of an OxPAPC-specific antibody. These findings suggest that TRPA1 is a molecular target for OxPAPC and OxPAPC may contribute to chronic inflammatory pain through TRPA1 activation. Targeting against OxPAPC and TRPA1 signaling pathway may be promising in inflammatory pain treatment. PMID:27812120

  14. Bendamustine Plus Alemtuzumab for Refractory Chronic Lymphocytic Leukemia (CLL) (United States)


    Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

  15. Chronic Venous Disease under pressure

    NARCIS (Netherlands)

    S.W.I. Reeder (Suzan)


    textabstractIn chapter 1 we provide a general introduction of this thesis. Chronic venous disease (CVD) is a common medical condition that affects 2-64% of the worldwide population and leads to leg ulcers in 1% of the Western population. Venous leg ulceration (VLU) has an unfavorable prognosis with

  16. Electroacupuncture treatment of chronic insomniacs

    Institute of Scientific and Technical Information of China (English)

    RUAN Jing-wen; WANG Chu-huai; LIAO Xin-xue; YAN Ying-shuo; HU Yue-hua; RAO Zhong-dong; WEN Ming; ZENG Xiao-xiang; LAI Xin-sheng


    Background Due to the quick rhythm of life and work pressure, more and more people suffer from sleep quality problems. In this study, we investigated the effect of electroacupuncture on sleep quality of chronic insomniacs and the safety of electroacupuncture therapy.Methods Four courses of electroacupuncture treatment were applied to 47 patients. With pre-treatment and post-treatment self-control statistical method, Pittsburgh sleep quality index (PSQI) scores were used for evaluating sleep quality. Polysomnogram was used for detecting insomniacs' changes in sleep architecture. The safety of electroacupuncture was evaluated by monitoring the self-designed adverse events and side effects during treatment and post-treatment.Results Electroacupuncture considerably improved insomniacs' sleep quality and social function during the daytime.Electroacupuncture had certain repairing effect on the disruption in sleep architecture. At the same time,electroacupuncture prolonged slow wave sleep (SWS) time and relatively rapid eye movement sleep (REM sleep) time.There was no hangover, addiction or decrements in vigilance during the daytime (incidence rate was 0). However,insomnia rebound rate was about 23% within one month.Conclusions These results suggest that electroacupuncture has beneficial effect on sleep quality improvement in the patients with chronic insomnia, which may be associated with repairing sleep architecture, reconstructing sleep continuity,as well as prolonging SWS time and REM sleep time. Electroacupuncture treatment for chronic insomnia is safe.Therefore, electroacupuncture therapy could be a promising avenue of treatment for chronic insomnia.

  17. [Chronic prostatitis and Bechterew's disease]. (United States)

    Kohlicek, J; Svec, V


    A group of patients between 35 and 65 years old with chronic prostatitis were examined for the presence of Becherew's disease. In this connection the New York and Roman criterions for morbus Bechterew were applied. There were found one ankyosing spondylarthritis, one ankylosis of the sacroiliac joint, and 11 times a tentative sacroileitis were stated. Altogether the proved and tentative findings were only 3.68 per cent of all examinations. In our countries the morbus Bechterew is found in 0,21 per cent of the normal population. So the protion of the Bechterew's disease in patients with chronic prostatitis is indeed a little higher than average, but not so frequent as often pretended in recent times. After a second series 58 patients being treated because of Bechterew's disease of different stages and different terms were examined for the possibility of a simultaneously elapsing chronic prostatitis. A chronic prostatitis was found in 38 per cent of these patients which correspondents to the incidence published in literature for the medium-age manhood. Nobody of the test persons had complaints on the part of the urologenital tract.

  18. Treatment of chronic lymphocytic leukemia. (United States)

    Ferrajoli, Alessandra; O'Brien, Susan M


    Treatment options for patients with chronic lymphocytic leukemia have changed over the past two decades. This article reviews the experience accumulated with the use of alkylating agents alone and in combination; purine analogues alone and in combination and monoclonal antibodies such as rituximab, and alemtuzumab alone and in combination. The results obtained with different treatment strategies are summarized, compared, and reviewed.

  19. [Operative treatment of chronic pleuritis]. (United States)

    Duzhyĭ, I D; Hres'ko, I Ia; Chumak, S O; Elastal, R Z


    Basing on the literature data and own experience, grounded on results of follow-up on 2000 patients, suffering an acute pleuritis and performance of more than 200 operative interventions--pleurectomy, the clinic-radiological classification of chronic pleuritis, mostly answering the practical health care necessities, was proposed by the authors.

  20. Chronic sphenoid rhinosinusitis: management challenge

    Directory of Open Access Journals (Sweden)

    Charakorn N


    Full Text Available Natamon Charakorn, Kornkiat Snidvongs Department of Otolaryngology Head and Neck Surgery, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand Abstract: Chronic sphenoid rhinosinusitis is a spectrum of inflammatory diseases in isolated sphenoid sinus which may persist over a period of 12 weeks. It is a different entity from other types of rhinosinusitis because clinical presentations include headache, visual loss or diplopia, and patients may or may not have nasal obstruction or nasal discharge. Nasal endoscopic examination is useful, and computed tomography is mandatory. The disease requires comprehensive knowledge and appropriate imaging technique for diagnosis. To treat patients with chronic sphenoid rhinosinusitis, surgical treatment with endoscopic transnasal sphenoidotomy is often required. As there are no recent updated reviews of chronic sphenoid rhinosinusitis, in this article, we review the anatomy of the sphenoid sinus and its clinical relationship with the clinical signs and symptoms of the disease, the imaging findings of each diagnosis and the comprehensive surgical techniques. Keywords: sphenoid sinus, sphenoid sinusitis, chronic, rhinosinusitis, fungal rhinosinusitis, mucocele

  1. Management of chronic hand eczema

    NARCIS (Netherlands)

    Diepgen, Thomas L.; Agner, Tove; Aberer, Werner; Berth-Jones, John; Cambazard, Frederic; Elsner, Peter; McFadden, John; Coenraads, Pieter Jan


    Hand eczema (HE) is one of the most frequent skin diseases and has often a chronically relapsing course with a poor prognosis resulting in a high social and economic impact for the individual and the society. In this article, we highlight the results of an expert workshop on the 'management of sever

  2. Fibromyalgia and Chronic Pain Syndromes (United States)

    Choy, Ernest; Clauw, Daniel J.; Goldenberg, Don L.; Harris, Richard E.; Helfenstein, Milton; Jensen, Troels Staehelin; Noguchi, Koichi; Silverman, Stuart L.; Ushida, Takahiro; Wang, Guochun


    This manuscript, developed by a group of chronic pain researchers and clinicians from around the world, aims to address the state of knowledge about fibromyalgia (FM) and identify ongoing challenges in the field of FM and other chronic pain syndromes that may be characterized by pain centralization/amplification/hypersensitivity. There have been many exciting developments in research studies of the pathophysiology and treatment of FM and related syndromes that have the potential to improve the recognition and management of patients with FM and other conditions with FM-like pain. However, much of the new information has not reached all clinicians, especially primary care clinicians, who have the greatest potential to use this new knowledge to positively impact their patients’ lives. Furthermore, there are persistent misconceptions about FM and a lack of consensus regarding the diagnosis and treatment of FM. This paper presents a framework for future global efforts to improve the understanding and treatment of FM and other associated chronic pain syndromes, disseminate research findings, identify ways to enhance advocacy for these patients, and improve global efforts to collaborate and reach consensus about key issues related to FM and chronic pain in general. PMID:27022674

  3. Children, Sports, and Chronic Disease. (United States)

    Goldberg, Barry


    Discusses four chronic diseases (cystic fibrosis, congenital heart disease, rheumatoid arthritis, and asthma) that affect American children. Many have their physical activities unnecessarily restricted, though sports and exercise can actually alleviate symptoms and improve their psychosocial development. Physicians are encouraged to prescribe…

  4. Lymphocyte 'homing' and chronic inflammation. (United States)

    Sakai, Yasuhiro; Kobayashi, Motohiro


    Chronic inflammation is a response to prolonged exposure to injurious stimuli that harm and destroy tissues and promote lymphocyte infiltration into inflamed sites. Following progressive accumulation of lymphocytes, the histology of inflamed tissue begins to resemble that of peripheral lymphoid organs, which can be referred to as lymphoid neogenesis or formation of tertiary lymphoid tissues. Lymphocyte recruitment to inflamed tissues is also reminiscent of lymphocyte homing to peripheral lymphoid organs. In the latter, under physiological conditions, homing receptors expressed on lymphocytes adhere to vascular addressin expressed on high endothelial venules (HEVs), initiating a lymphocyte migration process composed of sequential adhesive interactions. Intriguingly, in chronic inflammation, HEV-like vessels are induced de novo, despite the fact that the inflamed site is not originally lymphoid tissue, and these vessels contribute to lymphocyte recruitment in a manner similar to physiological lymphocyte homing. In this review, we first describe physiological lymphocyte homing mechanisms focusing on vascular addressins. We then describe HEV-like vessel-mediated pathogenesis seen in various chronic inflammatory disorders such as Helicobacter pylori gastritis, inflammatory bowel disease (IBD), autoimmune pancreatitis and sclerosing sialadenitis, as well as chronic inflammatory cell neoplasm MALT lymphoma, with reference to our work and that of others.

  5. Hyperglycemia, tumorigenesis, and chronic inflammation. (United States)

    Chang, Shu-Chun; Yang, Wei-Chung Vivian


    Hyperglycemia is the most prominent sign that characterizes diabetes. Hyperglycemia favors malignant cell growth by providing energy to cancer cells. Clinical studies also showed an increased risk of diabetes being associated with different types of cancers. In addition, poorly regulated glucose metabolism in diabetic patients is often found with increased levels of chronic inflammatory markers, e.g., interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, and emerging evidence has highlighted activation of the immune response in the progression and development of cancer cells. Therefore, uncontrolled proinflammatory responses could conceivably create a chronic inflammatory state, promoting a tumor-favorable microenvironment and potentially triggering immune overactivation and cancer growth. To further understand how hyperglycemia contributes to immune overactivation, the tumor microenvironment and the development of chronic inflammation-associated tumors may provide insights into tumor biology and immunology. This paper provides a brief introduction to hyperglycemia-associated diseases, followed by a comprehensive overview of the current findings of regulatory molecular mechanisms of glycosylation on proteoglycans in the extracellular matrix under hyperglycemic conditions. Then, the authors discuss the role of hyperglycemia in tumorigenesis (particularly in prostate, liver, colorectal, and pancreatic cancers), as well as the contribution of hyperglycemia to chronic inflammation. The authors end with a brief discussion on the future perspectives of hyperglycemia/tumorigenesis and potential applications of alternative/effective therapeutic strategies for hyperglycemia-associated cancers.

  6. Chronic Kidney Disease and Kidney Failure (United States)

    ... Education Visitor Information RePORT NIH Fact Sheets Home > Chronic Kidney Disease and Kidney Failure Small Text Medium Text Large Text Chronic Kidney Disease and Kidney Failure YESTERDAY One third of diabetic ...

  7. Pregabalin for Pain Treatment in Chronic Pancreatitis

    DEFF Research Database (Denmark)

    Olesen, Søren Schou; Bowense, S; Wilder-Smith, Oliver


    Intractable pain usually dominates the clinical presentation of chronic pancreatitis (CP). Slowing of electroencephalogram (EEG) rhythmicity has been associated with abnormal cortical pain processing in other chronic pain disorders. The aim of this study was to investigate the spectral distribution...

  8. Helping a Child Manage a Chronic Illness (United States)

    ... Helping a Child Manage a Chronic Illness Feeling they have control over their ... News) -- Children and teens who feel confident handling a chronic illness on their own appear better able ...

  9. Chronic Fatigue Syndrome in Gulf War Veterans (United States)

    ... Enter ZIP code here Enter ZIP code here Chronic Fatigue Syndrome in Gulf War Veterans Gulf War ... and be at least 10 percent disabling. About Chronic Fatigue Syndrome CFS is an unexplained, severe and ...

