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Sample records for adult-onset gh deficiency

  1. Adult-Onset Deficiency in Growth Hormone and Insulin-Like Growth Factor-I Alters Oligodendrocyte Turnover in the Corpus Callosum

    PubMed Central

    Hua, Kun; Forbes, M. Elizabeth; Lichtenwalner, Robin J.; Sonntag, William E.; Riddle, David R.

    2009-01-01

    Growth hormone (GH) and insulin-like growth factor-I (IGF-I) provide trophic support during development and also appear to influence cell structure, function and replacement in the adult brain. Recent studies demonstrated effects of the GH/IGF-I axis on adult neurogenesis, but it is unclear whether the GH/IGF-I axis influences glial turnover in the normal adult brain. In the current study we used a selective model of adult-onset GH and IGF-I deficiency to evaluate the role of GH and IGF-I in regulating glial proliferation and survival in the adult corpus callosum. GH/IGF-I-deficient dwarf rats of the Lewis strain were made GH/IGF-I replete via twice daily injections of GH starting at postnatal day 28 (P28), approximately the age at which GH pulse amplitude increases in developing rodents. GH/IGF-I deficiency was initiated in adulthood by removing animals from GH treatment. Quantitative analyses revealed that adult-onset GH/IGF-I deficiency decreased cell proliferation in the white matter and decreased the survival of newborn oligodendrocytes. These findings are consistent with the hypothesis that aging-related changes in the GH/IGF-I axis produce deficits in ongoing turnover of oligodendrocytes, which may contribute to aging-related cognitive changes and deficits in remyelination after injury. PMID:19115393

  2. A mouse model of adult-onset anaemia due to erythropoietin deficiency.

    PubMed

    Yamazaki, Shun; Souma, Tomokazu; Hirano, Ikuo; Pan, Xiaoqing; Minegishi, Naoko; Suzuki, Norio; Yamamoto, Masayuki

    2013-01-01

    Erythropoietin regulates erythropoiesis in a hypoxia-inducible manner. Here we generate inherited super-anaemic mice (ISAM) as a mouse model of adult-onset anaemia caused by erythropoietin deficiency. ISAM express erythropoietin in the liver but lack erythropoietin production in the kidney. Around weaning age, when the major erythropoietin-producing organ switches from the liver to the kidney, ISAM develop anaemia due to erythropoietin deficiency, which is curable by administration of recombinant erythropoietin. In ISAM severe chronic anaemia enhances transgenic green fluorescent protein and Cre expression driven by the complete erythropoietin-gene regulatory regions, which facilitates efficient labelling of renal erythropoietin-producing cells. We show that the majority of cortical and outer medullary fibroblasts have the innate potential to produce erythropoietin, and also reveal a new set of erythropoietin target genes. ISAM are a useful tool for the evaluation of erythropoiesis-stimulating agents and to trace the dynamics of erythropoietin-producing cells. PMID:23727690

  3. Case report: An adult-onset type II citrin deficiency patient in the emergency department

    PubMed Central

    TANG, LUJIA; CHEN, LIANG; WANG, HAIRONG; DAI, LIHUA; PAN, SHUMING

    2016-01-01

    Mutations in the solute carrier family 25 (SLC25A13) gene may result in neonatal intrahepatic cholestasis caused by citrin deficiency and/or adult-onset type II citrullinemia. These conditions are inherited in an autosomal recessive manner. The current case report describes a 43-year-old man who presented with sudden delirium and upper limb weakness. Upon admission, the patient was fully conscious and alert but later lost consciousness subsequent to a sudden convulsive seizure. Hyperammonemia was detected and analysis of the SLC25A13 gene identified an 851del4 mutation. Thus, the possibility of genetic disease should be considered as a potential cause of the symptoms of patients with altered states of consciousness, such as delirium and loss of consciousness, in cases where the cause of the disturbance is unknown. PMID:27347070

  4. GH deficiency status combined with GH receptor polymorphism affects response to GH in children

    PubMed Central

    Valsesia, Armand; Chatelain, Pierre; Stevens, Adam; Peterkova, Valentina A; Belgorosky, Alicia; Maghnie, Mohamad; Antoniazzi, Franco; Koledova, Ekaterina; Wojcik, Jerome; Farmer, Pierre; Destenaves, Benoit; Clayton, Peter

    2015-01-01

    Meta-analysis has shown a modest improvement in first-year growth response to recombinant human GH (r-hGH) for carriers of the exon 3-deleted GH receptor (GHRd3) polymorphism but with significant interstudy variability. The associations between GHRd3 and growth response to r-hGH over 3 years in relation to severity of GH deficiency (GHD) were investigated in patients from 14 countries. Treatment-naïve pre-pubertal children with GHD were enrolled from the PREDICT studies (NCT00256126 and NCT00699855), categorized by peak GH level (peak GH) during provocation test: ≤4 μg/l (severe GHD; n=45) and >4 to <10 μg/l mild GHD; n=49) and genotyped for the GHRd3 polymorphism (full length (fl/fl, fl/d3, d3/d3). Gene expression (GE) profiles were characterized at baseline. Changes in growth (height (cm) and SDS) over 3 years were measured. There was a dichotomous influence of GHRd3 polymorphism on response to r-hGH, dependent on peak GH level. GH peak level (higher vs lower) and GHRd3 (fl/fl vs d3 carriers) combined status was associated with height change over 3 years (P<0.05). GHRd3 carriers with lower peak GH had lower growth than subjects with fl/fl (median difference after 3 years −3.3 cm; −0.3 SDS). Conversely, GHRd3 carriers with higher peak GH had better growth (+2.7 cm; +0.2 SDS). Similar patterns were observed for GH-dependent biomarkers. GE profiles were significantly different between the groups, indicating that the interaction between GH status and GHRd3 carriage can be identified at a transcriptomic level. This study demonstrates that responses to r-hGH depend on the interaction between GHD severity and GHRd3 carriage. PMID:26340968

  5. GH deficiency status combined with GH receptor polymorphism affects response to GH in children.

    PubMed

    Valsesia, Armand; Chatelain, Pierre; Stevens, Adam; Peterkova, Valentina A; Belgorosky, Alicia; Maghnie, Mohamad; Antoniazzi, Franco; Koledova, Ekaterina; Wojcik, Jerome; Farmer, Pierre; Destenaves, Benoit; Clayton, Peter

    2015-12-01

    Meta-analysis has shown a modest improvement in first-year growth response to recombinant human GH (r-hGH) for carriers of the exon 3-deleted GH receptor (GHRd3) polymorphism but with significant interstudy variability. The associations between GHRd3 and growth response to r-hGH over 3 years in relation to severity of GH deficiency (GHD) were investigated in patients from 14 countries. Treatment-naïve pre-pubertal children with GHD were enrolled from the PREDICT studies (NCT00256126 and NCT00699855), categorized by peak GH level (peak GH) during provocation test: ≤4 μg/l (severe GHD; n=45) and >4 to <10 μg/l mild GHD; n=49) and genotyped for the GHRd3 polymorphism (full length (fl/fl, fl/d3, d3/d3). Gene expression (GE) profiles were characterized at baseline. Changes in growth (height (cm) and SDS) over 3 years were measured. There was a dichotomous influence of GHRd3 polymorphism on response to r-hGH, dependent on peak GH level. GH peak level (higher vs lower) and GHRd3 (fl/fl vs d3 carriers) combined status was associated with height change over 3 years (P<0.05). GHRd3 carriers with lower peak GH had lower growth than subjects with fl/fl (median difference after 3 years -3.3 cm; -0.3 SDS). Conversely, GHRd3 carriers with higher peak GH had better growth (+2.7 cm; +0.2 SDS). Similar patterns were observed for GH-dependent biomarkers. GE profiles were significantly different between the groups, indicating that the interaction between GH status and GHRd3 carriage can be identified at a transcriptomic level. This study demonstrates that responses to r-hGH depend on the interaction between GHD severity and GHRd3 carriage. PMID:26340968

  6. An adult onset case of alpha-methyl-acyl-CoA racemase deficiency.

    PubMed

    Smith, Emily Helen; Gavrilov, Dimitar K; Oglesbee, Devin; Freeman, William D; Vavra, Michael W; Matern, Dietrich; Tortorelli, Silvia

    2010-12-01

    α-Methyl-acyl-CoA-racemase (AMACR) deficiency (OMIM 604489) is a rare peroxisomal disorder with a variable age of onset from infancy to late adulthood. We describe a 45-year-old male with a history of seizures who presented with relapsing encephalopathy. Laboratory studies revealed an elevated serum pristanic acid concentration, an elevated pristanic/phytanic acid ratio, as well as the previously described homozygous mutation in the AMACR gene, c.154T>C, consistent with AMACR deficiency. This homozygous mutation is associated with a variable phenotype ranging from neonatal cholestasis to late-onset sensorimotor neuropathy. Dietary pristanic acid restriction was attempted to improve clinical status and the patient has remained in remission for more than 16 months. PMID:20821052

  7. Adult-onset multiple acyl CoA dehydrogenation deficiency associated with an abnormal isoenzyme pattern of serum lactate dehydrogenase.

    PubMed

    Sugai, Fuminobu; Baba, Kousuke; Toyooka, Keiko; Liang, Wen-Chen; Nishino, Ichizo; Yamadera, Misaki; Sumi, Hisae; Fujimura, Harutoshi; Nishikawa, Yoshiro

    2012-02-01

    We report a case of a 37 year-old male with multiple acyl-CoA dehydrogenation deficiency (MADD). The patient had suffered from exercise intolerance in his hip and thigh muscles for one year. Then, restriction of carbohydrates for a diet made his symptoms rapidly deteriorate. Blood test revealed compound heterozygosity for two novel missense mutations in the electron transfer flavoprotein dehydrogenase gene (ETFDH), and an abnormal LDH isoenzyme pattern: LDH-1 (60.0%) and LDH-2 (26.0%) predominated with abnormally elevated LDH-1/LDH-2 ratio (2.3), compared with muscle-derived LDH-5 (4.0%). Oral riboflavin treatment significantly improved his exercise intolerance and the LDH profile: LDH-1 (34.4%), LDH-2 (34.9%), LDH-5 (6.9%) and LDH-1/LDH-2 ratio (1.0). The abnormal LDH isoenzyme pattern may be one feature of adult-onset MADD selectively affecting type I muscle fibers with relatively high LDH-1 content. PMID:21907580

  8. Adult combined GH, prolactin, and TSH deficiency associated with circulating PIT-1 antibody in humans

    PubMed Central

    Yamamoto, Masaaki; Iguchi, Genzo; Takeno, Ryoko; Okimura, Yasuhiko; Sano, Toshiaki; Takahashi, Michiko; Nishizawa, Hitoshi; Handayaningshi, Anastasia Evi; Fukuoka, Hidenori; Tobita, Maya; Saitoh, Takatoshi; Tojo, Katsuyoshi; Mokubo, Atsuko; Morinobu, Akio; Iida, Keiji; Kaji, Hidesuke; Seino, Susumu; Chihara, Kazuo; Takahashi, Yutaka

    2010-01-01

    The pituitary-specific transcriptional factor-1 (PIT-1, also known as POU1F1), is an essential factor for multiple hormone-secreting cell types. A genetic defect in the PIT-1 gene results in congenital growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH) deficiency. Here, we investigated 3 cases of adult-onset combined GH, PRL, and TSH deficiencies and found that the endocrinological phenotype in each was linked to autoimmunity directed against the PIT-1 protein. We detected anti–PIT-1 antibody along with various autoantibodies in the patients’ sera. An ELISA-based screening revealed that this antibody was highly specific to the disease and absent in control subjects. Immunohistochemical analysis revealed that PIT-1–, GH-, PRL-, and TSH-positive cells were absent in the pituitary of patient 2, who also had a range of autoimmune endocrinopathies. These clinical manifestations were compatible with the definition of autoimmune polyendocrine syndrome (APS). However, the main manifestations of APS-I — hypoparathyroidism and Candida infection — were not observed and the pituitary abnormalities were obviously different from the hypophysitis associated with APS. These data suggest that these patients define a unique “anti–PIT-1 antibody syndrome,” related to APS. PMID:21123951

  9. The robustness of diagnostic tests for GH deficiency in adults.

    PubMed

    Andersen, Marianne

    2015-06-01

    Since the 1970s, GH treatment has been an important tool in paediatric endocrinology for the management of growth retardation. It is now accepted that adults with severe GH deficiency (GHD) demonstrate impaired physical and psychological well-being and may benefit from replacement therapy with recombinant human GH. There is, however, an ongoing debate on how to diagnose GHD, especially in adults. A GH response below the cut-off limit of a GH-stimulation test is required in most cases for establishing GHD in adults. No 'gold standard' GH-stimulation test exists, but some GH stimulation tests may be more robust to variations in patient characteristics such as age and gender, as well as to pre-test conditions like heat exposure due to a hot bath or bicycling. However, body mass index (BMI) is negatively associated with GH-responses to all available GH-stimulation tests and glucocorticoid treatment, including conventional substitution therapy, influences the GH-responses. Recently, the role of IGF-I measurements in the clinical decision making has been discussed. The aim of this review is to discuss the available GH-stimulation tests. In this author's opinion, tests which include growth-hormone-releasing hormone (GHRH) tend to be more potent and robust, especially the GHRH+arginine test which has been proven to be of clinical use. In contrast, the insulin tolerance test (ITT) and the glucagon test appear to have too many drawbacks. PMID:25900364

  10. Considering GH replacement for GH-deficient adults with a previous history of cancer: a conundrum for the clinician.

    PubMed

    Yuen, Kevin C J; Heaney, Anthony P; Popovic, Vera

    2016-05-01

    Previous studies have shown that GH and IGF-I may enhance tumorigenesis, metastasis, and cell proliferation in humans and animals. Evidence supporting this notion is derived from animal model studies, epidemiological studies, experience from patients with acromegaly, molecular therapeutic manipulation of GH and IGF-I actions, and individuals with GH receptor and congenital IGF-I deficiencies. Prior exposure to radiation therapy, aging, family history of cancer, and individual susceptibility may also contribute to increase this risk. Therefore, the use of GH replacement in patients with a history of cancer raises hypothetical safety concerns for patients, caregivers, and providers. Studies of GH therapy in GH-deficient adults with hypopituitarism and childhood cancer survivors have not convincingly demonstrated an increased cancer risk. Conversely, the risk of occurrence of a second neoplasm (SN) in childhood cancer survivors may be increased, with meningiomas being the most common tumor; however, this risk appears to decline over time. In light of these findings, if GH replacement is to be considered in patients with a previous history of cancer, we propose this consideration to be based on each individual circumstance and that such therapy should only be initiated at least 2 years after cancer remission is achieved with the understanding that in some patients (particularly those with childhood cancers), GH may potentially increase the risk of SNs. In addition, close surveillance should be undertaken working closely with the patient's oncologist. More long-term data are thus needed to determine if GH replacement in GH-deficient adults with a history of cancer is associated with the development of de novo tumors and tumor recurrence. PMID:26732039

  11. Adult neuronal ceroid lipofuscinosis with palmitoyl-protein thioesterase deficiency: first adult-onset patients of a childhood disease.

    PubMed

    van Diggelen, O P; Thobois, S; Tilikete, C; Zabot, M T; Keulemans, J L; van Bunderen, P A; Taschner, P E; Losekoot, M; Voznyi, Y V

    2001-08-01

    The fluorogenic enzyme assay for palmitoyl-protein thioesterase (PPT) has greatly facilitated the diagnosis of infantile neuronal ceroid lipofuscinosis (Santavuori-Haltia disease) and the search for possible new variants with atypical clinical presentation. Here, we present the first cases of adult neuronal ceroid lipofuscinosis with onset in the fourth decade of life due to a profound deficiency of PPT. The causative mutations in the CLN1 gene were the known, deleterious mutation R151X and the novel missense mutation G108R. Patients presented at onset (31 and 38 years), with psychiatric symptoms only. At present (ages 56 and 54 years), visual, verbal, and cognitive losses have progressed and both patients have cerebellar ataxia and cannot walk without support. PMID:11506414

  12. Adult onset retinoblastoma.

    PubMed

    Sengupta, Sabyasachi; Pan, Utsab; Khetan, Vikas

    2016-07-01

    Retinoblastoma (RB) is the most common primary malignant intraocular tumor of childhood presenting usually before 5 years of age. RB in adults older than 20 years is extremely rare. A literature search using PubMed/PubMed Central, Scopus, Google Scholar, EMBASE, and Cochrane databases revealed only 45 cases till date. Over the past decade, there has been a significant increase in the number of such reports, indicating heightened level of suspicion among ophthalmologists. Compared to its pediatric counterpart, adult onset RB poses unique challenges in diagnosis and treatment. This article summarizes available literature on adult onset RB and its clinical and pathologic profile, genetics, association with retinocytoma, diagnostics, treatment, and outcomes. PMID:27609158

  13. Subjects with isolated GH deficiency due to a null GHRHR mutation eat proportionally more, but healthier than controls.

    PubMed

    Oliveira-Santos, Alécia A; Salvatori, Roberto; Gomes-Santos, Elenilde; Santana, João A M; Leal, Ângela C G B; Barbosa, Rita A A; Oliveira, Carla R P; Souza, Anita H O; Valença, Eugênia H O; Aguiar-Oliveira, Manuel H

    2016-02-01

    The GH/IGF-I axis has important interactions with the alimentary system and with the balance between energy intake (EI) and energy requirement (ER). Reduced EI has been described in adult-onset acquired GH deficiency (GHD). Individuals from the Brazilian Itabaianinha cohort, with isolated GHD (IGHD) due to a homozygous mutation (c.57+1G→A) in the GHRH receptor gene, are an ideal model to study the consequences of lifetime GHD. The purpose of this study is to evaluate EI and ER in this untreated IGHD cohort. Cross-sectional study of 24 adult IGHD patients and 23 controls from the same region, matched for age and gender. Estimated EI (EEI) was evaluated by dietary recall, and estimated ER (EER) by the equation of the Dietary Reference Intakes. Fat mass was assessed by DXA. Both EEI and EER were lower in IGHD than controls. However, when corrected by body weight, EEI was higher in IGHD (p = 0.005). IGHD individuals consume in percentage more proteins (p < 0.0001), less carbohydrates (p = 0.013), and equal amount of lipids in comparison to controls. The higher EEI per body weight suggests a possible increase of orexigenic mechanisms in untreated IGHD individuals, ensuring greater caloric intake, which would have adaptive advantages for small-sized individuals in environments with limited access to food. IGHD individuals seem to have a healthier dietary pattern than CO. PMID:26100788

  14. A case of GH deficiency and beta-thalassemia.

    PubMed

    Smacchia, M P; Mercuri, V; Antonetti, L; Bassotti, G; D'Amico, T; Pietrobono, D; Gargiulo, P

    2012-06-01

    A 23-year-old male patient, who suffers from beta-thalassemia major, came to us for an endocrine-metabolic evaluation. Medical history showed a diagnosis of heart disease with heart failure since the age of 16, type 1 diabetes mellitus diagnosed at the age of 18, treated with an intensive insulin therapy with a poor glycometabolic control. Patient performed regular blood transfusions and iron chelation with deferasirox. An echocardiogram revealed an enlarged left ventricle. Patient had undergone a comprehensive study of buoyancy both basal and hormone-stimulated and it was therefore carried out a diagnosis of GH deficiency and hypogonadotropic hypogonadism. A recombinant GH replacement therapy was then prescribed. After six months of therapy, the patient reported a net improvement of asthenic symptoms. Physical examination showed a reduction in abdominal adiposity in waist and an increase of 5 cm in stature. Laboratory tests showed an amelioration of glycometabolic control, such as to justify a reduction in daily insulin dose. The stature observed was thought appropriate to begin the administration of testosterone. Moreover, the cardiological framework showed a reduction of left ventricular dilatation, good ventricular motility, global minimum persistent tricuspid but not mitral regurgitation and no alteration on ECG. PMID:22691893

  15. Effect of biosynthetic methionyl growth hormone (GH) therapy on the immune function in GH-deficient children.

    PubMed

    Bozzola, M; Cisternino, M; Valtorta, A; Moretta, A; Biscaldi, I; Maghnie, M; De Amici, M; Schimpff, R M

    1989-01-01

    The ability of growth hormone (GH) to influence certain immune functions has been studied in 21 GH-deficient children aged 1.8-17.7 years, before and during therapy with biosynthetic methionyl-hGH (12 IU/m2) injected intramuscularly 3 times weekly. Blood was collected prior to GH treatment, then after 1 week, again at 3-6 months, and finally at 9-12 months of therapy. We studied (1) the distribution of the T lymphocyte subpopulations: T total (CD3), helper/inducer (CD4) and suppressor/cytotoxic (CD8) cells, using monoclonal antibodies (OKT3, OKT4, OKT8) and (2) the in vitro IgM production stimulated by pokeweed mitogen. Pretreatment CD3, CD4, CD8 values were within the normal range. They did not change after 1 week of GH therapy. Following 3-6 months of GH treatment, CD3 significantly increased (p less than 0.001), CD4 decreased (p less than 0.01), CD8 increased (p less than 0.001) and the CD4/CD8 ratio decreased (p less than 0.001). At 9-12 months of therapy, the percentages of the different groups of T cells was not significantly different from the pretreatment values. In vitro IgM production before and following 3-6 months of GH treatment was significantly lower (p less than 0.005) than that of 15 age-matched controls. At 9-12 months, GH therapy restored the in vitro IgM production. No variations in the levels of serum immunoglobulins were observed throughout the treatment period. These data suggest that GH plays a role in the development of the immune function in children. PMID:2571554

  16. Therapeutic Efficacy and Safety of GH in Japanese Children with Down Syndrome Short Stature Accompanied by GH Deficiency

    PubMed Central

    Meguri, Kyoko; Inoue, Masaru; Narahara, Koji; Sato, Takahiro; Takata, Ami; Ohki, Nobuhiko; Ozono, Keiichi

    2013-01-01

    In this study, we investigated the effects of GH treatment in children with Down syndrome who had been diagnosed with GH deficiency (GHD). A total of 20 subjects were investigated in this study. Fourteen Down syndrome children (5 boys and 9 girls) with short stature due to GHD were treated with GH at Okayama Red Cross General Hospital, and 6 Down syndrome children (4 boys and 2 girls) with short stature due to GHD were registered in the Pfizer International Growth Database (KIGS). Height SD score (SDS) increased throughout the three-year GH treatment period. The overall mean height SDS increased from –3.5 at baseline to –2.5 after 3 yr of treatment. The mean change in height SDS during these 3 yr was 1.1. In addition, height assessment of SD score based on Down syndrome-specific growth data in the Japanese population revealed that the height SDS (Down syndrome) also increased across the 3-yr GH treatment period. The mean change in height SDS (Down syndrome) during these three years was 1.3. GH therapy was effective for Down syndrome short stature accompanied by GHD, and no new safety concerns were found in this study. PMID:24170963

  17. Estrogen priming effect on growth hormone (GH) provocative test: a useful tool for the diagnosis of GH deficiency.

    PubMed

    Martínez, A S; Domené, H M; Ropelato, M G; Jasper, H G; Pennisi, P A; Escobar, M E; Heinrich, J J

    2000-11-01

    We have studied the effect of estradiol (E2) on the GH-insulin-like growth factor (GH-IGF) axis in 15 prepubertal GH deficiency (GHD) children and 44 prepubertal or early pubertal children with idiopathic short stature (SS). All of them received a daily dose of micronized E2 (1 or 2 mg) or placebo, for 3 days, before a sequential arginine-clonidine test. In SS children, GH maximal responses were 17.8+/-10.9 on placebo and 27.9+/-14.5 microg/L on estrogen (P < 0.0001). The lower 95% confidence limits for GH maximal response changed from 3.7 microg/L (without E2) to 8.3 microg/L (on E2). In GHD children, no significant stimulatory effect of estrogen on GH levels was observed. After placebo, a cut-off limit of 3.7 microg/L (the lower 95% confidence interval limit) resulted in 73% sensitivity, 95% specificity, and an overall 90% diagnostic efficiency. After E2, a cut-off limit of 8.3 microg/L resulted in a sensitivity of 87%, a specificity of 98%, and a diagnostic efficiency of 95%. After placebo, 68% of SS showed normal IGF-I levels, and the mean did not change on E2 (13.7+/-6.3 vs. 14.3+/-6.8 nmol/L, not significant). In 93% of SS, IGF binding protein (IGFBP)-3 levels were normal during placebo. On E2, mean IGFBP-3 did not change (2.63+/-0.70 vs. 2.70+/-0.70 mg/L, not significant). In 14 of 15 GHD patients, IGF-I values were below normal on placebo, and the mean of the group did not change after E2. During placebo, 13 of 15 GHD children presented low IGFBP-3 values. During E2, there was a small significant increase in IGFBP-3 values (1.06+/-0.58 vs. 1.20+/-0.69 mg/L, P < 0.02). The highest diagnostic efficiencies for IGF-I and IGFBP-3 were observed during placebo (75% and 91%, respectively). We conclude that GH stimulation tests after E2 priming had the highest diagnostic efficiency. Our findings suggest that the effect of estrogen priming on GH stimulated levels, by reducing the number of false nonresponders, might be useful to better discriminate between normal and

  18. Liver status in congenital, untreated, isolated GH deficiency

    PubMed Central

    Diniz, Rachel D C A; Souza, Renata M; Salvatori, Roberto; Franca, Alex; Gomes-Santos, Elenilde; Ferrão, Thiago O; Oliveira, Carla R P; Santana, João A M; Pereira, Francisco A; Barbosa, Rita A A; Souza, Anita H O; Pereira, Rossana M C; Oliveira-Santos, Alécia A; Silva, Allysson M P; Santana-Júnior, Francisco J; Valença, Eugênia H O; Campos, Viviane C; Aguiar-Oliveira, Manuel H

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is known to be associated with insulin resistance, atherosclerosis, and low serum IGF1 levels. We have described a large cohort of patients with isolated GH deficiency (IGHD) due to the c.57+1G→A mutation in the GHRH receptor gene. These subjects have increased insulin sensitivity (IS), delayed atherosclerosis, and normal longevity. We hypothesized that, despite visceral obesity, NAFLD would be absent or mild due to the increased IS. To assess the prevalence and severity of NAFLD in adult subjects with lifetime, congenital, untreated IGHD, we studied 22 IGHD adults and 25 controls (COs) matched for age and sex. NAFLD was assessed by a comprehensive liver function panel, and ultrasonographic pattern (hyperechogenic pattern, HP) coded as follows: 0, absent; 1, mild; 2, moderate; and 3, severe. Compared with COs, IGHD individual had lower serum IGF1 (P<0.0001), higher total cholesterol (P=0.027), lower prothrombin time (P=0.017), and similar activated partial thromboplastin time and fibrinogen values. Alanine transaminase (ALT) values were similar in the two groups, but aspartate transaminase was higher in IGHD (P=0.013). However, more IGHD subjects (7/22) than COs (3/23) had ALT above the upper limit of normal (P=0.044). The prevalence of NAFLD was higher in IGHD than COs (61 vs 29%, P=0.032), and the HP score was higher in IGHD than COs (P=0.041), but severe NAFLD was not observed in any IGHD (or CO) individual. Liver HP score is increased in lifetime, untreated, congenital IGHD, but the increase in transaminases is mild, suggesting a lack of advanced forms of NAFLD. PMID:25117570

  19. Adult-Onset Hypogonadism.

    PubMed

    Khera, Mohit; Broderick, Gregory A; Carson, Culley C; Dobs, Adrian S; Faraday, Martha M; Goldstein, Irwin; Hakim, Lawrence S; Hellstrom, Wayne J G; Kacker, Ravi; Köhler, Tobias S; Mills, Jesse N; Miner, Martin; Sadeghi-Nejad, Hossein; Seftel, Allen D; Sharlip, Ira D; Winters, Stephen J; Burnett, Arthur L

    2016-07-01

    In August 2015, an expert colloquium commissioned by the Sexual Medicine Society of North America (SMSNA) convened in Washington, DC, to discuss the common clinical scenario of men who present with low testosterone (T) and associated signs and symptoms accompanied by low or normal gonadotropin levels. This syndrome is not classical primary (testicular failure) or secondary (pituitary or hypothalamic failure) hypogonadism because it may have elements of both presentations. The panel designated this syndrome adult-onset hypogonadism (AOH) because it occurs commonly in middle-age and older men. The SMSNA is a not-for-profit society established in 1994 to promote, encourage, and support the highest standards of practice, research, education, and ethics in the study of human sexual function and dysfunction. The panel consisted of 17 experts in men's health, sexual medicine, urology, endocrinology, and methodology. Participants declared potential conflicts of interest and were SMSNA members and nonmembers. The panel deliberated regarding a diagnostic process to document signs and symptoms of AOH, the rationale for T therapy, and a monitoring protocol for T-treated patients. The evaluation and management of hypogonadal syndromes have been addressed in recent publications (ie, the Endocrine Society, the American Urological Association, and the International Society for Sexual Medicine). The primary purpose of this document was to support health care professionals in the development of a deeper understanding of AOH, particularly in how it differs from classical primary and secondary hypogonadism, and to provide a conceptual framework to guide its diagnosis, treatment, and follow-up. PMID:27343020

  20. Prolonged retention after aggregation into secretory granules of human R183H-growth hormone (GH), a mutant that causes autosomal dominant GH deficiency type II.

    PubMed

    Zhu, Yong Lian; Conway-Campbell, Becky; Waters, Michael J; Dannies, Priscilla S

    2002-11-01

    Human R183H-GH causes autosomal dominant GH deficiency type II. Because we show here that the mutant hormone is fully bioactive, we have sought to locate an impairment in its progress through the secretory pathway as assessed by pulse chase experiments. Newly synthesized wild-type and R183H-GH were stable when expressed transiently in AtT20 cells, and both formed equivalent amounts of Lubrol-insoluble aggregates within 40 min after synthesis. There was no evidence for intermolecular disulfide bond formation in aggregates of wild-type hormone or the R183H mutant. Both wild-type and R183H-GH were packaged into secretory granules, assessed by the ability of 1 mM BaCl2 to stimulate release and by immunocytochemistry. The mutant differed from wild-type hormone in its retention in the cells after packaging into secretory granules; 50% more R183H-GH than wild-type aggregates were retained in AtT20 cells 120 min after synthesis, and stimulated release of R183H-GH or a mixture of R183H-GH and wild-type that had been retained in the cell was reduced. The longer retention of R183H-GH aggregates indicates that a single point mutation in a protein contained in secretory granules affects the rate of secretory granule release. PMID:12399418

  1. Elevated GH/IGF-I promotes mammary tumors in high-fat, but not low-fat, fed mice.

    PubMed

    Gahete, Manuel D; Córdoba-Chacón, José; Lantvit, Daniel D; Ortega-Salas, Rosa; Sanchez-Sanchez, Rafael; Pérez-Jiménez, Francisco; López-Miranda, José; Swanson, Steven M; Castaño, Justo P; Luque, Raúl M; Kineman, Rhonda D

    2014-11-01

    Growth hormone (GH) and/or insulin-like growth factor I (IGF-I) are thought to promote breast cancer based on reports showing circulating IGF-I levels correlate, in epidemiological studies, with breast cancer risk. Also, mouse models with developmental GH/IGF-I deficiency/resistance are less susceptible to genetic- or chemical-induced mammary tumorigenesis. However, given the metabolic properties of GH, medical strategies have been considered to raise GH to improve body composition and metabolic function in elderly and obese patients. Since hyperlipidemia, inflammation, insulin resistance and obesity increase breast cancer risk, elevating GH may serve to exacerbate cancer progression. To better understand the role GH/IGF-I plays in tumor formation, this study used unique mouse models to determine if reducing GH/IGF-I in adults protects against 7,12-dimethylbenz[α]anthracene (DMBA)-induced mammary tumor development, and if moderate elevations in endogenous GH/IGF-I alter DMBA-induced tumorigenesis in mice fed a standard-chow diet or in mice with altered metabolic function due to high-fat feeding. We observed that adult-onset isolated GH-deficient mice, which also have reduced IGF-I levels, were less susceptible to DMBA-treatment. Specifically, fewer adult-onset isolated GH-deficient mice developed mammary tumors compared with GH-replete controls. In contrast, chow-fed mice with elevated endogenous GH/IGF-I (HiGH mice) were not more susceptible to DMBA-treatment. However, high-fat-fed, HiGH mice showed reduced tumor latency and increased tumor incidence compared with diet-matched controls. These results further support a role of GH/IGF-I in regulating mammary tumorigenesis but suggest the ultimate consequences of GH/IGF-I on breast tumor development are dependent on the diet and/or metabolic status. PMID:25085903

  2. Short-Term, Low-Dose GH Therapy Improves Insulin Sensitivity Without Modifying Cortisol Metabolism and Ectopic Fat Accumulation in Adults With GH Deficiency

    PubMed Central

    Roberts, Charles T.; Frystyk, Jan; Rooney, William D.; Pollaro, James R.; Klopfenstein, Bethany J.; Purnell, Jonathan Q.

    2014-01-01

    Context: Low-dose GH (LGH) therapy has been reported to improve insulin sensitivity in GH-deficient adults; however, the mechanism is unclear. Hypothesis: Effects of LGH therapy on insulin sensitivity are mediated through changes in cortisol metabolism and ectopic fat accumulation. Design and Setting: This was a double-blind, placebo-controlled, parallel, 3-month study. Participants and Intervention: Seventeen GH-deficient adults were randomized to receive either daily LGH or placebo injections. Fasting blood samples were collected at baseline, and months 1 and 3, whereas hyperinsulinemic-euglycemic clamps, magnetic resonance spectroscopy scans, 24-hour cortisol production rates (CPRs), and sc abdominal fat biopsies were performed at baseline and month 3. Main Outcome Measures: Clamp glucose infusion rate, intramyocellular, extramyocellular, and intrahepatic lipid content, 24-hour CPRs, adipocyte size, and adipocyte 11β-hydroxysteroid dehydrogenase activity in adults with GH deficiency were evaluated. Results: At month 1, LGH did not alter fasting levels of glucose, insulin, C-peptide, free fatty acid, adiponectin, total IGF-1, IGF-1 bioactivity, IGF-2, IGF binding protein (IGFBP)-2, or IGF-1 to IGFBP-3 molar ratio. At month 3, LGH increased clamp glucose infusion rates (P < .01) and IGF-1 to IGFBP-3 molar ratio (P < .05), but fasting glucose, insulin, C-peptide, free fatty acid, adiponectin, IGF-1 bioactivity, IGF-2, IGFBP-2, 24-hour CPRs, adipocyte size, adipocyte 11β-hydroxysteroid dehydrogenase activity, intrahepatic lipid, extramyocellular, or intramyocellular were unchanged. In the placebo group, all within-group parameters from months 1 and 3 compared with baseline were unchanged. Conclusions: Short-term LGH therapy improves insulin sensitivity without inducing basal lipolysis and had no effect on cortisol metabolism and ectopic fat accumulation in GH-deficient adults. This may reflect an LGH-induced increase in IGF-1 to IGFBP-3 molar ratio exerting

  3. Late-adult onset Leigh syndrome.

    PubMed

    McKelvie, Penelope; Infeld, Bernard; Marotta, Rosetta; Chin, Judy; Thorburn, David; Collins, Steven

    2012-02-01

    We report an illustrative case of a 74-year-old man who, in the absence of intercurrent illness, presented with rapid cognitive decline. MRI showed bilateral, symmetrical, high T2-weighted signal in the anterior basal ganglia and medial thalami, extending to the periaqueductal grey matter, basal ganglia and basal frontal lobes. A (18)F-fluorodeoxyglucose-positron emission tomography scan showed widespread reduction of metabolism in the cortex of the frontal, temporal and parietal lobes, posterior cingulate gyrus, precuneus and caudate nuclei, with sparing of the sensorimotor cortex, thalami and lentiform nuclei. A mild vitamin B12 deficiency was found and despite normal thiamine levels, intravenous (IV) thiamine and vitamin B therapy was commenced, with a short course of IV methylprednisolone and tetracycline. Repeat neuropsychological assessment four weeks following treatment revealed increased alertness and interactiveness but significant cognitive decline persisted. Unexpectedly, the patient suffered a transmural anterior myocardial infarction six weeks after presentation and died within 24hours. An a autopsy showed: global reduction in cytochrome oxidase (COX) activity in all skeletal muscles examined; bilateral, symmetrical, hypervascular, focally necrotizing lesions in the substantia nigra, periaqueductal grey matter, superior colliculi, medial thalami anteriorly and posteriorly, as well as in the putamena but the mammillary bodies were not affected. Biochemical analysis of fresh muscle confirmed selective deficiency of complex IV of the oxidative phosphorylation chain. A diagnosis of late-adult onset Leigh syndrome was made. Multiple genetic studies failed to identify the specific underlying mutation. The relevant literature is reviewed. PMID:22273117

  4. [Adult-onset rare diseases].