  10. Chronic Condition Public Use File (PUF) (United States)

    U.S. Department of Health & Human Services — This release contains the Chronic Conditions Public Use Files (PUF) with information from Medicare claims. The CMS Chronic Conditions PUF is an aggregated file in...

  11. Effects of Mindfulness Meditation on Chronic Pain

    DEFF Research Database (Denmark)

    la Cour, Peter; Petersen, Marian


    OBJECTIVE: This randomized controlled clinical trial investigated the effects of mindfulness meditation on chronic pain. DESIGN: A total of 109 patients with nonspecific chronic pain were randomized to either a standardized mindfulness meditation program (mindfulness-based stress reduction [MBSR...

  12. Communication About Chronic Critical Illness (United States)

    Nelson, Judith E.; Mercado, Alice F.; Camhi, Sharon L.; Tandon, Nidhi; Wallenstein, Sylvan; August, Gary I.; Morrison, R. Sean


    Background Despite poor outcomes, life-sustaining treatments including mechanical ventilation are continued for a large and growing population of patients with chronic critical illness. This may be owing in part to a lack of understanding resulting from inadequate communication between clinicians and patients and families. Our objective was to investigate the informational needs of patients with chronic critical illness and their families and the extent to which these needs are met. Methods In this prospective observational study conducted at 5 adult intensive care units in a large, university-affiliated hospital in New York, New York, 100 patients with chronic critical illness (within 3–7 days of elective tracheotomy for prolonged mechanical ventilation) or surrogates for incapacitated patients were surveyed using an 18-item questionnaire addressing communication about chronic critical illness. Main outcome measures included ratings of importance and reports of whether information was received about questionnaire items. Results Among 125 consecutive, eligible patients, 100 (80%) were enrolled; questionnaire respondents included 2 patients and 98 surrogates. For all items, more than 78% of respondents rated the information as important for decision making (>98% for 16 of 18 items). Respondents reported receiving no information for a mean (SD) of 9.0 (3.3) of 18 items, with 95% of respondents reporting not receiving information for approximately one-quarter of the items. Of the subjects rating the item as important, 77 of 96 (80%) and 69 of 74 (93%) reported receiving no information about expected functional status at hospital discharge and prognosis for 1-year survival, respectively. Conclusions Many patients and their families may lack important information for decision making about continuation of treatment in the chronic phase of critical illness. Strategies for effective communication in this clinical context should be investigated and implemented. PMID

  13. Chinese medicinal herbs for chronic hepatitis B

    DEFF Research Database (Denmark)

    Liu, J; McIntosh, H; Lin, Haili


    Chronic hepatitis B is a serious health problem worldwide. Chinese medicinal herbs are widely used for treatment of chronic hepatitis B in China and many clinical trials have been conducted. This systematic review is to assess the efficacy and safety of Chinese medicinal herbs for chronic hepatitis...

  14. Shared genetic factors underlie chronic pain syndromes

    NARCIS (Netherlands)

    Vehof, Jelle; Zavos, Helena M. S.; Lachance, Genevieve; Hammond, Christopher J.; Williams, Frances M. K.


    Chronic pain syndromes (CPS) are highly prevalent in the general population, and increasingly the evidence points to a common etiological pathway. Using a large cohort of twins (n = 8564) characterized for chronic widespread musculoskeletal pain (CWP), chronic pelvic pain (PP), migraine (MIG), dry e

  15. Chronic pain management: nonpharmacological therapies for chronic pain. (United States)

    Chang, Ku-Lang; Fillingim, Roger; Hurley, Robert W; Schmidt, Siegfried


    Nonpharmacologic therapies have become a vital part of managing chronic pain (CP). Although these can be used as stand-alone therapies, nonpharmacologic treatments often are used to augment and complement pharmacologic treatments (ie, multimodal therapy). Nonpharmacologic approaches can be classified as behavioral, cognitive, integrative, and physical therapies. Core principles in developing a treatment plan are explaining the nature of the CP condition, setting appropriate goals, and developing a comprehensive treatment approach and plan for adherence. Clinicians should become familiar with these interventions so that they can offer patients flexibility in the pain management approach. Effective noninvasive treatment modalities for CP include behavioral therapy for short-term pain relief; cognitive behavioral therapy for reducing long-term pain and disability; hypnosis as adjunctive therapy; guided imagery, diaphragmatic breathing, and muscle relaxation, especially for cancer-related pain; mindfulness-based stress reduction for patients with chronic low back pain; acupuncture for multiple pain conditions; combination manipulation, manual therapy, endurance exercise, stretching, and strengthening for chronic neck pain; animal-assisted therapy; and S-adenosyl-L-methionine for joint pain. Guidelines for use of these treatment modalities are based on expert panel recommendations in combination with data from randomized controlled trials.

  16. Chronic Pancreatitis and Neoplasia: Correlation or Coincidence

    Directory of Open Access Journals (Sweden)

    G. N. Zografos


    Full Text Available Any link between pancreatic carcinoma and chronic pancreatitis could reflect the malignant potential of a chronic inflammatory process. Four patients with ductal adenocarcinomas had a long history of pancreatic pain (median duration 5 years and showed clearcut evidence of chronic pancreatitis “downstream” of the tumour. Four were alcoholics and two heavy smokers. These four cases arose within a surgical series of approximately 250 patients with chronic pancreatitis, giving an incidence of 1.6 per cent. The incidence and anatomical distribution of carcinoma and chronic pancreatitis could possibly be consistent with a casual relationship.

  17. Magnetic resonance images of chronic patellar tendinitis

    Energy Technology Data Exchange (ETDEWEB)

    Bodne, D.; Quinn, S.F.; Murray, W.T.; Cochran, C.; Bolton, T.; Rudd, S.; Lewis, K.; Daines, P.; Bishop, J.


    Chronic patellar tendinitis can be a frustrating diagnostic and therapeutic problem. This report evaluates seven tendons in five patients with chronic patellar tendinitis. The etiologies included 'jumper's knee' and Osgood-Schlatter disease. In all cases magnetic resonance images (MRI) showed thickening of the tendon. Some of the tendons had focal areas of thickening which helped establish the etiology. All cases had intratendinous areas of increased signal which, in four cases, proved to be chronic tendon tears. MRI is useful in evaluating chronic patellar tendinitis because it establishes the diagnosis, detects associated chronic tears, and may help determine appropriate rehabilitation. (orig.)

  18. Prevalence of maternal chronic diseases during pregnancy

    DEFF Research Database (Denmark)

    Jølving, Line Riis; Nielsen, Jan; Kesmodel, Ulrik Schiøler


    chronic diseases were chronic lung diseases/asthma (1.73%), thyroid disorders (1.50%) and anxiety and personality disorders (1.33%). Taking increasing maternal age at birth into account, the relative risk for women to have a chronic disease from 2009 to 2013 was 4.14 (95% CI 4.05-4.22), compared...... pregnancy. We aimed to analyze the prevalence of chronic diseases during pregnancy. MATERIAL AND METHODS: This register-based cohort study included all women giving birth in Denmark between 1989 and 2013 based on data from Danish health registers. Maternal chronic diseases included 23 disease categories...

  19. Endothelins in chronic liver disease

    DEFF Research Database (Denmark)

    Møller, S; Henriksen, Jens Henrik Sahl


    This review describes recent progress in the accumulation of knowledge about the endothelins (ETs), a family of vasoactive 21-amino acid polypeptides, in chronic liver disease. Particular prominence is given to the dynamics of ET-1 and ET-3 and their possible relation to the disturbed circulation...... and neurohumoral dysregulation found in cirrhosis. Recent studies have shown that the ET system is highly activated in most cirrhotic patients. Circulating ET-1 and ET-3 levels have a positive relation to the severity of the disease and fluid retention, with the highest values recorded in patients with functional....... In addition, marked associations with disturbance of systemic haemodynamics and with abnormal distribution of blood volume have been reported. Although the pathophysiological importance of the ET system in chronic liver disease is not completely understood, similarities to other vasopressive...

  20. Endothelins in chronic liver disease

    DEFF Research Database (Denmark)

    Møller, Søren; Henriksen, Jens Henrik


    This review describes recent progress in the accumulation of knowledge about the endothelins (ETs), a family of vasoactive 21-amino acid polypeptides, in chronic liver disease. Particular prominence is given to the dynamics of ET-1 and ET-3 and their possible relation to the disturbed circulation....... In addition, marked associations with disturbance of systemic haemodynamics and with abnormal distribution of blood volume have been reported. Although the pathophysiological importance of the ET system in chronic liver disease is not completely understood, similarities to other vasopressive...... and neurohumoral dysregulation found in cirrhosis. Recent studies have shown that the ET system is highly activated in most cirrhotic patients. Circulating ET-1 and ET-3 levels have a positive relation to the severity of the disease and fluid retention, with the highest values recorded in patients with functional...

  1. Vouchers for chronic disease care. (United States)

    Watts, Jennifer J; Segal, Leonie


    This paper explores the economic implications of vouchers for chronic disease management with respect to achieving objectives of equity and efficiency. Vouchers as a payment policy instrument for health care services have a set of properties that suggest they may address both demand-side and supply-side issues, and contribute to equity and efficiency. They provide a means whereby health care services can be targeted at selected groups, enabling consumer choice of provider, and encouraging competition in the supply of health services. This analysis suggests that, when structured appropriately, vouchers can support consumers to choose services that will meet their health care needs and encourage competition among providers. Although they may not be appropriate across the entire health care system, there are features of vouchers that make them a potentially attractive option, especially for the management of chronic disease.

  2. Chronic folliculitis in Sri Lanka

    Directory of Open Access Journals (Sweden)

    Kumarasinghe S


    Full Text Available Chronic folliculitis (CF is a chronic infection of hair follicles leading to atrophy and loss of the affected hairs. This study was done on 51 patients with CF presenting at the Dermatology Clinic at General Hospital Matara, Sri Lanka, to identify specific clinical features and aetiological factors, and to study histopathology. Pus cultures were done on 25 cases. Biopsies were done on 6 patients. CF was commoner in males (59%; 76% were under 34 years, and 39% had occupational exposure to possible irritants. Thirty five precent admitted of scrubbing legs with rough objects. Ichthyosis vulgaris was evident in 47%. All pus cultures revealed Staphylococcus aureus. Clinical features and histopathological features were similar to those described by Harman (1968. Rough scrubbing, ichthyosis and occupational exposure to irritants may be aetiologically relevant.

  3. Clinicomicrobiological study of chronic paronychia

    Directory of Open Access Journals (Sweden)

    Guha P


    Full Text Available A total of 261 digits affected in 100 patients of chronic paronychia were studied for clinical features. The bacteriological and mycological flora have been examined in 25 cases of the above 100 cases which were most severely affected. Aerobic bacteria were found in all cases. Staphylococcus aureus was seen in 60 percent. Klebsiella in 16 percent, Escherichia coli in 12 percent, Pseudomonas aeruginosa in 12 percent, Proteus mirabillis in 8 percent, Staphylococcus epidermidis in 4 percent and Streptococcus viridans in 4 percent. Culture for fungus revealed Candida albicans in 64 percent and other species such as C. krusei, C. stellatoides, C. viswanathi, C. parapsilosis and C. tropicalis were present in 1 case each. No fungus was detected in 4 cases(16percent. The present investigation was designed to compare the bacterial and mycotic flora of the nail folds of patients of chronic paronychia with that of western countries.

  4. Management of chronic Achilles tendinopathy. (United States)


    Tendons transmit force between muscles and bones and, when stretched, store elastic energy that contributes to movement.(1) The tendinous portion of the gastrocnemius and soleus muscles merge to form the Achilles tendon, which is the largest and strongest in the body, but one of the most frequently injured.(2,3) Conservative management options for chronic Achilles tendinopathy include eccentric (lengthening) exercises, extracorporeal shockwave therapy (ESWT), topical nitroglycerin, low level laser therapy, orthoses, splints or injections (e.g. corticosteroids, hyperosmolar dextrose, polidocanol, platelet-rich plasma), while a minority of patients require surgery (using open, percutaneous or endoscopic methods).(4-8) Here we assess the management options for patients with chronic Achilles tendinopathy (lasting over 6 weeks).