    PubMed

    Pfliegler, György; Kovács, Erzsébet; Kovács, György; Urbán, Krisztián; Nagy, Valéria; Brúgós, Boglárka

    2014-03-01

    The present paper is focusing on rare diseases manifesting in late childhood or adulthood. A part of these syndromes are not of genetic origin, such as relatively or absolutely rare infections, autoimmune diseases, tumours, or diseases due to rare environmental toxic agents. In addition, even a large proportion of genetic disorders may develop in adulthood or may have adult forms as well, affecting are almost each medical specialization. Examples are storage disorders (e.g. adult form of Tay-Sachs disease, Gaucher-disease), enzyme deficiencies (e.g. ornithin-transcarbamylase deficiency of the urea cycle disorders), rare thrombophilias (e.g. homozygous factor V. Leiden mutation, antithrombin deficiency), or some rare monogenic disorders such as Huntington-chorea and many others. It is now generally accepted that at least half of the 6-8000 "rare diseases" belong either to the scope of adult-care (e.g. internal medicine, neurology), or to "age-neutral" specialities such as ophtalmology, dermatology etc.). PMID:24566697

  5. Long-term effects of growth hormone (GH) replacement therapy on hematopoiesis in a large cohort of children with GH deficiency.

    PubMed

    Esposito, Andrea; Capalbo, Donatella; De Martino, Lucia; Rezzuto, Martina; Di Mase, Raffaella; Pignata, Claudio; Salerno, Mariacarolina

    2016-07-01

    The aim of our prospective case-control study was to evaluate long-term effects of GH replacement therapy on erythrocytes parameters, leukocytes, and platelets numbers in a large cohort of children with isolated GH deficiency (GHD). Hemoglobin (Hb) concentration, hematocrit (Hct), mean corpuscular volume, mean corpuscular hemoglobin, red cell distribution width, number of erythrocytes, leukocytes, neutrophils, lymphocytes, monocytes and platelets, ferritin, and C-reactive protein were evaluated in 85 children with isolated GHD (10.20 ± 3.50 years) before and annually during the first 5 years of GH replacement therapy and in 85 healthy children age and sex comparable to patients during 5 years of follow-up. Compared with controls, GHD children at study entry showed lower Hb (-1.18 ± 0.87 vs. -0.40 ± 0.90 SDS, p < 0.0001), red cells number (-0.24 ± 0.81 vs. 0.25 ± 1.14 SDS, p < 0.0001), and Hct (-1.18 ± 0.86 vs. -0.68 ± 0.99 SDS, p < 0.0001). Twelve GHD patients (14 %) showed a normocytic anemia. GH therapy was associated with a significant increase in Hb, Hct, and red cells number which became all comparable to controls within the first 2 years of treatment. Moreover, hemoglobin levels normalized in all anemic GHD patients after 5 years of therapy. No difference between patients and controls was found in leukocytes and platelets numbers neither at baseline nor during the study. GHD in childhood is associated with an impairment of erythropoiesis which causes a normocytic anemia in a considerable percentage of patients. GH replacement therapy exerts a beneficial effect leading to a significant increase of erythrocytes parameters and recovery from anemia. Neither GHD nor GH replacement treatment exerts effects on leukocytes or platelets numbers. PMID:26511947

  6. Exclusion of growth hormone (GH)-releasing hormone gene mutations in familial isolated GH deficiency by linkage and single strand conformation analysis

    SciTech Connect

    Perez Jurado, L.A.; Francke, U.; Phillips, J.A. III

    1994-03-01

    The molecular basis and the locus responsible for most familial cases of isolated GH deficiency (IGHD) are still unknown. The GH-releasing hormone (GHRH) gene has been evaluated as a possible candidate in 23 unrelated families with IGHD, 14 of whom were classified as having autosomal recessive IGHD type IB and 9 of whom had autosomal dominant IGHD type II. Three highly polymorphic microsatellites (dinucleotide repeats), mapped close to GHRH on chromosome 20 by previous linkage studies, were analyzed as markers for the GHRH locus. All available family members were genotyped for D20S44 [no recombination with GHRH at a LOD (logarithm of the odds) score of 3.6]. Noninformative families were also genotyped for D20S45 and/or D20S54 (located at {approximately} 1 and 3 centiMorgan of genetic distance from GHRH, respectively). Twenty families were informative for linkage analysis with 1 or more of these markers. They found at least 1 obligate recombinant with discordance between phenotype and genotype in 19 of the 23 families (83%). There is only a very small chance (1-3% or less) that the discordances observed are due to recombination between the GHRH locus and the marker tested. Concordant segregation was seen in only 1 type IB family (4%). When probands from this and the 3 noninformative families were screened for sequence variants in the 5 exons of the GHRH gene by single strand conformation analysis, no abnormal patterns were observed. They conclude that mutations responsible for IGHD are not within or near the structural gene for GHRH on chromosome 20 in the 23 families studied. As linkage to the GH-1 gene has also been previously excluded in 65% of these families, mutations in a locus or loci unlinked to GH-1 and GHRH must be responsible for the majority of these IGHD families. 31 refs., 4 figs., 1 tab.

  7. Update in mortality in GH-treated patients.

    PubMed

    Erfurth, Eva Marie

    2013-11-01

    During GH therapy for 2.3-9.6 years, male adult-onset GH-deficient patients with a diagnosis of a nonfunctioning adenoma have no increased all-cause mortality. However, women with adult-onset GH deficiency (GHD) are still at slightly higher risk. This general improvement in mortality is due to a more contemporary regimen of cardiovascular drugs, a refinement of surgical procedures, besides the introduction of GH therapy improved hormone replacement regimens with lowered glucocorticoid replacement, updated approaches of sex steroids for women, and less use of cranial radiotherapy. The underlying disease is the most important predictor for mortality: eg, a craniopharyngioma, malignant causes of hypopituitarism, previous Cushing's disease, and the presence of diabetes insipidus/aggressive tumors. The main cause of increased mortality was cerebrovascular diseases and infectious/respiratory diseases in ACTH-deficient patients. Furthermore, there was a significant impact of young age at disease onset and of death from secondary brain tumors, with a higher risk after cranial radiotherapy. Reports on four cohorts of GH-treated childhood-onset GHD patients have been published. Two of them included only patients with idiopathic isolated GHD, neurosecretory dysfunction, idiopathic short stature, or being born short for gestational age. Increased mortality in circulatory disorders, ill-defined diseases, and bone cancer were recorded in one study, but not in the other smaller study, where suicide and accidents caused the majority of deaths. A third childhood-onset GHD cohort included patients with a background of malignant tumors, craniopharyngioma, pituitary adenomas, pituitary aplasia/hypoplasia, and trauma. An increase of all-cause mortality was recorded in both males and females. The fourth cohort included isolated GHD and idiopathic short stature (60%), but also diagnosis of chronic renal failure and Turner's syndrome. In these latter studies, an underlying serious

  8. Adult onset xanthogranuloma presenting as laryngeal mass.

    PubMed

    Li, Shawn; Weidenbecher, Mark

    2016-01-01

    Histiocytic disorders can be classified according to the distribution pattern of the lesions and the organs involved. Non-Langerhans-cell histiocytosis is a rare group of diseases that have varied clinical presentations ranging from isolated masses to diffuse systemic eruptions. We discuss a patient who initially presented with a vocal cord lesion and was ultimately diagnosed with adult onset xanthogranuloma. PMID:26954863

  9. Induction of chronic growth hormone deficiency by anti-GH serum

    NASA Technical Reports Server (NTRS)

    Grindeland, R. E.; Smith, A. T.; Ellis, S.; Evans, E. S.

    1974-01-01

    The observations reported indicate that the growth rate of neonatal rats can be specifically inhibited for at least 78 days following the administration of antisera against growth hormone (GH) for only four days after birth. The inhibition can be correlated with a marked deficit of tibial growth promoting activity in the pituitary but not with the plasma concentrations of immuno-reactive GH.

  10. Reversible Albumin-Binding GH Possesses a Potential Once-Weekly Treatment Profile in Adult Growth Hormone Deficiency

    PubMed Central

    Janukonyté, Jurgita; Klose, Marianne; Marina, Djordje; Tanvig, Mette; Nielsen, Lene F.; Höybye, Charlotte; Andersen, Marianne; Feldt-Rasmussen, Ulla; Christiansen, Jens Sandahl

    2016-01-01

    Context: NNC0195-0092 is a reversible, albumin-binding GH derivative, developed for once-weekly administration. Objectives: The objective of the study was to evaluate safety, local tolerability, pharmacodynamics, and pharmacokinetics of multiple, once-weekly doses of NNC0195-0092, compared with daily GH. Design and Setting: This was a phase 1, randomized, open-label, active-controlled, multiple-dose, dose-escalation trial. Patients: Thirty-four GH-treated adult subjects (male, n = 25) with GH deficiency participated in the study. Interventions and Main Outcome Measures: Subjects were sequentially assigned into four cohorts of eight subjects, randomized within each cohort (3:1) to once-weekly NNC0195-0092 (n = 6) for 4 weeks (0.02, 0.04, 0.08, and 0.12 mg/kg) or daily injections of Norditropin NordiFlex (n = 2) for 4 weeks with a dose replicating the pretrial dose of somatropin. A safety assessment was performed prior to initiating treatment at the next dose level of NNC0195-0092. Daily GH treatment was discontinued 14 days before the trial start. Blood samples were drawn for assessment of safety, pharmacokinetics, pharmacodynamics (IGF-1 and IGF-binding protein-3) profiles, and immunogenicity studies. Results: Numbers of adverse events were similar at the dose levels of 0.02, 0.04, and 0.08 mg/kg NNC0195-0092 vs daily injections of Norditropin NordiFlex, whereas the number of adverse events was greater at the highest dose level of NNC0195-0092 (0.12 mg/kg). NNC0195-0092 (area under the curve[0–168h]) and peak plasma concentration) increased in a dose-dependent manner, and a dose-dependent increase in IGF-1 levels was observed. IGF-1 profiles were elevated for at least 1 week, and for the 0.02-mg/kg and 0.04-mg/kg NNC0195-0092 doses, the observed IGF-1 levels were similar to the levels for the active control group. Conclusion: Four once-weekly doses of NNC0195-0092 (dose range 0.02–0.12 mg/kg) administered to adult patients with GH deficiency were well tolerated

  11. Adult onset retinoblastoma: A diagnostic dilemma.

    PubMed

    Raj, Amit; Arya, Sudesh Kumar; Punia, Rajpal Singh; Kohli, Piyush

    2016-01-01

    Retinoblastoma is the most common intraocular tumor of childhood. About 95% of retinoblastoma cases are diagnosed before the age of 5 years. Not more than 30 cases of Adult-onset retinoblastoma have been reported in literature. A 32 year old male presented with a painful blind eye. There was sudden loss of vision accompanied by severe pain and redness in right eye about 1 year ago, for which some surgery was done with neither a gain in vision nor any relief from pain. Then he was put on maximum tolerable medical therapy, later cyclocryotherapy was done. Now he presented to us with complains of extreme pain and bleeding from right eye since 2 days. There is no history of any ocular trauma. Right eye had no perception of light & showed anterior staphyloma with perforation. Right eye evisceration was done & material sent for histopathological examination, which revealed an adult-onset retinoblastoma. CECT scan revealed thickening of optic nerve throughout its entire length with contrast enhancement. He was further taken up for enucleation of residual sclera with maximum optic nerve stump removal to reconfirm the diagnosis. Histopathological examination revealed tumor deposits present in orbital soft tissue, resection margins and optic nerve cut end.Retinoblastoma presenting in adult age creates a diagnostic dilemma because of its low frequency and atypical features. We want to highlight the importance of high clinical suspicion and imaging modalities before taking any patient for evisceration with unexplained vision loss. One should send the eviscerated material for histopathological examination. PMID:26709674

  12. Phenotypes, Risk Factors, and Mechanisms of Adult-Onset Asthma

    PubMed Central

    Ilmarinen, Pinja; Tuomisto, Leena E.; Kankaanranta, Hannu

    2015-01-01

    Asthma is a heterogeneous disease with many phenotypes, and age at disease onset is an important factor in separating the phenotypes. Genetic factors, atopy, and early respiratory tract infections are well-recognized factors predisposing to childhood-onset asthma. Adult-onset asthma is more often associated with obesity, smoking, depression, or other life-style or environmental factors, even though genetic factors and respiratory tract infections may also play a role in adult-onset disease. Adult-onset asthma is characterized by absence of atopy and is often severe requiring treatment with high dose of inhaled and/or oral steroids. Variety of risk factors and nonatopic nature of adult-onset disease suggest that variety of mechanisms is involved in the disease pathogenesis and that these mechanisms differ from the pathobiology of childhood-onset asthma with prevailing Th2 airway inflammation. Recognition of the mechanisms and mediators that drive the adult-onset disease helps to develop novel strategies for the treatment. The aim of this review was to summarize the current knowledge on the pathogenesis of adult-onset asthma and to concentrate on the mechanisms and mediators involved in establishing adult-onset asthma in response to specific risk factors. We also discuss the involvement of these mechanisms in the currently recognized phenotypes of adult-onset asthma. PMID:26538828

  13. Adult-onset Satoyoshi syndrome and response to plasmapheresis

    PubMed Central

    Aghoram, Rajeshwari; Srijithesh, P. R.; Kannoth, Sudheeran

    2016-01-01

    Satoyoshi syndrome is a rare disease characterized by alopecia, recurrent muscle spasms, diarrhea, and skeletal abnormalities Adult-onset disease is reported only in five patients. Most of the reports have not characterized the nature of muscle spasm in the disease. In this paper, we report the first case of adult-onset Satoyoshi syndrome from India and the clinical and electrophysiological response to plasmapheresis. PMID:27011647

  14. A nursing challenge: adult-onset Tay-Sachs disease.

    PubMed

    Hamilton, D

    1991-12-01

    Adult-onset GM2 gangliosidosis (AOG), also labelled Adult-Onset Tay-Sachs disease, is a slowly progressing disease caused by a gradual accumulation of the GM2 ganglioside in neurons due to defective hexosaminidase A. Recent research findings and clinical experiences suggest that AOG may be more widespread than previously believed. Moreover, the diagnosis of AOG is often delayed because patients present with psychotic symptoms that mimic dementia, schizophrenia, mania, and depression. Because AOG patients typically respond poorly to psychiatric drug therapy and the symptomatology is so diverse, nurses must design and implement nursing care that ensures safety, structure, and comfort. PMID:1759864

  15. Adult-onset laryngomalacia: case reports and review of management.

    PubMed

    Hey, Shi Ying; Oozeer, Nashreen Banon; Robertson, Stuart; MacKenzie, Kenneth

    2014-12-01

    Laryngomalacia is a dynamic airway condition characterised by inward collapse of flaccid supraglottic structures during inspiration. Although the most common cause of stridor in the paediatric population, adult-onset laryngomalacia remains a rare entity and its management, challenging. Two cases of adult-onset laryngomalacia are reported. A review of the English literature is performed and additional publications identified by hand-searching relevant papers; 13 case reports/series comprising 28 cases of adult-onset laryngomalacia were identified, divided into two main groups: idiopathic (6/28) and acquired (22/28). The aetiology of the acquired form includes neurological, traumatic and iatrogenic. Reported therapeutic measures used are laser supraglottoplasty, epiglottopexy, partial epiglottidectomy, defunctioning tracheostomy and intubation whilst correcting the underlying cause. The majority of patients only required one therapeutic procedure (follow-up of 2-24 months). A strong index of suspicion is required to diagnose adult-onset laryngomalacia aided by in-office laryngoscopy. The rarity of this condition prevents management-based randomised controlled trials. PMID:24615649

  16. Alcohol-Induced Developmental Origins of Adult-Onset Diseases.

    PubMed

    Lunde, Emilie R; Washburn, Shannon E; Golding, Michael C; Bake, Shameena; Miranda, Rajesh C; Ramadoss, Jayanth

    2016-07-01

    Fetal alcohol exposure may impair growth, development, and function of multiple organ systems and is encompassed by the term fetal alcohol spectrum disorders (FASD). Research has so far focused on the mechanisms, prevention, and diagnosis of FASD, while the risk for adult-onset chronic diseases in individuals exposed to alcohol in utero is not well explored. David Barker's hypothesis on Developmental Origins of Health and Disease (DOHaD) suggests that insults to the milieu of the developing fetus program it for adult development of chronic diseases. In the 25 years since the introduction of this hypothesis, epidemiological and animal model studies have made significant advancements in identifying in utero developmental origins of chronic adult-onset diseases affecting cardiovascular, endocrine, musculoskeletal, and psychobehavioral systems. Teratogen exposure is an established programming agent for adult diseases, and recent studies suggest that prenatal alcohol exposure correlates with adult onset of neurobehavioral deficits, cardiovascular disease, endocrine dysfunction, and nutrient homeostasis instability, warranting additional investigation of alcohol-induced DOHaD, as well as patient follow-up well into adulthood for affected individuals. In utero epigenetic alterations during critical periods of methylation are a key potential mechanism for programming and susceptibility of adult-onset chronic diseases, with imprinted genes affecting metabolism being critical targets. Additional studies in epidemiology, phenotypic characterization in response to timing, dose, and duration of exposure, as well as elucidation of mechanisms underlying FASD-DOHaD inter relation, are thus needed to clinically define chronic disease associated with prenatal alcohol exposure. These studies are critical to establish interventional strategies that decrease incidence of these adult-onset diseases and promote healthier aging among individuals affected with FASD. PMID:27254466

  17. Extracellular Water and Blood Pressure in Adults with Growth Hormone (GH) Deficiency: A Genotype-Phenotype Association Study

    PubMed Central

    Nilsson, Anna G.; Bosaeus, Niklas; Nyström, Helena Filipsson; Svensson, Per-Arne; Bengtsson, Bengt-Åke; Nilsson, Staffan; Bosaeus, Ingvar; Boguszewski, Cesar Luiz; Johannsson, Gudmundur

    2014-01-01

    Objectives Growth hormone deficiency (GHD) in adults is associated with decreased extracellular water volume (ECW). In response to GH replacement therapy (GHRT), ECW increases and blood pressure (BP) reduces or remains unchanged. Our primary aim was to study the association between polymorphisms in genes related to renal tubular function with ECW and BP before and 1 year after GHRT. The ECW measures using bioimpedance analysis (BIA) and bioimpedance spectroscopy (BIS) were validated against a reference method, the sodium bromide dilution method (Br−). Design and Methods Using a candidate gene approach, fifteen single-nucleotide polymorphisms (SNPs) in nine genes with known impact on renal tubular function (AGT, SCNN1A, SCNN1G, SLC12A1, SLC12A3, KCNJ1, STK39, WNK1 and CASR) were genotyped and analyzed for associations with ECW and BP at baseline and with their changes after 1 year of GHRT in 311 adult GHD patients. ECW was measured with the Br−, BIA, and BIS. Results Both BIA and BIS measurements demonstrated similar ECW results as the reference method. At baseline, after adjustment for sex and BMI, SNP rs2291340 in the SLC12A1 gene was associated with ECW volume in GHD patients (p = 0.039). None of the SNPs influenced the ECW response to GHRT. One SNP in the SLC12A3 gene (rs11643718; p = 0.024) and three SNPs in the SCNN1G gene [rs5723 (p = 0.02), rs5729 (p = 0.016) and rs13331086 (p = 0.035)] were associated with the inter-individual differences in BP levels at baseline. A polymorphism in the calcium-sensing receptor (CASR) gene (rs1965357) was associated with changes in systolic BP after GHRT (p = 0.036). None of these associations remained statistically significant when corrected for multiple testing. Conclusion The BIA and BIS are as accurate as Br− to measure ECW in GHD adults before and during GHRT. Our study provides the first evidence that individual polymorphisms may have clinically relevant effects on ECW and BP in GHD adults

  18. Etiopathogenesis and Therapeutic Approach to Adult Onset Acne

    PubMed Central

    Kaur, Sarabjit; Verma, Poonam; Sangwan, Ankita; Dayal, Surabhi; Jain, Vijay Kumar

    2016-01-01

    Acne vulgaris is usually considered as a skin disorder that primarily affects adolescents reaching a peak at the age of 14–17 years in females and 16–19 years in males. However, recent epidemiologic studies have shown that a significant number of female patients aged >25 years experience acne. As it is regarded as a disease of teenagers, adults are more apprehensive and experience social anxiety. Hence, adult onset acne has become a matter of concern. PMID:27512185

  19. Etiopathogenesis and Therapeutic Approach to Adult Onset Acne.

    PubMed

    Kaur, Sarabjit; Verma, Poonam; Sangwan, Ankita; Dayal, Surabhi; Jain, Vijay Kumar

    2016-01-01

    Acne vulgaris is usually considered as a skin disorder that primarily affects adolescents reaching a peak at the age of 14-17 years in females and 16-19 years in males. However, recent epidemiologic studies have shown that a significant number of female patients aged >25 years experience acne. As it is regarded as a disease of teenagers, adults are more apprehensive and experience social anxiety. Hence, adult onset acne has become a matter of concern. PMID:27512185

  20. Endothelial function and vascular oxidative stress in long-lived GH/IGF-deficient Ames dwarf mice

    PubMed Central

    Csiszar, Anna; Labinskyy, Nazar; Perez, Viviana; Recchia, Fabio A.; Podlutsky, Andrej; Mukhopadhyay, Partha; Losonczy, Gyorgy; Pacher, Pal; Austad, Steven N.; Bartke, Andrzej; Ungvari, Zoltan

    2008-01-01

    Hypopituitary Ames dwarf mice have low circulating growth hormone (GH)/IGF-I levels, and they have extended longevity and exhibit many symptoms of delayed aging. To elucidate the vascular consequences of Ames dwarfism we compared endothelial O2•− and H2O2 production, mitochondrial reactive oxygen species (ROS) generation, expression of antioxidant enzymes, and nitric oxide (NO) production in aortas of Ames dwarf and wild-type control mice. In Ames dwarf aortas endothelial O2•− and H2O2 production and ROS generation by mitochondria were enhanced compared with those in vessels of wild-type mice. In Ames dwarf aortas there was a less abundant expression of Mn-SOD, Cu,Zn-SOD, glutathione peroxidase (GPx)-1, and endothelial nitric oxide synthase (eNOS). NO production and acetylcholine-induced relaxation were also decreased in aortas of Ames dwarf mice. In cultured wild-type mouse aortas and in human coronary arterial endothelial cells treatment with GH and IGF significantly reduced cellular O2•− and H2O2 production and ROS generation by mitochondria and upregulated expression of Mn-SOD, Cu,Zn-SOD, GPx-1, and eNOS. Thus GH and IGF-I promote antioxidant phenotypic changes in the endothelial cells, whereas Ames dwarfism leads to vascular oxidative stress. PMID:18757483

  1. MPV17 Mutations Causing Adult-Onset Multisystemic Disorder With Multiple Mitochondrial DNA Deletions

    PubMed Central

    Garone, Caterina; Rubio, Juan Carlos; Calvo, Sarah E.; Naini, Ali; Tanji, Kurenai; DiMauro, Salvatore; Mootha, Vamsi K.; Hirano, Michio

    2014-01-01

    Objective To identify the cause of an adult-onset multisystemic disease with multiple deletions of mitochondrial DNA (mtDNA). Design Case report. Setting University hospitals. Patient A 65-year-old man with axonal sensorimotor peripheral neuropathy, ptosis, ophthalmoparesis, diabetes mellitus, exercise intolerance, steatohepatopathy, depression, parkinsonism, and gastrointestinal dysmotility. Results Skeletal muscle biopsy revealed ragged-red and cytochrome-c oxidase–deficient fibers, and Southern blot analysis showed multiple mtDNA deletions. No deletions were detected in fibroblasts, and the results of quantitative polymerase chain reaction showed that the amount of mtDNA was normal in both muscle and fibroblasts. Exome sequencing using a mitochondrial library revealed compound heterozygous MPV17 mutations (p.LysMet88-89MetLeu and p.Leu143*), a novel cause of mtDNA multiple deletions. Conclusions In addition to causing juvenile-onset disorders with mtDNA depletion, MPV17 mutations can cause adult-onset multisystemic disease with multiple mtDNA deletions. PMID:22964873

  2. Office Work Exposures and Adult-Onset Asthma

    PubMed Central

    Jaakkola, Maritta S.; Jaakkola, Jouni J.K.

    2007-01-01

    Background Office exposures have been linked to symptoms of sick building syndrome, but their relation to the development of asthma has not been studied previously. These exposures have increasing importance because an increasing proportion of the workforce is working in office environments. Objectives The aim of this study was to assess the relations of exposure to carbonless copy paper (CCP), paper dust, and fumes from photocopiers and printers to adult-onset asthma. Methods We conducted a population-based incident case–control study of adults 21–63 years of age living in the Pirkanmaa District in South Finland. All new clinically diagnosed cases (n = 521) of asthma were recruited during a 3-year study period. A random sample of the source population formed the controls (n = 1,016). This part focused on 133 cases and 316 controls who were office workers according to their current occupation classified by the 1988 International Standard Classification of Occupations. All participants answered a questionnaire on health, smoking, occupation, and exposures at work and home. Subjects with previous asthma were excluded. Results Exposures to paper dust [adjusted odds ratio (OR) = 1.97; 95% confidence interval (CI), 1.25–3.10] and CCP (OR = 1.66; 95% CI, 1.03–2.66) were related to significantly increased risk of adult-onset asthma. An exposure–response relation was observed between exposure to paper dust and risk of asthma. Conclusions This study provides new evidence that exposures to paper dust and CCP in office work are related to increased risk of adult-onset asthma. Reduction of these exposures could prevent asthma in office workers. Clinicians seeing asthma patients should be aware of this link to office exposures. PMID:17637914

  3. Season of Birth and Risk for Adult Onset Glioma

    PubMed Central

    Efird, Jimmy T.

    2010-01-01

    Adult onset glioma is a rare cancer which occurs more frequently in Caucasians than African Americans, and in men than women. The etiology of this disease is largely unknown. Exposure to ionizing radiation is the only well established environmental risk factor, and this factor explains only a small percentage of cases. Several recent studies have reported an association between season of birth and glioma risk. This paper reviews the plausibility of evidence focusing on the seasonal interrelation of farming, allergies, viruses, vitamin D, diet, birth weight, and handedness. To date, a convincing explanation for the occurrence of adult gliomas decades after a seasonal exposure at birth remains elusive. PMID:20623001

  4. [Macrophage activation syndrome associated with adult-onset Still's disease].

    PubMed

    Iwamoto, Masahiro

    2007-12-01

    Macrophage activation syndrome (MAS) is a rare and potentially lethal disease, resulting from uncontrolled activation and proliferation of T lymphocytes and macrophages. Adult-onset Still's disease (AOSD) is an inflammatory disease. AOSD resemble reactive MAS in its symptoms and laboratory data. Moreover, AOSD per se induces MAS. It is, therefore, quite difficult to differentiate these syndrome and disease. The immunodeficiency state induced by treatment in AOSD could reactivate latent viruses such as Epstein-Barr virus, which could potentially lead to MAS. The therapeutic agents for AOSD, such as sulfasalazine, also could provoke reactive MAS. Because multiple factors are involved in inducing MAS to a different degree, the main cause should be searched for and targeted for the therapy. PMID:18174671

  5. Diagnosis of congenital and adult-onset hypothyroidism in cats.

    PubMed

    Greco, Deborah S

    2006-02-01

    Whereas hyperthyroidism is the most common endocrine disorder in the cat, hypothyroidism is the least common feline endocrine disorder. This is a the result of several factors including low index of suspicion, rarity of the naturally occurring hypothyroidism in cats, and a lack of species specific tests for endogenous TSH and antithyroglobulin antibodies. Nonetheless, hypothyroidism does occur in cats, especially in kittens and after radioactive treatment for hyperthyroidism. The clinician should become familiar with the common presentations of congenital and adult-onset hypothyroidism in cats. In addition, some of the tests specific to dogs (such as endogenous canine TSH) may be utilized to diagnose subclinical hypothyroidism in cats. Fortunately, the treatment of feline hypothyroidism with synthetic levothyroxine is both straightforward and effective. PMID:16584030

  6. Refractory Genital HPV Infection and Adult-Onset Still Disease

    PubMed Central

    Yu, Xin; Zheng, Heyi

    2016-01-01

    Abstract Adult-onset Still disease (AOSD) is a systemic autoimmune disease (AIID) that can develop after exposure to infectious agents. Genital human papillomavirus (HPV) infection has been reported to induce or exacerbate AIIDs, such as systemic lupus erythematosus (SLE). No guidelines are available for the management of genital warts in AOSD. Case report and literature review. We report a patient who was diagnosed AOSD in the setting of refractory and recurrent genital HPV infection, demonstrating a possible link between HPV infection and AOSD. In addition, we also discuss the management of genital warts in patients with AOSD. To the best of our knowledge, no previous cases of AOSD with genital HPV infection have been reported in literature. We then conclude that the patient AOSD may be triggered by primary HPV infection. Larger number of patient samples is needed to confirm whether HPV could trigger AOSD. PMID:27082556

  7. A Randomized Safety and Efficacy Study of Somavaratan (VRS-317), a Long-Acting rhGH, in Pediatric Growth Hormone Deficiency

    PubMed Central

    Moore, Wayne V.; Nguyen, Huong Jil; Kletter, Gad B.; Miller, Bradley S.; Rogers, Douglas; Ng, David; Moore, Jerome A.; Humphriss, Eric; Cleland, Jeffrey L.

    2016-01-01

    Context: Somavaratan (VRS-317) is a long-acting form of recombinant human GH under development for children and adults with GH deficiency (GHD). Objectives: To determine the optimal somavaratan dose regimen to normalize IGF-1 in pediatric GHD and to evaluate safety and efficacy of somavaratan over 6 months. Design: Open-label, multicenter, single ascending dose study followed by 6-month randomized comparison of 3 dosing regimens. Setting: Twenty-five United States pediatric endocrinology centers. Patients: Naive-to-treatment, prepubertal children with GHD (n = 68). Intervention(s): Patients received single sc doses of somavaratan (0.8, 1.2, 1.8, 2.7, 4.0, or 6.0 mg/kg) during the 30-day dose-finding phase, then were randomized to somavaratan 1.15 mg/kg weekly, 2.5 mg/kg twice monthly, or 5.0 mg/kg monthly for 6 months. Main Outcome Measures: Safety, pharmacokinetics, pharmacodynamics, 6-month height velocity (HV). Results: Somavaratan pharmacokinetics was linearly proportional to dose; dose-dependent increases in the magnitude and duration of IGF-1 responses enabled weekly, twice-monthly or monthly dosing. A single dose of somavaratan sustained IGF-1 responses for up to 1 month. No somavaratan or IGF-1 accumulation occurred with repeat dosing. Mean annualized HVs for somavaratan administered monthly, twice monthly, or weekly (7.86 ± 2.5, 8.61 ± 2.7, and 7.58 ± 2.5 cm/y, respectively) were similar between groups. Adverse events were mostly mild and transient. Conclusions: Somavaratan demonstrated clinically meaningful improvements in HV and IGF-1 in prepubertal children with GHD, with no significant differences between monthly, twice-monthly, or weekly dosing. PMID:26672637

  8. Intermittent rhabdomyolysis with adult onset associated with a mutation in the ACADVL gene.

    PubMed

    Antunes, Ana Patrícia; Nogueira, Célia; Rocha, Hugo; Vilarinho, Laura; Evangelista, Teresinha

    2013-12-01

    Deficiency of very-long-chain acyl-CoA dehydrogenase (VLCAD) is an autosomal recessive disease. Most common phenotypes occur in the neonatal period or in childhood with cardiomyopathy, hepatomegaly, and hypoketogenic hypoglycemia. Juvenile/adult-onset is characterized by exercise intolerance and recurrent rhabdomyolysis triggered by prolonged exercise or fasting. This article reports a patient with the homozygous mutation c.1097G>A (p.R366H) in the ACADVL gene. In Portugal, VLCAD deficiency became part of the neonatal screening plan in 2004, and as of 2012, 8 early-onset cases have been diagnosed, giving an incidence rate of 1:97.238 per 737.902 newborns. This patient was diagnosed outside of the neonatal screening plan. Beta-oxidation defects pose a diagnostic challenge because of their transient clinical and laboratorial manifestations and the absence of morphological changes in muscle biopsy further complicate matters, especially in the late-onset forms of the disease. The adult phenotype of VLCAD deficiency is highlighted, emphasizing the need for a high suspicion index and the value of tandem mass spectrometry for the diagnosis. PMID:24263034

  9. A search for the primary abnormality in adult-onset type II citrullinemia

    SciTech Connect

    Kobayashi, Keiko; Shaheen, Nazma; Saheki, Takeyori ); Kumashiro, Ryukichi; Tanikawa, Kyuichi ); O'Brien, W.E.; Beaudet, A.L. )

    1993-11-01

    Deficiency of argininosuccinate synthetase (ASS) causes citrullinemia in human beings. Type II citrullinemia is found in most patients with adult-onset citrullinemia in Japan, and ASS deficiency is found specifically in the liver. Previous studies have shown that the decrease of hepatic ASS activity is caused by a decrease in enzyme protein with normal kinetic properties and that there were no apparent abnormalities in the amount, translational activity, and gross structure of hepatic ASS mRNA. In the present work, the authors show by sequencing analysis that there was no mutation in the ASS mRNA from two patients with type II citrullinemia. The authors also report RFLP analysis of a consanguineous family with type II citrullinemia, by using three DNA polymorphisms located within the ASS gene locus. In spite of having consanguineous parents, the patient was not a homozygous haplotype for the ASS gene. The RFLP analysis of 16 affected patients from consanguineous parents showed that 5 of 16 patients had the heterozygous pattern for one of the three DNA probes and that the frequency of the heterozygous haplotype was not different from the control frequency. These results suggest that the primary defect of type II citrullinemia is not within the ASS gene locus. 29 refs., 1 fig., 3 tabs.