  5. Lithium clearance in chronic nephropathy

    DEFF Research Database (Denmark)

    Kamper, A L; Holstein-Rathlou, N H; Leyssac, P P


    1. Lithium clearance measurements were made in 72 patients with chronic nephropathy of different aetiology and moderate to severely reduced renal function. 2. Lithium clearance was strictly correlated with glomerular filtration rate, and there was no suggestion of distal tubular reabsorption...... clearance data were independent of whether renal disease was of primarily glomerular or tubular origin and, further, were not influenced by long-term conventional antihypertensive treatment. 6. It is concluded that, even with a reduced kidney function, the data are compatible with the suggestion...... that lithium clearance may be a measure of the delivery of sodium and water from the renal proximal tubule. With this assumption it was found that adjustment of the sodium excretion in chronic nephropathy initially takes place in the distal parts of the nephron (loop of Henle, distal tubule and collecting duct...

  6. [Pharmacological treatment of chronic pain]. (United States)

    Willimann, Patrick


    The pharmacological treatment of chronic pain differs from acute pain management. In chronic non-cancer pain patients pharmacological treatment is only one element of an interdisciplinary approach. Not pain reduction only but gain in physical and social functioning is mandatory for continuation of therapy. The developpement of a strategy is the most important and difficult step toward an individual and sustained pharmacological pain treatment. Simple practical guidelines can help to find an individual therapeutic straight. Outcome parameters have to be determined. Check-ups for discontinuation of the therapy have to be done periodically. Exact documentation of effect and side effects prevents ungrateful and potential dangerous treatments. The WHO ladder remains the cornerstone of pharmacological pain treatment. Further analgesics as antidepressants and anticonvulsants are important in treatment of neuropathic or mixed pain states. Special considerations have to be done in opioid treatment of non-cancer pain regarding the lack of evidence in long term outcome and possible side effects and risks.

  7. Management of chronic visceral pain. (United States)

    Olesen, Anne E; Farmer, Adam D; Olesen, Søren S; Aziz, Qasim; Drewes, Asbjørn M


    Despite marked differences in underlying pathophysiology, the current management of visceral pain largely follows the guidelines derived from the somatic pain literature. The effective management of patients with chronic visceral pain should be multifaceted, including both pharmacological and psychological interventions, thereby providing a mechanism-orientated approach to treatment. Patients can frequently become disenfranchised, and subsequently disengaged, with healthcare providers leading to repeated consultations. Thus, a key aspect of management is to break this cycle by validating patients' symptoms, adopting an empathic approach and taking time to educate patients. To optimize treatment and outcomes in chronic visceral pain we need to move away from approaches exclusively based on dealing with peripheral nociceptive input toward more holistic strategies, taking into account alterations in central pain processing.

  8. Chronic radiation enteritis and malnutrition. (United States)

    Webb, Gwilym James; Brooke, Rachael; De Silva, Aminda Niroshan


    Radiation enteritis is defined as the loss of absorptive capacity of the intestine following irradiation, which is most commonly seen after radiotherapy for pelvic and abdominal malignancies. It is divided into acute and chronic forms and usually presents with diarrhea and malabsorption. Malnutrition is a common complication of chronic radiation enteritis (CRE). We reviewed the etiology, prevalence, symptoms, diagnosis and management of CRE and CRE with malnutrition in this article. Functional short bowel syndrome as a cause of malnutrition in CRE is also considered. The diagnostic work-up includes serum markers, endoscopy, cross-sectional imaging and the exclusion of alternative diagnoses such as recurrent malignancy. Management options of CRE include dietary manipulation, anti-motility agents, electrolyte correction, probiotics, parenteral nutrition, surgical resection and small bowel transplantation. Treatment may also be required for coexisting conditions including vitamin B12 deficiency, bile acid malabsorption and depression.

  9. Lithium clearance in chronic nephropathy

    DEFF Research Database (Denmark)

    Kamper, A L; Holstein-Rathlou, N H; Leyssac, P P


    1. Lithium clearance measurements were made in 72 patients with chronic nephropathy of different aetiology and moderate to severely reduced renal function. 2. Lithium clearance was strictly correlated with glomerular filtration rate, and there was no suggestion of distal tubular reabsorption...... of lithium or influence of osmotic diuresis. 3. Fractional reabsorption of lithium was reduced in most patients with glomerular filtration rates below 25 ml/min. 4. Calculated fractional distal reabsorption of sodium was reduced in most patients with glomerular filtration rates below 50 ml/min. 5. Lithium...... that lithium clearance may be a measure of the delivery of sodium and water from the renal proximal tubule. With this assumption it was found that adjustment of the sodium excretion in chronic nephropathy initially takes place in the distal parts of the nephron (loop of Henle, distal tubule and collecting duct...

  10. Nitric oxide and chronic colitis

    Directory of Open Access Journals (Sweden)

    Matthew B Grisham


    Full Text Available Nitric oxide (NO is thought to play an important role in modulating the inflammatory response by virtue of its ability to affect bloodflow, leukocyte function and cell viability. The objective of this study was to assess the role that NO may play in mediating the mucosal injury and inflammation in a model of chronic granulomatous colitis using two pharmacologically different inhibitors of nitric oxide synthase (NOS. Chronic granulomatous colitis with liver and spleen inflammation was induced in female Lewis rats via the subserosal (intramural injection of peptidoglycan/polysaccharide (PG/PS derived from group A streptococci. Chronic NOS inhibition by oral administration of NG-nitro-L-arginine methyl ester (L-NAME (15 µmol/kg/day or amino-guanidine (AG (15 µmol/ kg/day was found to attenuate the PG/PS-induced increases in macroscopic colonic inflammation scores and colonic myeloperoxidase activity. Only AG -- not L-NAME – attenuated the PG/PS-induced increases in colon dry weight. Both L-NAME and AG significantly attenuated the PG/PS-induced increases in spleen weight whereas neither was effective at significantly attenuating the PG/PS-induced increases in liver weight. Although both L-NAME and AG inhibited NO production in vivo, as measured by decreases in plasma nitrite and nitrate levels, only AG produced significantly lower values (38±3 versus 83±8 µM, respectively, P<0.05. Finally, L-NAME, but not AG, administration significantly increased mean arterial pressure from 83 mmHg in colitic animals to 105 mmHg in the PG/PS+ L-NAME-treated animals (P<0.05. It is concluded that NO may play an important role in mediating some of the pathophysiology associated with this model of chronic granulomatous colitis.


    Directory of Open Access Journals (Sweden)

    G.A Dian Puspitha Candra


    Full Text Available Insomnia is defined as difficulty to start sleeping, maintain it, or low quality sleeping, if the condition persist for more than one month, it is called chronic insomnia. Diagnosis is made through anamnesa and sleep wake diaries, aktigraphy, polisomnography. Pharmachologycally drugs that have been used to treat insomnia are benzodiazepin reseptor agonis, antihistamine, antidepressant. Non pharmacological ways include behavioural intervention for insomnia, give significant result in decreasing sleep latency, reducing awakness duration during the night and improving total sleeping time.

  12. Tackling chronic migraine: current perspectives

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    Carod-Artal FJ


    Full Text Available Francisco Javier Carod-Artal Neurology Department, Raigmore Hospital, Inverness, UK; Universitat Internacional de Catalunya, Barcelona, Spain Abstract: In the last decade, several diagnostic criteria and definitions have been proposed for chronic migraine (CM. The third edition of the International Classification of Headache Disorders–3 beta, published in 2013, has revised CM diagnostic criteria. CM is defined as “headache occurring on 15 or more days per month for more than 3 months, which has the features of migraine headache on at least 8 days per month.” Patients who meet the criteria for CM and for medication-overuse headache should be given both diagnoses. Worldwide, CM prevalence ranges 1%–3%, and its incidence has been estimated to be 2.5% per year. CM is associated with disability and poor quality of life. Modifiable risk factors include (among others: migraine progression (defined as an increase in frequency and severity of migraine attacks; medication and caffeine overuse; obesity; stressful life events; and snoring. CM patients have a significantly higher frequency of some comorbid conditions, including chronic pain, psychiatric disorders, respiratory illness, and some vascular risk factors. Management includes identification and control of comorbidities and risk factors that predispose to CM; treatment and prevention for medication overuse; early treatment for migraine attacks; and an adequate preventive therapy for CM. Several randomized controlled clinical trials have shown the efficacy of topiramate, amitriptyline, onabotulinumtoxinA, and cognitive-behavioral therapy in CM. Keywords: chronic daily headache, chronic migraine, epidemiology, medication overuse headache, risk factors, treatment

  13. Biomarkers in chronic adult hydrocephalus

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    Kitchen Neil D


    Full Text Available Abstract Awareness of the importance of chronic adult hydrocephalus has been raised again with the recent emergence of epidemiological studies. It is estimated that between 5 and 10% of patients suffering from dementia might, in fact, have chronic hydrocephalus. Although, surgical diversion of the cerebrospinal fluid (CSF represents the only known procedure able to treat the symptoms of this condition, the selection of surgical patients has always been problematic. In the last 40 years, we have become wiser in using appropriate diagnostic tests for the selection of these patients; however, the area of biological markers has so far been overlooked in this condition, in contrast to that for other neurodegenerative disorders and dementias. Biomarkers are biological substances that may be used to indicate either the onset or the presence, and the progression of a clinical condition, being closely linked to its pathophysiology. In such a setting they might assist in the more appropriate selection of patients for shunt surgery. In this article, we have reviewed research carried out in the last 25 years regarding the identification of serum and CSF biomarkers for chronic hydrocephalus, discussed the potential for each one, and finally discussed the limitations for use, as well as future directions and possibilities in this field. It is concluded that tumour-necrosis factor, tau protein, lactate, sulfatide and neurofilament triple protein are the most promising CSF markers for chronic hydrocephalus. At present however, none of these meet the criteria required to justify a change clinical practice. In the future, collaborative multi-centre projects will be needed to obtain more substantial data that overcome the problems that arise from small individual and uncoordinated studies.

  14. Chronic sphenoid rhinosinusitis: management challenge



    Natamon Charakorn, Kornkiat Snidvongs Department of Otolaryngology Head and Neck Surgery, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand Abstract: Chronic sphenoid rhinosinusitis is a spectrum of inflammatory diseases in isolated sphenoid sinus which may persist over a period of 12 weeks. It is a different entity from other types of rhinosinusitis because clinical presentations include headache, visual loss or diplop...

  15. Uveitis in juvenile chronic arthritis. (United States)

    Kanski, J J


    About 20% of patients with juvenile chronic arthritis develop uveitis which is frequently bilateral. Risk factors for uveitis are: female gender, pauciarticular onset of arthritis, presence of circulating antinuclear antibodies, and the antigens HLA-DW5 and HLA-DPw2. The visual prognosis in patients with uveitis is good in 25% and fair in 50%. The remaining 25% develop cataract and/or glaucoma. The management of glaucoma is unsatisfactory, but the results of cataract surgery by lensectomy are good.

  16. Conversations with chronic schizophrenic patients. (United States)

    Morgan, R


    An account is given of some of the topics discussed during a small informal weekly open group meeting of chronic schizophrenic patients, based on occasional notes compiled over eleven years. The main feature of the patients' condition as displayed was poverty--clinical, social, behavioural, material and financial--and certain features suggested an organic aetiology. Reasons are given for considering that the patients' condition was predominantly caused by schizophrenia rather than by institutionalism.

  17. Comprehensive management of chronic pain in haemophilia. (United States)

    Young, G; Tachdjian, R; Baumann, K; Panopoulos, G


    Chronic pain, most often due to haemophilic arthropathy, is a pervasive problem in persons with haemophilia (PWH) that adversely impacts function and quality of life. PWH with inhibitors and older PWH may be especially vulnerable to progressive arthropathy and resulting chronic pain. The development of chronic pain from acute pain involves a complex interplay of biological and psychosocial factors that may all contribute to the perpetuation of chronic pain and the outcome of therapy. In the absence of evidence-based guidelines, an individualized, multimodal approach to chronic pain management is proposed, as it is in individuals without haemophilia who have chronic pain. Pharmacological treatment is central to the management of chronic pain and must be modified based on pain intensity, ongoing response to therapy and the risk for adverse events. Non-pharmacological interventions, including physiotherapy, complementary treatments and surgical (e.g. orthopaedic) or other invasive procedures, may be integral to chronic pain management in this population. Ongoing psychosocial assessment is critical to identify those factors that may be contributing to the perpetuation of chronic pain or acting as barriers to effective management. Additional study is needed to identify optimal pharmacological treatments for chronic pain in PWH based on the unique pathophysiology of haemophilic arthropathy and on risk profile. Systematic determination of the particular psychosocial factors impacting the experience and management of chronic pain in PWH would likewise add value to the treatment of this pervasive problem.

  18. Chronic Daily Headache - A Reappraisal

    Directory of Open Access Journals (Sweden)

    Chakravarty A


    Full Text Available Chronic Daily Headache (CDH generally refers to frequent headache occuring more than 15 days/month for over three months. Such headaches may be primary or secondary - the latter referring to headaches related to identifiable intra and extracranial vascular or other pathologies or systemic illnesses. The primary type may be subclassified as short and long lasting ones, depending upon whether the headache spells are more or less than four hours in duration. The present review would deal with the four major types of long lasting primary CDH which include Chronic migraine (CM, Chronic tension type headache (CTTH, New daily persistent headache (NDPH and Hemicrania continua (HC. The first part of the article would focus on the clinical pattern recognising features of these types. The relationship of medication overuse to CM would be critically evaluated. In the second part, the status of CDH in the recently proposed classification of headache disorders by the International Headache Society would be briefly evaluated. In the next section the clinical Profile or CDH in Indian patients would be highlighted based on available published data. Lastly, the pathophysiology of this vexing condition would be discussed specially in relation to CM and postulating on how it may evolve from episodic migraine.

  19. Meditation's impact on chronic illness. (United States)

    Bonadonna, Ramita


    Meditation is becoming widely popular as an adjunct to conventional medical therapies. This article reviews the literature regarding the experience of chronic illness, theories about meditation, and clinical effects of this self-care practice. Eastern theories of meditation include Buddhist psychology. The word Buddha means the awakened one, and Buddhist meditators have been called the first scientists, alluding to more than 2500 years of precise, detailed observation of inner experience. The knowledge that comprises Buddhist psychology was derived inductively from the historical figure's (Prince Siddhartha Gautama) diligent self-inquiry. Western theories of meditation include Jungian, Benson's relaxation response, and transpersonal psychology. Clinical effects of meditation impact a broad spectrum of physical and psychological symptoms and syndromes, including reduced anxiety, pain, and depression, enhanced mood and self-esteem, and decreased stress. Meditation has been studied in populations with fibromyalgia, cancer, hypertension, and psoriasis. While earlier studies were small and lacked experimental controls, the quality and quantity of valid research is growing. Meditation practice can positively influence the experience of chronic illness and can serve as a primary, secondary, and/or tertiary prevention strategy. Health professionals demonstrate commitment to holistic practice by asking patients about use of meditation, and can encourage this self-care activity. Simple techniques for mindfulness can be taught in the clinical setting. Living mindfully with chronic illness is a fruitful area for research, and it can be predicted that evidence will grow to support the role of consciousness in the human experience of disease.

  20. NAFLD and Chronic Kidney Disease. (United States)

    Marcuccilli, Morgan; Chonchol, Michel


    Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in developed countries and it is now considered a risk factor for cardiovascular disease. Evidence linking NAFLD to the development and progression of chronic kidney disease (CKD) is emerging as a popular area of scientific interest. The rise in simultaneous liver-kidney transplantation as well as the significant cost associated with the presence of chronic kidney disease in the NAFLD population make this entity a worthwhile target for screening and therapeutic intervention. While several cross-sectional and case control studies have been published to substantiate these theories, very little data exists on the underlying cause of NAFLD and CKD. In this review, we will discuss the most recent publications on the diagnosis of NAFLD as well new evidence regarding the pathophysiology of NAFLD and CKD as an inflammatory disorder. These mechanisms include the role of obesity, the renin-angiotensin system, and dysregulation of fructose metabolism and lipogenesis in the development of both disorders. Further investigation of these pathways may lead to novel therapies that aim to target the NAFLD and CKD. However, more prospective studies that include information on both renal and liver histology will be necessary in order to understand the relationship between these diseases.

  1. Superoxide dismutases in chronic gastritis. (United States)

    Švagelj, Dražen; Terzić, Velimir; Dovhanj, Jasna; Švagelj, Marija; Cvrković, Mirta; Švagelj, Ivan


    Human gastric diseases have shown significant changes in the activity and expression of superoxide dismutase (SOD) isoforms. The aim of this study was to detect Mn-SOD activity and expression in the tissue of gastric mucosa, primarily in chronic gastritis (immunohistochemical Helicobacter pylori-negative gastritis, without other pathohistological changes) and to evaluate their possible connection with pathohistological diagnosis. We examined 51 consecutive outpatients undergoing endoscopy for upper gastrointestinal symptoms. Patients were classified based on their histopathological examinations and divided into three groups: 51 patients (archive samples between 2004-2009) with chronic immunohistochemical Helicobacter pylori-negative gastritis (mononuclear cells infiltration were graded as absent, moderate, severe) divided into three groups. Severity of gastritis was graded according to the updated Sydney system. Gastric tissue samples were used to determine the expression of Mn-SOD with anti-Mn-SOD Ab immunohistochemically. The Mn-SOD expression was more frequently present in specimens with severe and moderate inflammation of gastric mucosa than in those with normal mucosa. In patients with normal histological finding, positive immunoreactivity of Mn-SOD was not found. Our results determine the changes in Mn-SOD expression occurring in the normal gastric mucosa that had undergone changes in the intensity of chronic inflammatory infiltrates in the lamina propria.


    Institute of Scientific and Technical Information of China (English)

    Hua Ren; Pi-xiong Su; Chao-ji Zhang; Song Gu; Heng Zhang; Chen Wang


    Objective To evaluate the improving reliability and safety of thromboendarterectomy and perioperative management for chronic pulmonary thromboembolism. Methods The clinical data of 12 cases with chronic pulmonary thromboembolism, who underwent thromboendarterec tomy assisted by low flow or circulation arrest with deep hypothermia, were reviewed retrospectively. Results Pulmonary artery pressure decreased 20 to 40 mmHg immediately after surgical procedures in 9 cases. The postoperative pulmonary edema at various degrees happened in 12 cases, among them, 1 died of severe lung infection and pulmonary re-embolism at 19 days postoperation. Computed tomography pulmonary angiography and angiography of 11 cases indicated that the original obstruction of pulmonary artery disappeared. During the follow-up period of 2 months to 5 years, the clinical symptoms and activity was improved. Conclusion Thromboendarterectomy is an effective treatment for chronic pulmonary thromboembolism. The outcome of the surgical procedure needs to be further investigated and followed up regularly according to an evaluative system, because it might be influenced by multiple factors.

  3. Ultrasonography in chronic renal failure

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    Buturovic-Ponikvar, Jadranka E-mail:; Visnar-Perovic, Alenka


    Many chronic renal diseases lead to the final common state of decrease in renal size, parenchymal atrophy, sclerosis and fibrosis. The ultrasound image show a smaller kidney, thinning of the parenchyma and its hyperechogenicity (reflecting sclerosis and fibrosis). The frequency of renal cysts increases with the progression of the disease. Ultrasound generally does not allow for the exact diagnosis of an underlying chronic disease (renal biopsy is usually required), but it can help to determine an irreversible disease, assess prognosis and avoid unnecessary diagnostic or therapeutic procedures. The main exception in which the ultrasound image does not show a smaller kidney with parenchymal atrophy is diabetic nephropathy, the leading cause of chronic and end-stage renal failure in developed countries in recent years. In this case, both renal size and parenchymal thickness are preserved until end-stage renal failure. Doppler study of intrarenal vessels can provide additional information about microvascular and parenchymal lesions, which is helpful in deciding for or against therapeutic intervention and timely planning for optimal renal replacement therapy option.

  4. [Nutrition and chronic renal failure]. (United States)

    Ayúcar Ruiz de Galarreta, A; Cordero Lorenzana, M L; Martínez-Puga y López, E; Gómez Seijo, A; Escudero Alvarez, E


    The causes of malnutrition in chronic terminal kidney failure are reviewed in the situation both before and after dialysis, as are the malnutrition rates in both circumstances and their treatment. Malnutrition has a high prevalence in terminal kidney patients, partly as a result of the therapeutic restriction on calories and proteins, but also due to the metabolic reactions typical of the disease and to anorexia. In patients subjected to dialytical methods, certain other mechanisms are added. In addition to malnutrition, there are alterations in the metabolism of calcium, phosphorus and potassium, as well as lipids, thus limiting nutritional therapy's ability to restore the nutritional status to normal. An awareness of energy expenditure in chronic terminal kidney failure and the consequences of malnutrition have led to new challenges in nutritional therapy, both in the dose and quality of the proteins, with a debate raging over the advantages of ketoanalogues, and also in the methods for providing nutrients. The ideal nutritional method for repletion is oral administration, but this can be enhanced with artificial support such as oral supplements, parenteral nutrition during dialysis or such alternatives as enteral nutrition at home in the case of chronic kidney problems in children, using percutaneous endoscopic gastrostomy (PEG), in order to nourish the patients and minimize growth disorders.

  5. Gut microbiome and chronic prostatitis/chronic pelvic pain syndrome. (United States)

    Arora, Hans C; Eng, Charis; Shoskes, Daniel A


    Analysis of the human microbiome continues to reveal new and previously unrealized associations between microbial dysbiosis and disease. Novel approaches to bacterial identification using culture-independent methods allow practitioners to discern the presence of alterations in the taxa and diversity of the microbiome and identify correlations with disease processes. While some of these diseases that have been extensively studied are well-defined in their etiology and treatment methods (colorectal cancer), others have provided much more significant challenges in both diagnosis and treatment. One such condition, chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), has several etiological and potentiating contributions from infection, inflammation, central nervous system (CNS) changes, stress, and central sensitization-all factors that play important roles in the crosstalk between the human body and its microbiome. No singular cause of CP/CPPS has been identified and it is most likely a syndrome with multifactorial causes. This heterogeneity and ambiguity are sources of significant frustration for patients and providers alike. Despite multiple attempts, treatment of chronic prostatitis with monotherapy has seen limited success, which is thought to be due to its heterogeneous nature. Phenotypic approaches to both classify the disease and direct treatment for CP/CPPS have proven beneficial in these patients, but questions still remain regarding etiology. Newer microbiome research has found correlations between symptom scores and disease severity and the degree of dysbiosis in urine and gut (stool) microbiomes in these patients as compared to un-afflicted controls. These findings present potential new diagnostic and therapeutic targets in CP/CPPS patients.