  10. A search for the primary abnormality in adult-onset type II citrullinemia.

    PubMed

    Kobayashi, K; Shaheen, N; Kumashiro, R; Tanikawa, K; O'Brien, W E; Beaudet, A L; Saheki, T

    1993-11-01

    Deficiency of argininosuccinate synthetase (ASS) causes citrullinemia in human beings. Type II citrullinemia is found in most patients with adult-onset citrullinemia in Japan, and ASS deficiency is found specifically in the liver. Previous studies have shown that the decrease of hepatic ASS activity is caused by a decrease in enzyme protein with normal kinetic properties and that there were no apparent abnormalities in the amount, translational activity, and gross structure of hepatic ASS mRNA. In the present work, we show by sequencing analysis that there was no mutation in the ASS mRNA from two patients with type II citrullinemia. We also report RFLP analysis of a consanguineous family with type II citrullinemia, by using three DNA polymorphisms located within the ASS gene locus. In spite of having consanguineous parents, the patient was not a homozygous haplotype for the ASS gene. The RFLP analysis of 16 affected patients from consanguineous parents showed that 5 of 16 patients had the heterozygous pattern for one of the three DNA probes and that the frequency of the heterozygous haplotype was not different from the control frequency. These results suggest that the primary defect of type II citrullinemia is not within the ASS gene locus. PMID:8105687

  11. Comparing illness presentation, treatment and functioning between patients with adolescent- and adult-onset psychosis.

    PubMed

    Hui, Christy Lai-Ming; Li, Adrienne Wing-Yee; Leung, Chung-Ming; Chang, Wing-Chung; Chan, Sherry Kit-Wa; Lee, Edwin Ho-Ming; Chen, Eric Yu-Hai

    2014-12-30

    Studies have shown that early- and adult-onset schizophrenia patients differ in pre-morbid traits, illness presentation, psychopathology, and prognosis. We aimed to compare adult-onset patients (age range 26-55 years) with an adolescent-onset cohort (15-25 years) in demographics, illness presentation and functioning at baseline. Participants were from two territory-wide early intervention services for adolescent-onset (n=671) and adult-onset psychosis patients (n=360) in Hong Kong. The adolescent-onset cohort had their initial psychotic episode from 2001-2003; retrospective data collection was done through systematic case note review. The adult-onset cohort was recruited for a larger interventional study from 2009-2011; information was collected via face-to-face interviews. Adult-onset psychosis was significantly associated with more females, more smokers, more non-local birth, more full-time employment, better functioning, poorer medication adherence, more psychiatric hospitalization and fewer with schizophrenia than adolescent-onset psychosis (mean age: 20.4). The effect sizes were small, except for medication adherence where a robust effect was found. No group difference in DUP was found. The finding that adult-onset patients had better functioning challenges the view that adolescent- and adult-onset psychoses share a similar prognostic trajectory. Implications for adapting intervention processes for adolescent- and adult-onset psychosis are discussed. PMID:25238985

  12. Warming up Improves Speech Production in Patients with Adult Onset Myotonic Dystrophy

    ERIC Educational Resources Information Center

    de Swart, B.J.M.; van Engelen, B.G.M.; Maassen, B.A.M.

    2007-01-01

    This investigation was conducted to study whether warming up decreases myotonia (muscle stiffness) during speech production or causes adverse effects due to fatigue or exhaustion caused by intensive speech activity in patients with adult onset myotonic dystrophy. Thirty patients with adult onset myotonic dystrophy (MD) and ten healthy controls…

  13. Adult-onset foveomacular vitelliform dystrophy: A fresh perspective.

    PubMed

    Chowers, Itay; Tiosano, Liran; Audo, Isabelle; Grunin, Michelle; Boon, Camiel J F

    2015-07-01

    Adult-onset foveomacular vitelliform dystrophy (AFVD) was first described by Gass four decades ago. AFVD is characterized by subretinal vitelliform macular lesions and is usually diagnosed after the age of 40. The lesions gradually increase and then decrease in size over the years, leaving an area of atrophic outer retina and retinal pigment epithelium. This process is accompanied by a loss of visual acuity. Vitelliform lesions are hyperautofluorescent and initially have a dome-shaped appearance on optical coherence tomography. The electro-oculogram and full-field electroretinogram are typically normal, indicating localized retinal pathology. Phenocopies are also associated with other ocular disorders, such as vitreomacular traction, age-related macular degeneration, pseudodrusen, and central serous chorioretinopathy. A minority of AFVD patients have a mutation in the PRPH2, BEST1, IMPG1, or IMPG2 genes. A single-nucleotide polymorphism in the HTRA1 gene has also been associated with this phenotype. Accordingly, the phenotype can arise from alterations in the photoreceptors, retinal pigment epithelium, and/or interphotoreceptor matrix depending on the underlying gene defect. Excess photoreceptor outer segment production and/or impaired outer segment uptake due to impaired phagocytosis are likely underlying mechanisms. At present, no cure is available for AFVD. Thus, the current challenges in the field include identifying the underlying cause in the majority of AFVD cases and the development of effective therapeutic approaches. PMID:25681578

  14. Efficacy of Anakinra in Refractory Adult-Onset Still's Disease

    PubMed Central

    Ortiz-Sanjuán, Francisco; Blanco, Ricardo; Riancho-Zarrabeitia, Leyre; Castañeda, Santos; Olivé, Alejandro; Riveros, Anne; Velloso-Feijoo, María.L.; Narváez, Javier; Jiménez-Moleón, Inmaculada; Maiz-Alonso, Olga; Ordóñez, Carmen; Bernal, José A.; Hernández, María V.; Sifuentes-Giraldo, Walter A.; Gómez-Arango, Catalina; Galíndez-Agirregoikoa, Eva; Blanco-Madrigal, Juan; Ortiz-Santamaria, Vera; del Blanco-Barnusell, Jordi; De Dios, Juan R.; Moreno, Mireia; Fiter, Jordi; Riscos, Marina de los; Carreira, Patricia; Rodriguez-Valls, María J.; González-Vela, M. Carmen; Calvo-Río, Vanesa; Loricera, Javier; Palmou-Fontana, Natalia; Pina, Trinitario; Llorca, Javier; González-Gay, Miguel A.

    2015-01-01

    Abstract Adult-onset Still's disease (AOSD) is often refractory to standard therapy. Anakinra (ANK), an interleukin-1 receptor antagonist, has demonstrated efficacy in single cases and small series of AOSD. We assessed the efficacy of ANK in a series of AOSD patients. Multicenter retrospective open-label study. ANK was used due to lack of efficacy to standard synthetic immunosuppressive drugs and in some cases also to at least 1 biologic agent. Forty-one patients (26 women/15 men) were recruited. They had a mean age of 34.4 ± 14 years and a median [interquartile range (IQR)] AOSD duration of 3.5 [2–6] years before ANK onset. At that time the most common clinical features were joint manifestations 87.8%, fever 78%, and cutaneous rash 58.5%. ANK yielded rapid and maintained clinical and laboratory improvement. After 1 year of therapy, the frequency of joint and cutaneous manifestations had decreased to 41.5% and to 7.3% respectively, fever from 78% to 14.6%, anemia from 56.1% to 9.8%, and lymphadenopathy from 26.8% to 4.9%. A dramatic improvement of laboratory parameters was also achieved. The median [IQR] prednisone dose was also reduced from 20 [11.3–47.5] mg/day at ANK onset to 5 [0–10] at 12 months. After a median [IQR] follow-up of 16 [5–50] months, the most important side effects were cutaneous manifestations (n = 8), mild leukopenia (n = 3), myopathy (n = 1), and infections (n = 5). ANK is associated with rapid and maintained clinical and laboratory improvement, even in nonresponders to other biologic agents. However, joint manifestations are more refractory than the systemic manifestations. PMID:26426623

  15. Adult-Onset Hypothyroidism Enhances Fear Memory and Upregulates Mineralocorticoid and Glucocorticoid Receptors in the Amygdala

    PubMed Central

    Montero-Pedrazuela, Ana; Fernández-Lamo, Iván; Alieva, María; Pereda-Pérez, Inmaculada; Venero, César; Guadaño-Ferraz, Ana

    2011-01-01

    Hypothyroidism is the most common hormonal disease in adults, which is frequently accompanied by learning and memory impairments and emotional disorders. However, the deleterious effects of thyroid hormones deficiency on emotional memory are poorly understood and often underestimated. To evaluate the consequences of hypothyroidism on emotional learning and memory, we have performed a classical Pavlovian fear conditioning paradigm in euthyroid and adult-thyroidectomized Wistar rats. In this experimental model, learning acquisition was not impaired, fear memory was enhanced, memory extinction was delayed and spontaneous recovery of fear memory was exacerbated in hypothyroid rats. The potentiation of emotional memory under hypothyroidism was associated with an increase of corticosterone release after fear conditioning and with higher expression of glucocorticoid and mineralocorticoid receptors in the lateral and basolateral nuclei of the amygdala, nuclei that are critically involved in the circuitry of fear memory. Our results demonstrate for the first time that adult-onset hypothyroidism potentiates fear memory and also increases vulnerability to develop emotional memories. Furthermore, our findings suggest that enhanced corticosterone signaling in the amygdala is involved in the pathophysiological mechanisms of fear memory potentiation. Therefore, we recommend evaluating whether inappropriate regulation of fear in patients with post-traumatic stress and other mental disorders is associated with abnormal levels of thyroid hormones, especially those patients refractory to treatment. PMID:22039511

  16. Genetics Home Reference: adult-onset leukoencephalopathy with axonal spheroids and pigmented glia

    MedlinePlus

    ... it causes a severe decline in thinking and reasoning abilities (dementia). Over time, motor skills are affected, ... Schmahmann JD. Adult onset leukodystrophy with neuroaxonal spheroids: clinical, neuroimaging and neuropathologic observations. Brain Pathol. 2009 Jan; ...

  17. Generation of a novel mouse model that recapitulates early and adult onset glycogenosis type IV.

    PubMed

    Akman, H Orhan; Sheiko, Tatiana; Tay, Stacey K H; Finegold, Milton J; Dimauro, Salvatore; Craigen, William J

    2011-11-15

    Glycogen storage disease type IV (GSD IV) is a rare autosomal recessive disorder caused by deficiency of the glycogen branching enzyme (GBE). The diagnostic feature of the disease is the accumulation of a poorly branched form of glycogen known as polyglucosan (PG). The disease is clinically heterogeneous, with variable tissue involvement and age of disease onset. Absence of enzyme activity is lethal in utero or in infancy affecting primarily muscle and liver. However, residual enzyme activity (5-20%) leads to juvenile or adult onset of a disorder that primarily affects muscle as well as central and peripheral nervous system. Here, we describe two mouse models of GSD IV that reflect this spectrum of disease. Homologous recombination was used to insert flippase recognition target recombination sites around exon 7 of the Gbe1 gene and a phosphoglycerate kinase-Neomycin cassette within intron 7, leading to a reduced synthesis of GBE. Mice bearing this mutation (Gbe1(neo/neo)) exhibit a phenotype similar to juvenile onset GSD IV, with wide spread accumulation of PG. Meanwhile, FLPe-mediated homozygous deletion of exon 7 completely eliminated GBE activity (Gbe1(-/-)), leading to a phenotype of lethal early onset GSD IV, with significant in utero accumulation of PG. Adult mice with residual GBE exhibit progressive neuromuscular dysfunction and die prematurely. Differently from muscle, PG in liver is a degradable source of glucose and readily depleted by fasting, emphasizing that there are structural and regulatory differences in glycogen metabolism among tissues. Both mouse models recapitulate typical histological and physiological features of two human variants of branching enzyme deficiency. PMID:21856731

  18. [Adult onset Still's disease with the initial symptom of pharyngalgia: a case report].

    PubMed

    Zhou, Enhui; Chen, Xiaoping; Zhang, Jingfei

    2015-09-01

    Adult onset Still's disease is a rare inflammatory disease characterized by spiking fevers, arthritis/ arthralgias, typical salmon-colored bumpy rash, pharyngalgia, myalgia and possible involvement of visceral organs. The diagnosis is exclusively based on clinical symptoms, according to the criteria, after the exclusion of well-known infectious, neoplastic, or other autoimmune/autoinflammatory disorders. This report includes one case of adult onset Still's disease with the initial symptom of pharyngalgia. PMID:26647549

  19. Growth hormone (GH) replacement decreases serum total and LDL-cholesterol in hypopituitary patients on maintenance HMG CoA reductase inhibitor (statin) therapy

    PubMed Central

    Monson, John P; Jönsson, Peter; Koltowska-Häggström, Maria; Kourides, Ione

    2007-01-01

    Objective Adult onset GH deficiency (GHD) is characterized by abnormalities of serum lipoprotein profiles and GH replacement results in favourable alterations in serum total and low density lipoprotein (LDL)-cholesterol. Preliminary evidence has indicated that the effect of GH replacement in this respect may be additive to that of HMG CoA reductase inhibitor (statin) therapy. We have examined this possibility during prospective follow-up of adult onset hypopituitary patients enrolled in KIMS (Pfizer International Metabolic Database), a pharmacoepidemiological study of GH replacement in adult hypopituitary patients. Design Lipoprotein profiles were measured centrally at baseline and after 12 months GH replacement therapy. Patients Sixty-one hypopituitary patients (30 male, 31 female) on maintenance statin therapy (mean 2·5 ± 2·7 SD years before GH) (statin group – SG) and 1247 (608 male, 639 female) patients not on hypolipidaemic therapy (nonstatin group – NSG) were studied. All patients were naïve or had not received GH replacement during the 6 months prior to study. Patients who developed diabetes mellitus during the first year of GH therapy or in the subsequent year and those with childhood onset GHD were excluded from this analysis. An established diagnosis of diabetes mellitus was present in 18% SG and 4·4% NSG at baseline. Measurements Serum concentrations of total, high density lipoprotein (HDL)-cholesterol, triglycerides and IGF-I were measured centrally in all patients and LDL-cholesterol was estimated using Friedewald's formula. Results The relative frequency of various statin use was simvastatin 52% (15·8 ± 8·1 mg, mean ± SD), atorvastatin 30% (14·4 ± 7·8 mg), pravastatin 9·8% (31·6 mg ± 13·9 mg), lovastatin 6·6% (17·5 ± 5 mg) and fluvastatin 1·6% (40 mg). Baseline serum total and LDL-cholesterol (mean ± SD) were 5·2 ± 1·4 and 3·1 ± 1·3 mmol/l in SG and 5·8 ± 1·2 and 3·7 ± 1·0 mmol/l in NSG, respectively (P < 0·0001

  20. Steatogenesis in adult-onset type II citrullinemia is associated with down-regulation of PPARα.

    PubMed

    Komatsu, Michiharu; Kimura, Takefumi; Yazaki, Masahide; Tanaka, Naoki; Yang, Yang; Nakajima, Takero; Horiuchi, Akira; Fang, Zhong-Ze; Joshita, Satoru; Matsumoto, Akihiro; Umemura, Takeji; Tanaka, Eiji; Gonzalez, Frank J; Ikeda, Shu-Ichi; Aoyama, Toshifumi

    2015-03-01

    SLC25A13 (citrin or aspartate-glutamate carrier 2) is located in the mitochondrial membrane in the liver and its genetic deficiency causes adult-onset type II citrullinemia (CTLN2). CTLN2 is one of the urea cycle disorders characterized by sudden-onset hyperammonemia due to reduced argininosuccinate synthase activity. This disorder is frequently accompanied with hepatosteatosis in the absence of obesity and ethanol consumption. However, the precise mechanism of steatogenesis remains unclear. The expression of genes associated with fatty acid (FA) and triglyceride (TG) metabolism was examined using liver samples obtained from 16 CTLN2 patients and compared with 7 healthy individuals. Although expression of hepatic genes associated with lipogenesis and TG hydrolysis was not changed, the mRNAs encoding enzymes/proteins involved in FA oxidation (carnitine palmitoyl-CoA transferase 1α, medium- and very-long-chain acyl-CoA dehydrogenases, and acyl-CoA oxidase 1), very-low-density lipoprotein secretion (microsomal TG transfer protein), and FA transport (CD36 and FA-binding protein 1), were markedly suppressed in CTLN2 patients. Serum concentrations of ketone bodies were also decreased in these patients, suggesting reduced mitochondrial β-oxidation activity. Consistent with these findings, the expression of peroxisome proliferator-activated receptor α (PPARα), a master regulator of hepatic lipid metabolism, was significantly down-regulated. Hepatic PPARα expression was inversely correlated with severity of steatosis and circulating ammonia and citrulline levels. Additionally, phosphorylation of c-Jun-N-terminal kinase was enhanced in CTLN2 livers, which was likely associated with lower hepatic PPARα. Collectively, down-regulation of PPARα is associated with steatogenesis in CTLN2 patients. These findings provide a novel link between urea cycle disorder, lipid metabolism, and PPARα. PMID:25533124

  1. Sandhoff disease mimicking adult-onset bulbospinal neuronopathy.

    PubMed

    Thomas, P K; Young, E; King, R H

    1989-09-01

    A 32 year old male is described with an onset of upper limb postural tremor in adolescence followed by muscle cramps. Progressive proximal amyotrophy and weakness in the limbs developed late in the third decade. Examination disclosed, in addition, bilateral facial weakness and mild dysarthria. Enzyme studies revealed hexosaminidase A and B deficiency, indicating a diagnosis of Sandhoff disease. Intra-axonal membranocytoplasmic bodies were present in a rectal biopsy. The presentation, which resembled that of X-linked bulbospinal neuronopathy, widens the clinical spectrum for disorders related to G(M2) gangliosidosis. PMID:2795083

  2. Adult-Onset Still's Disease and Cardiac Tamponade: A Rare Association

    PubMed Central

    Silva, Doroteia; de Jesus Silva, Maria; André, Rui; Varela, Manuel Gato; Diogo, António Nunes

    2015-01-01

    Adult-onset Still's disease is a rare disorder with potentially severe clinical features, including cardiac involvement. This systemic inflammatory disease of unknown origin should be considered in the differential diagnosis of pericarditis, with or without pericardial effusion. Cardiac tamponade is a very rare sequela that requires an invasive approach, such as percutaneous or surgical pericardial drainage, in addition to the usual conservative therapy. The authors describe a case of adult-onset Still's disease rendered more difficult by pericarditis and cardiac tamponade, and they briefly review the literature on this entity. PMID:26175648

  3. Is Adolescent-Onset First-Episode Psychosis Different from Adult Onset?

    ERIC Educational Resources Information Center

    Ballageer, Trevor; Malla, Ashok; Manchanda, Rahul; Takhar, Jatinder; Haricharan, Raj

    2005-01-01

    Objective: To examine whether first-episode psychosis patients with onset during adolescence (ages 15-18) differ significantly from those with young-adult onset (ages 19-30). Method: Consecutive patients presenting with first-episode psychosis (N = 242) were assessed for demographic and illness characteristics such as duration of untreated…

  4. Adult-Onset Antisocial Behavior Trajectories: Associations with Adolescent Family Processes and Emerging Adulthood Functioning

    ERIC Educational Resources Information Center

    Mata, Andrea D.; van Dulmen, Manfred H. M.

    2012-01-01

    Guided by conceptual and empirical work on emerging adulthood, this study investigated the role of closeness to mother and father and behavioral autonomy during adolescence on the development of adult-onset antisocial behavior. Using data from the National Longitudinal Study of Adolescent Health (Add Health), we identified four aggressive…

  5. Seven years of follow up of trabecular bone score, bone mineral density, body composition and quality of life in adults with growth hormone deficiency treated with rhGH replacement in a single center

    PubMed Central

    Allo Miguel, Gonzalo; Serraclara Plá, Alicia; Partida Muñoz, Myriam Lorena; Martínez Díaz-Guerra, Guillermo; Hawkins, Federico

    2016-01-01

    Background: Adult growth hormone deficiency (AGHD) is characterized by impaired physical activity, diminished quality of life (QoL), weight and fat mass gain, decreased muscle mass and decreased bone mineral density (BMD). The aim of this study was to evaluate the effects of long-term treatment (7 years) with recombinant human growth hormone (rhGH) on metabolic parameters, body composition (BC), BMD, bone microarchitecture and QoL. Patients and Methods: In this prospective study, BMD and BC were assessed by dual-energy X-ray absorptiometry (DXA). Bone microarchitecture was assessed with the trabecular bone score (TBS). The QoL-AGHDA test was used to assess QoL. Results: A total of 18 AGHD patients (mean age, 37.39 ± 12.42) were included. Body weight and body mass index (BMI) showed a significant increase after 7 years (p = 0.03 and p = 0.001, respectively). There was a significant tendency of body fat mass (BFM) (p = 0.028) and lean body mass (LBM) (p = 0.005) to increase during the 7 years of rhGH treatment. There was a significant increase in lumbar spine (LS) BMD (p = 0.01). TBS showed a nonsignificant decrease after 7 years of treatment, with a change of -0.86% ± 1.95. QoL showed a large and significant improvement (p = 0.02). Conclusion: Long-term rhGH treatment in AGHD patients induces a large and sustained improvement in QoL. Metabolic effects are variable with an increase in LBM as well as in BMI and BFM. There is a positive effect on BMD based on the increase in LS BMD, which stabilizes during long-term therapy and is not associated with a similar increase in bone microarchitecture. PMID:27293538

  6. GH-related and extra-endocrine actions of GH secretagogues in aging.

    PubMed

    Muller, Eugenio E; Rigamonti, Antonello E; Colonna, Vito De Gennaro; Locatelli, Vittorio; Berti, Ferruccio; Cella, Silvano G

    2002-01-01

    Growth hormone (GH) secretion declines with aging in mammals, including humans. Defective pituitary function does not play a major role in this event. Rather, age-related changes involving the function of specific hypothalamic peptides for GH regulation, GH-releasing hormone (GHRH) and somatostatin (SS), appear to be the fundamental factors. Experimental evidence indicates that GHRH synthesis is impaired with aging in the rat hypothalamus, and that a relative hyperfunction of the SS-ergic system is present. In the elderly, systemic, short-term administration of GHRH enhances GH secretion and increases the formation of the GH-dependent peptide IGF-1. In old dogs, a combination of GHRH and clonidine (CLO), an alpha(2)-adrenoceptor agonist, reportedly acting via GHRH stimulation and SS inhibition, is the most effective stimulus to rejuvenate the apulsatile GH secretion. Discovery of GH secretagogues (GHSs), a series of peptydil and non-peptydil synthetic molecules endowed with a strong GH-releasing activity, the cloning of a GHS receptor (GHS-R), present in the hypothalamus and the pituitary, the isolation of the endogenous ligand of GHS-R, ghrelin, a 28-amino acid peptide whose main source is the stomach, pose the issue for the physiologic role of the GHS/ghrelin system and forces revision of our current understanding of GH regulation in different GH deficiency (GHD) states, including aging. GHSs are very effective for enhancing GH secretion in old subjects, but long-term studies are needed to assess their safety and the real biological impact of GHS replacement therapy in aging. Therapeutic use of GHSs can also be envisaged to restore, via GH-independent mechanisms, functional, and structural age-related alterations, such as anorexia, sexual dysfunction, cardiovascular damage, bone loss. PMID:12392795

  7. Growth hormone (GH)–releasing hormone and GH secretagogues in normal aging: Fountain of Youth or Pool of Tantalus?

    PubMed Central

    Hersch, Elizabeth C; Merriam, George R

    2008-01-01

    Although growth hormone (GH) is primarily associated with linear growth in childhood, it continues to have important metabolic functions in adult life. Adult GH deficiency (AGHD) is a distinct clinical entity, and GH replacement in AGHD can improve body composition, strength, aerobic capacity, and mood, and may reduce vascular disease risk. While there are some hormone-related side effects, the balance of benefits and risks is generally favorable, and several countries have approved GH for clinical use in AGHD. GH secretion declines progressively and markedly with aging, and many age-related changes resemble those of partial AGHD. This suggests that replacing GH, or stimulating GH with GH-releasing hormone or a GH secretagogue could confer benefits in normal aging similar to those observed in AGHD – in particular, could reduce the loss of muscle mass, strength, and exercise capacity leading to frailty, thereby prolonging the ability to live independently. However, while most GH studies have shown body composition effects similar to those in AGHD, functional changes have been much less inconsistent, and older adults are more sensitive to GH side effects. Preliminary reports of improved cognition are encouraging, but the overall balance of benefits and risks of GH supplementation in normal aging remains uncertain. PMID:18488883

  8. Regulation of the growth hormone (GH) receptor and GH-binding protein mRNA

    SciTech Connect

    Kaji, Hidesuke; Ohashi, Shin-Ichirou; Abe, Hiromi; Chihara, Kazuo

    1994-12-31

    In fasting rats, a transient increase in growth hormone-binding protein (GHBP) mRNA levels was observed after 1 day, in muscle, heart, and liver, but not in fat tissues. The liver GH receptor (GHR) mRNA level was significantly increased after 1 day (but not after 5 days) of bovine GH (bGH) treatment in fed rats. Both the liver GHR mRNA level and the net increment of plasma IGF-I markedly decreased after 5 days of bGH administration in fasting rats. These findings suggest that GHR and GHBP mRNAs in the liver are expressed in a different way and that the expression of GHBP mRNA is regulated differently between tissues, at least in rats. The results also suggest that refractoriness to GH in a sustained fasting state might be beneficial in preventing anabolic effects of GH. In humans, GHR mRNA in lymphocytes, from subjects with either GH-deficiency or acromegaly, could be detected by the reverse transcription-polymerase chain reaction method. In one patient with partial GH insensitivity, a heterozygous missense mutation (P561T) was identified in the cytoplasmic domain of GHR. 15 refs., 4 figs.

  9. Adult-onset Still's disease as a mask of Hodgkin lymphoma

    PubMed Central

    Pawlak-Buś, Katarzyna; Leszczyński, Piotr

    2015-01-01

    Adult-onset Still's disease is a rare disorder, which creates difficulties in making a proper diagnosis. Ambiguous symptoms and results of auxiliary tests, lack of unequivocal diagnostic tests and the need to exclude other causes of the disease are major problems in clinical practice. A case of a 22-year-old woman with dominated recurrent fever, significantly elevated inflammation markers and arthritis is presented. Based on clinical signs after exclusion of infection, hematological and other reasons, the patient was diagnosed with adult-onset Still's disease. Standard treatment, with high doses of glucocorticoids and a disease-modifying drug, was applied, without the anticipated effects. The diagnostic tests were conducted again due to the lack of clinical improvement, increase of inflammatory markers and unusual response to treatment. A new symptom of significance, i.e. mediastinal lymphadenopathy, was found. After the histopathological examination of lymph nodes, Hodgkin's disease was diagnosed and targeted therapy for hematological malignancy was applied.

  10. The juvenile-onset, adolescent-onset and adult-onset obese.

    PubMed

    Garn, S M; Sullivan, T V; Hawthorne, V M

    1991-02-01

    As shown in more than 8000 proband-parent pairs derived from a total-community sample and followed in longitudinal fashion, the 5-year incidence of obesity (new cases per 5-year period) approximates 8 percent for the juvenile-onset, adolescent-onset and adult-onset obese alike. Parents of juvenile-onset (ages 5-9), adolescent-onset (10-19) and adult-onset obese (20-39) tend to be of above-average fatness level, +0.25Z scores, overall, regardless of the age at onset of obesity in their progeny. Except for the parents of the juvenile-onset obese, educational level of the parents tends to be below average for the sample as a whole. These new data acquired in longitudinal context and explored in retrospective-prospective fashion do not substantiate the notion that different onset ages of obesity indicate separate etiologies and different family constellations. PMID:2040547

  11. Mapping a gene for adult-onset primary open-angle glaucoma to chromosome 3q

    SciTech Connect

    Wirtz, M.K.; Samples, J.R.; Kramer, P.L.

    1997-02-01

    Glaucoma is the third-leading cause of blindness in the world, affecting >13.5 million people. Adult-on-set primary open-angle glaucoma (POAG) is the most common form of glaucoma in the United States. We present a family in which adult-onset POAG is inherited as an autosomal dominant trait. Twelve affected family members were identified from 44 at-risk individuals. The disease-causing gene was mapped to chromosome 3q21-24, with analysis of recombinant haplotypes suggesting a total inclusion region of 11.1 cM between markers D3S3637 and D3S1744. This is the first report of mapping of an adult-onset POAG gene to chromosome 3q, gene symbol GLC1C. 57 refs., 3 figs., 3 tabs.

  12. Genetics of GHRH, GHRH-receptor, GH and GH-receptor: its impact on pharmacogenetics.

    PubMed

    Mullis, Primus-E

    2011-02-01

    When a child is not following the normal, predicted growth curve, an evaluation for underlying illnesses and central nervous system abnormalities is required and, appropriate consideration should be given to genetic defects causing GH deficiency (GHD). Because Insulin-like-Growth Factor-I (IGF-I) plays a pivotal role, GHD could also be considered as a form of IGF-I deficiency (IGFD). Although IGFD can develop at any level of the GHRH-GH-IGF axis, a differentiation should be made between GHD (absent to low GH in circulation) and IGFD (normal to high GH in circulation). The main focus of this review is on the GH-gene, the various gene alterations and their possible impact on the pituitary gland. However, although transcription factors regulating the pituitary gland development may cause multiple pituitary hormone deficiency they may present initially as GHD. These defects are discussed in various different chapters within this book, whereas, the impact of alterations of the GHRH-, GHRH-receptor- --as well as the GH-receptor (GHR) gene--will be discussed here. PMID:21396573

  13. Urticaria and dermographism in patients with adult-onset Still's disease.

    PubMed

    Criado, Paulo Ricardo; de Carvalho, Jozélio Freire; Ayabe, Liliane Akemi; Brandt, Hebert Roberto Clivati; Romiti, Ricardo; Maruta, Celina W

    2012-08-01

    Adult-onset Still's disease (AOSD) patients typically present with arthralgia, fever, lymphadenopathy and a transient salmon maculopapular rash. Only approximately 25 cases of AOSD with urticaria were described in the literature. In this article, the authors report three additional cases of AOSD with urticarial and dermographic lesions who had a good clinical response to glucocorticoid and antihistamines. A review of the literature concerning this issue is also herein written. PMID:21785958

  14. Epidemiology of adult-onset hydrocephalus: institutional experience with 2001 patients.

    PubMed

    Bir, Shyamal C; Patra, Devi Prasad; Maiti, Tanmoy K; Sun, Hai; Guthikonda, Bharat; Notarianni, Christina; Nanda, Anil

    2016-09-01

    OBJECTIVE Adult-onset hydrocephalus is not commonly discussed in the literature, especially regarding its demographic distribution. In contrast to pediatric hydrocephalus, which is related to a primary CSF pathway defect, its development in adults is often secondary to other pathologies. In this study, the authors investigated the epidemiology of adult-onset hydrocephalus as it pertains to different etiologies and in reference to age, sex, and race distributions. METHODS The authors retrospectively reviewed the clinical notes of 2001 patients with adult-onset hydrocephalus who presented to Louisiana State University Health Sciences Center within a 25-year span. Significant differences between the groups were analyzed by a chi-square test; p < 0.05 was considered significant. RESULTS The overall mean (± SEM) incidence of adult hydrocephalus in this population was 77 ± 30 per year, with a significant increase in incidence in the past decade (55 ± 3 [1990-2003] vs 102 ± 6 [2004-2015]; p < 0.0001). Hydrocephalus in a majority of the patients had a vascular etiology (45.5%) or was a result of a tumor (30.2%). The incidence of hydrocephalus in different age groups varied according to various pathologies. The incidence was significantly higher in males with normal-pressure hydrocephalus (p = 0.03) or head injury (p = 0.01) and higher in females with pseudotumor cerebri (p < 0.0001). In addition, the overall incidence of hydrocephalus was significantly higher in Caucasian patients (p = 0.0002) than in those of any other race. CONCLUSIONS Knowledge of the demographic variations in adult-onset hydrocephalus is helpful in achieving better risk stratification and better managing the disease in patients. For general applicability, these results should be validated in a large-scale meta-analysis based on a national population database. PMID:27581317

  15. Adult onset unilateral systematized porokeratotic eccrine ostial and dermal duct nevus: a case report.

    PubMed

    Bandoyopadhyay, Debabrata; Saha, Abanti

    2014-06-01

    Porokeratotic eccrine ostial and dermal duct nevus (PEODDN) is an uncommon, benign dermatosis that is characterized by asymptomatic grouped keratotic papules and plaques with a linear pattern on the extremities with distinct porokeratotic histopathological features. The lesions usually appear at birth or in childhood, although rare cases of late-onset adult PEODDN have been described. Herein we report a case of adult onset PEODDN with unilateral and segmental involvement. PMID:24945650

  16. Niemann-Pick type C: focus on the adolescent/adult onset form.

    PubMed

    Di Lazzaro, Vincenzo; Marano, Massimo; Florio, Lucia; De Santis, Stefano

    2016-11-01

    Niemann-Pick disease type C (NP-C) is an inherited sphingolipidosis characterized by progressive neurological deterioration and early mortality. The symptomatology and disease progression of NP-C are markedly affected by the age at onset of neurological manifestations, and categorization into early-infantile, late-infantile, juvenile, adolescent/adult neurological onset forms can aid evaluation of disease course and responses to therapy. Here, we review current information on the detection, diagnosis, monitoring and treatment of NP-C, with a focus on the adolescent/adult-onset form. A recent analysis indicated that the combined incidence of NP-C related to NPC1 gene mutations (NPC1) and NP-C related to NPC2 gene mutations (NPC2) is approximately 1 case in every 89 000 live births. In particular, late-onset phenotypes might well provide a greater contribution to the overall incidence than has previously been reported. Some neuropathological features in NP-C are held in common with other advanced age-onset diseases such as Alzheimer's disease. Visceral symptoms such as splenomegaly are frequently asymptomatic in patients with adolescent/adult-onset NP-C, and are only occasionally detected during routine ultrasound assessments. In contrast, most patients with adolescent/adult-onset exhibit some degree of slowly progressive, non-disease-specific movement disorders (e.g. cerebellar ataxia), and/or more pathognomonic neurological signs such as vertical supranuclear gaze palsy. An increasing number of adolescent/adult-onset cases have been reported following initial recognition of cognitive impairment and/or psychiatric signs. The recent development and implementation of new clinical screening tools (e.g. the NP-C suspicion index) and biomarkers (e.g. plasma oxysterols) should help identify patients who warrant further investigation and possible treatment. PMID:26998855

  17. Intra-arterial Chemotherapy for Adult Onset Retinoblastoma in a 32-Year-Old Man.

    PubMed

    Magan, Tejal; Khoo, Chloe T L; Jabbour, Pascal M; Fuller, Dwain G; Shields, Carol L

    2016-01-01

    A 32-year-old man with active unilateral group D retinoblastoma that was recurrent following external beam radiotherapy was treated with intra-arterial chemotherapy, leading to tumor regression. Additional plaque radiotherapy and intravitreal chemotherapy were required for complete control. Final visual acuity was 20/40. In selected cases, adult-onset retinoblastoma can be managed with intra-arterial chemotherapy. [J Pediatr Ophthalmol Strabismus. 2016;53:e43-e46.]. PMID:27486894

  18. Adult-onset Still's disease revealed by perimyocarditis and a concomitant reactivation of an EBV infection

    PubMed Central

    Meckenstock, Roderich; Therby, Audrey; Gibault-Genty, Geraldine; Khau, David; Monnier, Sebastien; Greder-Belan, Alix

    2012-01-01

    We describe a 17-year-old patient presenting perimyocarditis as the initial manifestation of the adult-onset Still's disease. Corticotherapy was rapidly successful but induced major acute hepatitis in relation with Epstein-Barr virus reactivation. After 1 year, even if the global outcome is favourable, a slightly lowered ejection fraction still persists. Former case reports and differential diagnosis with reactive haemophagocytic syndrome would be discussed. PMID:23166163

  19. Clinical Characteristics of Pediatric-Onset and Adult-Onset Multiple Sclerosis in Hispanic Americans.

    PubMed

    Langille, Megan M; Islam, Talat; Burnett, Margaret; Amezcua, Lilyana

    2016-07-01

    Multiple sclerosis can affect pediatric patients. Our aim was to compare characteristics between pediatric-onset multiple sclerosis and adult-onset multiple sclerosis in Hispanic Americans. This was a cross-sectional analysis of 363 Hispanic American multiple scleroses cases; demographic and clinical characteristics were analyzed. A total of 110 Hispanic patients presented with multiple sclerosis before age 18 and 253 as adult multiple sclerosis. The most common presenting symptoms for both was optic neuritis. Polyfocal symptoms, seizures, and cognitive symptoms at presentation were more prevalent in pediatric-onset multiple sclerosis (P ≤ .001). Transverse myelitis was more frequent in adult-onset multiple sclerosis (P ≤ .001). Using multivariable analysis, pediatric-onset multiple sclerosis (adjusted odds ratio, 0.3OR 95% confidence interval 0.16-0.71, P = .004) and being US born (adjusted odds ratio, 0.553, 95% confidence interval 0.3-1.03, P = .006) were less likely to have severe ambulatory disability. Results suggest that pediatric-onset multiple sclerosis and adult-onset multiple sclerosis in Hispanics have differences that could be important for treatment and prognosis. PMID:27021143

  20. Dioxin (TCDD) Induces Epigenetic Transgenerational Inheritance of Adult Onset Disease and Sperm Epimutations

    PubMed Central

    Manikkam, Mohan; Tracey, Rebecca; Guerrero-Bosagna, Carlos; Skinner, Michael K.