  6. Physical Activity and Chronic Prostatitis/Chronic Pelvic Pain Syndrome (United States)

    Zhang, Ran; Chomistek, Andrea K.; Dimitrakoff, Jordan D.; Giovannucci, Edward L.; Willett, Walter C.; Rosner, Bernard A.; Wu, Kana


    Purpose Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent urologic disorder among men, but its etiology is still poorly understood. Our objective was to examine the relationship between physical activity and incidence of CP/CPPS in a large cohort of male health professionals. Methods We conducted a prospective cohort study among men in the Health Professionals Follow-up Study followed from 1986 to 2008. The study population included 20,918 men who completed all CP/CPPS questions on the 2008 questionnaire. Leisure-time physical activity, including type and intensity of activity, was measured by questionnaire in 1986. A National Institute of Health Chronic Prostatitis Symptom Index pain score was calculated based on the responses on the 2008 questionnaire. Participants with pain scores ≥ 8 were considered CP/CPPS cases (n=689). Results Higher leisure-time physical activity was associated with lower risk of CP/CPPS. The multivariable-adjusted odds ratio (OR) comparing >35.0 to ≤3.5 MET-h/wk of physical activity was 0.72 (95% confidence interval (CI): 0.56, 0.92, p for trend <0.001). Observed inverse associations between physical activity and CP/CPPS were similar for both moderate- and vigorous-intensity activities. Sedentary behavior, measured as time spent watching television, was not associated with risk of CP/CPPS (p for trend 0.64). Conclusions Findings from this study, the first large scale and most comprehensive study to date on this association, suggest that higher levels of leisure-time physical activity may lower risk of CP/CPPS in middle-aged and older men. PMID:25116086

  7. Endoplasmic reticulum stress is chronically activated in chronic pancreatitis. (United States)

    Sah, Raghuwansh P; Garg, Sushil K; Dixit, Ajay K; Dudeja, Vikas; Dawra, Rajinder K; Saluja, Ashok K


    The pathogenesis of chronic pancreatitis (CP) is poorly understood. Endoplasmic reticulum (ER) stress has now been recognized as a pathogenic event in many chronic diseases. However, ER stress has not been studied in CP, although pancreatic acinar cells seem to be especially vulnerable to ER dysfunction because of their dependence on high ER volume and functionality. Here, we aim to investigate ER stress in CP, study its pathogenesis in relation to trypsinogen activation (widely regarded as the key event of pancreatitis), and explore its mechanism, time course, and downstream consequences during pancreatic injury. CP was induced in mice by repeated episodes of acute pancreatitis (AP) based on caerulein hyperstimulation. ER stress leads to activation of unfolded protein response components that were measured in CP and AP. We show sustained up-regulation of unfolded protein response components ATF4, CHOP, GRP78, and XBP1 in CP. Overexpression of GRP78 and ATF4 in human CP confirmed the experimental findings. We used novel trypsinogen-7 knock-out mice (T(-/-)), which lack intra-acinar trypsinogen activation, to clarify the relationship of ER stress to intra-acinar trypsinogen activation in pancreatic injury. Comparable activation of ER stress was seen in wild type and T(-/-) mice. Induction of ER stress occurred through pathologic calcium signaling very early in the course of pancreatic injury. Our results establish that ER stress is chronically activated in CP and is induced early in pancreatic injury through pathologic calcium signaling independent of trypsinogen activation. ER stress may be an important pathogenic mechanism in pancreatitis that needs to be explored in future studies.

  8. Chronic pelvic pain: comorbidity between chronic musculoskeletal pain and vulvodynia

    Directory of Open Access Journals (Sweden)

    G. Biasi


    Full Text Available Chronic pelvic pain (CPP is a common condition that has a major impact on the quality of life of both men and women. Male CPP is usually attributable to well-defined urogenital conditions (most frequently infectious/non infectious prostatic diseases or musculoskeletal or bowel diseases, whereas the features of female CPP are much more complex and are of particular clinical and epidemiological importance. It is a multifactorial syndrome that can be due to diseases of the urogenital, gastrointestinal, or musculoskeletal systems, or to neurological or neuropsychiatric disorders. It is not always easy to identify its predominant pathogenesis, although it often occurs as a central sensitization syndrome triggered by an initial stimulus which is no longer detectable and only manifests itself clinically through pain. In this respect, there are some very interesting relationships between vulvodynia and fibromyalgic syndrome, as identified in a preliminary study of women with chronic musculoskeletal pain in which it was demonstrated that vulvar pain plays an important role, although it is often overlooked and undiagnosed.

  9. Nonpharmacologic Management of Chronic Insomnia. (United States)

    Maness, David L; Khan, Muneeza


    Insomnia affects 10% to 30% of the population with a total cost of $92.5 to $107.5 billion annually. Short-term, chronic, and other types of insomnia are the three major categories according to the International Classification of Sleep Disorders, 3rd ed. The criteria for diagnosis are difficulty falling asleep, difficulty staying asleep, or early awakening despite the opportunity for sleep; symptoms must be associated with impaired daytime functioning and occur at least three times per week for at least one month. Factors associated with the onset of insomnia include a personal or family history of insomnia, easy arousability, poor self-reported health, and chronic pain. Insomnia is more common in women, especially following menopause and during late pregnancy, and in older adults. A comprehensive sleep history can confirm the diagnosis. Psychiatric and medical problems, medication use, and substance abuse should be ruled out as contributing factors. Treatment of comorbid conditions alone may not resolve insomnia. Patients with movement disorders (e.g., restless legs syndrome, periodic limb movement disorder), circadian rhythm disorders, or breathing disorders (e.g., obstructive sleep apnea) must be identified and treated appropriately. Chronic insomnia is associated with cognitive difficulties, anxiety and depression, poor work performance, decreased quality of life, and increased risk of cardiovascular disease and all-cause mortality. Insomnia can be treated with nonpharmacologic and pharmacologic therapies. Nonpharmacologic therapies include sleep hygiene, cognitive behavior therapy, relaxation therapy, multicomponent therapy, and paradoxical intention. Referral to a sleep specialist may be considered for refractory cases.

  10. Managing acute and chronic pancreatitis. (United States)

    Skipworth, James R A; Shankar, Arjun; Pereira, Stephen P


    Pancreatitis may be acute or chronic. Although both can be caused by similar aetiologies, they tend to follow distinct natural histories. Around 80% of acute pancreatitis (AP) diagnoses occur secondary to gallstone disease and alcohol misuse. AP is commonly associated with sudden onset of upper abdominal pain radiating to the back that is usually severe enough to warrant the patient seeking urgent medical attention. Onset of pain may be related to a recent alcohol binge or rich, fatty meal. The patient may appear unwell, be tachycardic and have exquisite tenderness in the upper abdomen. Overall, 10-25% of AP episodes are classified as severe, leading to an associated mortality rate of 7.5%. Disease severity is best predicted from a number of clinical scoring systems which can be applied at diagnosis in association with repeated clinical assessment, measurement of acute inflammatory markers, and CT. All patients with suspected AP should be referred urgently. Chronic pancreatitis (CP) follows continued, repetitive or sustained injury to the pancreas and 70% of diagnoses occur secondary to alcohol abuse. The characteristic presenting feature of CP is insidious progression of chronic, severe, upper abdominal pain, radiating to the back, caused by a combination of progressive pancreatic destruction, inflammation and duct obstruction. Signs and symptoms include weight loss and steatorrhoea and later on diabetes. CP patients may also present with recurrent episodes mimicking AP, both symptomatically and metabolically. Diagnosis of CP should be based on symptom profile, imaging and assessment of exocrine and endocrine pancreatic function. CT should be the first-line imaging investigation.

  11. Chronic urticaria and Helicobacter pylori

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    Yadav Mukesh


    Full Text Available Background: Helicobacter pylori (HP have recently emerged as a novel eliciting factor for chronic urticaria (CU. The possible association between HP and CU has enormous potential, as eradicating HP could cure CU. Aims and Objectives: We conducted a study to assess the prevalence of HP infection and effect of bacterium eradication on skin lesions in patients of chronic idiopathic urticaria (CIU. Settings and Design: Four hundred sixty patients of CU attending the allergy clinic, SMS hospital, Jaipur during the period February 6, 2004, to February 6, 2006, were screened for possible eliciting factors. Patients with CIU were enrolled and others were excluded. Materials and Methods: Sixty-eight patients of CIU and similar number of age and sex matched controls, attending the allergy clinic, SMS Hospital, Jaipur were enrolled in the study. All patients underwent endoscopy with antral biopsy for urease and histopathology to identify HP-associated gastritis. Infected patients were given HP eradication therapy. Eradication of bacterium was confirmed by fecal antigen assay. Subjective response to treatment was judged using chronic urticaria quality-of-life questionnaire (CU-Q 2 oL while objective response to treatment was judged by need for ′rescue medication′ (antihistaminics. Statistical Analysis: Data were analyzed using Chi square and paired′t′ test for their level of significance. Results: HP associated gastritis was present in 48 (70.58% patients, out of which 39 (81.25% patients responded to eradication therapy. Ten (50.00% patients without HP associated gastritis showed response to symptomatic therapy. Overall 49 (72.05% patients responded and 19 (27.94% showed no response. The value of χ2 was 28.571 (P = 0.003, which showed significant association between presence of HP and response to eradication regimen. Conclusion: The response of HP eradication therapy in infected patients of CIU is significant. HP should be included in diagnostic

  12. T-cell production of matrix metalloproteinases and inhibition of parasite clearance by TIMP-1 during chronic Toxoplasma infection in the brain

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    Emma H Wilson


    Full Text Available Chronic infection with the intracellular protozoan parasite Toxoplasma gondii leads to tissue remodelling in the brain and a continuous requirement for peripheral leucocyte migration within the CNS (central nervous system. In the present study, we investigate the role of MMPs (matrix metalloproteinases and their inhibitors in T-cell migration into the infected brain. Increased expression of two key molecules, MMP-8 and MMP-10, along with their inhibitor, TIMP-1 (tissue inhibitor of metalloproteinases-1, was observed in the CNS following infection. Analysis of infiltrating lymphocytes demonstrated MMP-8 and -10 production by CD4+ and CD8+ T-cells. In addition, infiltrating T-cells and CNS resident astrocytes increased their expression of TIMP-1 following infection. TIMP-1-deficient mice had a decrease in perivascular accumulation of lymphocyte populations, yet an increase in the proportion of CD4+ T-cells that had trafficked into the CNS. This was accompanied by a reduction in parasite burden in the brain. Taken together, these findings demonstrate a role for MMPs and TIMP-1 in the trafficking of lymphocytes into the CNS during chronic infection in the brain.

  13. Treatment of refractory chronic urticaria

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    Aayushi Mehta


    Full Text Available Chronic spontaneous urticaria is a distressing disease encountered frequently in clinical practice. The current mainstay of therapy is the use of second-generation, non-sedating antihistamines. However, in patients who do not respond satisfactorily to these agents, a variety of other drugs are used. This article examines the available literature for frequently used agents including systemic corticosteroids, leukotriene receptor antagonists, dapsone, sulfasalazine, hydroxychloroquine, H2 antagonists, methotrexate, cyclosporine A, omalizumab, autologous serum therapy, and mycophenolate mofetil, with an additional focus on publications in Indian literature.

  14. Perspectives on "chronic Lyme disease". (United States)

    Baker, Phillip J


    There is much controversy about the treatment of Lyme disease with respect to 2 poorly defined entities: "chronic Lyme disease" and "posttreatment Lyme disease syndrome." In the absence of direct evidence that these conditions are the result of a persistent infection, some mistakenly advocate extended antibiotic therapy (>/=6 months), which can do great harm and has resulted in at least 1 death. The purpose of this brief report is to review what is known from clinical research about these conditions to assist both practicing physicians and lawmakers in making sound and safe decisions with respect to treatment.

  15. Chronic pancreatitis and pancreatic cancer. (United States)

    Maisonneuve, Patrick; Lowenfels, Albert B


    Pancreatic cancer is the fourth leading cause of cancer deaths in the USA in both sexes. Early diagnosis is difficult and the overall mortality rate is high. Individuals at high risk for pancreatic cancer include smokers, and persons with all forms of chronic alcoholic, metabolic, tropical or hereditary pancreatitis. The duration of exposure to inflammation seems to be the major factor involved in the transition from benign to malignant condition. Smoking, which appears to further accelerate the carcinogenic transformation, remains the strongest risk factor amenable to preventive intervention.