    2012-01-01

    Environmental compounds can promote epigenetic transgenerational inheritance of adult-onset disease in subsequent generations following ancestral exposure during fetal gonadal sex determination. The current study examined the ability of dioxin (2,3,7,8-tetrachlorodibenzo[p]dioxin, TCDD) to promote epigenetic transgenerational inheritance of disease and DNA methylation epimutations in sperm. Gestating F0 generation females were exposed to dioxin during fetal day 8 to 14 and adult-onset disease was evaluated in F1 and F3 generation rats. The incidences of total disease and multiple disease increased in F1 and F3 generations. Prostate disease, ovarian primordial follicle loss and polycystic ovary disease were increased in F1 generation dioxin lineage. Kidney disease in males, pubertal abnormalities in females, ovarian primordial follicle loss and polycystic ovary disease were increased in F3 generation dioxin lineage animals. Analysis of the F3 generation sperm epigenome identified 50 differentially DNA methylated regions (DMR) in gene promoters. These DMR provide potential epigenetic biomarkers for transgenerational disease and ancestral environmental exposures. Observations demonstrate dioxin exposure of a gestating female promotes epigenetic transgenerational inheritance of adult onset disease and sperm epimutations. PMID:23049995

  1. Globus pallidus deep brain stimulation for adult-onset axial dystonia

    PubMed Central

    Shaikh, Aasef G.; Mewes, Klaus; Jinnah, H.A.; DeLong, Mahlon R.; Gross, Robert E.; Triche, Shirley; Freeman, Alan; Factor, Stewart A.

    2016-01-01

    Introduction Generalized dystonia, both primary and secondary forms, and axial dystonias such as tardive dystonia, and idiopathic cervical dystonia are responsive to globus pallidus interna (GPi) DBS. There is a paucity of investigations probing the impact of DBS on adult-onset axial dystonia. We assessed the efficacy of GPi DBS in four patients with rare adult-onset axial dystonia. Methods Primary outcome measure was improvement in the motor component of the Burke-Fahn-Marsden (BFM) rating scale. Secondary outcome measures were quality of life as determined by the SF-36 questionnaire, time to achieve best possible benefit and DBS parameters that accounted for the best response. In patients with prominent concomitant cervical dystonia we also used the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). Results GPi DBS improved BFM scores by 87.63 ± 11.46%. Improvement in total severity scale of TWSTRS was 71.5 ± 12.7%. Quality of life also remarkably improved as evidenced by 109.38 ± 82.97 and 7.05 ± 21.48% percent change in psychometrically-based physical component summary (PCS), and a mental component summary (MCS) score respectively. Conclusions GPi DBS is a very effective treatment for adult-onset axial dystonia. Considering its refractoriness to medical therapy and significant impact on quality of life DBS should be considered for this disorder. PMID:25260969

  2. Pesticide Methoxychlor Promotes the Epigenetic Transgenerational Inheritance of Adult-Onset Disease through the Female Germline

    PubMed Central

    Manikkam, Mohan; Haque, M. Muksitul; Guerrero-Bosagna, Carlos; Nilsson, Eric E.; Skinner, Michael K.

    2014-01-01

    Environmental compounds including fungicides, plastics, pesticides, dioxin and hydrocarbons can promote the epigenetic transgenerational inheritance of adult-onset disease in future generation progeny following ancestral exposure during the critical period of fetal gonadal sex determination. This study examined the actions of the pesticide methoxychlor to promote the epigenetic transgenerational inheritance of adult-onset disease and associated differential DNA methylation regions (i.e. epimutations) in sperm. Gestating F0 generation female rats were transiently exposed to methoxychlor during fetal gonadal development (gestation days 8 to 14) and then adult-onset disease was evaluated in adult F1 and F3 (great-grand offspring) generation progeny for control (vehicle exposed) and methoxychlor lineage offspring. There were increases in the incidence of kidney disease, ovary disease, and obesity in the methoxychlor lineage animals. In females and males the incidence of disease increased in both the F1 and the F3 generations and the incidence of multiple disease increased in the F3 generation. There was increased disease incidence in F4 generation reverse outcross (female) offspring indicating disease transmission was primarily transmitted through the female germline. Analysis of the F3 generation sperm epigenome of the methoxychlor lineage males identified differentially DNA methylated regions (DMR) termed epimutations in a genome-wide gene promoters analysis. These epimutations were found to be methoxychlor exposure specific in comparison with other exposure specific sperm epimutation signatures. Observations indicate that the pesticide methoxychlor has the potential to promote the epigenetic transgenerational inheritance of disease and the sperm epimutations appear to provide exposure specific epigenetic biomarkers for transgenerational disease and ancestral environmental exposures. PMID:25057798

  3. The Incidence and Clinical Characteristics of Adult-Onset Convergence Insufficiency

    PubMed Central

    Ghadban, Rafif; Martinez, Jennifer M.; Diehl, Nancy N.; Mohney, Brian G.

    2015-01-01

    Objective The purpose of this study was to describe the clinical characteristics and natural history of convergence insufficiency (CI) in a population-based cohort of adults. Design Retrospectively reviewed population-based cohort. Participants Adult (≥19 years of age) residents of Olmsted County, Minnesota. Methods The medical records of all adults diagnosed with CI over a 20-year period were retrospectively reviewed. Main outcome measures Clinical characteristics and outcomes for adult-onset convergence insufficiency. Results A total of 118 adults (annual incidence of 8.44 per 100 000 patients older than 19 years) were diagnosed with CI during the 20-year period, comprising 15.7% of all forms of adult-onset strabismus observed in this population. The median age at diagnosis was 68.5 years (range 21.7 to 97.1 years) and 68 (57.6%) were female. The mean initial exodeviation at near was 14.1 PD (range 1 to 30 PD) and 1.7 PD (range 0 to 10 PD) at distance. The Kaplan-Meier rate of exotropia increasing by 7 prism diopters or more at near over time was 4.2% at 5 years, 13.5% at 10 years, and 24.4% at 20 years. Approximately 88% were managed with prisms while less than 5% underwent surgical correction. Conclusions Adult-onset convergence insufficiency comprised approximately 1 in 6 adults who were newly diagnosed with strabismus in this 20-year cohort. There was a significant increase in incidence with increasing age. Nearly one-fourth had an increase of their near exodeviation of at least 7 PD by 20 years after their diagnosis and most patients were managed conservatively. PMID:25626756

  4. Bartonella henselae infection presenting with a picture of adult-onset Still's disease.

    PubMed

    Durey, Areum; Kwon, Hea Yoon; Im, Jae-Hyoung; Lee, Sun Myoung; Baek, JiHyeon; Han, Seung Baik; Kang, Jae-Seung; Lee, Jin-Soo

    2016-05-01

    We report a patient with a clinical picture of suggestive for adult-onset Still's Disease (ASOD) due to Bartonella infection. A 42-year-old immunocompetent man was admitted with fever, rash, arthralgia and sore throat. As his clinical picture suggested ASOD except unusual skin manifestation, we treated him on steroid and ibuprofen. His fever and constitutional symptoms responded immediately within 24hrs of commencing therapy, yet rash and leukocytosis remained. Meanwhile, Bartonella infection was proved by culture of bone marrow. Minocyclin treatment started combined with hydroxychloroquine sulfate and the patient discharged with overall improvement. PMID:27000538

  5. Adult Onset Still's Disease: A Review on Diagnostic Workup and Treatment Options

    PubMed Central

    Gopalarathinam, Rajesh; Orlowsky, Eric; Kesavalu, Ramesh; Yelaminchili, Sreeteja

    2016-01-01

    Adult onset Still's disease (AOSD) is a rare systemic inflammatory disease of unknown etiology and pathogenesis that presents in 5 to 10% of patients as fever of unknown origin (FUO) accompanied by systemic manifestations. We report an interesting case of a 33-year-old African-American male who presented with one-month duration of FUO along with skin rash, sore throat, and arthralgia. After extensive workup, potential differential diagnoses were ruled out and the patient was diagnosed with AOSD based on the Yamaguchi criteria. The case history, incidence, pathogenesis, clinical manifestations, differential diagnoses, diagnostic workup, treatment modalities, and prognosis of AOSD are discussed in this case report. PMID:27042373

  6. Cord Blood Transplantation Following Reduced-intensity Conditioning for Adult-onset Inherited Hemophagocytic Lymphohistiocytosis.

    PubMed

    Kuriyama, Takuro; Kato, Koji; Sakamoto, Keiji; Hayashi, Masayasu; Takashima, Shuichiro; Mori, Yasuo; Takenaka, Katsuto; Iwasaki, Hiromi; Teshima, Takanori; Harada, Naoki; Nagafuji, Koji; Miyamoto, Toshihiro; Akashi, Koichi

    2016-01-01

    Inherited hemophagocytic lymphohistiocytosis (HLH) is a genetic anomaly disorder in which abnormally activated cytotoxic T lymphocytes cannot induce the apoptosis of target cells and antigen-presenting cells, leading to hemophagocytosis, pancytopenia, and a variety of symptoms such as a high fever. The present patient with adult-onset HLH developed refractory disease despite receiving immunosuppressive treatments. He underwent a reduced-intensity conditioning (RIC) regimen that comprised antithymocyte globulin (ATG) followed by cord blood transplantation (RIC-CBT). He achieved and maintained a complete donor type. The incorporation of ATG into RIC-CBT may prevent graft failure and control hemophagocytosis, however, further efforts are necessary to reduce infectious complications. PMID:26984088

  7. Herpes Zoster Meningitis Complicating Combined Tocilizumab and Cyclosporine Therapy for Adult-Onset Still's Disease

    PubMed Central

    Tsurukawa, Shinichiro; Iwanaga, Nozomi; Izumi, Yasumori; Shirakawa, Atsunori; Kawahara, Chieko; Shukuwa, Tetsuo; Inamoto, Miwako; Kawakami, Atsushi; Migita, Kiyoshi

    2016-01-01

    A 56-year-old female with refractory adult-onset Still's disease presented with ocular herpes zoster infection during TCZ treatment. After three days of acyclovir treatment (5 mg/kg), she developed a severe headache and high fever. Viral DNA isolation and cerebral spinal fluid abnormalities led to a herpes zoster meningitis diagnosis. Her meningitis was cured by high doses of intravenous acyclovir (10 mg/kg for 14 days). To our knowledge, this is the first report of meningeal herpes zoster infection in rheumatic diseases under TCZ treatment. PMID:27092286

  8. Herpes Zoster Meningitis Complicating Combined Tocilizumab and Cyclosporine Therapy for Adult-Onset Still's Disease.

    PubMed

    Tsurukawa, Shinichiro; Iwanaga, Nozomi; Izumi, Yasumori; Shirakawa, Atsunori; Kawahara, Chieko; Shukuwa, Tetsuo; Inamoto, Miwako; Kawakami, Atsushi; Migita, Kiyoshi

    2016-01-01

    A 56-year-old female with refractory adult-onset Still's disease presented with ocular herpes zoster infection during TCZ treatment. After three days of acyclovir treatment (5 mg/kg), she developed a severe headache and high fever. Viral DNA isolation and cerebral spinal fluid abnormalities led to a herpes zoster meningitis diagnosis. Her meningitis was cured by high doses of intravenous acyclovir (10 mg/kg for 14 days). To our knowledge, this is the first report of meningeal herpes zoster infection in rheumatic diseases under TCZ treatment. PMID:27092286

  9. Growth Hormone Deficiency, Brain Development, and Intelligence

    ERIC Educational Resources Information Center

    Meyer-Bahlburg, Heino F. L.; And Others

    1978-01-01

    Available from: American Medical Association, 535 N. Dearborn Street, Chicago, Illinois 60610. In order to determine what effect, if any, growth hormone (GH) has on human brain development, 29 patients (mean age 11.7 years) with GH deficiency were selected according to the following criteria: no evidence of reversible GH deficiency, onset of…

  10. A Unique Case of Pica of Adult Onset with Interesting Psychosexual Aspects

    PubMed Central

    Chakraborty, Suddhendu; Sanyal, D.; Bhattacharyya, R.

    2011-01-01

    Pica has been considered as the ingestion of inedible substances or atypical food combinations. Pica has been reported widely in pediatric age group and often found to be co existing with obsessive compulsive or major depressive disorder. Reports of pica in elderly age group are relatively uncommon and rarely does it have an adult onset. In this article we present a case of adult onset pica. A young lady with unusual sensation in her abdomen was found to consume iron nails over years and there was history of dyspareunia since her marriage three months back. On query it was known that the lady is having same sex relationship over years. There unique conglomeration of cultural, psychodynamic and physiological determinants which together is responsible for this unusual habit of this lady. Moreover the onset of the disease at a late age and different psychodynamic issues make the case all the more interesting. Whether the pica is an eating disorder or obsessive compulsive disorder is still controversial. Pica has been mentioned in Diagnostic and Statistical Manual IV TR. The present case report warrants the need to look into this entity more closely with regards to its occurrence and etiology. PMID:22021963

  11. Electrophysiological characterization of adult-onset Niemann-Pick type C disease.

    PubMed

    Iodice, Rosa; Dubbioso, Raffaele; Topa, Antonietta; Ruggiero, Lucia; Pisciotta, Chiara; Esposito, Marcello; Tozza, Stefano; Santoro, Lucio; Manganelli, Fiore

    2015-01-15

    In infantile and juvenile Niemann-Pick type C (NPC) disease electrophysiological studies have shown central (CNS) and peripheral (PNS) nervous system abnormalities. However, an extensive electrophysiological evaluation of CNS and PNS in adult form of NPC is still lacking. The aim of the study is to assess in adult-onset NPC disease the involvement of CNS and PNS by a multimodal electrophysiological approach. Three patients affected by adult form of NPC disease underwent electrophysiological evaluation including nerve conduction study (NCS), magnetic motor (MEPs), visual (VEPs), somatosensory (SSEPs) and brainstem auditory (BAEPs) evoked potentials. NCS, MEPs, VEPs and upper limb SSEPs were normal. Lower limb SSEPs were abnormal in all patients and abnormalities were consistent with a length-dependent process affecting the central somatosensory pathway. BAEPs were abnormal in all patients with both peripheral and central impairment of auditory pathway. Our electrophysiological findings suggest that auditory and lower limb somatosensory pathways are constantly affected in adult-onset form of NPC disease. The involvement of PNS, pyramidal, visual and upper limb somatosensory pathways might occur later during the course of disease. PMID:25537619

  12. Compound heterozygote mutations in SPG7 in a family with adult-onset primary lateral sclerosis

    PubMed Central

    Yang, Yi; Lynch, David R.; Lukas, Thomas; Ahmeti, Kreshnik; Sleiman, Patrick M.A.; Ryan, Eanna; Schadt, Kimberly A.; Newman, Jordan H.; Deng, Han-Xiang; Siddique, Nailah

    2016-01-01

    Objective: To identify the genetic defect for adult-onset primary lateral sclerosis (PLS) in a family with 5 patients. Methods: Whole-exome sequencing was performed to identify the shared genetic variants in 3 affected members in a PLS family with 5 affected individuals. Sanger sequencing was used for validation of the variants and for cosegregation analysis. Mitochondrial activity for both patients and unaffected siblings was measured using a SeaHorse metabolic analyzer. Results: Whole-exome sequencing and subsequent cosegregation analysis demonstrated that compound heterozygous missense variants L695P and I743T in SPG7 were the only mutations cosegregating with the disease in an autosomal recessive fashion in this family. The parents and siblings are genetically heterozygous and clinically unaffected. Functional studies suggested that the PLS-associated SPG7 mutants affect mitochondrial function when glucose is reduced. Conclusions: Compound heterozygote mutations in SPG7 are associated with adult-onset PLS, extending the spectrum of SPG7-linked neurologic diseases. Patients with the PLS phenotype should have genetic testing for paraplegin, especially when the condition is familial. PMID:27123479

  13. Adult-Onset Presentations of Genetic Immunodeficiencies: Genes Can Throw Slow Curves

    PubMed Central

    Nelson, Katharine S.; Lewis, David B.

    2016-01-01

    Purpose of Review The molecular and genetic mechanisms behind adult presentations of primary immunodeficiency diseases are examined, with particular emphasis on cases where this was heralded by severe, recurrent or opportunistic infection. Recent Findings A detailed analysis over the last two decades of the relationship between genotype and clinical phenotype for a number of genetic immunodeficiencies has revealed multiple mechanisms that can account for the delayed presentation of genetic disorders that typically present in childhood, including hypomorphic gene mutations and X-linked gene mutations with age-related skewing in random X-chromosome inactivation. Adult-onset presentations of chronic granulomatous disease, X-linked agammaglobulinemia, interleukin-12/T helper 1/interferon-gamma and interleukin-23/T helper 17/interleukin-17 pathway defects, and X-linked lymphoproliferative disorder are used to illustrate these mechanisms. Finally, certain genetic types of common variable immunodeficiency are used to illustrate that inherited null mutations can take decades to manifest immunologically. Summary Both genetic mechanisms and environmental factors can account for adult-onset infectious and non-infectious complications as manifestations of disorders that typically present in childhood. This emphasizes the potential complexity in the relationship between genotype and phenotype with natural human mutations. PMID:20581672

  14. Prevalence of adult-onset multifactorial disease among offspring of atomic bomb survivors.

    PubMed

    Fujiwara, S; Suyama, A; Cologne, J B; Akahoshi, M; Yamada, M; Suzuki, G; Koyama, K; Takahashi, N; Kasagi, E; Grant, E J; Lagarde, E; Hsu, W L; Furukawa, K; Ohishi, W; Tatsukawa, Y; Neriishi, K; Takahashi, I; Ashizawa, K; Hida, A; Imaizumi, M; Nagano, J; Cullings, H M; Katayama, H; Ross, N P; Kodama, K; Shore, R E

    2008-10-01

    The first study to examine whether parental radiation exposure leads to increased heritable risk of common adult-onset multifactorial diseases (i.e., hypertension, diabetes mellitus, hypercholesterolemia, ischemic heart disease, and stroke) was conducted among 11,951 participants in the clinical examination program out of a potential of 24,673 mail survey subjects who were offspring of survivors born from May 1946 through December 1984. Logistic regression analyses demonstrated no evidence of an association between the prevalence of multifactorial diseases in the offspring and parental radiation exposure, after adjusting for age, city, gender and various risk factors. The odds ratio (OR) for a paternal dose of 1 Gy was 0.91 [95% confidence interval (CI) 0.81-1.01, P = 0.08], and that for a maternal dose of 1 Gy was 0.98 (95% CI 0.86-1.10, P = 0.71). There was no apparent effect of parental age at exposure or of elapsed time between parental exposure and birth, but male offspring had a low odds ratio (OR = 0.76 at 1 Gy) for paternal exposure, but cautious interpretation is needed for this finding. The clinical assessment of nearly 12,000 offspring of A-bomb survivors who have reached a median age of about 50 years provided no evidence for an increased prevalence of adult-onset multifactorial diseases in relation to parental radiation exposure. PMID:19024652

  15. Chinese new immigrant mothers' perception about adult-onset non-communicable diseases prevention during childhood.

    PubMed

    Wang, Linda Dong Ling; Lam, Wendy Wing Tak; Wu, Joseph Tsz Kei; Fielding, Richard

    2015-12-01

    Many non-communicable diseases (NCDs) are largely preventable via behaviour change and healthy lifestyle, which may be best established during childhood. This study sought insights into Chinese new immigrant mothers' perceptions about adult-onset NCDs prevention during childhood. Twenty-three semi-structured interviews were carried out with new immigrant mothers from mainland China who had at least one child aged 14 years or younger living in Hong Kong. Interviews were audio taped, transcribed and analysed using a Grounded Theory approach. The present study identified three major themes: perceived causes of adult NCDs, beliefs about NCDs prevention and everyday health information practices. Unhealthy lifestyle, contaminated food and environment pollution were perceived as the primary causes of adult NCDs. Less than half of the participants recognized that parents had responsibility for helping children establish healthy behaviours from an early age to prevent diseases in later life. Most participants expressed helplessness about chronic diseases prevention due to lack of knowledge of prevention, being perceived as beyond individual control. Many participants experienced barriers to seeking health information, the most common sources of health information being interpersonal conversation and television. Participants' everyday information practice was passive and generally lacked awareness regarding early prevention of adult-onset NCDs. Updated understanding of this issue has notable implications for future health promotion interventions. PMID:24842077

  16. Distinguishing adult-onset asthma from COPD: a review and a new approach

    PubMed Central

    Abramson, Michael J; Perret, Jennifer L; Dharmage, Shyamali C; McDonald, Vanessa M; McDonald, Christine F

    2014-01-01

    Adult-onset asthma and chronic obstructive pulmonary disease (COPD) are major public health burdens. This review presents a comprehensive synopsis of their epidemiology, pathophysiology, and clinical presentations; describes how they can be distinguished; and considers both established and proposed new approaches to their management. Both adult-onset asthma and COPD are complex diseases arising from gene–environment interactions. Early life exposures such as childhood infections, smoke, obesity, and allergy influence adult-onset asthma. While the established environmental risk factors for COPD are adult tobacco and biomass smoke, there is emerging evidence that some childhood exposures such as maternal smoking and infections may cause COPD. Asthma has been characterized predominantly by Type 2 helper T cell (Th2) cytokine-mediated eosinophilic airway inflammation associated with airway hyperresponsiveness. In established COPD, the inflammatory cell infiltrate in small airways comprises predominantly neutrophils and cytotoxic T cells (CD8 positive lymphocytes). Parenchymal destruction (emphysema) in COPD is associated with loss of lung tissue elasticity, and small airways collapse during exhalation. The precise definition of chronic airflow limitation is affected by age; a fixed cut-off of forced expiratory volume in 1 second/forced vital capacity leads to overdiagnosis of COPD in the elderly. Traditional approaches to distinguishing between asthma and COPD have highlighted age of onset, variability of symptoms, reversibility of airflow limitation, and atopy. Each of these is associated with error due to overlap and convergence of clinical characteristics. The management of chronic stable asthma and COPD is similarly convergent. New approaches to the management of obstructive airway diseases in adults have been proposed based on inflammometry and also multidimensional assessment, which focuses on the four domains of the airways, comorbidity, self-management, and

  17. Adult onset Still's disease accompanied by acute respiratory distress syndrome: A case report

    PubMed Central

    Xi, Xiao-Tu; Wang, Mao-Jie; Huang, Run-Yue; Ding, Bang-Han

    2016-01-01

    Adult onset Still's disease (AOSD) is a systemic inflammatory disorder characterized by rash, leukocytosis, fever and arthralgia/arthritis. The most common pulmonary manifestations associated with AOSD are pulmonary infiltrates and pleural effusion. The present study describes a 40-year-old male with AOSD who developed fever, sore throat and shortness of breath. Difficulty breathing promptly developed, and the patient was diagnosed with acute respiratory distress syndrome (ARDS). The patient did not respond to antibiotics, including imipenem, vancomycin, fluconazole, moxifloxacin, penicillin, doxycycline and meropenem, but was sensitive to glucocorticoid treatment, including methylprednisolone sodium succinate. ARDS accompanied by AOSD has been rarely reported in the literature. In conclusion, in a patient with ARDS who does not respond to antibiotic treatment, the involvement of AOSD should be considered. PMID:27588099

  18. Hidden in plain sight: macrophage activation syndrome complicating Adult Onset Still's Disease.

    PubMed

    Benitez, Lourdes; Vila, Salvador; Mellado, Robert Hunter

    2010-01-01

    Hemophagocytic Lymphystiocytosis is a rare and fatal complication of rheumatic diseases, particularly Adult Onset Still's Disease (AOSD). It may be precipitated with immunosuppressive drugs and with viral and bacterial infections. A diagnosis depends on a high index of suspicion associated to certain clinical manifestations (fever, rash, Splemomegaly, any cytology blood dyscrasia, hipertrigliceridemia, hiperfibrinogenemia, and others), as well as pathologic evidence of hemophagocitosis from bone marrow biopsy or tissue samples of affected organs. Therapy consists of high dose corticosteroids and immunosuppressive drugs. We present a 42 year old woman with AOSD in remission who developed HLH in spite of receiving therapy with high dose steroids and immunosuppressive drugs. She had 2 negative bone marrow aspirates. Evidence of Hemophagocytosis was detected in both bone marrow biopsies. Timely evaluation and recognition of the signs and symptoms of HLH is crucial for the prompt management and a decrease in the mortality associated with this disease. PMID:23875527

  19. Predictive Medicine: Recombinant DNA Technology and Adult-Onset Genetic Disorders

    PubMed Central

    Hayden, Michael

    1988-01-01

    Genetic factors are of great importance in common adult-onset disorders such as atherosclerosis, cancer, and neuro-degenerative diseases. Advances in DNA technology now allow identification of persons at high-risk of developing some of these diseases. This advance is leading to predictive medicine. In some genetic disorders, such as those leading to atherosclerosis and cancer, identification of high-risk individuals allows intervention which alters the natural history of the disorder. In other diseases, for which there is no treatment, such as Huntington's disease, the application of this technology provides information that relieves uncertainty and may affect quality of life, but does not alter the course of the illness. General implementation of predictive testing programs awaits the results of pilot projects, which will demonstrate the needs, appropriate levels of support, and guidelines for delivery of such testing. PMID:21253100

  20. Blepharospasm-oromandibular dystonia syndrome (Brueghel's syndrome). A variant of adult-onset torsion dystonia?

    PubMed Central

    Marsden, C D

    1976-01-01

    Thirty-nine patients with the idiopathic blepharospasm-oromandibular dystonia syndrome are described. All presented in adult life, usually in the sixth decade; women were more commonly affected than men. Thirteen had blepharospasm alone, nine had oromandibular dystonia alone, and 17 had both. Torticollis or dystonic writer's camp preceded the syndrome in two patients. Eight other patients developed toritocollis, dystonic posturing of the arms, or involvement of respiratory muscles. No cause or hereditary basis for the illness were discovered. The evidence to indicate that this syndrome is due to an abnormality of extrapyramidal function, and that it is another example of adult-onset focal dystonia akin to spasmodic torticollis and dystonic writer's cramp, is discussed. Images PMID:1011031

  1. Genes and Pathways Involved in Adult Onset Disorders Featuring Muscle Mitochondrial DNA Instability

    PubMed Central

    Ahmed, Naghia; Ronchi, Dario; Comi, Giacomo Pietro

    2015-01-01

    Replication and maintenance of mtDNA entirely relies on a set of proteins encoded by the nuclear genome, which include members of the core replicative machinery, proteins involved in the homeostasis of mitochondrial dNTPs pools or deputed to the control of mitochondrial dynamics and morphology. Mutations in their coding genes have been observed in familial and sporadic forms of pediatric and adult-onset clinical phenotypes featuring mtDNA instability. The list of defects involved in these disorders has recently expanded, including mutations in the exo-/endo-nuclease flap-processing proteins MGME1 and DNA2, supporting the notion that an enzymatic DNA repair system actively takes place in mitochondria. The results obtained in the last few years acknowledge the contribution of next-generation sequencing methods in the identification of new disease loci in small groups of patients and even single probands. Although heterogeneous, these genes can be conveniently classified according to the pathway to which they belong. The definition of the molecular and biochemical features of these pathways might be helpful for fundamental knowledge of these disorders, to accelerate genetic diagnosis of patients and the development of rational therapies. In this review, we discuss the molecular findings disclosed in adult patients with muscle pathology hallmarked by mtDNA instability. PMID:26251896

  2. The distinction between juvenile and adult-onset primary open-angle glaucoma

    SciTech Connect

    Wiggs, J.L.; Haines, J.L.; Damji, K.F.

    1996-01-01

    Because of the significant differences between the juvenile and adult forms of open-angle glaucoma, especially with regard to inheritance, prevalence, severity, and age of onset, we read with interest the recent publication by Morissette et al., describing a pedigree with a phenotype that overlaps the distinctive features of juvenile-onset open-angle glaucoma (JOAG) and adult-onset primary open-angle glaucoma (usually abbreviated as POAG or COAG). These authors conclude that a gene mapped to human chromosome 1q21-q31 (GLC1A) can be responsible for both juvenile and adult forms of open-angle glaucoma. The implications of such a result could be extremely important, in light of the high prevalence of the adult form of the disease. However, while the data presented in this report suggest that variable expressivity of the GLC1A gene may lead to a broader range of onset for this form of juvenile glaucoma, these data do not identify the GLC1A gene as an important cause of POAG. To prevent misleading interpretations of this and similar studies, we wish to clarify the distinction between the juvenile and adult forms of open-angle glaucoma. 8 refs.

  3. Adult onset sinonasal rhabdomyosarcoma - a rare case report with cytohistological features.

    PubMed

    Sood, N; Sehrawat, N

    2016-08-01

    Rhabdomyosarcoma (RMS) is a fast growing, malignant tumour arising from immature mesenchymal cells, committed to skeletal muscle differentiation. It is more often seen in the paediatric population and constitutes less than 1% of all malignancies and less than 3% of all soft tissue tumours. RMS of the paranasal sinuses constitutes 10-15% of adult head and neck RMS, ethmoidal and maxillary sinuses being the most common. We report a 56-year-oldman presenting with left nasal obstruction, epistaxis on and off and left cheek swelling. Nasal endoscopy revealed a reddish friable mass, bleeding on touch, in the left nasal cavity. CECT scan showed a heterogeneous growth in the left maxillary sinus eroding the medial orbital wall and lateral nasal wall. FNAC of the left cheek swelling yielded highly cellular smears showing predominantly singly scattered round to ovoid neoplastic cells with scanty cytoplasm and indistinct nucleoli. Few of the cells had eccentric nuclei with moderate amount of eosinophilic cytoplasm. Attempted pseudorossette formation was seen. An impression of round cell tumour was given. A diagnosis of an adult onset sinonasal rhabdomyosarcoma was made on histopathological examination of the nasal biopsy, supported by immunohistochemistry (IHC) showing strong myogenin positivity, focal positivity for PAX8 and negativity for CK, LCA, S-100 and CD99. Parameningeal RMS is rare in adults especially the elderly. However, it needs to be considered whenever a poorly-differentiated neoplasm is seen in this age and IHC is a useful aid. PMID:27568676

  4. Effects of Aging and Adult-Onset Hearing Loss on Cortical Auditory Regions

    PubMed Central

    Cardin, Velia

    2016-01-01

    Hearing loss is a common feature in human aging. It has been argued that dysfunctions in central processing are important contributing factors to hearing loss during older age. Aging also has well documented consequences for neural structure and function, but it is not clear how these effects interact with those that arise as a consequence of hearing loss. This paper reviews the effects of aging and adult-onset hearing loss in the structure and function of cortical auditory regions. The evidence reviewed suggests that aging and hearing loss result in atrophy of cortical auditory regions and stronger engagement of networks involved in the detection of salient events, adaptive control and re-allocation of attention. These cortical mechanisms are engaged during listening in effortful conditions in normal hearing individuals. Therefore, as a consequence of aging and hearing loss, all listening becomes effortful and cognitive load is constantly high, reducing the amount of available cognitive resources. This constant effortful listening and reduced cognitive spare capacity could be what accelerates cognitive decline in older adults with hearing loss. PMID:27242405

  5. A nonsense mutation of human XRCC4 is associated with adult-onset progressive encephalocardiomyopathy

    PubMed Central

    Bee, Leonardo; Nasca, Alessia; Zanolini, Alice; Cendron, Filippo; d'Adamo, Pio; Costa, Rodolfo; Lamperti, Costanza; Celotti, Lucia; Ghezzi, Daniele; Zeviani, Massimo

    2015-01-01

    We studied two monozygotic twins, born to first cousins, affected by a multisystem disease. At birth, they both presented with bilateral cryptorchidism and malformations. Since early adulthood, they developed a slowly progressive neurological syndrome, with cerebellar and pyramidal signs, cognitive impairment, and depression. Dilating cardiomyopathy is also present in both. By whole-exome sequencing, we found a homozygous nucleotide change in XRCC4 (c.673C>T), predicted to introduce a premature stop codon (p.R225*). XRCC4 transcript levels were profoundly reduced, and the protein was undetectable in patients' skin fibroblasts. XRCC4 plays an important role in non-homologous end joining of DNA double-strand breaks (DSB), a system that is involved in repairing DNA damage from, for example, ionizing radiations. Gamma-irradiated mutant cells demonstrated reduction, but not abolition, of DSB repair. In contrast with embryonic lethality of the Xrcc4 KO mouse, nonsense mutations in human XRCC4 have recently been associated with primordial dwarfism and, in our cases, with adult-onset neurological impairment, suggesting an important role for DNA repair in the brain. Surprisingly, neither immunodeficiency nor predisposition to malignancy was reported in these patients. PMID:25872942

  6. Multimodal Image Analysis in Acquired Vitelliform Lesions and Adult-Onset Foveomacular Vitelliform Dystrophy

    PubMed Central

    Rocha Bastos, Ricardo; Ferreira, Carla Sofia; Brandão, Elisete; Falcão-Reis, Fernando; Carneiro, Ângela M.