  16. Myeloperoxidase in Chronic Kidney Disease


    Madhusudhana Rao, A.; Anand, Usha; Anand, C. V.


    Numerous lines of evidence implicate a role of myeloperoxidase (MPO) in the pathogenesis of cardiovascular disease (CVD). It is a well accepted fact that patients with chronic kidney disease (CKD) are at an increased risk for CVD. MPO is a pro-oxidant enzyme which could be involved in the increased susceptibility of these patients to CVD. Hence, the levels of plasma MPO was determined in healthy controls as well as in patients with CKD [stratified with the level of their kidney failure as CKD...

  17. Chronic Venous Disease under pressure


    Reeder, Suzan


    textabstractIn chapter 1 we provide a general introduction of this thesis. Chronic venous disease (CVD) is a common medical condition that affects 2-64% of the worldwide population and leads to leg ulcers in 1% of the Western population. Venous leg ulceration (VLU) has an unfavorable prognosis with regard to non-healing and recurrence rates. Annually 6% of the total healthcare costs are spent on the treatment of venous diseases. CVD results from ambulatory venous hypertension and is the conse...

  18. Neuropsychological functioning in chronic Lyme disease. (United States)

    Westervelt, Holly James; McCaffrey, Robert J


    Lyme disease is currently the most common vector-borne illness in the United States. The disease is multisystemic, and chronic disease, in particular, may be associated with neuropsychological deficits. However, to date, only a few empirical studies exist, which examine the neuropsychological sequelae associated with chronic Lyme disease. A review of the literature shows that the deficits observed in adults with chronic Lyme disease are generally consistent with the deficits that can be seen in processes with primarily frontal systems involvement. These observations are generally consistent with neuroradiologic findings. The clinical presentation in chronic Lyme disease and the nature of the neuropsychological deficits are discussed, as are several central issues in understanding neuropsychological functioning in chronic Lyme disease, such as the impact of chronic illness, response to treatment, and the relationship between neuropsychological performance and depression, fatigue, and neurological indicators of disease.

  19. New Directions in Chronic Disease Management

    Directory of Open Access Journals (Sweden)

    Hun-Sung Kim


    Full Text Available A worldwide epidemic of chronic disease, and complications thereof, is underway, with no sign of abatement. Healthcare costs have increased tremendously, principally because of the need to treat chronic complications of non-communicable diseases including cardiovascular disease, blindness, end-stage renal disease, and amputation of extremities. Current healthcare systems fail to provide an appropriate quality of care to prevent the development of chronic complications without additional healthcare costs. A new paradigm for prevention and treatment of chronic disease and the complications thereof is urgently required. Several clinical studies have clearly shown that frequent communication between physicians and patients, based on electronic data transmission from medical devices, greatly assists in the management of chronic disease. However, for various reasons, these advantages have not translated effectively into real clinical practice. In the present review, we describe current relevant studies, and trends in the use of information technology for chronic disease management. We also discuss limitations and future directions.

  20. Is acute recurrent pancreatitis a chronic disease?


    Mariani, Alberto; Testoni, Pier Alberto


    Whether acute recurrent pancreatitis is a chronic disease is still debated and a consensus is not still reached as demonstrated by differences in the classification of acute recurrent pancreatitis. There is major evidence for considering alcoholic pancreatitis as a chronic disease ab initio while chronic pancreatitis lesions detectable in biliary acute recurrent pancreatitis (ARP) seem a casual association. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation, hereditary a...

  1. Eccentric Strengthening for Chronic Lateral Epicondylosis


    Wen, Dennis Y.; Schultz, Brian J.; Schaal, Bob; Graham, Scott T.; Kim, Byung Sung


    Background: Effective treatments for chronic lateral epicondylosis have not been studied adequately. Eccentric overload exercises have been used with success for other chronic tendinopathy, mainly Achilles and patellar. Hypothesis/Purpose: To compare a wrist extensor eccentric strengthening exercise program with a wrist extensor stretching/modality program for the treatment of chronic lateral epicondylosis. The authors hypothesized that the eccentric strengthening program would produce more f...

  2. [Chronic inflammatory bowel diseases in cats]. (United States)

    Ghermai, A K


    The aetiology of chronic idiopathic intestinal inflammation is unknown. It is characterized by a diffuse infiltration with inflammatory cells into the intestinal mucosa and sometimes submucosa. Cats with chronic intermittent vomiting and diarrhoea, later on accompanied by anorexia and weight loss, are presented. Definitive diagnosis can be obtained by intestinal biopsy only. An immune pathogenesis is suspected, which is supported by the fact, that chronic inflammatory bowel disease responds to steroid therapy.

  3. Chronic pain after inguinal hernia repair



    : BACKGROUND: Chronic post herniorrhaphy groin pain is defined as pain lasting > 6 months after surgery, which is one of the most important complication occurring after inguinal hernia repair, occurs with greater frequency than previously thought. Chronic groin pain is one of the most significant complications following inguinal hernia repair, and majority of chronic pain has been attributed to ilioinguinal nerve entrapment. Various other factors are involved in development of...

  4. HBV Vaccination in Chronic Renal Failure Patients


    Mir-davood Omrani; Mohammad Hassan Khadem Ansari


    HBV infection in chronic renal failure (CRF) becomes chronic in 30 to 60% compared with less than 10% in nonuremic patients. Immunological dysfunction in patients on hemodialysis may be related to imbalanced cytokine systems, such as tumor necrosis factor (TNF-|α|) and interleukin (IL) 6,1 by retention of renal metabolite in uremia and chronic inflammation and have a poor immunological reaction to T-cell-dependent antigens, like hepatitis B vaccination. Immunocompromised patients who are unre...

  5. Multiple chronic conditions and life expectancy

    DEFF Research Database (Denmark)

    DuGoff, Eva H; Canudas-Romo, Vladimir; Buttorff, Christine


    condition. A 67-year-old individual with no chronic conditions will live on average 22.6 additional years. A 67-year-old individual with 5 chronic conditions and ≥10 chronic conditions will live 7.7 fewer years and 17.6 fewer years, respectively. The average marginal decline in life expectancy is 1.8 years...... and increasing numbers of comorbid conditions. CONCLUSIONS: Social Security and Medicare actuaries should account for the growing number of beneficiaries with multiple chronic conditions when determining population projections and trust fund solvency....

  6. Oriental Medical Treatment of chronic Acalculous Cholecystitis

    Directory of Open Access Journals (Sweden)

    Hae-Yeon Lee


    Full Text Available Chronic acalculous cholecystitis gets possession of about 12 to 13 percent of patients with chronic cholecystitis. Pathologically it is characterised by chronic inflammation and thickening of the gallbladder wall but doesn't come across stones. Clinical symptoms are vague and include abdominal discomfort and distension, nausea, flatulence and intolerance of fatty foods. A patient on chronic acalculous cholecystitis diagnosed from his clinical symtoms and abdominal ultrasonogram was treated by Geonbihwan, acupuncture and herbal acupuncture. Satisfactory symptomatic improvement was achieved and findings of abdominal ultrasonogram came also normal.

  7. Susceptibility to chronic inflammation: an update. (United States)

    Nasef, Noha Ahmed; Mehta, Sunali; Ferguson, Lynnette R


    Chronic inflammation is defined by the persistence of inflammatory processes beyond their physiological function, resulting in tissue destruction. Chronic inflammation is implicated in the progression of many chronic diseases and plays a central role in chronic inflammatory and autoimmune disease. As such, this review aims to collate some of the latest research in relation to genetic and environmental susceptibilities to chronic inflammation. In the genetic section, we discuss some of the updates in cytokine research and current treatments that are being developed. We also discuss newly identified canonical and non-canonical genes associated with chronic inflammation. In the environmental section, we highlight some of the latest updates and evidence in relation to the role that infection, diet and stress play in promoting inflammation. The aim of this review is to provide an overview of the latest research to build on our current understanding of chronic inflammation. It highlights the complexity associated with chronic inflammation, as well as provides insights into potential new targets for therapies that could be used to treat chronic inflammation and consequently prevent disease progression.

  8. Vitamin D deficiency in chronic idiopathic urticaria. (United States)

    Movahedi, Masoud; Tavakol, Marzieh; Hirbod-Mobarakeh, Armin; Gharagozlou, Mohammad; Aghamohammadi, Asghar; Tavakol, Zahra; Momenzadeh, Kaveh; Nabavi, Mohammad; Dabbaghzade, Abbas; Mosallanejad, Asieh; Rezaei, Nima


    Chronic urticaria is the most common skin diseases, characterized by chronic cutaneous lesions which severely debilitates patients in several aspects of their everyday life. Vitamin D is known to exert several actions in the immune system and to influence function and differentiation of mast cells, central role players in the pathogenesis of chronic idiopathic urticaria. This study was performed to evaluate the relationship between vitamin D levels and susceptibility to chronic idiopathic urticaria. One hundred and fourteen patients with chronic idiopathic urticaria were recruited in this study along with one hundred and eighty seven sex-matched and age-matched healthy volunteers as the control group. For each patient, urticaria activity score was calculated and autologous serum skin test was done. Vitamin D metabolic statue was measured in serum as 25 hydroxyvitamin D using enzyme immunoassay method. Patients with chronic idiopathic urticaria significantly showed lower levels of vitamin D. Vitamin D deficiency was significantly associated with increased susceptibility to chronic idiopathic urticaria. There was a significant positive correlation between vitamin D levels and urticaria activity score. This study showed that patients with chronic idiopathic urticaria had reduced levels of vitamin D, while vitamin D deficiency could increase susceptibility to chronic idiopathic urticaria.

  9. Neurodegenerative Properties of Chronic Pain: Cognitive Decline in Patients with Chronic Pancreatitis

    NARCIS (Netherlands)

    Jongsma, M.L.A.; Postma, S.A.E.; Souren, P.M.; Arns, M.W.; Gordon, E.; Vissers, K.C.P.; Wilder-Smith, O.H.G.; Rijn, C.M. van; Goor, H. van


    Chronic pain has been associated with impaired cognitive function. We examined cognitive performance in patients with severe chronic pancreatitis pain. We explored the following factors for their contribution to observed cognitive deficits: pain duration, comorbidity (depression, sleep disturbance),

  10. Anemia of Chronic Liver Diseases

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Hyun Chung; Lee, Jhung Sang; Koh, Chang Soon; Lee, Mun Ho [Seoul National University College of Medicine, Seoul (Korea, Republic of)


    The pathogenetic mechanisms of anemia in patients with chronic liver disease were observed. Seventeen patients with moderate to advanced hepatic diseases were studied by various methods. Only patients without previous blood loss were included : 14 had cirrhosis, 2 had active chronic hepatitis, and one had inferior vena cava obstruction with associated liver cirrhosis. The followings were the results: 1. The anemia based on red blood cell count, Hb., and Ht. was found in 76.5-78.6% of the patients. 2. Red cell indices indicated that normo-macrocytic and normochromic anemia was present is the majority of the patients. 3. No evidence of megaloblastic anemia was found on the basis of the morphological examinations. 4. Serum iron, TIBC, % saturation and iron content in the bone marrow indicated that iron deficiency anemia was present in about half of the patients. 5. In the view of the erythrocyte dynamics, primary increase in the red cell destruction was ascribed to the cause of the anemia. 6. Decrease in the red cell survival time was not correlated with MCV, % saturation and S.L. ratio. Also, hemoglobin level was not correlated with MCV, % saturation and T{sub 50} Cr. Therefore, multiple causes may be involved in the pathogenesis of the anemia. 7. Anemia as determined by the red cell volume was found in only 60% of the patients. It may be possible that hemodilutional anemia is present.