    2016-01-01

    Purpose. To characterize vitelliform lesions (VLs) in adult-onset foveomacular vitelliform dystrophy (AOFVD) and acquired vitelliform (AVL) patients using multimodal image analysis. Methods. Retrospective study of twenty-eight eyes from nineteen patients diagnosed with AVL or AOFVD. They were evaluated by color fundus photographs, fundus autofluorescence (FAF), fluorescein angiography (FA), and spectral-domain optical coherence tomography (SD-OCT). Results. Bilateral VLs were associated with AOFVD (p = 0.013). Regular and centered VLs were associated with AOFVD (p = 0.004 and p = 0.016), whereas irregular and noncentered lesions were more frequent in AVL patients. Visual acuity, greatest linear dimension (GLD), lesion height (LH), and pseudohypopyon were similar between groups. Whereas median LH and GLD in AVL group diminished significantly during follow-up (p = 0.009 and p = 0.001), AOFVD lesions tended to become larger and thicker. Conclusions. When consulting a patient presenting a VL with unknown age of onset, familial history, or previous retinal diseases, some aspects of multimodal imaging assessment may lead the ophthalmologist to a correct diagnosis. PMID:27190637

  7. Targeting Hsp90/Hsp70-based protein quality control for treatment of adult onset neurodegenerative diseases.

    PubMed

    Pratt, William B; Gestwicki, Jason E; Osawa, Yoichi; Lieberman, Andrew P

    2015-01-01

    Currently available therapies for adult onset neurodegenerative diseases provide symptomatic relief but do not modify disease progression. Here we explore a new neuroprotective approach based on drugs targeting chaperone-directed protein quality control. Critical target proteins that unfold and aggregate in these diseases, such as the polyglutamine androgen receptor in spinal and bulbar muscular atrophy, huntingtin in Huntington's disease, α-synuclein in Parkinson's disease, and tau in Alzheimer's disease, are client proteins of heat shock protein 90 (Hsp90), and their turnover is regulated by the protein quality control function of the Hsp90/Hsp70-based chaperone machinery. Hsp90 and Hsp70 have opposing effects on client protein stability in protein quality control; Hsp90 stabilizes the clients and inhibits their ubiquitination, whereas Hsp70 promotes ubiquitination dependent on CHIP (C terminus of Hsc70-interacting protein) and proteasomal degradation. We discuss how drugs that modulate proteostasis by inhibiting Hsp90 function or promoting Hsp70 function enhance the degradation of the critical aggregating proteins and ameliorate toxic symptoms in cell and animal disease models. PMID:25292434

  8. Cathepsin F mutations cause Type B Kufs disease, an adult-onset neuronal ceroid lipofuscinosis

    PubMed Central

    Smith, Katherine R.; Dahl, Hans-Henrik M.; Canafoglia, Laura; Andermann, Eva; Damiano, John; Morbin, Michela; Bruni, Amalia C.; Giaccone, Giorgio; Cossette, Patrick; Saftig, Paul; Grötzinger, Joachim; Schwake, Michael; Andermann, Frederick; Staropoli, John F.; Sims, Katherine B.; Mole, Sara E.; Franceschetti, Silvana; Alexander, Noreen A.; Cooper, Jonathan D.; Chapman, Harold A.; Carpenter, Stirling; Berkovic, Samuel F.; Bahlo, Melanie

    2013-01-01

    Kufs disease, an adult-onset neuronal ceroid lipofuscinosis, is challenging to diagnose and genetically heterogeneous. Mutations in CLN6 were recently identified in recessive Kufs disease presenting as progressive myoclonus epilepsy (Type A), whereas the molecular basis of cases presenting with dementia and motor features (Type B) is unknown. We performed genome-wide linkage mapping of two families with recessive Type B Kufs disease and identified a single region on chromosome 11 to which both families showed linkage. Exome sequencing of five samples from the two families identified homozygous and compound heterozygous missense mutations in CTSF within this linkage region. We subsequently sequenced CTSF in 22 unrelated individuals with suspected recessive Kufs disease, and identified an additional patient with compound heterozygous mutations. CTSF encodes cathepsin F, a lysosomal cysteine protease, dysfunction of which is a highly plausible candidate mechanism for a storage disorder like ceroid lipofuscinosis. In silico modeling suggested the missense mutations would alter protein structure and function. Moreover, re-examination of a previously published mouse knockout of Ctsf shows that it recapitulates the light and electron-microscopic pathological features of Kufs disease. Although CTSF mutations account for a minority of cases of type B Kufs, CTSF screening should be considered in cases with early-onset dementia and may avoid the need for invasive biopsies. PMID:23297359

  9. Multimodal Image Analysis in Acquired Vitelliform Lesions and Adult-Onset Foveomacular Vitelliform Dystrophy.

    PubMed

    Rocha Bastos, Ricardo; Ferreira, Carla Sofia; Brandão, Elisete; Falcão-Reis, Fernando; Carneiro, Ângela M

    2016-01-01

    Purpose. To characterize vitelliform lesions (VLs) in adult-onset foveomacular vitelliform dystrophy (AOFVD) and acquired vitelliform (AVL) patients using multimodal image analysis. Methods. Retrospective study of twenty-eight eyes from nineteen patients diagnosed with AVL or AOFVD. They were evaluated by color fundus photographs, fundus autofluorescence (FAF), fluorescein angiography (FA), and spectral-domain optical coherence tomography (SD-OCT). Results. Bilateral VLs were associated with AOFVD (p = 0.013). Regular and centered VLs were associated with AOFVD (p = 0.004 and p = 0.016), whereas irregular and noncentered lesions were more frequent in AVL patients. Visual acuity, greatest linear dimension (GLD), lesion height (LH), and pseudohypopyon were similar between groups. Whereas median LH and GLD in AVL group diminished significantly during follow-up (p = 0.009 and p = 0.001), AOFVD lesions tended to become larger and thicker. Conclusions. When consulting a patient presenting a VL with unknown age of onset, familial history, or previous retinal diseases, some aspects of multimodal imaging assessment may lead the ophthalmologist to a correct diagnosis. PMID:27190637

  10. Pathologic staging of white matter lesions in adult-onset leukoencephalopathy/leukodystrophy with axonal spheroids.

    PubMed

    Alturkustani, Murad; Keith, Julia; Hazrati, Lili-Naz; Rademakers, Rosa; Ang, Lee-Cyn

    2015-03-01

    The pathologic features of adult-onset leukoencephalopathy/leukodystrophy with axonal spheroids (ALAS) are variable, and this has led to different hypotheses as to whether primarily demyelination or axonopathy may underlie this disorder. Typical ALAS pathology is rarely accompanied by focal multiple sclerosis (MS)-like plaques. In ALAS pathology accompanied by focal multiple sclerosis (MS)-like plaques cases, the pathologic features cannot be distinguished from those of progressive MS with diffusely abnormal white matter. To clarify these issues, we examined neuropathologic features in 159 representative samples from 5 ALAS cases (3 men and 2 women aged 39-61 years) and in 95 representative samples from 3 chronic MS cases (1 man and 2 women aged 50-73 years). The white matter abnormalities in ALAS cases were characterized by 3 evolving stages: 1) white matter with numerous spheroids in a background of well-myelinated fibers; 2) moderate loss of myelinated fibers with sparse to moderate number of spheroids; and 3) leukodystrophy-like pattern of confluent axonal and myelin loss. The application of this staging system suggests that myelin loss in ALAS is preceded by axonopathy. In progressive MS cases, the diffusely abnormal white matter pathology could be attributed to both primary demyelination and axonopathy. Some cases with predominant axonopathy are difficult to distinguish from cases with ALAS. PMID:25668567

  11. Health-related quality of life in sporadic adult-onset ataxia.

    PubMed

    Abele, Michael; Klockgether, Thomas

    2007-02-15

    Despite progressive disability in sporadic adult-onset ataxia (SAOA), little is known about patients' assessment of their ataxic disorder and its impact on health-related quality of life (Hr-QoL). This study investigated Hr-QoL by means of the following self-administered scales: Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, Beck Depression Inventory (BDI), and the Medical Outcome Study Short Form (SF-36). Twenty-two unselected ataxia patients were included. Sleep-related complaints were found in 9 (41%) of 22 and symptoms of depression in 6 (38%) of 16 patients. Compared to a large german control group, SAOA patients had lower scores in all SF-36 dimensions except for bodily pain. The greatest impairment was found in the domain physical functioning, followed by the domains social functioning and role limitations (emotional problems). There was a significant negative correlation of all nonmotor SF-36 dimensions with the BDI score. Walking aid dependency was significantly correlated with poorer health status perception in several motor and nonmotor domains. In addition, impaired sleep quality was correlated with an impaired general health perception and with bodily pain. The study demonstrates a great impact of SAOA on Hr-QoL. Adequate treatment of depression, motor disability, and impaired sleep quality is essential to improve Hr-QoL in ataxic patients. PMID:17149704

  12. [A case of adult-onset type II citrullinemia (CTLN2) triggered by an overseas travel].

    PubMed

    Yamasaki, Masayoshi; Shimada, Takuya; Hamaoka, Shima; Shibata, Masunari; Naito, Yutaka

    2014-01-01

    A 43-year-old male presented with abnormal behavior and consciousness disturbance on the day after traveling abroad and was admitted to our hospital. Laboratory tests showed hyperammonemia and hypercitrullinemia. The electro-encephalogram showed frontal dominant bilateral slow δ burst. He had a peculiar taste for nuts. But he didn't take nuts during the overseas travel for 3 days. The family history revealed that his younger brother died of a status epilepticus of unknown cause at the age of 29. These findings were compatible with hepatic encephalopathy due to adult-onset type II citrullinemia (CTLN2). Gene analysis provided a definite diagnosis of CTLN2. Diet and drug therapy have improved his condition. He is due to have liver transplantation which is the only established radical treatment for CTLN2 if his condition becomes worse. The present case shows that cessation of the habitual intake of nuts only for 3 days could lead to onset of CTLN2. PMID:25283831

  13. Multiple sclerosis and risk of young-adult-onset Hodgkin lymphoma

    PubMed Central

    Hajiebrahimi, Mohammadhossein; Burkill, Sarah; Hillert, Jan; Olsson, Tomas; Bahmanyar, Shahram

    2016-01-01

    Objective: To determine whether there is an association between multiple sclerosis (MS) and young-adult-onset Hodgkin lymphoma (YAHL) as this will signal etiologic similarities relevant both to inherited characteristics and environmental exposures in childhood. Methods: Swedish general population registers identified a cohort of 29,617 with an MS diagnosis between 1968 and 2012, matched with a cohort of 296,164 without MS. Cox regression was used to assess the association of MS with subsequent YAHL (defined as onset between ages 15 and 39 years; n = 20), with adjustment, for age/period, sex, county of residence, and level of education. Results: The adjusted hazard ratio (and 95% confidence interval) for the association of MS with YAHL is 3.30 (1.01–10.73), resulting from 4 and 16 events in the MS and non-MS cohorts, respectively. All 4 of the YAHL diagnoses in MS occurred in women, and the association of MS with YAHL has a hazard ratio of 4.04 (1.17–13.94) among women. There was no notable association of MS with older-onset Hodgkin lymphoma. Conclusion: There may be common risks for YAHL and MS, consistent with an etiologic role in MS for early-life exposures, such as to infectious agents. PMID:27144218

  14. Prevalence of reticular pseudodrusen in newly presenting adult onset foveomacular vitelliform dystrophy.

    PubMed

    Wilde, C; Lakshmanan, A; Patel, M; Morales, M U; Dhar-Munshi, S; Amoaku, W M K

    2016-06-01

    PurposeTo report the association and prevalence of reticular pseudodrusen (RPD) in eyes with newly presenting adult onset foveomacular vitelliform dystrophy (AFVD). To compare the strength of association with other pathologies resulting from dysfunction of the choroid-Bruch's membrane-retinal pigment epithelium (RPE) complex, including eyes with geographic atrophy (GA) and angioid streaks.MethodsRetrospective single-centre review of all consecutive newly presenting AFVD. Multimodal imaging with spectral domain optical coherence tomography, fundus photographs, red-free/blue light images, and fundus fluorescein angiograms were graded for the presence of RPD. For comparison, all consecutive newly presenting cases of GA and eyes with angioid streaks were studied.ResultsFifteen (15) patients were identified with AFVD (mean age of 77.3 years; 73.3% female). Mean age of patients with AFVD and RPD was 80.5 years (SD 3.7), whereas that of patients with AFVD without RPD was 75.1 years (SD 7.0). This age difference did not reach statistical significance, P=0.1. Six (40%) had identifiable RPD; being a bilateral finding in 100% of patients. No males with AFVD and RPD were identified. A total of 92 eyes presented with GA. Twenty-three (23) of these (25.0%) had RPD. Twelve (12) patients presented with identifiable angioid streaks, with 4 (36.4%) having RPD.ConclusionRPD are a frequent finding in eyes with newly presenting AFVD; not being restricted to AMD, but a finding common among diseases where pathophysiological mechanisms involve damage to Bruch's membrane and the RPE, whether genetic or degenerative. Our study supports the concept that they occur with high but variable frequencies in eyes with various pathologies. PMID:27034200

  15. [Adult-onset Hartnup disease presenting with neuropsychiatric symptoms but without skin lesions].

    PubMed

    Mori, E; Yamadori, A; Tsutsumi, A; Kyotani, Y

    1989-06-01

    Hartnup disease is an inborn abnormality of renal and intestinal transport involving the neutral amino acids. Intermittent pellagra-like rash, attacks of cerebellar ataxia and psychiatric disturbance are characteristic symptoms of this disease. We described here a patient with adult-onset Hartnup disease who presented unique neuropsychiatric symptoms but no dermatologic symptoms, and reported features of amino acids transport in this patient and his family. The patient, a man aged 37 years, was referred to us because of lasting daytime bruxism. He is the second child of healthy parents who are first cousin; his elder brother who has been mentally retarded became bed-ridden and died at 32 years of age. His younger brother is completely healthy. Although the patient's development in infancy has been slightly retarded, he completed compulsory 9-year education. At 29 years of age, he experienced episodes of diplopia, ataxic gait and insomnia, and at 33 years of age, of transient stupor. There had been no history of photosensitivity or dermatitis. On neurological examination, there were trunkal ataxia, increased muscular tone and decreased mental activity besides bruxism. These symptoms remained unchanged despite of several medications including trihexyphenidyl, diazepam, halloperidol, tiapride and sulpiride. Two months later, the patient became stuporous; bruxism and hypertonicity became exaggerated. Myerson's sign, sucking reflex and grasp reflex in both hand appeared. There was no dermal lesion. A cranial computed tomography revealed a small calcification in the right frontal subcortical region and a single photon emission tomography indicated possible bifrontal hypoperfusion. Electroencephalograms demonstrated non-specific slowing. Somatosensory evoked potentials and nerve conduction velocities were normal. There were constant indicanuria and amino-aciduria.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2582682

  16. Astrocyte Leptin Receptor (ObR) and Leptin Transport in Adult-Onset Obese Mice

    PubMed Central

    Pan, Weihong; Hsuchou, Hung; He, Yi; Sakharkar, Amul; Cain, Courtney; Yu, Chuanhui; Kastin, Abba J.

    2008-01-01

    The agouti viable yellow (Avy) spontaneous mutation generates an unusual mouse phenotype of agouti-colored coat and adult-onset obesity with metabolic syndrome. Persistent production of agouti signaling protein in Avy mice antagonizes melanocortin receptors in the hypothalamus. To determine how this disruption of neuroendocrine circuits affects leptin transport across the blood-brain barrier (BBB), we measured leptin influx in Avy and B6 control mice after the development of obesity, hyperleptinemia, and increased adiposity. After iv bolus injection, 125I-leptin crossed the BBB significantly faster in young (2 month old) B6 mice than in young Avy mice or in older (8 month old) mice of either strain. This difference was not observed by in situ brain perfusion studies, indicating the cause being circulating factors, such as elevated leptin levels or soluble receptors. Thus, Avy mice showed peripheral leptin resistance. ObRa, the main transporting receptor for leptin at the BBB, showed no change in mRNA expression in the cerebral microvessels between the age-matched (2 month old) Avy and B6 mice. Higher ObRb mRNA was seen in the Avy microvasculature with unknown significance. Immunofluorescent staining unexpectedly revealed that many of the ObR(+) cells were astrocytes and that the Avy mice showed significantly more ObR(+) astrocytes in the hypothalamus than the B6 mice. Although leptin permeation from the circulation was slower in the Avy mice, the increased ObR expression in astrocytes and increased ObRb mRNA in microvessels suggest the possibility of heightened central nervous system sensitivity to circulating leptin. PMID:18292187

  17. Hereditary leukoencephalopathy with axonal spheroids: a spectrum of phenotypes from CNS vasculitis to parkinsonism in an adult onset leukodystrophy series

    PubMed Central

    Jaunmuktane, Zane; Sheerin, Una-Marie; Phadke, Rahul; Brandner, Sebastian; Milonas, Ionnis; Dean, Andrew; Bajaj, Nin; McNicholas, Nuala; Costello, Daniel; Cronin, Simon; McGuigan, Chris; Rossor, Martin; Fox, Nick; Murphy, Elaine; Chataway, Jeremy; Houlden, Henry

    2016-01-01

    Background Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) is a hereditary, adult onset leukodystrophy which is characterised by the presence of axonal loss, axonal spheroids and variably present pigmented macrophages on pathological examination. It most frequently presents in adulthood with dementia and personality change. HDLS has recently been found to be caused by mutations in the colony stimulating factor-1 receptor (CSF1R) gene. Methods In this study, we sequenced the CSF1R gene in a cohort of 48 patients from the UK, Greece and Ireland with adult onset leukodystrophy of unknown cause. Results Five pathogenic mutations were found, including three novel mutations. The presentations ranged from suspected central nervous system (CNS) vasculitis to extrapyramidal to cognitive phenotypes. The case histories and imaging are presented here, in addition to neuropathological findings from two cases with novel mutations. Conclusion We estimate that CSF1R mutations account for 10% of idiopathic adult onset leukodystrophies and that genetic testing for CSF1R mutations is essential in adult patients presenting with undefined CNS vasculitis or a leukodystrophy with prominent neuropsychiatric signs or dementia. PMID:25935893

  18. Exclusion of one pedigree affected by adult onset primary open angle glaucoma from linkage to the juvenile glaucoma locus on chromosome 1q21-q31.

    PubMed Central

    Avramopoulos, D; Kitsos, G; Economou-Petersen, E; Grigoriadou, M; Vassilopoulos, D; Papageorgiou, C; Psilas, K; Petersen, M B

    1996-01-01

    A locus for autosomal dominant juvenile onset primary open angle glaucoma (POAG) was recently assigned to chromosome region 1q21-q31. In the present study, a large Greek family with autosomal dominant adult onset POAG was investigated using microsatellite markers. Exclusion of linkage of the adult onset POAG gene to the region D1S194-D1S191 was obtained in this pedigree. Therefore, the data provide evidence that juvenile and adult onset POAG are genetically distinct disease entities. PMID:9004141

  19. Genetics of growth hormone deficiency.

    PubMed

    Mullis, Primus E

    2007-03-01

    When a child is not following the normal, predicted growth curve, an evaluation for underlying illness and central nervous system abnormalities is required and appropriate consideration should be given to genetic defects causing growth hormone (GH) deficiency. This article focuses on the GH gene, the various gene alterations, and their possible impact on the pituitary gland. Transcription factors regulating pituitary gland development may cause multiple pituitary hormone deficiency but may present initially as GH deficiency. The role of two most important transcription factors, POU1F1 (Pit-1) and PROP 1, is discussed. PMID:17336732

  20. Stroke prevention by direct revascularization for patients with adult-onset moyamoya disease presenting with ischemia.

    PubMed

    Kim, Tackeun; Oh, Chang Wan; Kwon, O-Ki; Hwang, Gyojun; Kim, Jeong Eun; Kang, Hyun-Seung; Cho, Won-Sang; Bang, Jae Seung

    2016-06-01

    . CONCLUSIONS Direct or combined revascularization for patients with adult-onset moyamoya disease presenting with ischemia can prevent further stroke. PMID:26636391

  1. An increased incidence of Hodgkin's lymphoma in patients with adult-onset sarcoma

    PubMed Central

    2012-01-01

    Background Sarcomas are rare, often fatal malignancies of connective tissues that can occur in genetic predisposition syndromes or result from carcinogen exposure. Hodgkin's lymphoma (HL) is not known to contribute to any recognised familial cancer syndrome comprising sarcomas, but is known to be associated with a variety of second cancers, including sarcomas. This study describes the prevalence of HL in families affected by sarcoma. Methods The International Sarcoma Kindred Study (ISKS) is a prospective cohort of 561 families ascertained via a proband with adult-onset sarcoma. Cancer-specific standardised incidence ratios (SIR) for multiple primary malignancies in probands were estimated. Clinical characteristics of individuals reporting both sarcoma and HL were described. Standardised incidence ratios for the occurrence of cancer in ISKS families were also estimated. Results Multiple primary cancers were reported in 16% of probands, significantly higher than in the general population. The risk of HL in probands was increased 15.8-fold (95%CI 7.9-31.6) and increased risks were also seen for breast cancer (SIR 2.9, 95%CI 1.9-4.4) and thyroid cancer (SIR 8.4, 95%CI 4.2-16.8). In 8 probands with both HL and sarcoma, the diagnosis of HL preceded that of sarcoma in 7 cases, and occurred synchronously in one case. Only 3 cases of sarcoma occurred in or close to prior radiotherapy fields. The overall incidence of HL in the ISKS cohort was not significantly increased by comparison with age- and gender-specific population estimates (SIR 1.63, 95%CI 1.05-2.43), suggesting that the association between HL and sarcomas did not extend to other family members. The age of onset of non-sarcoma, non-HL cancers in families affected by both HL and sarcoma was younger than the general population (56.2 y vs 65.6 y, P < 0.0001). Conclusions The basis for the association between HL and sarcomas may include the carcinogenic effects of therapy combined with excellent survival rates for HL

  2. Adult onset-hypothyroidism increases response latency and long-term potentiation (LTP) in rat hippocampus

    EPA Science Inventory

    Thyroid hormones (TH) influence central nervous system (CNS) function during both development and in adulthood. The hippocampus is critical for some types of learning and memory and is particularly sensitive to thyroid hormone deficiency. Hypothyroidism in adulthood has been ass...

  3. Molecular basis of adult-onset and chronic G sub M2 gangliosidoses in patients of Ashkenazi Jewish origin: Substitution of serine for glycine at position 269 of the. alpha. -subunit of. beta. -hexosaminidase

    SciTech Connect

    Paw, B.H.; Kaback, M.M.; Neufeld, E.F. )

    1989-04-01

    Chronic and adult-onset G{sub M2} gangliosidoses are neurological disorders caused by marked deficiency of the A isoenzyme of {beta}-hexosaminidase; they occur in the Ashkenazi Jewish population, though less frequently than classic (infantile) Tay-Sachs disease. Earlier biosynthetic studies had identified a defective {alpha}-subunit that failed to associate with the {beta}-subunit. The authors have now found a guanosine to adenosine transition at the 3{prime} end of exon 7, which causes substitution of serine for glycine at position 269 of the {alpha}-subunit. An RNase protection assay was used to localize the mutation to a segment of mRNA from fibroblasts of a patient with the adult-onset disorder. That segment of mRNA (after reverse transcription) and a corresponding segment of genomic DNA were amplified by the polymerase chain reaction and sequenced by the dideoxy method. The sequence analysis, together with an assay based on the loss of a ScrFI restriction site, showed that the patient was a compound heterozygote who had inherited the 269 (Gly {yields} Ser) mutation from his father and an allelic null mutation from his mother. The 269 (Gly {yields} Ser) mutation, in compound heterozygosity with a presumed null allele, was also found in fetal fibroblasts with an association-defective phenotype and in cells from five patients with chronic G{sub M2} gangliosidosis.

  4. Identification of two novel mutations in the SLC25A13 gene and detection of seven mutations in 102 patients with adult-onset type II citrullinemia.

    PubMed

    Yasuda, T; Yamaguchi, N; Kobayashi, K; Nishi, I; Horinouchi, H; Jalil, M A; Li, M X; Ushikai, M; Iijima, M; Kondo, I; Saheki, T

    2000-12-01

    Adult-onset type II citrullinemia (CTLN2) is characterized by a liver-specific deficiency of argininosuccinate synthetase (ASS) protein. We have recently identified the gene responsible for CTLN2, viz., SLC25A13, which encodes a calcium-binding mitochondrial carrier protein, designated citrin, and found five mutations of the SLC25A13 gene in CTLN2 patients. In the present study, we have identified two novel mutations, 1800ins1 and R605X, in SLC25A13 mRNA and the SLC25A13 gene. Diagnostic analysis for the seven mutations in 103 CTLN2 patients diagnosed by biochemical and enzymatic studies has revealed that 102 patients had one or two of the seven mutations and 93 patients were homozygotes or compound heterozygotes. These results indicate that CTLN2 is caused by an abnormality in the SLC25A13 gene, and that our criteria for CTLN2 before DNA diagnosis are correct. Five of 22 patients from consanguineous unions have been shown to be compound heterozygotes, suggesting a high frequency of the mutated genes. The frequency of homozygotes is calculated to be more than 1 in 20,000 from carrier detection (6 in 400 individuals tested) in the Japanese population. We have detected no cross-reactive immune materials in the liver of CTLN2 patients with any of the seven mutations by Western blot analysis with anti-human citrin antibody. From these findings, we hypothesize that CTLN2 is caused by a complete deletion of citrin, although the mechanism of ASS deficiency is still unknown. PMID:11153906

  5. Obesity-related abnormalities couple environmental triggers with genetic susceptibility in adult-onset T1D.

    PubMed

    Nguyen, K Hoa; Ande, Sudharsana R; Mishra, Suresh

    2016-01-29

    The incidence of adult-onset T1D in low-risk non-HLA type has increased several folds, whereas the contemporaneous incidence in high-risk HLA-type remains stable. Various factors behind this selective increase in T1D in young adults remain unclear. Obesity and its associated abnormalities appear to be an important determinant; however, the underlying mechanism involved is not understood. Recently, we have developed two novel transgenic obese mice models, Mito-Ob and m-Mito-Ob, by expressing a pleiotropic protein prohibitin (PHB) and a phospho mutant form of PHB (Y114F-PHB or m-PHB) from the aP2 gene promoter, respectively. Both mice models develop obesity in a sex-neutral manner, independent of diet; but obesity associated chronic low-grade inflammation and insulin resistance in a male sex-specific manner. Interestingly, on a high fat diet (HFD) only male m-Mito-Ob mice displayed marked mononuclear cell infiltration in pancreas and developed insulitis that mimic adult-onset T1D. Male Mito-Ob mice that share the metabolic phenotype of male m-Mito-Ob mice, and female m-Mito-Ob that harbor m-PHB similar to male m-Mito-Ob mice, did not develop insulitis. Thus, insulitis development in male m-Mito-Ob in response to HFD requires both, obesity-related abnormalities and m-PHB. Collectively, this data provides a proof-of-concept that obesity-associated abnormalities couple environmental triggers with genetic susceptibility in adult-onset T1D and reveals PHB as a potential susceptibility gene for T1D. PMID:26766792

  6. Piriform sinus carcinoma with a paraneoplastic syndrome misdiagnosed as adult onset Still’s disease: a case report

    PubMed Central

    Yang, Liu; Li, Wen; Du, Jintao

    2015-01-01

    Paraneoplastic syndromes (PS) occur less commonly in association with otolaryngologic neoplasms than other carcinomas such as those of lung or breast. Piriform sinus carcinoma with PS is extremely rare. We here report a case of piriform sinus carcinoma accompanied by PS that was initially misdiagnosed as adult onset Still’s disease and describe our diagnosis and treatment. One lesson we have drawn from the experience of this misdiagnosis is that PS symptoms may manifest before the primary tumor is evident and complicate the diagnostic process. PMID:26770614

  7. Memory Loss and Frontal Cognitive Dysfunction in a Patient with Adult-onset Neuronal Intranuclear Inclusion Disease.

    PubMed

    Araki, Kunihiko; Sone, Jun; Fujioka, Yusuke; Masuda, Michihito; Ohdake, Reiko; Tanaka, Yasuhiro; Nakamura, Tomohiko; Watanabe, Hirohisa; Sobue, Gen

    2016-01-01

    Neuronal intranuclear inclusion disease (NIID) is an uncommon progressive neurodegenerative disorder. Adult-onset NIID can result in prominent dementia. We herein describe the case of a 74-year-old man who presented with dementia, cerebellar ataxia, neuropathy, and autonomic dysfunction. Diffusion-weighted imaging showed hyperintensity of the corticomedullary junction. Fluid-attenuated inversion recovery images showed frontal-dominant white matter hyperintensity. NIID was diagnosed from the presence of intranuclear inclusions in a skin biopsy sample. Neuropsychological testing revealed memory loss and frontal cognitive dysfunction, especially in relation to language and executive functions. We were therefore able to confirm the association of NIID with cognitive dysfunction. PMID:27523009

  8. Genetic testing of children for adult-onset conditions: opinions of the British adult population and implications for clinical practice.

    PubMed

    Shkedi-Rafid, Shiri; Fenwick, Angela; Dheensa, Sandi; Lucassen, Anneke M

    2015-10-01

    This study set out to explore the attitudes of a representative sample of the British public towards genetic testing in children to predict disease in the future. We sought opinions about genetic testing for adult-onset conditions for which no prevention/treatment is available during childhood, and about genetic 'carrier' status to assess future reproductive risks. The study also examined participants' level of agreement with the reasons professional organisations give in favour of deferring such testing. Participants (n=2998) completed a specially designed questionnaire, distributed by email. Nearly half of the sample (47%) agreed that parents should be able to test their child for adult-onset conditions, even if there is no treatment or prevention at time of testing. This runs contrary to professional guidance about genetic testing in children. Testing for carrier status was supported by a larger proportion (60%). A child's future ability to decide for her/himself if and when to be tested was the least supported argument in favour of deferring testing. PMID:25370041

  9. Reactive macrophage activation syndrome possibly triggered by canakinumab in a patient with adult-onset Still's disease.

    PubMed

    Banse, Christopher; Vittecoq, Olivier; Benhamou, Ygal; Gauthier-Prieur, Maud; Lequerré, Thierry; Lévesque, Hervé

    2013-12-01

    Macrophage activation syndrome (MAS) is a rare and serious complication of adult-onset Still's disease. We describe a case in a 49-year-old woman with Still's disease refractory to glucocorticoids, methotrexate, and infliximab. Anakinra provided satisfactory disease control for 1 year, after which escape phenomenon occurred. After four tocilizumab injections, cutaneous melanoma developed. The persistent systemic manifestations prompted treatment with two canakinumab injections. Ten days later, she had a spiking fever, dyspnea, low back pain, abdominal pain, odynophagia, and hepatomegaly. Laboratory tests showed liver cytolysis (180 IU/L; N: 10-35), acute renal failure (creatinine, 407 μmol/L; N:50-100), thrombocytopenia (60 G/L; N: 150-400), leukocytosis (12,200/mm(3); N: 4000-10,000), hypertriglyceridemia (5070 mmol/L; N: 0.4-1.6), lactate dehydrogenase elevation (4824 IU/L; N: 135-250), and hyperferritinemia (97 761 μg/L; N:15-150). Examination of a bone marrow biopsy showed phagocytosis. Tests were negative for viruses and other infectious agents. Glucocorticoid therapy (1.5 mg/Kg/d) and intravenous polyvalent immunoglobulins (0.5 g/Kg/d) were given. Her condition improved despite the many factors of adverse prognostic significance (thrombocytopenia, absence of lymphadenopathy, and glucocorticoid therapy at diagnosis). This is the first reported case of MAS after canakinumab therapy in a patient with adult-onset Still's disease. PMID:23751410

  10. Uteroplacental insufficiency alters nephrogenesis and downregulates cyclooxygenase-2 expression in a model of IUGR with adult-onset hypertension.

    PubMed

    Baserga, Mariana; Hale, Merica A; Wang, Zheng Ming; Yu, Xing; Callaway, Christopher W; McKnight, Robert A; Lane, Robert H

    2007-05-01

    Clinical and animal studies indicate that intrauterine growth restriction (IUGR) following uteroplacental insufficiency (UPI) reduces nephron number and predisposes toward renal insufficiency early in life and increased risk of adult-onset hypertension. In this study, we hypothesized that the inducible enzyme cyclooxygenase-2 (COX-2), a pivotal protein in nephrogenesis, constitutes a mechanism through which UPI and subsequent glucocorticoid overexposure can decrease nephron number. We further hypothesized that UPI downregulates the key enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which converts corticosterone to inert 11-dehydrocorticosterone, thereby protecting both the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) from the actions of corticosterone. Following bilateral uterine ligation on the pregnant rat, UPI significantly decreased renal COX-2, 11beta-HSD2, and GR mRNA and protein levels, but upregulated expression of MR at birth. At day 21 of life, 11beta-HSD2, GR, and also MR mRNA and protein levels were downregulated. UPI did not affect blood pressures (BP) at day 21 of life but significantly increased systolic BP in both genders at day 140. We conclude that in our animal model, UPI decreases fetal COX-2 expression during a period of active nephrogenesis in the IUGR rat, which is also characterized by decreased nephron number and adult-onset hypertension. PMID:17272666

  11. Effect of adult onset hypothyroidism on behavioral parameters and acetylcholinesterase isoforms activity in specific brain regions of male mice.

    PubMed

    Vasilopoulou, Catherine G; Constantinou, Caterina; Giannakopoulou, Dimitra; Giompres, Panagiotis; Margarity, Marigoula

    2016-10-01

    Thyroid hormones (TH) are essential for normal development and function of mammalian central nervous system (CNS); TH dysregulation has been implicated in several cognitive and behavioral deficits related to dysfunctions of neurotransmitter systems. In the present study, we investigated the effects of adult onset hypothyroidism on the activity of acetylcholinesterase (AChE) and on related behavioral parameters. For this purpose we used adult male Balb/cJ mice that were divided randomly into euthyroid and hypothyroid animal groups. Animals were rendered hypothyroid through administration of 1% w/v KClO4 in their drinking water for 8weeks. At the end of the treatment, learning/memory procedures were examined through step-through passive avoidance task while fear/anxiety was assessed using elevated plus-maze (EPM) and open-field (OF) tests. AChE activity was determined colorimetrically in two different fractions, salt-soluble fraction (SS) (containing mainly the G1 isoform) and detergent-soluble fraction (DS) (containing mainly the G4 isoform) in cerebral cortex, cerebellum, midbrain, hippocampus and striatum. Our results indicate that adult onset hypothyroidism caused significant memory impairment and increased fear/anxiety. Moreover, the activity of both isoforms of AChE was reduced in all brain regions examined in a brain region- and isoform-specific manner. PMID:27317840

  12. Preclinical and Clinical In Vitro In Vivo Correlation of an hGH Dextran Microsphere Formulation

    PubMed Central

    de Vrueh, R.; Gresnigt, M. G.; Hoogerbrugge, C. M.; van Buul-Offers, S. C.; de Leede, L. G. J.; Sterkman, L. G. W.; Crommelin, D. J. A.; Hennink, W. E.; Verrijk, R.

    2007-01-01

    Purpose To investigate the in vitro in vivo correlation of a sustained release formulation for human growth hormone (hGH) based on hydroxyethyl methacrylated dextran (dex-HEMA) microspheres in Pit-1 deficient Snell dwarf mice and in healthy human volunteers. Materials and Methods A hGH-loaded microsphere formulation was developed and tested in Snell dwarf mice (pharmacodynamic study) and in healthy human volunteers (pharmacokinetic study). Results Single subcutaneous administration of the microspheres in mice resulted in a good correlation between hGH released in vitro and in vivo effects for the hGH-loaded microsphere formulation similar to daily injected hGH indicating a retained bioactivity. Testing the microspheres in healthy volunteers showed an increase (over 7–8 days) in hGH serum concentrations (peak concentrations: 1–2.5 ng/ml). A good in vitro in vivo correlation was obtained between the measured and calculated (from in vitro release data) hGH serum concentrations. Moreover, an increased serum concentration of biomarkers (insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3) was found again indicating that bioactive hGH was released from the microspheres. Conclusions Good in vitro in vivo correlations were obtained for hGH-loaded dex-HEMA microspheres, which is an important advantage in predicting the effect of the controlled drug delivery product in a clinical situations. PMID:17929148

  13. Netherton syndrome associated with growth hormone deficiency.

    PubMed

    Aydın, Banu Küçükemre; Baş, Firdevs; Tamay, Zeynep; Kılıç, Gürkan; Süleyman, Ayşe; Bundak, Rüveyde; Saka, Nurçin; Özkaya, Esen; Güler, Nermin; Darendeliler, Feyza

    2014-01-01

    Netherton syndrome (NS) is a rare autosomal recessive disorder characterized by ichthyosiform scaling, hair abnormalities, and variable atopic features. Mutations in the serine protease inhibitor Kazal type 5 (SPINK5) gene leading to lymphoepithelial Kazal-type-related inhibitor (LEKTI) deficiency cause NS. Growth retardation is a classic feature of NS, but growth hormone (GH) deficiency with subsequent response to GH therapy is not documented in the literature. It is proposed that a lack of inhibition of proteases due to a deficiency of LEKTI in the pituitary gland leads to the overprocessing of human GH in NS. Herein we report three patients with NS who had growth retardation associated with GH deficiency and responded well to GH therapy. PMID:24015757

  14. Echocardiographic assessment of subclinical left ventricular eccentric hypertrophy in adult-onset GHD patients by geometric remodeling: an observational case-control study

    PubMed Central

    de Gregorio, Cesare; Curtò, Lorenzo; Recupero, Antonino; Grimaldi, Patrizia; Almoto, Barbara; Venturino, Marilena; Cento, Domenico; Narbone, Maria Carola; Trimarchi, Francesco; Coglitore, Sebastiano; Cannavò, Salvatore

    2006-01-01

    Background Most patients with growth hormone deficiency (GHD) show high body mass index. Overweight subjects, but GHD patients, were demonstrated to have high left ventricular mass index (LVMi) and abnormal LV geometric remodeling. We sought to study these characteristics in a group of GHD patients, in an attempt to establish the BMI-independent role of GHD. Methods Fifty-four patients, 28 F and 26 M, aged 45.9 ± 13.1, with adult-onset GHD (pituitary adenomas 48.2%, empty sella 27.8%, pituitary inflammation 5.5%, cranio-pharyngioma 3.7%, not identified pathogenesis 14.8%) were enrolled. To minimize any possible interferences of BMI on the aim of this study, the control group included 20 age- and weight-matched healthy subjects. The LV geometry was identified by the relationship between LVMi (cut-off 125 g/m2) and relative wall thickness (cut-off 0.45) at echocardiography. Results There was no significant between-group difference in resting cardiac morphology and function, nor when considering age-related discrepancy. The majority of patients had normal-low LVM/LVMi, but about one fourth of them showed higher values. These findings correlated to relatively high circulating IGF-1 and systolic blood pressure at rest. The main LV geometric pattern was eccentric hypertrophy in 22% of GHD population (26% of with severe GHD) and in 15% of controls (p = NS). Conclusion Though the lack of significant differences in resting LV morphology and function, about 25% of GHD patients showed high LVMi (consisting of eccentric hypertrophy), not dissimilarly to overweight controls. This finding, which prognostic role is well known in obese and hypertensive patients, is worthy to be investigated in GHD patients through wider controlled trials. PMID:16507109

  15. Quality of Life and Psychological Well-Being in GH-Treated, Adult PWS Patients: A Longitudinal Study

    ERIC Educational Resources Information Center

    Bertella, L.; Mori, I.; Grugni, G.; Pignatti, R.; Ceriani, F.; Molinari, E.; Ceccarelli, A.; Sartorio, A.; Vettor, R.; Semenza, C.

    2007-01-01

    Background: Prader-Willi syndrome (PWS) is a congenital alteration of chromosome pair 15. It is characterized by short stature, muscular hypotonia, hyperphagia, obesity, behavioural and emotional disturbances, hypogonadism and partial Growth Hormone (GH) deficiency. The aim of this study was to assess the long-term effect of GH treatment on the…

  16. Possible macrophage activation syndrome following initiation of adalimumab in a patient with adult-onset Still's disease.

    PubMed

    Souabni, Leila; Dridi, Leila; Ben Abdelghani, Kawther; Kassab, Selma; Chekili, Selma; Laater, Ahmed; Zakraoui, Leith

    2014-01-01

    Macrophage activation syndrome (MAS) has been rarely reported in the course of adult-onset Still's disease (AOSD) and in the majority of cases, it was triggered by an infection. Here, we report, to our knowledge, the first case of MAS occurring after adalimumab treatment initiation and not triggered by an infection. A 26-yearold woman with classical features of AOSD developed persistent fever, severe bicytopenia associated with extreme hyperferritinemia, hyponatremia and abnormal liver function tow months after the initiation of adalimumab treatment. The diagnosis of MAS was made without histological proof. The patient was treated with methylprednisolone pulse therapy and her condition improved. During the disease course, extensive studies could not identify any viral infection or other known underlying etiology for the reactive MAS. The adalimumab was incriminated in this complication. Currently, the patient is in remission on tocilizumab and low-dose prednisolone. PMID:25018831

  17. Wiki-Based Clinical Practice Guidelines for the Management of Adult Onset Sarcoma: A New Paradigm in Sarcoma Evidence

    PubMed Central

    Neuhaus, S. J.; Thomas, D.; Desai, J.; Vuletich, C.; von Dincklage, J.; Olver, I.

    2015-01-01

    In 2013 Australia introduced Wiki-based Clinical Practice Guidelines for the Management of Adult Onset Sarcoma. These guidelines utilized a customized MediaWiki software application for guideline development and are the first evidence-based guidelines for clinical management of sarcoma. This paper presents our experience with developing and implementing web-based interactive guidelines and reviews some of the challenges and lessons from adopting an evidence-based (rather than consensus-based) approach to clinical sarcoma guidelines. Digital guidelines can be easily updated with new evidence, continuously reviewed and widely disseminated. They provide an accessible method of enabling clinicians and consumers to access evidence-based clinical practice recommendations and, as evidenced by over 2000 views in the first four months after release, with 49% of those visits being from countries outside of Australia. The lessons learned have relevance to other rare cancers in addition to the international sarcoma community. PMID:25784832

  18. HPV Type 6 and 18 Coinfection in a Case of Adult-Onset Laryngeal Papillomatosis: Immunization with Gardasil.

    PubMed

    Fancello, Virginia; Melis, Andrea; Piana, Andrea Fausto; Castiglia, Paolo; Cossu, Andrea; Sotgiu, Giovanni; Bozzo, Corrado; King, Emma Victoria; Meloni, Francesco

    2015-01-01

    Laryngeal papillomatosis (LP) is a rare human papillomavirus (HPV) related disease that often requires multiple surgical interventions and residual impairment of voice is almost inevitable. We report the case of a patient with adult onset recurrent LP, showing moderate dysplasia and coinfection with HPV types 6 and 18. The tetravalent HPV vaccine Gardasil was prescribed off label, with the aim of triggering an immunogenic response and consequently reducing the probability of further recurrences. The patient was followed for 9 months with no sign of relapse of his LP. The postexposure use of the anti-HPV vaccine could represent a promising therapeutic agent in established LP. Unfortunately, the potential efficacy of this new therapeutic option in this situation has been suggested only by isolated case reports. Further controlled studies, with a longer follow-up and a larger sample size, are needed to assess efficacy of Gardasil in LP. PMID:26783482

  19. HPV Type 6 and 18 Coinfection in a Case of Adult-Onset Laryngeal Papillomatosis: Immunization with Gardasil

    PubMed Central

    Fancello, Virginia; Melis, Andrea; Piana, Andrea Fausto; Castiglia, Paolo; Cossu, Andrea; Sotgiu, Giovanni; Bozzo, Corrado; King, Emma Victoria; Meloni, Francesco

    2015-01-01

    Laryngeal papillomatosis (LP) is a rare human papillomavirus (HPV) related disease that often requires multiple surgical interventions and residual impairment of voice is almost inevitable. We report the case of a patient with adult onset recurrent LP, showing moderate dysplasia and coinfection with HPV types 6 and 18. The tetravalent HPV vaccine Gardasil was prescribed off label, with the aim of triggering an immunogenic response and consequently reducing the probability of further recurrences. The patient was followed for 9 months with no sign of relapse of his LP. The postexposure use of the anti-HPV vaccine could represent a promising therapeutic agent in established LP. Unfortunately, the potential efficacy of this new therapeutic option in this situation has been suggested only by isolated case reports. Further controlled studies, with a longer follow-up and a larger sample size, are needed to assess efficacy of Gardasil in LP. PMID:26783482

  20. Adult Onset of BRAFV600E-Mutated Langerhans Cell Histiocytosis with Cutaneous Involvement Successfully Diagnosed by Immunohistochemical Staining

    PubMed Central

    Tono, Hisayuki; Fujimura, Taku; Kakizaki, Aya; Furudate, Sadanori; Ishibashi, Masaya; Aiba, Setsuya

    2015-01-01

    Langerhans cell histiocytosis (LCH) is characterized by the clonal proliferation of Langerhans cells; it is categorized as a single-system disease with single or multifocal lesions, and as a multi-system disease with or without the risk of organ involvement. Although the skin is not categorized as a risk organ, the precise diagnosis of skin lesions is necessary to determine the protocol for the treatment of LCH. In this report, we describe a 28-year-old Japanese man with adult onset of BRAFV600E-mutated LCH with cutaneous involvement successfully diagnosed by immunohistochemical staining. Our report suggests that immunohistochemical staining for the BRAFV600E gene could be a diagnostic tool to determine the clinical type of LCH. PMID:26500535

  1. Adult-onset focal expression of mutated human tau in the hippocampus impairs spatial working memory of rats

    PubMed Central

    Mustroph, M.L.; King, M.A.; Klein, R.L.; Ramirez, J.J.

    2012-01-01

    Tauopathy in the hippocampus is one of the earliest cardinal features of Alzheimer’s disease (AD), a condition characterized by progressive memory impairments. In fact, density of tau neurofibrillary tangles (NFTs) in the hippocampus strongly correlates with severity of cognitive impairments in AD. In the present study, we employed a somatic cell gene transfer technique to create a rodent model of tauopathy by injecting a recombinant adeno-associated viral vector with a mutated human tau gene (P301L) into the hippocampus of adult rats. The P301L mutation is causal for frontotemporal dementia with parkinsonism-17 (FTDP-17), but it has been used for studying memory effects characteristic of AD in transgenic mice. To ascertain if P301L-induced mnemonic deficits are persistent, animals were tested for 6 months. It was hypothesized that adult-onset, spatially restricted tau expression in the hippocampus would produce progressive spatial working memory deficits on a learned alternation task. Rats injected with the tau vector exhibited persistent impairments on the hippocampal-dependent task beginning at about 6 weeks post-transduction compared to rats injected with a green fluorescent protein vector. Histological analysis of brains for expression of human tau revealed hyperphosphorylated human tau and NFTs in the hippocampus in experimental animals only. Thus, adult-onset, vector-induced tauopathy spatially restricted to the hippocampus progressively impaired spatial working memory in rats. We conclude that the model faithfully reproduces histological and behavioral findings characteristic of dementing tauopathies. The rapid onset of sustained memory impairment establishes a preclinical model particularly suited to the development of potential tauopathy therapeutics. PMID:22561128

  2. An autopsied case of sporadic adult-onset amyotrophic lateral sclerosis with FUS-positive basophilic inclusions.

    PubMed

    Matsuoka, Takeshi; Fujii, Naoki; Kondo, Akira; Iwaki, Akiko; Hokonohara, Toshihiro; Honda, Hiroyuki; Sasaki, Kensuke; Suzuki, Satoshi O; Iwaki, Toru

    2011-02-01

    Basophilic inclusions (BIs), which are characterized by their staining properties of being weakly argyrophilic, reactive with Nissl staining, and immunohistochemically negative for tau and transactive response (TAR) DNA-binding protein 43 (TDP-43), have been identified in patients with juvenile-onset amyotrophic lateral sclerosis (ALS) and adult-onset atypical ALS with ophthalmoplegia, autonomic dysfunction, cerebellar ataxia, or a frontal lobe syndrome. Mutations in the fused in sarcoma gene (FUS) have been reported in cases of familial and sporadic ALS, and FUS immunoreactivity has been demonstrated in basophilic inclusion body disease (BIBD), neuronal intermediate filament inclusion disease (NIFID), and atypical frontotemporal lobar degeneration with ubiquitin-positive and tau-negative inclusions (aFTLD-U). In the present study, we immunohistochemically and ultrastructurally studied an autopsy case of sporadic adult-onset ALS with numerous BIs. The patient presented with the classical clinical course of ALS since 75 years of age and died at age 79. Postmortem examination revealed that both Betz cells in the motor cortex and motor neurons in the spinal cord were affected. The substantia nigra was spared. Notably, BIs were frequently observed in the motor neurons of the anterior horns, the inferior olivary nuclei, and the basal nuclei of Meynert. BIs were immunopositive for p62, LC3, and FUS, but immunonegative for tau, TDP-43, and neurofilament. Ultrastructurally, BIs consisted of filamentous or granular structures associated with degenerated organelles with no limiting membrane. There were no Bunina bodies, skein-like inclusions, or Lewy-like inclusions. All exons and exon/intron boundaries of the FUS gene were sequenced but no mutations were identified. PMID:20573033

  3. Usefulness of urinary growth hormone (GH) measurement for evaluating endogenous GH secretion in acromegaly.

    PubMed

    Mauri, M; Picó, A M; Alfayate, R; Dominguez, J R; Cámara, R; Miralles, C

    1993-01-01

    We investigated the relationship between urinary growth hormone (u-GH) and spontaneous 24-hour plasma GH secretion in 15 acromegalic patients. To measure u-GH, we have developed a method based on concentrating the sample by centrifugal ultrafiltration and then performing an immunoradiometric assay using commercially available reagents. u-GH correlated well with the integrated concentration of plasma GH (r = 0.66, p < 0.02). Additionally, u-GH excretion in acromegalic patients was significantly higher than in the control group (190 +/- 100 vs. 3.89 +/- 0.56 pg/min, mean +/- SEM, p < 0.001). Immunoreactive u-GH showed the same elution pattern in Sephadex G-75 as standard or labeled hGH, proving that the substance measured in urine is authentic GH. In conclusion, u-GH appears to be a simple, noninvasive and inexpensive test for evaluating GH secretion in active acromegaly. PMID:8406334

  4. Dominant-Negative Effects of Adult-Onset Huntingtin Mutations Alter the Division of Human Embryonic Stem Cells-Derived Neural Cells

    PubMed Central

    Lopes, Carla; Aubert, Sophie; Bourgois-Rocha, Fany; Barnat, Monia; Rego, Ana Cristina; Déglon, Nicole

    2016-01-01

    Mutations of the huntingtin protein (HTT) gene underlie both adult-onset and juvenile forms of Huntington’s disease (HD). HTT modulates mitotic spindle orientation and cell fate in mouse cortical progenitors from the ventricular zone. Using human embryonic stem cells (hESC) characterized as carrying mutations associated with adult-onset disease during pre-implantation genetic diagnosis, we investigated the influence of human HTT and of an adult-onset HD mutation on mitotic spindle orientation in human neural stem cells (NSCs) derived from hESCs. The RNAi-mediated silencing of both HTT alleles in neural stem cells derived from hESCs disrupted spindle orientation and led to the mislocalization of dynein, the p150Glued subunit of dynactin and the large nuclear mitotic apparatus (NuMA) protein. We also investigated the effect of the adult-onset HD mutation on the role of HTT during spindle orientation in NSCs derived from HD-hESCs. By combining SNP-targeting allele-specific silencing and gain-of-function approaches, we showed that a 46-glutamine expansion in human HTT was sufficient for a dominant-negative effect on spindle orientation and changes in the distribution within the spindle pole and the cell cortex of dynein, p150Glued and NuMA in neural cells. Thus, neural derivatives of disease-specific human pluripotent stem cells constitute a relevant biological resource for exploring the impact of adult-onset HD mutations of the HTT gene on the division of neural progenitors, with potential applications in HD drug discovery targeting HTT-dynein-p150Glued complex interactions. PMID:26863614

  5. Growth hormone deficiency in 18q deletion syndrome

    SciTech Connect

    Ghidoni, P.D.; Cody, J.; Danney, J.

    1994-09-01

    The 18q- syndrome is one of the most common chromosomal deletion syndromes. Clinical characteristics are variable but may include: hypotonia, cleft palate, mental retardation and hearing impairment. Growth failure (GF) (<3% weight/height) is present in 80% of affected individuals. We evaluated growth hormone (GH) sufficiency in 15 patients with 18q- syndrome. Of these 15 patients, 10 have growth failure (<3% weight/height); of the remaining 5, 3 had normal growth parameters and 2 had growth along the 5%. Twelve patients failed to produce adequate GH following standard stimulation testing. Of these 12 patients with inadequate GH production, 2 had normal growth (above 3%). Of the 15, only 1 has normal GH production and normal growth parameters. Bone age was obtained on 1 patient with both GH deficiency and GF, and revealed significant delays. GH levels in response to GH releasing factor were normal in 3 out of 4 patients. MRI studies of GH-deficient patients indicated normal midline structures. Myelination in the few studied GH-deficient patients appeared delayed. The gene for myelin basic protein (MBP) is known to be located on the terminal portion of the long arm of chromosome 18. Neither the gene for GH, GH releasing factor nor GH releasing factor receptor is on chromosome 18. These genes are located on chromosomes 17, chromosome 20 and chromosome 7, respectively. Findings to date suggest that GH deficiency is common in individuals with 18q- syndrome. The etiology of this finding is unknown. We postulate that a gene(s) on chromosome 18q is involved in GH expression.

  6. Relationship between neuropsychological impairment and grey and white matter changes in adult-onset myotonic dystrophy type 1.

    PubMed

    Baldanzi, Sigrid; Cecchi, Paolo; Fabbri, Serena; Pesaresi, Ilaria; Simoncini, Costanza; Angelini, Corrado; Bonuccelli, Ubaldo; Cosottini, Mirco; Siciliano, Gabriele

    2016-01-01

    Myotonic dystrophy type 1 (DM1) has a wide phenotypic spectrum and potentially may affect central nervous system with mild to severe involvement. Our aim was to investigate grey matter (GM) and white matter (WM) structural alterations in a sample of adult-onset DM1 patients and to evaluate relationship with clinical and cognitive variables. Thirty DM1 patients underwent neuropsychological investigation and 3T-MRI protocol. GM and WM changes were evaluated calculating brain parenchymal fraction (BPF), voxel-based morphometry (VBM), white matter lesion load (LL% and Fazekas scale) and tract based spatial statistical (TBSS). Patients showed main impairment in tests exploring executive and mnesic domains with visuo-spatial involvement, significantly related to BPF. VBM revealed clusters of widespread GM reduction and TBSS revealed areas of decreased fractional anisotropy (FA) and increased radial diffusivity (RD), mean diffusivity (MD) and axial diffusivity (AD) in patients compared to a group of matched healthy controls. Multiple regression analyses showed areas of significant negative relationship between left temporal atrophy and verbal memory, between RD and mnesic and visuo-spatial cognitive domains, and between AD and verbal memory. TBSS results indicate that the involvement of normal appearance WM, beyond the signal changes detected with conventional MR imaging (Fazekas scale and LL%), was associated with neuropsychological deficit. These data suggest that disrupted complex neuronal networks can underlie cognitive-behavioural dysfunctions in DM1. PMID:27437180

  7. Adult-onset Kawasaki disease (mucocutaneous lymph node syndrome) and concurrent Coxsackievirus A4 infection: a case report

    PubMed Central

    Ueda, Yuki; Kenzaka, Tsuneaki; Noda, Ayako; Yamamoto, Yu; Matsumura, Masami

    2015-01-01

    Introduction Kawasaki disease (KD) most commonly develops in infants, although its specific cause is still unclear. We report here a rare case of adult-onset KD which revealed to be concurrently infected by Coxsackievirus A4. Case presentation The patient was a 37-year-old Japanese man who presented with fever, exanthema, changes in the peripheral extremities, bilateral non-exudative conjunctival injection, and changes in the oropharynx, signs that meet the diagnostic criteria for KD defined by the Centers for Disease Control and Prevention. In this case, the patient had a significantly high antibody titer for Coxsackievirus A4, which led us to presume that the occurrence of KD was concurrent Coxsackievirus A4 infection. Conclusion We reported a very rare case of KD which suggests that the disease can be concurrent Coxsackievirus A4 infection. Although KD is an acute childhood disease, with fever as one of the principal features, KD should also be considered in the differential diagnosis when adult patients present with a fever of unknown cause associated with a rash. PMID:26491373

  8. Response to immunotherapy in a patient with adult onset Leigh syndrome and T9176C mtDNA mutation.

    PubMed

    Chuquilin, Miguel; Govindarajan, Raghav; Peck, Dawn; Font-Montgomery, Esperanza

    2016-09-01

    Leigh syndrome is a mitochondrial disease caused by mutations in different genes, including ATP6A for which no known therapy is available. We report a case of adult-onset Leigh syndrome with response to immunotherapy. A twenty year-old woman with baseline learning difficulties was admitted with progressive behavioral changes, diplopia, headaches, bladder incontinence, and incoordination. Brain MRI and PET scan showed T2 hyperintensity and increased uptake in bilateral basal ganglia, respectively. Autoimmune encephalitis was suspected and she received plasmapheresis with clinical improvement. She was readmitted 4 weeks later with dysphagia and aspiration pneumonia. Plasmapheresis was repeated with resolution of her symptoms. Given the multisystem involvement and suggestive MRI changes, genetic testing was done, revealing a homoplasmic T9176C ATPase 6 gene mtDNA mutation. Monthly IVIG provided clinical improvement with worsening when infusions were delayed. Leigh syndrome secondary to mtDNA T9176C mutations could have an autoimmune mechanism that responds to immunotherapy. PMID:27408822

  9. Mutations in DNAJC5, Encoding Cysteine-String Protein Alpha, Cause Autosomal-Dominant Adult-Onset Neuronal Ceroid Lipofuscinosis

    PubMed Central

    Nosková, Lenka; Stránecký, Viktor; Hartmannová, Hana; Přistoupilová, Anna; Barešová, Veronika; Ivánek, Robert; Hůlková, Helena; Jahnová, Helena; van der Zee, Julie; Staropoli, John F.; Sims, Katherine B.; Tyynelä, Jaana; Van Broeckhoven, Christine; Nijssen, Peter C.G.; Mole, Sara E.; Elleder, Milan; Kmoch, Stanislav

    2011-01-01

    Autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (ANCL) is characterized by accumulation of autofluorescent storage material in neural tissues and neurodegeneration and has an age of onset in the third decade of life or later. The genetic and molecular basis of the disease has remained unknown for many years. We carried out linkage mapping, gene-expression analysis, exome sequencing, and candidate-gene sequencing in affected individuals from 20 families and/or individuals with simplex cases; we identified in five individuals one of two disease-causing mutations, c.346_348delCTC and c.344T>G, in DNAJC5 encoding cysteine-string protein alpha (CSPα). These mutations—causing a deletion, p.Leu116del, and an amino acid exchange, p.Leu115Arg, respectively—are located within the cysteine-string domain of the protein and affect both palmitoylation-dependent sorting and the amount of CSPα in neuronal cells. The resulting depletion of functional CSPα might cause in parallel the presynaptic dysfunction and the progressive neurodegeneration observed in affected individuals and lysosomal accumulation of misfolded and proteolysis-resistant proteins in the form of characteristic ceroid deposits in neurons. Our work represents an important step in the genetic dissection of a genetically heterogeneous group of ANCLs. It also confirms a neuroprotective role for CSPα in humans and demonstrates the need for detailed investigation of CSPα in the neuronal ceroid lipofuscinoses and other neurodegenerative diseases presenting with neuronal protein aggregation. PMID:21820099

  10. Pathways of acetylcholine synthesis, transport and release as targets for treatment of adult-onset cognitive dysfunction.

    PubMed

    Amenta, F; Tayebati, S K

    2008-01-01

    Acetylcholine (ACh) is a neurotransmitter widely diffused in central, peripheral, autonomic and enteric nervous system. This paper has reviewed the main mechanisms of ACh synthesis, storage, and release. Presynaptic choline transport supports ACh production and release, and cholinergic terminals express a unique transporter critical for neurotransmitter release. Neurons cannot synthesize choline, which is ultimately derived from the diet and is delivered through the blood stream. ACh released from cholinergic synapses is hydrolyzed by acetylcholinesterase into choline and acetyl coenzyme A and almost 50% of choline derived from ACh hydrolysis is recovered by a high-affinity choline transporter. Parallel with the development of cholinergic hypothesis of geriatric memory dysfunction, cholinergic precursor loading strategy was tried for treating cognitive impairment occurring in Alzheimer's disease. Controlled clinical studies denied clinical usefulness of choline and lecithin (phosphatidylcholine), whereas for other phospholipids involved in choline biosynthetic pathways such as cytidine 5'-diphosphocholine (CDP-choline) or alpha-glyceryl-phosphorylcholine (choline alphoscerate) a modest improvement of cognitive dysfunction in adult-onset dementia disorders is documented. These inconsistencies have probably a metabolic explanation. Free choline administration increases brain choline availability but it does not increase ACh synthesis/or release. Cholinergic precursors to serve for ACh biosynthesis should be incorporate and stored into phospholipids in brain. It is probable that appropriate ACh precursors and other correlated molecules (natural or synthesized) could represent a tool for developing therapeutic strategies by revisiting and updating treatments/supplementations coming out from this therapeutic stalemate. PMID:18289004

  11. Adult-onset Still's disease: an Italian multicentre retrospective observational study of manifestations and treatments in 245 patients.

    PubMed

    Sfriso, Paolo; Priori, Roberta; Valesini, Guido; Rossi, Silvia; Montecucco, Carlo Maurizio; D'Ascanio, Anna; Carli, Linda; Bombardieri, Stefano; LaSelva, Gaetana; Iannone, Florenzo; Lapadula, Giovanni; Alivernini, Stefano; Ferraccioli, Gianfranco; Colaci, Michele; Ferri, Clodoveo; Iacono, Daniela; Valentini, Gabriele; Costa, Luisa; Scarpa, Raffaele; LoMonaco, Andrea; Bagnari, Valentina; Govoni, Marcello; Piazza, Ilaria; Adami, Silvano; Ciccia, Francesco; Triolo, Giovanni; Alessandri, Elisa; Cutolo, Maurizio; Cantarini, Luca; Galeazzi, Mauro; Ruscitti, Piero; Giacomelli, Roberto; Caso, Francesco; Galozzi, Paola; Punzi, Leonardo

    2016-07-01

    Adult-onset Still's disease (AOSD) is a systemic inflammatory condition of unknown aetiology characterized by typical episodes of spiking fever, evanescent rash, arthralgia, leukocytosis and hyperferritinemia. Given the lack of data in Italian series, we promote a multicentric data collection to characterize the clinical phenotype of Italian patients with AOSD. Data from 245 subjects diagnosed with AOSD were collected by 15 centres between March and May 2013. The diagnosis was made following Yamaguchi's criteria. Data regarding clinical manifestations, laboratory features, disease course and treatments were reported and compared with those presented in other published series of different ethnicity. The most frequent features were the following: arthritis (93 %), pyrexia (92.6 %), leukocytosis (89 %), negative ANA (90.4 %) and neutrophilia (82 %). As compared to other North American, North European, Middle Eastern and Far Eastern cohorts, Italian data show differences in clinical and laboratory findings. Regarding the treatments, in 21.9 % of cases, corticosteroids and traditional DMARDs have not been able to control the disease while biologics have been shown to be effective in 48 to 58 patients. This retrospective work summarizes the largest Italian multicentre series of AOSD patients and presents clinical and laboratory features that appear to be influenced by the ethnicity of the affected subjects. PMID:27207567

  12. Adult-onset type 1 diabetes patients display decreased IGRP-specific Tr1 cells in blood.

    PubMed

    Chujo, Daisuke; Nguyen, Thien-Son; Foucat, Emile; Blankenship, Derek; Banchereau, Jacques; Nepom, Gerald T; Chaussabel, Damien; Ueno, Hideki

    2015-12-01

    The breakdown of immune tolerance against islet antigens causes type 1 diabetes (T1D). The antigens associated with adult-onset T1D (AT1D) remain largely undefined. It is possible that AT1D patients display a unique type of CD4(+) T cells specific for a certain islet antigen. Here we analyzed the cytokine production profiles of CD4(+) helper T (Th) cells that are specific for three islet antigens; GAD65, preproinsulin, and IGRP in patients with AT1D, juvenile-onset T1D (JT1D), and age-, gender- and human leukocyte antigen (HLA)-matched control adults. While IGRP-specific Th cells in AT1D patients were dominantly Th1 cells, IGRP-specific Th cells in control adults and JT1D patients were dominantly Th2 and T regulatory type 1 (Tr1) cells. Notably, the frequency of IGRP-specific Tr1 cells was significantly lower in AT1D patients than in control adults and JT1D patients. In conclusion, our study suggests that IGRP-specific Th cells play a unique pathogenic role in AT1D. PMID:26341315

  13. Plerocercoid growth factor (PGF), a human growth hormone (hGH) analogue produced by the tapeworm Spirometra mansonoides, has direct insulin-like action in adipose tissue of normal rats in vitro

    SciTech Connect

    Salem, M.A.M.; Phares, C.K.

    1986-03-01

    The metabolic actions of GH can be divided into acute (insulin-like) and chronic (lipolytic/anti-insulin). The insulin-like actions of GH are most readily elicited in GH-deficient animals as GH induces resistance to its own insulin-like action. Like GH, PGF stimulates growth and cross-reacts with anti-hGH antibodies. Independent experiments were conducted comparing the direct actions of PGF to insulin or hGH in vitro. Insulin-like effects were determined by the ability of PGF, insulin or hGH to stimulate (U-/sup 14/C)glucose metabolism in epidydimal fat pads from normal rats and by inhibition of epinephrine-stimulated lipolysis. Direct stimulation of lipolysis was used as anti-insulin activity. To determine if PGF competes for insulin or GH receptors, adipocytes (3 x 10/sup 5/ cells/ml) were incubated with either (/sup 125/I)insulin or (/sup 125/I)hGH +/- PGF, +/- insulin or +/- hGH. PGF stimulated glucose oxidation and /sup 14/C-incorporation into lipids. Insulin, hGH and PGF inhibited lipolysis (33%, 29% and 34%, respectively). Adipose tissue was very sensitive to the lipolytic effect of hGH but PGF was neither lipolytic nor did it confer refractoriness to its insulin-like action. PGF bound to GH but not to insulin receptors. Therefore, PGF had direct insulin-like effects but did not stimulate lipolysis in tissue from normal rats in vitro.

  14. Growth hormone deficiency: an update.

    PubMed

    Audí, L; Fernández-Cancio, M; Camats, N; Carrascosa, A

    2013-03-01

    Growth hormone (GH) deficiency (GHD) in humans manifests differently according to the individual developmental stage (early after birth, during childhood, at puberty or in adulthood), the cause or mechanism (genetic, acquired or idiopathic), deficiency intensity and whether it is the only pituitary-affected hormone or is combined with that of other pituitary hormones or forms part of a complex syndrome. Growing knowledge of the genetic basis of GH deficiency continues to provide us with useful information to further characterise mutation types and mechanisms for previously described and new candidate genes. Despite these advances, a high proportion of GH deficiencies with no recognisable acquired basis continue to be labelled as idiopathic, although less frequently when they are congenital and/or familial. The clinical and biochemical diagnoses continue to be a conundrum despite efforts to harmonise biochemical assays for GH and IGF-1 analysis, probably because the diagnosis based on the so-called GH secretion stimulation tests will prove to be of limited usefulness for predicting therapy indications. PMID:23435439

  15. Prokaryotic overexpression of TEV-rhGH and characterization of its polyclonal antibody.

    PubMed

    Murad, Hossam; Ali, Bouthina; Makeya, Rima; Abbady, Abdul Qader

    2014-05-25

    Recombinant protein technology represents one of the best solutions to achieve rapid, efficient, and cost-effective protein expression and purification of therapeutic proteins. Growth hormone (GH) is an excellent example of these proteins used in the therapy of hormone deficiencies. In this work, a plasmid, pRSET-TEV-rhGH, has been constructed to overexpress recombinant human GH (rhGH) by cloning its gene downstream of an N-terminal 6 × His-tagged polypeptide (43 aa) in the T7 promoter-plasmid pRSET. This polypeptide was cleavable by means of the integrated recognition site for the tobaccos etch virus (TEV) protease, resulting in an rhGH protein at an exact length and sequence. After IPTG induction, this plasmid effectively expressed TEV-rhGH protein (27 kDa) in the cytoplasm of Escherichia coli, which accumulated in the form of inclusion bodies. The 6 × His-tagged protein, with a yield of ~150 mg/L of culture, was purified from the cell extract using metal affinity chromatography, as shown after SDS-PAGE blue staining, and was confirmed by immunoblotting using specific commercial monoclonal antibodies. In order to detect TEV-rhGH, in ELISA and immunoblotting, specific polyclonal antibody, with high titer (~10⁻⁵ fold dilution), was produced in a rabbit and purified using affinity chromatography. Preliminary tests have proved that TEV-rhGH protein and its specific purified IgG antibody could provide valuable tools for rhGH productive and diagnostic purposes. PMID:24534464

  16. Functional characterization of GH-like homolog in amphioxus reveals an ancient origin of GH/GH receptor system.

    PubMed

    Li, Mengyang; Gao, Zhan; Ji, Dongrui; Zhang, Shicui

    2014-12-01

    Amphioxus belongs to the subphylum cephalochordata, an extant representative of the most basal chordates. Despite many studies on the endocrine system of amphioxus, no evidence showed the presence of pituitary hormones. In this study, we clearly demonstrated the existence of a functional GH-like hormone in amphioxus, which is able to bind purified GH receptors, stimulate IGF-I expression, promote growth rate of fish, and rescue embryonic defects caused by a shortage of GH. We also showed the presence of a GH/prolactin-like-binding protein containing the entire hormone binding domain of GH/prolactin receptors in amphioxus, which is widely expressed among tissues, and interacts with the GH-like hormone. It is clear from these results that the GH/GH receptor-like system is present in amphioxus and, hence, in all classes of chordates. Notably, the GH-like hormone appears to be the only member of the vertebrate pituitary hormones family in amphioxus, suggesting that the hormone is the ancestral peptide that originated first in the molecular evolution of the pituitary hormones family in chordates. These data collectively suggest that a vertebrate-like neuroendocrine axis setting has already emerged in amphioxus, which lays a foundation for subsequent formation of hypothalamic-pituitary system in vertebrates. PMID:25333966

  17. A common gene for juvenile and adult-onset primary open-angle glaucomas confined on chromosome 1q

    SciTech Connect

    Morissette, J.; Plante, M.; Raymond, V.

    1995-06-01

    Primary open-angle glaucoma (POAG), which causes progressive loss of the visual fields, was subdivided into two groups according to age at onset: (1) chronic open-angle glaucoma (COAG) diagnosed after 40 years and (2) juvenile open-angle glaucoma (JOAG) diagnosed between 3 years of age and early adulthood. A JOAG gene (GLC1A) was recently mapped to chromosome 1q. We studied 142 members of a huge multigenerational French Canadian family affected with autosomal dominant POAG. Either JOAG or COAG was diagnosed with ocular hypertension (OHT), which may lead to POAG. To localize a common disease gene that might be responsible for both glaucoma subsets, we performed linkage analysis considering JOAG and COAG under the same phenotypic category. JOAG/COAG was tightly linked to seven microsatellite markers on chromosome 1q23-q25; a maximum lod score of 6.62 was obtained with AF-M278ye5. To refine the disease locus, we exploited a recombination mapping strategy based on a unique founder effect. The same characteristic haplotype, composed of 14 markers spanning 12 cM between loci D1S196 and D1S212, was recognized in all persons affected by JOAG, COAG, or OHT, but it did not occur in unaffected spouses and in normal family members >35 years of age, except for three obligatory carriers. Key combination events confined the disease region within a 9-cM interval between loci D1S445 and D1S416/D1S480. These observations demonstrate that the GLC1A gene is responsible for both adult-onset and juvenile glaucomas and suggest that the JOAG and COAG categories within this family may be part of a clinical continuum artificially divided at age 40 years. 49 refs., 4 figs., 2 tabs.