  11. Nutrition in chronic critical illness. (United States)

    Pingleton, S K


    Nutritional management of patients with respiratory failure can be a model of nutritional management in chronically critically ill patients. This model requires recognition of the differing metabolic states of starvation and hypermetabolism. Starvation can result in malnutrition, with adverse effect on respiratory muscle strength, ventilatory drive, and immune defense mechanisms. General nutritional goals include preservation of lean body mass by providing adequate energy and positive nitrogen balance. General nutritional prescriptions for both states include a substrate mix of 20% protein, 60% to 70% carbohydrates, and 20% to 30% fat. Positive nitrogen balance is difficult to attain in hypermetabolic patients and energy requirements are increased compared with starved patients. Enteral nutrition should be the mode of initial nutrient delivery unless the gastrointestinal tract is nonfunctional. Monitoring of nutritional support is essential. Complications of nutritional support are multiple. Nutritional hypercapnia is an important complication in a chronically critically ill patient. Outcomes of selected long-term acute patients are poor, with only 8% of patients fully functional 1 year after discharge. Appropriate nutritional therapy is one aspect of management of these patients that has the possibility of optimizing function and survival.

  12. Chronic Metabolic Acidosis Destroys Pancreas

    Directory of Open Access Journals (Sweden)

    Peter Melamed


    Full Text Available One primary reason for the current epidemic of digestive disorders might be chronic metabolic acidosis, which is extremely common in the modern population. Chronic metabolic acidosis primarily affects two alkaline digestive glands, the liver, and the pancreas, which produce alkaline bile and pancreatic juice with a large amount of bicarbonate. Even small acidic alterations in the bile and pancreatic juice pH can lead to serious biochemical/biomechanical changes. The pancreatic digestive enzymes require an alkaline milieu for proper function, and lowering the pH disables their activity. It can be the primary cause of indigestion. Acidification of the pancreatic juice decreases its antimicrobial activity, which can lead to intestinal dysbiosis. Lowering the pH of the pancreatic juice can cause premature activation of the proteases inside the pancreas with the potential development of pancreatitis.The acidification of bile causes precipitation of the bile acids, which irritate the entire biliary system and create bile stone formation. Aggressive mixture of the acidic bile and the pancreatic juice can cause erratic contractions of the duodenum’s walls and subsequent bile reflux into the stomach and the esophagus. Normal exocrine pancreatic function is the core of proper digestion. Currently, there is no effective and safe treatment for enhancing the exocrine pancreatic function. Restoring normal acid-base homeostasis can be a useful toolfor pathophysiological therapeutic approaches for various gastrointestinal disorders. There is strong research and practical evidence that restoring the HCO3 - capacity in the blood can improve digestion.

  13. Glucocorticoids, chronic stress, and obesity. (United States)

    Dallman, Mary F; Pecoraro, Norman C; La Fleur, Susanne E; Warne, James P; Ginsberg, Abigail B; Akana, Susan F; Laugero, Kevin C; Houshyar, Hani; Strack, Alison M; Bhatnagar, Seema; Bell, Mary E


    Glucocorticoids either inhibit or sensitize stress-induced activity in the hypothalamo-pituitary-adrenal (HPA) axis, depending on time after their administration, the concentration of the steroids, and whether there is a concurrent stressor input. When there are high glucocorticoids together with a chronic stressor, the steroids act in brain in a feed-forward fashion to recruit a stress-response network that biases ongoing autonomic, neuroendocrine, and behavioral outflow as well as responses to novel stressors. We review evidence for the role of glucocorticoids in activating the central stress-response network, and for mediation of this network by corticotropin-releasing factor (CRF). We briefly review the effects of CRF and its receptor antagonists on motor outflows in rodents, and examine the effects of glucocorticoids and CRF on monoaminergic neurons in brain. Corticosteroids stimulate behaviors that are mediated by dopaminergic mesolimbic "reward" pathways, and increase palatable feeding in rats. Moreover, in the absence of corticosteroids, the typical deficits in adrenalectomized rats are normalized by providing sucrose solutions to drink, suggesting that there is, in addition to the feed-forward action of glucocorticoids on brain, also a feedback action that is based on metabolic well being. Finally, we briefly discuss the problems with this network that normally serves to aid in responses to chronic stress, in our current overindulged, and underexercised society.

  14. Muscle histochemistry in chronic alcoholism

    Directory of Open Access Journals (Sweden)

    M. L. Ferraz


    Full Text Available Twenty-two chronic acoholic patients were assessed by neurologic examination and muscle biopsy. The patients manifested proximal muscular weakness to a variable extent. One case presented as an acute bout of myopathy, according to the Manual Muscle Test, MMT. The most prominent histologic feature observed was muscle atrophy (95.3% better evidenced through the ATPase stain with the predominance of type II A fibers (71.4%. Lack of the mosaic pattern (type grouping seen in 76% of the cases and an important mitochondrial proliferation with intrasarcoplasmatic lipid accumulation in 63% of the patients. In case of acute presentation of muscle weakness the. pathological substrate is quite different, i.e. presence of myositis mainly interstitial characterized by lymphoplasmocytic infiltrate and several spots of necrosis like Zencker degeneration. Based on histologic criteria, our data suggest that: the main determinant of muscle weakness seen in chronic alcoholic patients is neurogenic in origin (alcoholic polineuropathy; the direct toxic action of ethanol under the skeletal muscle is closely related to the mitochondrial metabolism; the so-called acute alcoholic myopathy has probably viral etiology.

  15. Chronic mucocutaneous candidiasis disease associated with inborn errors of IL-17 immunity (United States)

    Okada, Satoshi; Puel, Anne; Casanova, Jean-Laurent; Kobayashi, Masao


    Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections affecting the nails, skin and oral and genital mucosae caused by Candida spp., mainly Candida albicans. CMC is an infectious phenotype in patients with inherited or acquired T-cell deficiency. Patients with autosomal-dominant (AD) hyper IgE syndrome (HIES), AD signal transducer and activator of transcription 1 (STAT1) gain-of-function, autosomal-recessive (AR) deficiencies in interleukin (IL)-12 receptor β1 (IL-12Rβ1), IL-12p40, caspase recruitment domain-containing protein 9 (CARD9) or retinoic acid-related orphan receptor γT (RORγT) or AR autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) develop CMC as a major infectious phenotype that is categorized as Syndromic CMC. In contrast, CMC disease (CMCD) is typically defined as CMC in patients in the absence of any other prominent clinical signs. This definition is not strict; thus, CMCD is currently used to refer to patients presenting with CMC as the main clinical phenotype. The etiology of CMCD is not related to genes that cause severe combined immunodeficiency or combined immunodeficiency, nor to genes responsible for Syndromic CMC. Four genetic etiologies, AR IL-17 receptor A, IL-17 receptor C and ACT1 deficiencies, and AD IL-17F deficiency, are reported to underlie CMCD. Each of these gene defects directly has an impact on IL-17 signaling, suggesting their nonredundant role in host mucosal immunity to Candida. Here, we review current knowledge focusing on IL-17 signaling and the genetic etiologies responsible for, and associated with, CMC. PMID:28090315

  16. Chronic lead intoxication; Chronische Bleiintoxikation

    Energy Technology Data Exchange (ETDEWEB)

    Wieseler, B.; Leng, G. [Duesseldorf Univ. (Germany). Inst. fuer Hygiene; Lenz, S.; Schultz, C. [Klinikum Remscheid GmbH, Remscheid (Germany); Wilhelm, M. [Bochum Univ. (Germany). Inst. fuer Hygiene, Sozial- und Umweltmedizin


    The case of a female 68 years old patient is described. Here, a chronic lead intoxication was diagnosed after a two year old medical history with increasing attacks of colic-like abdominal pain often described as life-threatening. After repeated hospitalizations and intensive search for the cause of the symptoms, porphyria and anemia was found to be a sign of a chronic lead poisoning. The blood lead concentrations were always about a level of 600 {mu}g/L. The source of exposure could not be found by now. Neither home inspection nor environmental investigations have shown a recent source of lead intake by the patient. However, a possible occupational source of lead exposure at a blast furnace was established by anamnesis for 1952 to 1962. Thus, osteoporosis induced lead mobilisation was suspected. Noticeable are the results of the six abdominal survey radiographies taken during hospitalization within one year; three radiographies were taken following clinical admission and three before discharge of the patient. In comparison, the course shows a chronic relapsing alimentary supply from metallic particles of unknown genesis. The patient was treated with the sodium salt of 2,3-dimercapto-1-propansulfonic acid (DMPS, Dimaval{sup TM}). She was free of complain afterwards. Following therapy, the blood lead concentrations fell under a level of 400 {mu}m/L, but after several weeks the lead level raised up to the original level of 600 {mu}g/L. (orig.) [Deutsch] Es wird eine 68jaehrige Patientin vorgestellt, bei der nach fast zweijaehriger Krankengeschichte, die gekennzeichnet war durch rezidivierende, teils als lebensbedrohlich geschilderte Bauchkoliken, eine chronische Bleiintoxikation diagnostiziert wurde. Erst nach wiederholten stationaeren Krankenhausaufenthalten mit intensiver Suche nach der Krankheitsursache wurden das Krankheitsbild und die Laborwerte durch Zusatzuntersuchungen ergaenzt, so dass sich in der festgestellten Porphyrie und Anaemie die Diagnose der

  17. Ribavirin monotherapy for chronic hepatitis C infection

    DEFF Research Database (Denmark)

    Brok, Jesper; Gluud, Lise L; Gluud, Christian


    Adding ribavirin to interferon improves treatment response for patients with chronic hepatitis C, but the effects of ribavirin monotherapy are unclear. We conducted a systematic review to assess the benefits and harms of ribavirin monotherapy for patients with chronic hepatitis C....

  18. Benzodiazepine pathways in the chronically ill

    NARCIS (Netherlands)

    Van Hulten, Rolf; Heerdink, Eibert R.; Bakker, Albert; Leufkens, Hubert G.


    The association between patterns of use of benzodiazepines and chronic somatic morbidity was examined by applying the Chronic Disease Score (CDS). In the only pharmacy in a Dutch community, 6921 patients with data available covering a 10-year period (1983-1992) were included. In 1992, two-thirds of

  19. Syndrome Analysis: Chronic Alcoholism in Adults. (United States)

    Pendorf, James E.


    Provides outline narrative of most possible outcomes of regular heavy alcohol use, regular alcohol abuse, or chronic alcoholism. A systems analysis approach is used to expose conditions that may result when a human organism is subjected to excessive and chronic alcohol consumption. Such an approach illustrates the detrimental effects which alcohol…

  20. Chronic bronchitis in an elderly population

    DEFF Research Database (Denmark)

    Lange, Peter; Parner, Jan; Prescott, Eva


    in order to describe the prevalence and prognostic implications of chronic bronchitis in individuals 65 years or older we analysed data from The Copenhagen City Heart order to describe the prevalence and prognostic implications of chronic bronchitis in individuals 65 years or older we analysed data from The Copenhagen City Heart Study....

  1. [Computed tomographic semiotics of chronic subdural hematomas]. (United States)

    El'-Kadi, Kh A; Likhterman, L B; Kornichenko, V N


    Analysis of the results of investigation of 72 patients with verified chronic subdural hematomas (CSH) has revealed their CT dense characteristics, the peculiarities of their structure compared with the time of their formation, the patients' age, the clinical stage of disease, and operative findings. Direct and indirect CT signs of uni- and bilateral hemispherical chronic subdural hematomas were described.

  2. Comorbidity of chronic diseases in general practice.

    NARCIS (Netherlands)

    Schellevis, F.G.; Velden, J. van der; Lisdonk, E. van de; Eijk, J.T.M. van; Weel, C. van


    With the increasing number of elderly people in The Netherlands the prevalence of chronic diseases will rise in the next decades. It is recognized in general practice that many older patients suffer from more than one chronic disease (comorbidity). The aim of this study is to describe the extent of

  3. Muscle strength in patients with chronic pain

    NARCIS (Netherlands)

    van Wilgen, C.P.; Akkerman, L.; Wieringa, J.; Dijkstra, P.U.


    Objective: To analyse the influence of chronic pain on muscle strength. Design: Muscle strength of patients with unilateral nonspecific chronic pain, in an upper or lower limb, were measured according to a standardized protocol using a hand-held dynamometer. Before and after muscle strength measurem

  4. Urea synthesis in patients with chronic pancreatitis

    DEFF Research Database (Denmark)

    Hamberg, Ole; Sonne, J; Larsen, S


    Up-regulation of urea synthesis by amino acids and dietary protein intake may be impaired in patients with chronic pancreatitis (CP) due to the reduced glucagon secretion. Conversely, urea synthesis may be increased as a result of the chronic inflammation. The aims of the study were to determine...

  5. Chronic diseases among older cancer patients.

    NARCIS (Netherlands)

    Deckx, L.D.; Akker, M.A. van der; Metsemakers, J.M.; Knottnerus, A.K.; Schellevis, F.G.; Buntinx, F.B.


    Introduction: With the growing number of older cancer patients, the burden of chronic diseases among older cancer patients will become increasingly important. Chronic diseases often interfere with treatment decisions and prognosis for cancer patients. However, little is known about the occurrence of

  6. Hypertrophic osteoarthropathy of chronic inflammatory bowel disease

    Energy Technology Data Exchange (ETDEWEB)

    Oppenheimer, D.A.; Jones, H.H.


    The case of a 14-year old girl with painful periostitis and ulcerative colitis is reported. The association of chronic inflammatory bowel disease with osteoarthropathy is rare and has previously been reported in eight patients. The periosteal reaction found in association with inflammatory bowel disease is apparently related to a chronic disease course and may cause extreme localized pain.

  7. Reported barriers to evaluation in chronic care

    DEFF Research Database (Denmark)

    Knai, Cécile; Nolte, Ellen; Brunn, Matthias


    The growing movement of innovative approaches to chronic disease management in Europe has not been matched by a corresponding effort to evaluate them. This paper discusses challenges to evaluation of chronic disease management as reported by experts in six European countries....

  8. Pharmacological management of pain in chronic pancreatitis.

    NARCIS (Netherlands)

    Esch, A.A.J.; Wilder-Smith, O.H.G.; Jansen, J.B.M.J.; Goor, H. van; Drenth, J.P.H.


    Pain is the major presenting symptom of chronic pancreatitis. Patients with chronic pancreatitis experience substantial impairments in health-related quality of life. Pain may be considered as the most important factor affecting the quality of life. The pathogenesis of pancreatic pain is poorly unde

  9. Chronic autoimmune urticaria : Where we stand ?

    Directory of Open Access Journals (Sweden)

    Goh C


    Full Text Available It is well-recognized that 30-40% of chronic idiopathic urticaria is autoimmune in nature. Chronic autoimmune urticaria is caused by anti-FcåRI and less frequently, by anti-IgE autoantibodies that lead to mast cell and basophil activation, thereby giving rise to the release of histamine and other proinflammatory mediators. Activation of the classical complement pathway and formation of C5a are important in dermal mast cell activation. C5a is also a neutrophil and eosinophil chemoattractant. Chronic autoimmune urticaria has been found to be associated with autoimmune thyroid disease. The autologous serum skin test is used as a screening test for chronic autoimmune urticaria and has a sensitivity and specificity of about 70 and 80%, respectively. The current gold standard diagnostic test is the basophil histamine release assay. The treatment of chronic autoimmune urticaria, as in chronic idiopathic urticaria, is with H1 antihistamines. Oral corticosteroids may be used during acute flares. Refractory cases have been shown to respond to cyclosporine and other immunomodulators. The prevalence of chronic autoimmune urticaria in Singapore is similar to that reported in Western countries at about 42%. The presence of thyroid autoimmunity appears to be higher than reported, with 22.5% of patients with chronic idiopathic urticaria here, exhibiting presence of thyroid autoantibodies.

  10. Evaluation of telomerase expression in chronic periodontitis

    Directory of Open Access Journals (Sweden)

    Balaji T


    Full Text Available Background : Human telomerase is a multi subunit ribonucleoprotein enzyme concerned with telomeric lengthening and homeostasis in man. This enzyme has been found to be elevated in inflammatory conditions like rheumatoid arthritis and silica injury lung. Since chronic periodontitis is also an inflammatory condition where immune cells and cytokines mediate tissue destruction, we set out to evaluate telomerase in gingival tissue samples from healthy subjects and chronic periodontitis patients by reverse transcriptase polymerase chain reaction. Materials and Methods : Gingival biopsies were obtained from eight healthy subjects and eight chronic periodontitis patients. Reverse transcriptase polymerase chain reaction (RTPCR was carried out to evaluate telomerase gene expression in the samples. Results : None of the healthy gingival tissue samples expressed the telomerase gene while all the chronic periodontitis samples expressed it. The severe chronic periodontitis samples expressed the gene more intensely than the moderate chronic periodontitis samples. Conclusion : Various mechanisms have been explained to account for telomerase elevation in chronic periodontitis .This study helps us understand the role of telomerase in the pathogenesis of periodontal disease. It could be concluded that telomerase could be used as a marker to assess the severity of inflammation in chronic periodontitis.

  11. Future perspectives: pathogenesis of chronic muscle pain. (United States)

    Staud, Roland


    Chronic painful muscle conditions include non-inflammatory and inflammatory illnesses. This review is focused on chronic non-inflammatory pain conditions such as myofascial pain syndrome (MPS) and fibromyalgia syndrome (FM), and will not discuss metabolic, genetic or inflammatory muscle diseases such as McArdle's disease, muscular dystrophy, polymyositis, dermatomyositis, or inclusion body myositis.

  12. Osteoporosis in chronic obstructive pulmonary disease patients

    DEFF Research Database (Denmark)

    Jørgensen, Niklas Rye; Schwarz, Peter


    The purpose of this review is to examine the state of knowledge and clinical practice in the association of chronic obstructive pulmonary disease to osteoporosis and fracture incidence.......The purpose of this review is to examine the state of knowledge and clinical practice in the association of chronic obstructive pulmonary disease to osteoporosis and fracture incidence....

  13. Chronic inflammatory demyelinating polyneuropathy in two siblings.


    Gabreëls-Festen, A A; Hageman, A T; Gabreëls, F J; Joosten, E M; Renier, W.O.; Weemaes, C M; ter Laak, H J


    A familial occurrence of chronic inflammatory demyelinating polyneuropathy is reported. The diagnostic problems in distinguishing the progressive form of this disease in childhood from hereditary motor and sensory neuropathy types I and III are discussed. Criteria for a definite diagnosis of chronic inflammatory demyelinating polyneuropathy are proposed.

  14. Chronic Acquired Demyelinating Polyneuropathy following Renal Transplantation


    Younger, D. S.; Stuart Orsher


    The clinical, laboratory, and treatment findings of a patient with chronic acquired demyelinating polyneuropathy (CADP) in association with renal transplantation are described. Like the present case, many such patients have been described under the rubric of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).

  15. Ministry to the Chronically Ill Child. (United States)

    Spinetta, Pat Deasy; Collins, Denis E.


    Reports growth in the number of chronically ill children attending Catholic schools. Describes the separate roles of home, school, and hospital in children's long-term care. Urges educators to obtain necessary information on children's attendance, peer interaction, education, and medical compliance. Reviews issues specific to chronically ill…

  16. Counseling Adult Clients Experiencing Chronic Pain (United States)

    Burns, Stephanie T.


    Chronic pain affects 35% to 57% of the adult population in the United States and results in billions of dollars spent annually in direct health-care costs and lost productivity. Extensive research confirms the considerable role psychological factors play in the experience and expression of chronic pain. The author discusses implications for…

  17. Etiological approach to chronic urticaria

    Directory of Open Access Journals (Sweden)

    Krupa Shankar D


    Full Text Available Background: In 1769, William Cullen introduced the word "urticaria" (transient edematous papules, plaque with itching. Urticaria affects 15-25% of people at least once in their life time. It is a clinical reaction pattern triggered by many factors causing the liberation of vasoactive substances such as histamine, prostaglandins and kinins. Urticaria is classified according to its duration into acute (< 6 weeks duration and chronic (>6 weeks duration. Various clinical investigations may be initiated to diagnosis the cause. Aims: To evaluate the types of chronic urticaria with reference to etiology from history and investigations . Materials and Methods: A total of 150 patients with chronic urticaria of more than six weeks were studied. Autologous serum skin test (ASST was performed after physical urticarias were excluded. Standard batteries of tests were performed after ASST in all patients; and other specific investigations were done where necessary. Skin prick test was done in idiopathic urticaria. Results: The study sample consisted of 62 male and 88 female patients with a mean age of 21-40 years. About 50% of patients showed an ASST positive reaction, 3.9% were positive for antinuclear antibody (ANA, IgE titer was elevated in 37%, H. pylori antibodies was positive in 26.7%. Thyroid antibodies were positive in 6.2%. Giardia and entamoeba histolytica was reported in 3.3% on routine stool examination and on urinalysis 8% had elevated WBC counts; 12% showed para nasal sinusitis, with maxillary sinusitis of 7.3%. Random blood sugar was high in 5.3%. Four patients had ASOM, two had positive KOH mount for dermatophytes, abdominal USG showed cholecystitis in two patients. Recurrent tonsillitis was noted in two patients. Urticaria following intake of NSAIDs was observed in four patients and with oral contraceptive pills in one patient. Contact urticaria to condom (latex was seen in one patient. Cholinergic (4.7% and dermographic (4.7% urticaria were

  18. Lenalidomide and Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Ana Pilar González-Rodríguez


    Full Text Available Lenalidomide is an oral immunomodulatory drug used in multiple myeloma and myelodysplastic syndrome and most recently it has shown to be effective in the treatment of various lymphoproliferative disorders such as chronic lymphocytic leukemia (CLL and non-Hodgkin lymphoma. The mechanism of action of lenalidomide varies depending on the pathology, and in the case of CLL, it appears to primarily act by restoring the damaged mechanisms of tumour immunosurveillance. This review discusses the potential mechanism of action and efficacy of lenalidomide, alone or in combination, in treatment of CLL and its toxic effects such as tumor lysis syndrome (TLS and tumor flare reaction (TFR, that make its management different from other hematologic malignancies.

  19. Chronic Lyme disease: a review. (United States)

    Marques, Adriana


    Studies have shown that most patients diagnosed with chronic Lyme disease either have no objective evidence of previous or current infection with Borrelia burgdorferi or are patients who should be classified as having post-Lyme disease syndrome, which is defined as continuing or relapsing nonspecific symptoms (such as fatigue, musculoskeletal pain, and cognitive complaints) in a patient previously treated for Lyme disease. Despite extensive study, there is currently no clear evidence that post-Lyme disease syndrome is caused by persistent infection with B burgdorferi. Four randomized placebo-controlled studies have shown that antibiotic therapy offers no sustained benefit to patients who have post-Lyme disease syndrome. These studies also showed a substantial placebo effect and a significant risk of treatment-related adverse events. Further research to elucidate the mechanisms underlying persistent symptoms after Lyme disease and controlled trials of new approaches to the treatment and management of these patients are needed.

  20. Endoscopic treatment of chronic pancreatitis

    Institute of Scientific and Technical Information of China (English)


    Treatment of chronic pancreatitis has been exclusively surgical for a long time. Recently, endoscopic therapy has become widely used as a primary therapeutic option.Initially performed for drainage of pancreatic cysts and pseudocysts, endoscopic treatments were adapted to biliary and pancreatic ducts stenosis. Pancreatic sphincterotomy which allows access to pancreatic ducts was firstly reported. Secondly, endoscopic methods of stenting, dilatation, and stones extraction of the bile ducts were applied to pancreatic ducts. Nevertheless,new improvements were necessary: failures of pancreatic stone extraction justified the development of extra-corporeal shock wave lithotripsy; dilatation of pancreatic stenosis was improved by forage with a new device; moreover endosonography allowed guidance for celiac block, gastro-cystostomy, duodeno-cystostomy and pancreatico-gastrostomy. Although endoscopic treatments are more and more frequently accepted,indications are still debated.