  18. Experiences of Racism and the Incidence of Adult-Onset Asthma in the Black Women’s Health Study

    PubMed Central

    Yu, Jeffrey; O’Connor, George T.; Brown, Timothy A.; Cozier, Yvette C.; Palmer, Julie R.; Rosenberg, Lynn

    2014-01-01

    Background: Chronic stress resulting from experiences of racism may increase the incidence of adult-onset asthma through effects on the immune system and the airways. We conducted prospective analyses of the relation of experiences of racism with asthma incidence in the Black Women’s Health Study, a prospective cohort of black women in the United States followed since 1995 with mailed biennial questionnaires. Methods: Among 38,142 participants followed from 1997 to 2011, 1,068 reported incident asthma. An everyday racism score was created based on five questions asked in 1997 and 2009 about the frequency in daily life of experiences of racism (eg, poor service in stores), and a lifetime racism score was based on questions about racism on the job, in housing, and by police. We used Cox regression models to derive multivariable incidence rate ratios (IRRs) and 95% CIs for categories of each racism score in relation to incident asthma. Results: The IRRs were 1.45 (95% CI, 1.19-1.78) for the highest compared with the lowest quartile of the 1997 everyday racism score (P for trend <.0001) and 1.44 (95% CI, 1.18-1.75) for the highest compared with the lowest category of 1997 lifetime racism. Among women who reported the same levels of racism in 1997 and 2009, the IRRs for the highest categories of everyday and lifetime racism were 2.12 (95% CI, 1.55-2.91) and 1.66 (95% CI, 1.20-2.30), respectively. Conclusions: Given the high prevalence of experiences of racism and asthma in black women in the United States, a positive association between racism and asthma is of public health importance. PMID:23887828

  19. Adult onset Still's disease (AOSD) in the era of biologic therapies: dichotomous view for cytokine and clinical expressions.

    PubMed

    Maria, Alexandre Thibault Jacques; Le Quellec, Alain; Jorgensen, Christian; Touitou, Isabelle; Rivière, Sophie; Guilpain, Philippe

    2014-11-01

    Adult onset Still's disease (AOSD) is a rare inflammatory disorder characterized by hectic spiking fever, evanescent rash and joint involvement. Prognosis is highly variable upon disease course and specific involvements, ranging from benign and limited outcome to chronic destructive polyarthritis and/or life-threatening events in case of visceral complications or reactive hemophagocytic lymphohistiocytosis (RHL). AOSD remains a debatable entity at the frontiers of autoimmune diseases and autoinflammatory disorders. The pivotal role of macrophage cell activation leading to a typical Th1 cytokine storm is now well established in AOSD, and confirmed by the benefits using treatments targeting TNF-α, IL-1β or IL-6 in refractory patients. However, it remains difficult to determine predictive factors of outcome and to draw guidelines for patient management. Herein, reviewing literature and relying on our experience in a series of 8 refractory AOSD patients, we question nosology and postulate that different cytokine patterns could underlie contrasting clinical expressions, as well as responses to targeted therapies. We therefore propose to dichotomize AOSD according to its clinical presentation. On the one hand, 'systemic AOSD' patients, exhibiting the highest inflammation process driven by excessive IL-18, IL-1β and IL-6 production, would be at risk of life-threatening complications (such as multivisceral involvements and RHL), and would preferentially respond to IL-1β and IL-6 antagonists. On the other hand, 'rheumatic AOSD' patients, exhibiting pre-eminence of joint involvement driven by IL-8 and IFN-γ production, would be at risk of articular destructions, and would preferentially respond to TNF-α blockers. PMID:25183244

  20. Parenchymal lung involvement in adult-onset Still disease: A STROBE-compliant case series and literature review.

    PubMed

    Gerfaud-Valentin, Mathieu; Cottin, Vincent; Jamilloux, Yvan; Hot, Arnaud; Gaillard-Coadon, Agathe; Durieu, Isabelle; Broussolle, Christiane; Iwaz, Jean; Sève, Pascal

    2016-07-01

    Parenchymal lung involvement (PLI) in adult-onset Still's disease (AOSD) has seldom, if ever, been studied. We examine here retrospective cohort AOSD cases and present a review of the literature (1971-2014) on AOSD-related PLI cases.Patients with PLI were identified in 57 AOSD cases. For inclusion, the patients had to fulfill Yamaguchi or Fautrel classification criteria, show respiratory symptoms, and have imaging evidence of pulmonary involvement, and data allowing exclusion of infectious, cardiogenic, toxic, or iatrogenic cause of PLI should be available. This AOSD + PLI group was compared with a control group (non-PLI-complicated AOSD cases from the same cohort).AOSD + PLI was found in 3 out of the 57 patients with AOSD (5.3%) and the literature mentioned 27 patients. Among these 30 AOSD + PLI cases, 12 presented an acute respiratory distress syndrome (ARDS) and the remaining 18 another PLI. In the latter, a nonspecific interstitial pneumonia computed tomography pattern prevailed in the lower lobes, pulmonary function tests showed a restrictive lung function, the alveolar differential cell count was neutrophilic in half of the cases, and the histological findings were consistent with bronchiolitis and nonspecific interstitial pneumonia. Corticosteroids were fully efficient in all but 3 patients. Ten out of 12 ARDS cases occurred during the first year of the disease course. All ARDS-complicated AOSD cases received corticosteroids with favorable outcomes in 10 (2 deceased). Most PLIs occurred during the systemic onset of AOSD.PLI may occur in 5% of AOSDs, of which ARDS is the most severe. Very often, corticosteroids are efficient in controlling this complication. PMID:27472698

  1. Comparison of Glomerular Transcriptome Profiles of Adult-Onset Steroid Sensitive Focal Segmental Glomerulosclerosis and Minimal Change Disease

    PubMed Central

    Ren, Hong; Liu, Jian; Zhang, Weijia; Wei, Chengguo; Xu, Jing; Zhang, Wen; Li, Xiao; Wang, Weiming; Lv, Danfeng; He, John Cijiang; Chen, Nan

    2015-01-01

    Objective To search for biomarkers to differentiate primary focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD). Methods We isolated glomeruli from kidney biopsies of 6 patients with adult-onset steroid sensitiveFSGS and 5 patients with MCD, and compared the profiles of glomerular transcriptomes between the two groups of patients using microarray analysis. Results Analysis of differential expressed genes (DEGs) revealed that up-regulated DEGs in FSGS patients compared with MCD patients were primarily involved in spermatogenesis, gamete generation, regulation of muscle contraction, response to unfolded protein, cell proliferation and skeletal system development. The down-regulated DEGs were primarily related to metabolic process, intracellular transport, oxidation/reduction andestablishment of intracellular localization. We validated the expression of the top 6 up-regulated and top 6 down-regulated DEGs using real-time PCR. Membrane metallo-endopeptidase (MME) is a down-regulated gene that was previously identified as a key gene for kidney development. Immunostaining confirmed that the protein expression of MME decreased significantly in FSGS kidneys compared with MCD kidneys. Conclusions This report was the first study to examine transcriptomes in Chinese patients with various glomerular diseases. Expressions of MME both in RNA and protein level decreased significantly in glomeruli of FSGS kidneys compared with MCD kidneys. Our data suggested that MME might play a role in the normal physiological function of podocytes and a decrease in MME expression might be related to podocyte injury. We also identified genes and pathways specific for FSGS versus MCD, and our data could help identify potential new biomarkers for the differential diagnosis between these two diseases. PMID:26536600

  2. The influence of growth hormone deficiency, growth hormone replacement therapy, and other aspects of hypopituitarism on fracture rate and bone mineral density. .

    PubMed

    Wüster, C; Abs, R; Bengtsson, B A; Bennmarker, H; Feldt-Rasmussen, U; Hernberg-Ståhl, E; Monson, J P; Westberg, B; Wilton, P

    2001-02-01

    To assess the influence of factors affecting fracture risk and bone density in adult hypopituitary patients with growth hormone deficiency (GHD), data from a large-scale pharmacoepidemiological survey (the Pharmacia & Upjohn International Metabolic Database [KIMS]) were analyzed and compared with data from a control population (the European Vertebral Osteoporosis Study [EVOS]). The KIMS group consisted of 2084 patients (1112 men and 972 women) with various types of pituitary disease and EVOS consisted of 1176 individuals (581 men and 595 women). Fracture and bone mineral density (BMD) data were available from 2024 patients from the KIMS group and 392 patients from EVOS. The prevalence of fractures in patients with hypopituitarism was 2.66 times that in the non-GH-deficient EVOS population. Adult-onset hypopituitarism with GHD was associated with a higher fracture risk than childhood-onset disease, and patients with isolated GHD had a similar prevalence of fractures to those with multiple pituitary hormone deficiencies. Hormonal replacement therapy with L-thyroxine, glucocorticoids, and sex steroids did not affect the risk of fracture in KIMS patients. In addition, fracture rates in KIMS were independent of body mass index (BMI) and the country of origin. However, smoking was associated with a higher fracture rate in this group. In summary, this is the first large-scale analysis to support the hypothesis of an increased fracture risk in adult patients with hypopituitarism and GHD. This increased risk appears to be attributable to GHD alone, rather than to other pituitary hormone deficiencies or to their replacement therapy. PMID:11204440

  3. Regulation of Varicella-Zoster Virus-Induced Cell-to-Cell Fusion by the Endocytosis-Competent Glycoproteins gH and gE

    PubMed Central

    Pasieka, Tracy Jo; Maresova, Lucie; Shiraki, Kimiyasu; Grose, Charles

    2004-01-01

    The gH glycoprotein of varicella-zoster virus (VZV) is a major fusogen. The realigned short cytoplasmic tail of gH (18 amino acids) harbors a functional endocytosis motif (YNKI) that mediates internalization in both VZV-infected and transfected cells (T. J. Pasieka, L. Maresova, and C. Grose, J. Virol. 77: 4194-4202, 2003). During subsequent confocal microscopy studies of endocytosis-deficient gH mutants, we observed that cells transfected with the gH tail mutants exhibited marked fusion. Therefore, we postulated that VZV gH endocytosis served to regulate cell-to-cell fusion. Subsequent analyses of gH+gL transfection fusion assays by the Kolmogorov-Smirnov statistical test demonstrated that expression of the endocytosis-deficient gH mutants resulted in a statistically significant enhancement of cell-to-cell fusion (P < 0.0001) compared to wild-type gH. On the other hand, coexpression of VZV gE, another endocytosis-competent VZV glycoprotein, was able to temper the fusogenicity of the gH endocytosis mutants by facilitating internalization of the mutant gH protein from the cell surface. When the latter results were similarly analyzed, there was no longer any enhanced fusion by the endocytosis-deficient gH mutant protein. In summary, these studies support a role for gH endocytosis in regulating the cell surface expression of gH and thereby regulating gH-mediated fusion. The data also confirm and extend prior observations of a gE-gH interaction during viral glycoprotein trafficking in a VZV transfection system. PMID:14990707

  4. Morphea in Adults and Children Cohort VI: A cross-sectional comparison of outcomes between adults with pediatric-onset and adult-onset morphea

    PubMed Central

    Condie, Daniel; Grabell, Daniel; Jacobe, Heidi

    2014-01-01

    Objective Few studies have looked at outcomes of adults with pediatric-onset morphea. The objective of the present study was to compare clinical outcomes and health-related quality of life in adults with pediatric-onset morphea to those of patients with adult-onset morphea. Methods Participants in the study were drawn from the Morphea in Adults and Children Cohort and included 68 adults with pediatric-onset morphea and 234 patients with adult-onset morphea. Outcome measures included the Localized Scleroderma Cutaneous Assessment Tool (LoSCAT), physical exam findings, and quality of life questionnaires. Results Adults with pediatric-onset morphea were younger, had longer disease duration, and were more likely to have the linear subtype of morphea. Patients with pediatric-onset disease were less likely to have active disease. Among patients with active disease, those with pediatric-onset morphea had less disease activity as measured by the LoSCAT. Patients with pediatric-onset disease had higher disease damage as measured by the Physician Global Assessment of Damage, but similar disease damage as measured by the Localized Scleroderma Skin Damage Index. Patients with pediatric-onset disease had more favorable quality of life scores for all measures that reached statistical significance. Conclusion Adults with pediatric-onset morphea differ from patients with adult-onset disease with respect to subtype, disease activity, disease damage, and health-related quality of life. PMID:25156342

  5. Benefits of long-term GH therapy in Prader-Willi syndrome: a 4-year study.

    PubMed

    Carrel, Aaron L; Myers, Susan E; Whitman, Barbara Y; Allen, David B

    2002-04-01

    Obesity, poor growth, and hypotonia in children with Prader-Willi syndrome (PWS) are accompanied by abnormal body composition resembling a GH-deficient state. Hypothalamic dysfunction in PWS includes decreased GH secretion, suggesting a possible therapeutic role for GH treatment. While short-term benefits of treatment with GH have been shown, whether these beneficial effects are dose dependent and persist or wane with prolonged therapy remains uncertain. Effects of 24 additional months of GH treatment at varying doses (0.3, 1.0, and 1.5 mg/m(2).d) on growth, body composition, strength and agility, pulmonary function, resting energy expenditure (REE), and fat utilization were assessed in 46 children with PWS, who had previously been treated with GH therapy (1 mg/m(2).d) for 12-24 months. Percent body fat, lean muscle mass, and bone mineral density (BMD) were measured by dual x-ray absorptiometry. Indirect calorimetry was used to determine REE and to calculate respiratory quotient. A modified Bruininks-Oseretski test of physical performance evaluated strength and agility. During months 24-48 of GH therapy, continued beneficial effects on body composition (decrease in fat mass and increase in lean body mass), growth velocity, and REE occurred with GH therapy doses of 1.0 and 1.5 mg/m(2).d (P < 0.05), but not with 0.3 mg/m(2).d. BMD continued to improve at all doses of GH (P < 0.05). Prior improvements in strength and agility that occurred during the initial 24 months were sustained but did not improve further during the additional 24 months regardless of dose. Salutary and sustained GH-induced changes in growth, body composition, BMD, and physical function in children with PWS can be achieved with daily administration of GH doses > or =1 mg/m(2). Lower doses of GH, (0.3 mg/m(2).d) effective in improving body composition in GHD adults, do not appear to be effective in children with PWS at sustaining improvement in body composition. PMID:11932286

  6. Interleukin 1 inhibition with anakinra in adult-onset Still disease: a meta-analysis of its efficacy and safety

    PubMed Central

    Hong, Dongsheng; Yang, Zhihai; Han, Shuyin; Liang, Xingguang; Ma, Kuifen; Zhang, Xingguo

    2014-01-01

    Background Anakinra is the first interleukin-1 inhibitor to be used in clinical practice, and recent evidence showed that interleukin-1 plays a pivotal role in the pathogenesis of adult-onset Still disease (AoSD). However, data concerning efficacy with anakinra use in different clinical trials has not been evaluated, and the overall remission of AoSD with anakinra treatment has not been well defined. Methods We conducted a search on Embase, PubMed, and the Cochrane Library for relevant trials. Statistical analyses were conducted to calculate the overall remission rates, odds ratios (OR), and 95% confidence intervals (CI), by using either random effects or fixed effect models according to the heterogeneity. Results Of the 273 articles that were identified, 265 were excluded. Eight studies were eligible for inclusion. The overall remission rate and complete remission rate of anakinra in AoSD patients were 81.66% (95% CI: 69.51%–89.69%) and 66.75% (95% CI: 59.94%–75.3%), respectively. Compared with the controls, the use of anakinra was associated with a significant remission in AoSD, with an OR of 0.16 (95% CI: 0.06–0.44, P=0.0005). There were also significant reductions of the dosage of corticosteroid (mean difference =21.19) (95% CI: 13.2–29.18, P<0.0001) from anakinra onset to the latest follow up time. Clinical and laboratory parameters were all improved, and anakinra was well tolerated in patients with AoSD. No evidence of publication bias was observed. Conclusion Our study has shown that anakinra is effective in remitting the manifestations of AoSD, with reduction of the dose of corticosteroid in patients with AoSD. Further, anakinra therapy was not associated with increased risk of adverse events, and it was well tolerated in patients with AoSD. Further research is still recommended to investigate these findings. PMID:25473268

  7. Annual Research Review: Current limitations and future directions in MRI studies of child- and adult-onset developmental psychopathologies

    PubMed Central

    Horga, Guillermo; Kaur, Tejal; Peterson, Bradley S.

    2014-01-01

    The widespread use of magnetic resonance imaging (MRI) in the study of child- and adult-onset developmental psychopathologies has generated many investigations that have measured brain structure and function in vivo throughout development, often generating great excitement over our ability to visualize the living, developing brain using the attractive, even seductive images that these studies produce. Often lost in this excitement is the recognition that brain imaging generally, and MRI in particular, is simply a technology, one that does not fundamentally differ from any other technology, be it a blood test, a genotyping assay, a biochemical assay, or behavioral test. No technology alone can generate valid scientific findings. Rather, it is only technology coupled with a strong experimental design that can generate valid and reproducible findings that lead to new insights into the mechanisms of disease and therapeutic response. In this review we discuss selected studies to illustrate the most common and important limitations of MRI study designs as most commonly implemented thus far, as well as the misunderstanding that the interpretations of findings from those studies can create for our theories of developmental psychopathologies. Those limitations are in large part responsible thus far for the generally poor reproducibility of findings across studies, poor generalizability to the larger population, failure to identify developmental trajectories, inability to distinguish causes from effects of illness, and poor ability to infer causal mechanisms in most MRI studies of developmental psychopathologies. For each of these limitations in study design and the difficulties they entail for the interpretation of findings, we discuss various approaches that numerous laboratories are now taking to address those difficulties, which have in common the yoking of brain imaging technologies to studies with inherently stronger designs that permit more valid and more powerful

  8. Rearranged Anaplastic Lymphoma Kinase (ALK) Gene in Adult-Onset Papillary Thyroid Cancer Amongst Atomic Bomb Survivors

    PubMed Central

    Mukai, Mayumi; Takahashi, Keiko; Hayashi, Yuzo; Nakachi, Kei; Kusunoki, Yoichiro

    2012-01-01

    rearrangements, being observed in 6 of 10 PTC cases with ALK rearrangements versus 2 of 15 cases with no ALK rearrangements. The six radiation-exposed cases of PTC harboring both ALK rearrangements and solid/trabecular-like architecture were associated with higher radiation doses and younger ages at the time of the A-bombing and at diagnosis compared to the other 19 PTC with no detectable gene alterations. Conclusion Our findings suggest that ALK rearrangements are involved in the development of radiation-induced adult-onset PTC. PMID:23050789

  9. Growth hormone (GH) binding and effects of GH analogs in transgenic mice

    SciTech Connect

    Bartke, A.; Steger, R.W.; Turyn, D.

    1994-12-31

    Overexpression of human (h) or bovine (b) growth hormone (GH) in transgenic mice is associated with marked (2- to 12-fold) and significant increase in hepatic binding of GH and prolactin (PRL). This is due to an increase in the number of GH and PRL receptors (GHR, PRLR) per mg of microsomal protein without changes in binding affinity. Comparison of results obtained in transgenic animals expressing bGH with a mouse metallothionein (MT) or a rat phosphoenolpyruvate carboxykinase (PEPCK) promoter suggests that effects of bGH on hepatic GHR and PRLR do not require GH overexpression during fetal life and, within the dose range tested, the effects on PRLR are not dose dependent. The increase in hepatic GHR was accompanied by significant increases in plasma GH-binding protein (GHBP) and in mean residence time of injected GH. Thus life-long elevation of peripheral GH levels alters the availability of both free GH and GHR. Site-directed in vitro mutagenesis was used to produce hGH and bGH analogs mutated within one of the sites involved in binding to GHR and PRLR. Mutating hGH to produce amino acid identity with bGH at Position 11, 18 (within Helix 1), 57, or 60 (within the loop between Helix 1 and 2) did not affect binding to GHR in vitro, or somatotropic activity in transgenic mice in vivo but reduced lactogenic activity in Nb{sub 2} cells by 22%-45%. Mutations of bGH designed to produce amino acid identity with hGH at one to four of the corresponding positions in the bGH molecule did not interfere with binding to GHR or somatotropic activity in vivo, and failed to produce significant binding to PRLR but resulted in alterations in the effects on the hypothalamic and anterior pituitary function in transgenic mice. Apparently region(s) outside the domains examined are essential for lactogenic activity of hGH, and different portions of the GH molecule are responsible for its diverse actions in vivo. 35 refs.

  10. Unaltered ratio of circulating levels of growth hormone/GH isoforms in adults with Prader-Willi syndrome after GHRH plus arginine administration.

    PubMed

    Rigamonti, A E; Grugni, G; Marazzi, N; Bini, S; Bidlingmaier, M; Sartorio, A

    2015-08-01

    Human growth hormone (GH) is a heterogeneous protein hormone consisting of several isoforms, the most abundant being 22 kDa- and 20 kDa-GH. The availability of analytical methods to measure these GH isoforms might represent a valuable diagnostic tool to investigate GH hyposecretory states, including Prader-Willi syndrome (PWS), one of the most common causes of syndromic obesity. The aim of the present study was to measure circulating levels of 22 kDa- and 20 kDa-GH in PWS adults (n=14; M/F: 5/9; genotype DEL15/UPD15: 12/2; age: 19.0±3.7 years; BMI: 29.9±8.7 kg/m2) after combined GH releasing hormone (GHRH) plus arginine (ARG) administration. The results were analysed subdividing the study population in obese vs. nonobese (6/8) and GH deficient vs. nonGH deficient (GHD) (6/8) subjects, according to appropriate BMI-related diagnostic cut-off limits of GH peak response to the provocative test. Circulating levels of 22 kDa-GH were measured by a chemiluminescent method based on a detection monoclonal antibody targeting an epitope in the loop connecting helix 1 and 2 of GH, which is missing in 20 kDa-GH; the 20 kDa-GH was measured using a time resolved fluorescence assay based on two monoclonal antibodies with no cross-reactivity to 22-kDa GH. GHRH plus ARG significantly stimulated the secretions of 22 kDa- and 20 kDa-GH in nonobese (at 30, 45, 60 and 90 min and at 45, 60, 90 and 120 min vs. 0 min, p<0.05, with GH peaks of 15.8±10.3 ng/ml and 2.7±1.2 ng/ml, respectively) and in nonGHD PWS (at 30, 45 and 60 min and at 45, 60 and 90 min vs 0 min, p<0.05, with GH peaks of 12.5±9.0 ng/ml and 2.0±1.8 ng/ml, respectively). No significant GHRH plus ARG-induced changes in 22 kDa- and 20 kDa-GH were observed in obese or GHD PWS patients, the only exception being the increase of 22 kDa-GH (p<0.05) 60 min after the stimulus administration in GHD group (with GH peaks of 6.9±4.7 ng/ml and 0.8±0.6 ng/ml in obese subjects and 8.5±6.0 ng/ml and 1.2±1.0 ng/ml in GHD subjects

  11. Late onset arginase deficiency presenting with encephalopathy and midbrain hyperintensity

    PubMed Central

    Maramattom, Boby Varkey; Raja, Rajat; Balagopal, Anuroop

    2016-01-01

    Urea cycle disorders (UCD) are very rare metabolic disorders that present with encephalopathy and hyperammonemia. Of the UCDs, Arginase deficiency (ARD) is the rarest and presents in childhood with a progressive spastic diplegia or seizures. Acute presentation in adulthood is extremely unusual.[1] We present the first case of adult onset ARD presenting with encephalopathy and diffusion weighted MRI findings that resembled a moustache in the midbrain.

  12. Late onset arginase deficiency presenting with encephalopathy and midbrain hyperintensity.

    PubMed

    Maramattom, Boby Varkey; Raja, Rajat; Balagopal, Anuroop

    2016-01-01

    Urea cycle disorders (UCD) are very rare metabolic disorders that present with encephalopathy and hyperammonemia. Of the UCDs, Arginase deficiency (ARD) is the rarest and presents in childhood with a progressive spastic diplegia or seizures. Acute presentation in adulthood is extremely unusual.[1] We present the first case of adult onset ARD presenting with encephalopathy and diffusion weighted MRI findings that resembled a moustache in the midbrain. PMID:27570396

  13. Lymphocyte GH-axis hormones in immunity.

    PubMed

    Weigent, Douglas A

    2013-01-01

    The production and utilization of common ligands and their receptors by cells of the immune and neuroendocrine systems constitutes a biochemical information circuit between and within the immune and neuroendocrine systems. The sharing of ligands and receptors allows the immune system to serve as the sixth sense notifying the nervous system of the presence of foreign entities. Within this framework, it is also clear that immune cell functions can be altered by neuroendocrine hormones and that cells of the immune system have the ability to produce neuroendocrine hormones. This review summarizes a part of this knowledge with particular emphasis on growth hormone (GH). The past two decades have uncovered a lot of detail about the actions of GH, acting through its receptor, at the molecular and cellular level and its influence on the immune system. The production and action of immune cell-derived GH is less well developed although its important role in immunity is also slowly emerging. Here we discuss the production of GH, GH-releasing hormone (GHRH) and insulin-like growth factor-1 (IGF-1) and their cognate receptors on cells of the immune system and their influence via endocrine/autocrine/paracrine and intracrine pathways on immune function. The intracellular mechanisms of action of immune cell-derived GH are still largely unexplored, and it is anticipated that further work in this particular area will establish an important role for this source of GH in normal physiology and in pathologic situations. PMID:24177252

  14. When uncommon and common coalesce: adult onset Still's disease associated with breast augmentation as part of autoimmune syndrome induced by adjuvants (ASIA).

    PubMed

    Dagan, A; Kogan, M; Shoenfeld, Y; Segal, G

    2016-06-01

    Adult onset Still's disease (AOSD) is an uncommon, multisystemic, auto-inflammatory disorder, while breast augmentation is a very common cosmetic procedure. We describe a case in which these two coalesce, AOSD, manifested with pleuritis and pericarditis, developed after breast mammoplasty. The pathogenetic, missing link, behind the development of AOSD following mammoplasty, is thought to be the autoimmune (auto-inflammatory) syndrome induced by adjuvants (ASIA). We reviewed other cases of AOSD associated with breast mammoplasty published to date and the literature regarding AOSD and ASIA syndrome. The review is followed by a short debate of whether silicone implants should be explanted in similar, future cases. PMID:25604318

  15. Zinc-deficiency acrodermatitis in a patient with chronic alcoholism and gastric bypass: a case report

    PubMed Central

    Shahsavari, Dariush; Ahmed, Zubair; Karikkineth, Ajoy; Williams, Richard; Zigel, Carlos

    2014-01-01

    Acquired adult-onset zinc deficiency is occasionally reported in patients with malnutrition states, such as alcoholism, or malabsorptive states, such as post-bariatric surgery. The defining symptoms of hypozincemia include a classic triad of necrolytic dermatitis, diffuse alopecia, and diarrhea. We report a case of zinc deficiency in a 39-year-old man with history of gastric bypass surgery and alcoholism. For this patient, severe hypozincemia confirmed acrodermatitis, and zinc supplementation was met with gradual improvement. PMID:25147643

  16. Immobilization of Glycoside Hydrolase Families GH1, GH13, and GH70: State of the Art and Perspectives.

    PubMed

    Graebin, Natália G; Schöffer, Jéssie da N; Andrades, Diandra de; Hertz, Plinho F; Ayub, Marco A Z; Rodrigues, Rafael C

    2016-01-01

    Glycoside hydrolases (GH) are enzymes capable to hydrolyze the glycosidic bond between two carbohydrates or even between a carbohydrate and a non-carbohydrate moiety. Because of the increasing interest for industrial applications of these enzymes, the immobilization of GH has become an important development in order to improve its activity, stability, as well as the possibility of its reuse in batch reactions and in continuous processes. In this review, we focus on the broad aspects of immobilization of enzymes from the specific GH families. A brief introduction on methods of enzyme immobilization is presented, discussing some advantages and drawbacks of this technology. We then review the state of the art of enzyme immobilization of families GH1, GH13, and GH70, with special attention on the enzymes β-glucosidase, α-amylase, cyclodextrin glycosyltransferase, and dextransucrase. In each case, the immobilization protocols are evaluated considering their positive and negative aspects. Finally, the perspectives on new immobilization methods are briefly presented. PMID:27548117

  17. Cloning and expression of a novel chicken sulfotransferase cDNA regulated by GH.

    PubMed

    Cao, H; Agarwal, S K; Burnside, J

    1999-03-01

    We have used mRNA differential display to compare gene expression in normal and GH receptor-deficient dwarf chickens, and report here the characterization of one differentially expressed gene, which shows significant sequence identity to the sulfotransferase gene family. Partial cDNA clones were isolated from a chicken liver cDNA library and an additional sequence was obtained using 5' rapid amplification of cDNA ends. A complete cDNA probe hybridizes to three transcripts (2.4, 2.0 and 1.45 kb) on Northern blots of chicken liver RNA, which differ in the length of the 3' untranslated region. All three transcripts are expressed at higher levels in normal vs dwarf chickens, as expected for a GH-regulated gene. The expression of this sulfotransferase mRNA was also detected in skeletal muscle, but not other tissues. The administration of GH to chickens increased the hepatic expression within 1 h, suggesting this sulfotransferase could be directly regulated by GH. Sulfotransferase activity, using estradiol or corticosterone as substrate, is detected in cells transfected with an expression vector containing the full-length cDNA. The sequence of this sulfotransferase does not show significant similarity with any subfamily of the sulfotransferases and its endogenous substrate is presently unknown. However, we speculate that GH activation of sulfotransferase activity could play a role in reducing concentrations of growth-antagonistic steroid hormones in GH target tissues. These results demonstrate the usefulness of differential display in this model system to identify genes that play a role in mediating GH action. PMID:10076195

  18. T3 acutely increases GH mRNA translation rate and GH secretion in hypothyroid rats.

    PubMed

    Silva, F Goulart da; Giannocco, G; Luchessi, A D; Curi, R; Nunes, M T

    2010-04-12

    Cytoskeleton controls the stability of transcripts, by mechanisms that involve mRNAs and eEF1A attachment to it. Besides, it plays a key role in protein synthesis and secretion, which seems to be impaired in somatotrophs of hypothyroid rats, whose cytoskeleton is disarranged. This study investigated the: eEF1A and GH mRNA binding to cytoskeleton plus GH mRNA translation rate and GH secretion, in sham-operated and thyroidectomized rats treated with T3 or saline, and killed 30min thereafter. Thyroidectomy reduced: (a) pituitary F-actin content, and eEF1A plus GH mRNA binding to it; (b) GH mRNA recruitment to polysome; and (c) liver IGF-I mRNA expression, indicating that GH mRNA stability and translation rate, as well as GH secretion were impaired. T3 acutely reversed all these changes, which points toward a nongenomic action of T3 on cytoskeleton rearrangement, which might contribute to the increase on GH mRNA translation rate and GH secretion. PMID:20015464

  19. Evaluation of Permanent Growth Hormone Deficiency (GHD) in Young Adults with Childhood Onset GHD: A multicenter study

    PubMed Central

    Berberoğlu, Merih; Darendeliler, Feyza; Poyrazoğlu, Şükran; Darcan, Şükran; İşgüven, Pınar; Bideci, Aysun; Öcal, Gönül; Bundak, Rüveyde; Yüksel, Bilgin; Arslanoğlu, İlknur

    2008-01-01

    Background: Reconfirming the diagnosis of childhood onset growth hormone deficiency (GHD) in young adults is necessary to demonstrate the need for continuation of GH therapy. Objective: This nationally−based study was planned to establish GH status during adulthood in childhood−onset GH deficient patients and to evaluate factors that would predict persistency of the GHD. Methods: In this multicenter study, 70 GH deficient patients who had reached final height were evaluated after completion of GH treatment. Fifty−two patients (74%) had isolated GHD and 18 patients (26%) had multiple pituitary hormone deficiency (MPHD). Patients who had reached final height and the pubertal Tanner stage 5 were reevaluated for GH status. After at least 6 weeks of cessation of GH treatment, patients were retested with insulin induced hypoglycemia. Results: GHD was found to be transient in 64.3% of all patients. Of the isolated GH deficient patients 82.7% had transient GHD, whereas 88.9% of the MPHD patients showed persistent GHD. Comparison of isolated GH deficient and multiple hormone deficient patients indicated higher peak GH, IGF−I and IGFBP−3 levels in isolated GH deficient patients. No parameter was significantly different in the transiently and persistently GH deficient patients with respect to gender. Although specificity of IGF−I value of less than −2 SD showing persistency of GHD was lower than the specificity of IGFBP−3 value of less than −2 SD (65.7% vs 84%), negative predictive values were similar for the two parameters (85.2% and 84%, respectively). Conclusion: Most of the cases of childhood onset GHD are idiopathic and the GHD is transient. In patients with MPHD, GHD is generally permanent. Low IGF−I and IGFBP−3 levels are supporting findings to show persistency of the GHD. Conflict of interest:None declared. PMID:21318062

  20. Congenital encephalomyopathy and adult-onset myopathy and diabetes mellitus: different phenotypic associations of a new heteroplasmic mtDNA tRNA glutamic acid mutation.

    PubMed Central

    Hanna, M G; Nelson, I; Sweeney, M G; Cooper, J M; Watkins, P J; Morgan-Hughes, J A; Harding, A E

    1995-01-01

    We report the clinical, biochemical, and molecular genetic findings in a family with an unusual mitochondrial disease phenotype harboring a novel mtDNA tRNA glutamic acid mutation at position 14709. The proband and his sister presented with congenital myopathy and mental retardation and subsequently developed cerebellar ataxia. Other family members had either adult-onset diabetes mellitus with muscle weakness or adult-onset diabetes mellitus alone. Ragged-red and cytochrome c oxidase (COX)-negative fibers were present in muscle biopsies. Biochemical studies of muscle mitochondria showed reduced complex I and IV activities. The mtDNA mutation was heteroplasmic in blood and muscle in all matrilineal relatives analyzed. Primary myoblast, but not fibroblast, cultures containing high proportions of mutant mtDNA exhibited impaired mitochondrial translation. These observations indicate that mtDNA tRNA point mutations should be considered in the differential diagnosis of congenital myopathy. In addition they illustrate the diversity of phenotypes associated with this mutation in the same family and further highlight the association between mtDNA mutations and diabetes mellitus. Images Figure 1 Figure 3 Figure 4 PMID:7726155

  1. Adult-onset hypothyroidism and the cerebral metabolism of (1,2-13C2) acetate as detected by 13C nuclear magnetic resonance.

    PubMed

    Chapa, F; Künnecke, B; Calvo, R; Escobar del Rey, F; Morreale de Escobar, G; Cerdán, S

    1995-01-01

    The effects of adult-onset hypothyroidism on the metabolic compartmentation of the cerebral tricarboxylic acid cycle and the gamma-aminobutyric acid (GABA) shunt have been investigated by 13C nuclear magnetic resonance spectroscopy. Rats thyroidectomized as adults and age-matched controls were infused in the right jugular vein with unlabeled or (1,2-13C2) acetate solutions for 60 min. At the end of the infusion, the brains were frozen in situ and perchloric acid extracts were prepared and analyzed by 13C nuclear magnetic resonance and reverse-phase HPLC. Thyroidectomized animals showed a decrease in the incorporation of 13C from (1,2-13C2) acetate in cerebral metabolites and an increase in the concentrations of unlabeled glutamate and GABA. Computer-assisted interpretation of the 13C multiplets observed for the carbons of glutamate, glutamine, and GABA indicated that adult-onset hypothyroidism produced 1) a decrease in the contribution of infused (1,2-13C2) acetate to the glial tricarboxylic acid cycle; 2) an increase in the contribution of unlabeled acetyl-CoA to the neuronal tricarboxylic acid cycle; and 3) impairments in the exchange of glutamate, glutamine, and GABA between the neuronal and glial compartments. Despite the fact that the adult brain has often been considered metabolically unresponsive to thyroid hormone status, present results show metabolic alterations in the neuronal and glial compartments that are reversible with substitution therapy. PMID:7828544

  2. Longitudinal changes in cerebellar and subcortical volumes in adult-onset Niemann-Pick disease type C patients treated with miglustat.

    PubMed

    Bowman, Elizabeth A; Walterfang, Mark; Abel, Larry; Desmond, Patricia; Fahey, Michael; Velakoulis, Dennis

    2015-09-01

    Niemann-Pick disease type C (NPC) is a rare neurovisceral disorder resulting in impaired intracellular lipid trafficking. The only disease-modifying treatment available to date is miglustat, an iminosugar inhibiting the accumulation of lipid by-products in neurons. This study explored how changes in cerebellar grey and white matter volumes, and in subcortical volumes, related to patient treatment status and disability and ataxia ratings. Nine adult-onset NPC patients and 17 matched controls underwent T1-weighted MRI. One patient was not receiving miglustat, and pre-treatment data were available for a further patient. Semi-automated cerebellar and subcortical segmentation was undertaken, and the rates of change in putamen, hippocampal, thalamic and caudal volumes, and grey and white matter cerebellar volumes, were compared to rates of change in Iturriaga disability score, Brief Ataxia Rating Scale (BARS), and horizontal saccadic gain. Untreated NPC patients appeared to lose cerebellar grey and white matter, bilateral thalamic volume, and right caudate volume faster than treated patients. Cerebellar grey matter volume loss and volume loss in the left thalamus were significantly correlated with Iturriaga disability scale changes. Change in both cerebellar grey and white matter was correlated with decrease in horizontal saccadic gain, but not with change in BARS. This is the first study to examine longitudinal treatment effects of miglustat on cerebellar and subcortical volumes in patients with adult-onset NPC, and is evidence that miglustat may have a protective effect on cerebellar and subcortical structure and function. PMID:26092521

  3. Congenital encephalomyopathy and adult-onset myopathy and diabetes mellitus: Different phenotypic associations of a new heteroplasmic mtDNA tRNA glutamic acid mutation

    SciTech Connect

    Hanna, M.G.; Nelson, I.; Sweeney, M.G.; Cooper, J.M.; Watkins, P.J.; Morgan-Hughes, J.A.; Harding, A.E.

    1995-05-01

    We report the clinical, biochemical, and molecular genetic findings in a family with an unusual mitochondrial disease phenotype harboring a novel mtDNA tRNA glutamic acid mutation at position 14709. The proband and his sister presented with congenital myopathy and mental retardation and subsequently developed cerebellar ataxia. Other family members had either adult-onset diabetes mellitus with muscle weakness or adult-onset diabetes mellitus alone. Ragged-red and cytochrome c oxidase (COX)-negative fibers were present in muscle biopsies. Biochemical studies of muscle mitochondria showed reduced complex I and IV activities. The mtDNA mutation was heteroplasmic in blood and muscle in all matrilineal relatives analyzed. Primary myoblast, but not fibroblast, cultures containing high proportions of mutant mtDNA exhibited impaired mitochondrial translation. These observations indicate that mtDNA tRNA point mutations should be considered in the differential diagnosis of congenital myopathy. In addition they illustrate the diversity of phenotypes associated with this mutation in the same family and further highlight the association between mtDNA mutations and diabetes mellitus. 43 refs., 4 figs., 1 tab.

  4. Neuropsychiatric aspects of adult-onset Tay-Sachs disease: two case reports with several new findings.

    PubMed

    Hurowitz, G I; Silver, J M; Brin, M F; Williams, D T; Johnson, W G

    1993-01-01

    Deficiency of hexosaminidase A causes the GM2 gangliosidosis known as Tay-Sachs disease. It is now known that this condition has several late-onset variants that cause numerous neuropsychiatric disturbances. Early recognition is important because treatment with phenothiazines and heterocyclic antidepressants may worsen the course. The authors report two cases with several new findings, including prominent psychiatric symptoms without psychosis early in the course of the illness. PMID:8428133

  5. Brain Recovery after a Plane Crash: Treatment with Growth Hormone (GH) and Neurorehabilitation: A Case Report

    PubMed Central

    Devesa, Jesús; Díaz-Getino, Gustavo; Rey, Pablo; García-Cancela, José; Loures, Iria; Nogueiras, Sonia; Hurtado de Mendoza, Alba; Salgado, Lucía; González, Mónica; Pablos, Tamara; Devesa, Pablo

    2015-01-01

    The aim of this study is to describe the results obtained after growth hormone (GH) treatment and neurorehabilitation in a young man that suffered a very grave traumatic brain injury (TBI) after a plane crash. Methods: Fifteen months after the accident, the patient was treated with GH, 1 mg/day, at three-month intervals, followed by one-month resting, together with daily neurorehabilitation. Blood analysis at admission showed that no pituitary deficits existed. At admission, the patient presented: spastic tetraplegia, dysarthria, dysphagia, very severe cognitive deficits and joint deformities. Computerized tomography scanners (CT-Scans) revealed the practical loss of the right brain hemisphere and important injuries in the left one. Clinical and blood analysis assessments were performed every three months for three years. Feet surgery was needed because of irreducible equinovarus. Results: Clinical and kinesitherapy assessments revealed a prompt improvement in cognitive functions, dysarthria and dysphagia disappeared and three years later the patient was able to live a practically normal life, walking alone and coming back to his studies. No adverse effects were observed during and after GH administration. Conclusions: These results, together with previous results from our group, indicate that GH treatment is safe and effective for helping neurorehabilitation in TBI patients, once the acute phase is resolved, regardless of whether or not they have GH-deficiency (GHD). PMID:26703581

  6. Functional characterization of GhSOC1 and GhMADS42 homologs from upland cotton (Gossypium hirsutum L.).

    PubMed

    Zhang, Xiaohong; Wei, Jianghui; Fan, Shuli; Song, Meizhen; Pang, Chaoyou; Wei, Hengling; Wang, Chengshe; Yu, Shuxun

    2016-01-01

    In Arabidopsis flowering pathway, MADS-box genes encode transcription factors, with their structures and functions highly conserved in many species. In our study, two MADS-box genes GhSOC1 and GhMADS42 (Gossypium hirsutum L.) were cloned from upland cotton CCRI36 and transformed into Arabidopsis. GhSOC1 was additionally transformed into upland cotton. Comparative analysis demonstrated sequence conservation between GhSOC1 and GhMADS42 and genes of other plant species. Tissue-specific expression analysis of GhSOC1 and GhMADS42 revealed spatiotemporal expression patterns involving high transcript levels in leaves, shoot apical buds, and flowers. In addition, overexpression of both GhSOC1 and GhMADS42 in Arabidopsis accelerated flowering, with GhMADS42 transgenic plants showing abnormal floral organ phenotypes. Overexpression of GhSOC1 in upland cotton also produced variations in floral organs. Furthermore, chromatin immunoprecipitation assay demonstrated that GhSOC1 could regulate GhMADS41 and GhMADS42, but not FLOWERING LOCUS T, by directly binding to the genes promoter. Finally, yeast two-hybrid and bimolecular fluorescence complementation approaches were undertaken to better understand the interaction of GhSOC1 and other MADS-box factors. These experiments showed that GhSOC1 can interact with APETALA1/FRUITFULL-like proteins in cotton. PMID:26566835

  7. Differences in B7 and CD28 family gene expression in the peripheral blood between newly diagnosed young-onset and adult-onset type 1 diabetes patients.

    PubMed

    Pruul, K; Kisand, K; Alnek, K; Metsküla, K; Reimand, K; Heilman, K; Peet, A; Varik, K; Peetsalu, M; Einberg, Ü; Tillmann, V; Uibo, R

    2015-09-01

    Type-1 diabetes (T1D) is a heterogeneous autoimmune disease, and there are pathogenetic differences between young- and adult-onset T1D patients. We hypothesized that the expressions of genes involved in costimulatory immune system pathways in peripheral blood are differently regulated in young- and adult-onset T1D. Study group I consisted of 80 children, adolescents, and young adults (age range 1.4-21.4 y; 31 controls and 49 T1D patients). Study group II consisted of 48 adults (age range 22.0-78.4 y; 30 controls and 18 T1D patients). The mRNA expression levels of CD86, CD28, CD25, CD226, CD40, BTLA, GITR, PDCD1, FoxP3, TGF-β, ICOS, sCTLA4, flCTLA4, and CD80 were measured in peripheral blood. Genetic polymorphisms (HLA haplotypes; rs231806, rs231775, and rs3087243 in CTLA4; rs763361 in CD226; and rs706778 in CD25) and T1D-associated autoantibodies were analyzed. In group I, there was significantly lower expression of CD226 in T1D patients than in the controls. In group II, there were significantly higher expression levels of CD86 and TGF-β in T1D patients than in the controls. In the T1D patients in group I, the upregulated CD80 expression correlated with the expression of both CTLA4 splice variants (sCTLA4 and flCTLA4). In contrast, in group II, upregulated CD86 correlated with TGF-β and CD25. In group I, the inhibitory CD80-CTLA4 pathway was activated, whereas, in group II, the activation CD86-CD28 pathway and TGF-β production were activated. These results emphasize the differences between young-onset and adult-onset T1D in the regulation of costimulatory pathways. These differences should be considered when developing novel treatments for T1D. PMID:25980680

  8. Incidence of Adult-onset Asthma After Hypothetical Interventions on Body Mass Index and Physical Activity: An Application of the Parametric G-Formula

    PubMed Central

    Garcia-Aymerich, Judith; Varraso, Raphaëlle; Danaei, Goodarz; Camargo,, Carlos A.; Hernán, Miguel A.

    2014-01-01

    High body mass index (BMI) (calculated as weight (kg)/height (m)2) is associated with increased asthma risk, but uncertainty persists about the role of physical activity. We estimated the independent and joint associations of hypothetical interventions on BMI and physical activity with the risk of adult-onset asthma in 76,470 asthma-free women from the Nurses’ Health Study who were followed between 1988 and 1998. Information about asthma, BMI, physical activity, and other factors was updated every 2 years. We used the parametric g-formula to estimate the 10-year asthma risk in the following 4 scenarios: no intervention, 5% BMI reduction in a 2-year period for those who were overweight or obese, at least 2.5 hours/week of moderate-to-vigorous physical activity, and both of the previous 2 interventions. At baseline, women had a mean age of 55 (standard deviation, 7) years and a mean BMI of 25.4 (standard deviation, 4.8). Median time spent in physical activity was 0.7 hours/week. During follow-up, 1,146 women developed asthma. The 10-year asthma risk under no intervention was 1.5%. Compared with no intervention, the population risk ratios were 0.96 (95% confidence interval (CI): 0.93, 0.99) under the BMI intervention, 0.96 (95% CI: 0.81, 1.10) under the physical activity intervention, and 0.92 (95% CI: 0.78, 1.06) under the joint intervention. Interventions on BMI and physical activity may have a modest impact on the risk of adult-onset asthma in this population of US women. PMID:24107616

  9. Hypophysectomy eliminates and growth hormone (GH) maintains the midpregnancy elevation in GH receptor and serum binding protein in the mouse

    SciTech Connect

    Sanchez-Jimenez, F.; Fielder, P.J.; Martinez, R.R.; Smith, W.C.; Talamantes, F. )

    1990-02-01

    ({sup 125}I)Iodomouse GH (({sup 125}I)iodo-mGH) binding to samples of serum and hepatic microsomal membranes was measured in hypophysectomized pregnant, sham-operated pregnant, intact pregnant, and intact adult virgin mice. Surgeries were carried out on day 11 of pregnancy, and the animals were killed on day 14. The binding of mGH to both serum and hepatic microsomal membranes of intact virgin mice was much lower than to those of intact pregnant mice. In hypophysectomized mice, the mGH-binding capacity of both serum and hepatic microsomes decreased to values similar to those of nonpregnant mice. No significant differences were observed between intact and sham-operated pregnant animals in the maternal serum mGH concentration, the serum GH-binding protein concentration, or the hepatic GH receptor concentration. GH receptor and binding protein-encoding mRNAs were also higher in intact and sham-operated pregnant mice than in virgin and hypophysectomized mice. Hypophysectomized mice were treated with 200 micrograms/day bovine GH, administered by osmotic minipump; after 3 days of treatment, a significant elevation of hepatic GH receptor and serum GH-binding protein levels was observed. These results demonstrate an up-regulation of hepatic GH receptors and serum GH-binding protein by GH during pregnancy in the mouse.

  10. Arterial pulse wave velocity, inflammatory markers, pathological GH and IGF states, cardiovascular and cerebrovascular disease

    PubMed Central

    Graham, Michael R; Evans, Peter; Davies, Bruce; Baker, Julien S

    2008-01-01

    Blood pressure (BP) measurements provide information regarding risk factors associated with cardiovascular disease, but only in a specific artery. Arterial stiffness (AS) can be determined by measurement of arterial pulse wave velocity (APWV). Separate from any role as a surrogate marker, AS is an important determinant of pulse pressure, left ventricular function and coronary artery perfusion pressure. Proximal elastic arteries and peripheral muscular arteries respond differently to aging and to medication. Endogenous human growth hormone (hGH), secreted by the anterior pituitary, peaks during early adulthood, declining at 14% per decade. Levels of insulin-like growth factor-I (IGF-I) are at their peak during late adolescence and decline throughout adulthood, mirror imaging GH. Arterial endothelial dysfunction, an accepted cause of increased APWV in GH deficiency (GHD) is reversed by recombinant human (rh) GH therapy, favorably influencing the risk for atherogenesis. APWV is a noninvasive method for measuring atherosclerotic and hypertensive vascular changes increases with age and atherosclerosis leading to increased systolic blood pressure and increased left ventricular hypertrophy. Aerobic exercise training increases arterial compliance and reduces systolic blood pressure. Whole body arterial compliance is lowered in strength-trained individuals. Homocysteine and C-reactive protein are two inflammatory markers directly linked with arterial endothelial dysfunction. Reviews of GH in the somatopause have not been favorable and side effects of treatment have marred its use except in classical GHD. Is it possible that we should be assessing the combined effects of therapy with rhGH and rhIGF-I? Only multiple intervention studies will provide the answer. PMID:19337549

  11. Growth responses following a single intra-muscular hGH plasmid administration compared to daily injections of hGH in dwarf mice.

    PubMed

    Higuti, Eliza; Cecchi, Claudia R; Oliveira, Nelio A J; Vieira, Daniel P; Jensen, Thomas G; Jorge, Alexander A L; Bartolini, Paolo; Peroni, Cibele N

    2012-12-01

    In previous work, sustained levels of circulating human growth hormone (hGH) and a highly significant weight increase were observed after electrotransfer of naked plasmid DNA (hGH-DNA) into the muscle of immunodeficient dwarf mice (lit/scid). In the present study, the efficacy of this in vivo gene therapy strategy is compared to daily injections (5 μg/twice a day) of recombinant hGH (r-hGH) protein, as assessed on the basis of several growth parameters. The slopes of the two growth curves were found to be similar (P > 0.05): 0.095 g/mouse/d for protein and 0.094 g/mouse/d for DNA injection. In contrast, the weight increases averaged 35.5% (P < 0.001) and 23.1% (P < 0.01) for protein and DNA administration, respectively, a difference possibly related to the electroporation methodology. The nose-to-tail linear growth increases were 15% and 9.6% for the protein and DNA treatments, respectively, but mouse insulin-like growth factor I (mIGF-I) showed a greater increase over the control with DNA (5- to 7-fold) than with protein (3- to 4-fold) administration. The weight increases of several organs and tissues (kidneys, spleen, liver, heart, quadriceps and gastrocnemius muscles) were 1.3- to 4.6-fold greater for protein than for DNA administration, which gave a generally more proportional growth. Glucose levels were apparently unaffected, suggesting the absence of effects on glucose tolerance. A gene transfer strategy based on a single hGH-DNA administration thus appears to be comparable to repeated hormone injections for promoting growth and may represent a feasible alternative for the treatment of growth hormone deficiency. PMID:22974419

  12. Growth and maturational changes in dense fibrous connective tissue following 14 days of rhGH supplementation in the dwarf rat

    NASA Technical Reports Server (NTRS)

    Kyparos, Antonios; Orth, Michael W.; Vailas, Arthur C.; Martinez, Daniel A.

    2002-01-01

    The purpose of this study was to investigate the impact of recombinant human growth hormone (rhGH) on patella tendon (PT), medial collateral ligament (MCL), and lateral collateral ligament (LCL) on collagen growth and maturational changes in dwarf GH-deficient rats. Twenty male Lewis mutant dwarf rats, 37 days of age, were randomly assigned to Dwarf + rhGH (n = 10) and Dwarf + vehicle (n = 10) groups. The GH group received 1.25 mg rhGH/kg body wt twice daily for 14 days. rhGH administration stimulated dense fibrous connective tissue growth, as demonstrated by significant increases in hydroxyproline specific activity and significant decreases in the non-reducible hydroxylysylpyridinoline (HP) collagen cross-link contents. The increase in the accumulation of newly accreted collagen was 114, 67, and 117% for PT, MCL, and LCL, respectively, in 72 h. These findings suggest that a short course rhGH treatment can affect the rate of new collagen production. However, the maturation of the tendon and ligament tissues decreased 18-25% during the rapid accumulation of de novo collagen. We conclude that acute rhGH administration in a dwarf rat can up-regulate new collagen accretion in dense fibrous connective tissues, while causing a reduction in collagen maturation. Copyright 2002 Elsevier Science Ltd.

  13. The Dwarf Phenotype in GH240B Mice, Haploinsufficient for the Autism Candidate Gene Neurobeachin, Is Caused by Ectopic Expression of Recombinant Human Growth Hormone

    PubMed Central

    Fu, Quili; Stijnen, Pieter; Pruniau, Vincent; Meulemans, Sandra; Vankelecom, Hugo; Creemers, John W. M.

    2014-01-01

    Two knockout mouse models for the autism candidate gene Neurobeachin (Nbea) have been generated independently. Although both models have similar phenotypes, one striking difference is the dwarf phenotype observed in the heterozygous configuration of the GH240B model that is generated by the serendipitous insertion of a promoterless human growth hormone (hGH) genomic fragment in the Nbea gene. In order to elucidate this discrepancy, the dwarfism present in this Nbea mouse model was investigated in detail. The growth deficiency in Nbea+/− mice coincided with an increased percentage of fat mass and a decrease in bone mineral density. Low but detectable levels of hGH were detected in the pituitary and hypothalamus of Nbea+/− mice but not in liver, hippocampus nor in serum. As a consequence, several members of the mouse growth hormone (mGH) signaling cascade showed altered mRNA levels, including a reduction in growth hormone-releasing hormone mRNA in the hypothalamus. Moreover, somatotrope cells were less numerous in the pituitary of Nbea+/− mice and both contained and secreted significantly less mGH resulting in reduced levels of circulating insulin-like growth factor 1. These findings demonstrate that the random integration of the hGH transgene in this mouse model has not only inactivated Nbea but has also resulted in the tissue-specific expression of hGH causing a negative feedback loop, mGH hyposecretion and dwarfism. PMID:25333629

  14. The dwarf phenotype in GH240B mice, haploinsufficient for the autism candidate gene Neurobeachin, is caused by ectopic expression of recombinant human growth hormone.

    PubMed

    Nuytens, Kim; Tuand, Krizia; Fu, Quili; Stijnen, Pieter; Pruniau, Vincent; Meulemans, Sandra; Vankelecom, Hugo; Creemers, John W M

    2014-01-01

    Two knockout mouse models for the autism candidate gene Neurobeachin (Nbea) have been generated independently. Although both models have similar phenotypes, one striking difference is the dwarf phenotype observed in the heterozygous configuration of the GH240B model that is generated by the serendipitous insertion of a promoterless human growth hormone (hGH) genomic fragment in the Nbea gene. In order to elucidate this discrepancy, the dwarfism present in this Nbea mouse model was investigated in detail. The growth deficiency in Nbea+/- mice coincided with an increased percentage of fat mass and a decrease in bone mineral density. Low but detectable levels of hGH were detected in the pituitary and hypothalamus of Nbea+/- mice but not in liver, hippocampus nor in serum. As a consequence, several members of the mouse growth hormone (mGH) signaling cascade showed altered mRNA levels, including a reduction in growth hormone-releasing hormone mRNA in the hypothalamus. Moreover, somatotrope cells were less numerous in the pituitary of Nbea+/- mice and both contained and secreted significantly less mGH resulting in reduced levels of circulating insulin-like growth factor 1. These findings demonstrate that the random integration of the hGH transgene in this mouse model has not only inactivated Nbea but has also resulted in the tissue-specific expression of hGH causing a negative feedback loop, mGH hyposecretion and dwarfism. PMID:25333629

  15. Increased lodging resistance in long-culm, low-lignin gh2 rice for improved feed and bioenergy production.

    PubMed

    Ookawa, Taiichiro; Inoue, Kazuya; Matsuoka, Makoto; Ebitani, Takeshi; Takarada, Takeshi; Yamamoto, Toshio; Ueda, Tadamasa; Yokoyama, Tadashi; Sugiyama, Chisato; Nakaba, Satoshi; Funada, Ryo; Kato, Hiroshi; Kanekatsu, Motoki; Toyota, Koki; Motobayashi, Takashi; Vazirzanjani, Mehran; Tojo, Seishu; Hirasawa, Tadashi

    2014-01-01

    Lignin modification has been a breeding target for the improvements of forage digestibility and energy yields in forage and bioenergy crops, but decreased lignin levels are often accompanied by reduced lodging resistance. The rice mutant gold hull and internode2 (gh2) has been identified to be lignin deficient. GH2 has been mapped to the short arm of chromosome 2 and encodes cinnamyl-alcohol dehydrogenase (CAD). We developed a long-culm variety, 'Leaf Star', with superior lodging resistance and a gh phenotype similar to one of its parents, 'Chugoku 117'. The gh loci in Leaf Star and Chugoku 117 were localized to the same region of chromosome 2 as the gh2 mutant. Leaf Star had culms with low lignin concentrations due to a natural mutation in OsCAD2 that was not present in Chugoku 117. However, this variety had high culm strength due to its strong, thick culms. Additionally, this variety had a thick layer of cortical fiber tissue with well-developed secondary cell walls. Our results suggest that rice can be improved for forage and bioenergy production by combining superior lodging resistance, which can be obtained by introducing thick and stiff culm traits, with low lignin concentrations, which can be obtained using the gh2 variety. PMID:25298209

  16. Increased lodging resistance in long-culm, low-lignin gh2 rice for improved feed and bioenergy production

    PubMed Central

    Ookawa, Taiichiro; Inoue, Kazuya; Matsuoka, Makoto; Ebitani, Takeshi; Takarada, Takeshi; Yamamoto, Toshio; Ueda, Tadamasa; Yokoyama, Tadashi; Sugiyama, Chisato; Nakaba, Satoshi; Funada, Ryo; Kato, Hiroshi; Kanekatsu, Motoki; Toyota, Koki; Motobayashi, Takashi; Vazirzanjani, Mehran; Tojo, Seishu; Hirasawa, Tadashi

    2014-01-01

    Lignin modification has been a breeding target for the improvements of forage digestibility and energy yields in forage and bioenergy crops, but decreased lignin levels are often accompanied by reduced lodging resistance. The rice mutant gold hull and internode2 (gh2) has been identified to be lignin deficient. GH2 has been mapped to the short arm of chromosome 2 and encodes cinnamyl-alcohol dehydrogenase (CAD). We developed a long-culm variety, ‘Leaf Star’, with superior lodging resistance and a gh phenotype similar to one of its parents, ‘Chugoku 117’. The gh loci in Leaf Star and Chugoku 117 were localized to the same region of chromosome 2 as the gh2 mutant. Leaf Star had culms with low lignin concentrations due to a natural mutation in OsCAD2 that was not present in Chugoku 117. However, this variety had high culm strength due to its strong, thick culms. Additionally, this variety had a thick layer of cortical fiber tissue with well-developed secondary cell walls. Our results suggest that rice can be improved for forage and bioenergy production by combining superior lodging resistance, which can be obtained by introducing thick and stiff culm traits, with low lignin concentrations, which can be obtained using the gh2 variety. PMID:25298209

  17. Moving one step closer to catching the GH cheats: The GH-2004 experience.

    PubMed

    Holt, Richard I G; Bassett, E Eryl; Erotokritou-Mulligan, Ioulietta; McHugh, Cathy; Cowan, David; Bartlett, Christiaan; Sönksen, Peter H

    2009-08-01

    Growth hormone is abused by athletes for its anabolic and lipolytic properties. The detection of GH abuse is challenging because it is an endogenous hormone whose concentration varies widely in any one day. The GH-2000 project proposed a test based on the measurement of IGF-I and type III pro-collagen (P-III-P). When the results of the GH-2000 project were presented to an expert workshop, the method was supported but it was felt that several issues needed to be resolved before the method could be adopted. The first was a potential effect of ethnicity as most subjects in the GH-2000 were white Europeans and the second was a possible effect of injury as P-III-P is a marker of soft tissue turnover. The GH-2004 project was conceived to address these concerns. The GH-2004 project has shown that while there are minor differences in IGF-I and P-III-P between ethnicities, these are small and do not affect the performance of the test. Injury leads to a small rise in P-III-P but again this is not of sufficient magnitude to affect the performance of the test. The GH-2004 project has provided further support for the marker approach as a means of detecting GH abuse in athletes. As WADA have not developed their own immunoassays, however, further work is needed to validate newer commercial assays measuring IGF-I and P-III-P to establish reliable conversion factors to the original GH-2000 units to allow the published formulae to be used. PMID:19467613

  18. Identification and characterization of HolGH15: the holin of Staphylococcus aureus bacteriophage GH15.

    PubMed

    Song, Jun; Xia, Feifei; Jiang, Haiyan; Li, Xinwei; Hu, Liyuan; Gong, Pengjuan; Lei, Liancheng; Feng, Xin; Sun, Changjiang; Gu, Jingmin; Han, Wenyu

    2016-05-01

    Holins are phage-encoded hydrophobic membrane proteins that spontaneously and non-specifically accumulate and form lesions in the cytoplasmic membrane. The ORF72 gene (also designated HolGH15) derived from the genome of the Staphylococcus aureus phage GH15 was predicted to encode a membrane protein. An analysis indicated that the protein encoded by HolGH15 potentially consisted of two hydrophobic transmembrane helices. This protein exhibited the structural characteristics of class II holins and belonged to the phage_holin_1 superfamily. Expression of HolGH15 in Escherichia coli BL21 cells resulted in growth retardation of the host cells, which was triggered prematurely by the addition of 2,4-dinitrophenol. The expression of HolGH15 caused morphological alterations in engineered E. coli cells, including loss of the cell wall and cytoplasmic membrane integrity and release of intracellular components, which were visualized by transmission electron microscopy. HolGH15 exerted efficient antibacterial activity at 37 °C and pH 5.2. Mutation analysis indicated that the two transmembrane domains of HolGH15 were indispensable for the activity of the full-length protein. HolGH15 showed a broad antibacterial range: it not only inhibited Staphylococcus aureus, but also demonstrated antibacterial activity against other species, including Listeria monocytogenes, Bacillus subtilis, Pseudomonas aeruginosa, Klebsiella pneumoniae and E. coli. At the minimal inhibitory concentration, HolGH15 evoked the release of cellular contents and resulted in the shrinkage and death of Staphylococcus aureus and Listeria monocytogenes cells. To the best of our knowledge, this study is the first report of a Staphylococcus aureus phage holin that exerts antibacterial activity against heterogeneous pathogens. PMID:26873847

  19. Sleep disturbance in children with growth hormone deficiency.

    PubMed

    Hayashi, M; Shimohira, M; Saisho, S; Shimozawa, K; Iwakawa, Y

    1992-05-01

    We examined the effects of growth hormone (GH) deficiency on sleep development by performing all-night polysomnography in three female children with GH deficiency (GHD). The percentage of REM sleep seemed to be reduced before the treatment in 2 cases, and human GH (hGH) compensation slightly increased it. Submental twitch movements (mTMs), i.e., body movements during sleep localized in the submental muscle and lasting less than 0.5 seconds, were commonly disturbed in the three patients. Rapid eye movements in REM sleep (REMs) were reduced before the therapy in one case, this decrease being reversed on hGH compensation. REMs also seemed to increase after hGH treatment in the other two cases. Dopamines and cholinergic muscarinic agonists can cause GH release, while mTMs and REMs might be related to dopaminergic and cholinergic systems in the human brain. It is intriguing that GHD, and the disturbance of mTMs and REMs coexisted in children with GHD. Since a relatively poor social outcome in patients with GHD has been reported, even after hGH compensation, it is important to monitor their neurological development by means of evaluation of their sleep disturbance. PMID:1445594

  20. Delayed Adrenarche may be an Additional Feature of Immunoglobulin Super Family Member 1 Deficiency Syndrome.

    PubMed

    Hulle, Severine Van; Craen, Margarita; Callewaert, Bert; Joustra, Sjoerd; Oostdijk, Wilma; Losekoot, Monique; Wit, Jan Maarten; Turgeon, Marc Olivier; Bernard, Daniel J; Schepper, Jean De

    2016-03-01

    Immunoglobulin super family member 1 (IGSF1) deficiency syndrome is characterized by central hypothyroidism, delayed surge in testosterone during puberty, macro-orchidism, and in some cases, hypoprolactinemia and/or transient growth hormone (GH) deficiency. Our patient was a 19-year-old male adolescent who had been treated since the age of 9 years with GH and thyroxine for an idiopathic combined GH, thyroid-stimulating hormone (TSH), and prolactin (PRL) deficiency. His GH deficiency proved to be transient, but deficiencies of TSH and PRL persisted, and he had developed macro-orchidism since the end of puberty. Brain magnetic resonance imaging and PROP1 and POU1F1 sequencing were normal. A disharmonious puberty (delayed genital and pubic hair development, bone maturation, and pubertal growth spurt, despite normal testicular growth) was observed as well as a delayed adrenarche, as reflected by very low dehydroepiandrosterone sulfate and delayed pubarche. Direct sequencing of the IGSF1 gene revealed a novel hemizygous mutation, c.3127T>C, p.Cys1043Arg. Pathogenicity of the mutation was demonstrated in vitro. Male children with an idiopathic combined GH, PRL, and TSH deficiency, showing persistent central hypothyroidism but transient GH deficiency upon retesting at adult height, should be screened for mutations in the IGSF1 gene, especially when macro-orchidism and/or hypoprolactinemia are present. We suspect that delayed adrenarche, as a consequence of PRL deficiency, might be part of the clinical phenotype of patients with IGSF1 deficiency. PMID:26757742

  1. Delayed Adrenarche may be an Additional Feature of Immunoglobulin Super Family Member 1 Deficiency Syndrome

    PubMed Central

    Hulle, Severine Van; Craen, Margarita; Callewaert, Bert; Joustra, Sjoerd; Oostdijk, Wilma; Losekoot, Monique; Wit, Jan Maarten; Turgeon, Marc Olivier; Bernard, Daniel J.; Schepper, Jean De

    2016-01-01

    Immunoglobulin super family member 1 (IGSF1) deficiency syndrome is characterized by central hypothyroidism, delayed surge in testosterone during puberty, macro-orchidism, and in some cases, hypoprolactinemia and/or transient growth hormone (GH) deficiency. Our patient was a 19-year-old male adolescent who had been treated since the age of 9 years with GH and thyroxine for an idiopathic combined GH, thyroid-stimulating hormone (TSH), and prolactin (PRL) deficiency. His GH deficiency proved to be transient, but deficiencies of TSH and PRL persisted, and he had developed macro-orchidism since the end of puberty. Brain magnetic resonance imaging and PROP1 and POU1F1 sequencing were normal. A disharmonious puberty (delayed genital and pubic hair development, bone maturation, and pubertal growth spurt, despite normal testicular growth) was observed as well as a delayed adrenarche, as reflected by very low dehydroepiandrosterone sulfate and delayed pubarche. Direct sequencing of the IGSF1 gene revealed a novel hemizygous mutation, c.3127T>C, p.Cys1043Arg. Pathogenicity of the mutation was demonstrated in vitro. Male children with an idiopathic combined GH, PRL, and TSH deficiency, showing persistent central hypothyroidism but transient GH deficiency upon retesting at adult height, should be screened for mutations in the IGSF1 gene, especially when macro-orchidism and/or hypoprolactinemia are present. We suspect that delayed adrenarche, as a consequence of PRL deficiency, might be part of the clinical phenotype of patients with IGSF1 deficiency. PMID:26757742

  2. 48 CFR Appendixes G-H to Chapter 7 - [Reserved

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 5 2011-10-01 2011-10-01 false G Appendixes G-H to Chapter 7 Federal Acquisition Regulations System AGENCY FOR INTERNATIONAL DEVELOPMENT Appendixes G-H to Chapter 7...

  3. 48 CFR Appendixes G-H to Chapter 7 - [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false G Appendixes G-H to Chapter 7 Federal Acquisition Regulations System AGENCY FOR INTERNATIONAL DEVELOPMENT Appendixes G-H to Chapter 7...

  4. 48 CFR Appendixes G-H to Chapter 7 - [Reserved

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 5 2014-10-01 2014-10-01 false G Appendixes G-H to Chapter 7 Federal Acquisition Regulations System AGENCY FOR INTERNATIONAL DEVELOPMENT Appendixes G-H to Chapter 7...

  5. 48 CFR Appendixes G-H to Chapter 7 - [Reserved

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 5 2013-10-01 2013-10-01 false G Appendixes G-H to Chapter 7 Federal Acquisition Regulations System AGENCY FOR INTERNATIONAL DEVELOPMENT Appendixes G-H to Chapter 7...

  6. 48 CFR Appendixes G-H to Chapter 7 - [Reserved

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 5 2012-10-01 2012-10-01 false G Appendixes G-H to Chapter 7 Federal Acquisition Regulations System AGENCY FOR INTERNATIONAL DEVELOPMENT Appendixes G-H to Chapter 7...

  7. Effectiveness of GH isoform differential immunoassay for detecting rhGH doping on application of various growth factors.

    PubMed

    Okano, Masato; Nishitani, Yasunori; Sato, Mitsuhiko; Kageyama, Shinji

    2012-09-01

    The analytical method for detecting growth hormone (GH) doping, the so-called GH isoform differential immunoassay, is currently approved by the World Anti-Doping Agency (WADA). Anti-doping laboratories often face challenges by athletes' lawyers and need to have various types of scientific evidence against the claim that the adverse analytical finding (AAF) result was caused by excess ectopic or abnormal excretion. In this work, a population study of Japanese athletes (255 male and 256 female) and administration studies of recombinant human GH (rhGH) in Japanese females were conducted to confirm the applicability of GH isoform differential immunoassay. The present paper describes the effectiveness of the GH isoform differential immunoassay under abnormal excretion of endogenous GH as determined by administration studies of GH releasing hormone (GHRH(1-44)) and insulin-like growth factor-1 (IGF-1). No false positive findings were found in Japanese athletes. The GH isoform differential immunoassays could detect application of rhGH for approximately 12-24 h. The administration of GHRH(1-44) and IGF-1 as well as ghrelin receptor agonists did not affect the isoform ratio (no false positives). We conclude that the GH isoform differential immunoassay is a highly specific method for detecting rhGH doping. Subject-based profiling (i.e. athlete biological passport) very likely will represent a highly sensitive approach for detecting rhGH doping. PMID:22733714

  8. Evaluation of growth hormone (GH) action in mice: discovery of GH receptor antagonists and clinical indications.

    PubMed

    Kopchick, John J; List, Edward O; Kelder, Bruce; Gosney, Elahu S; Berryman, Darlene E

    2014-04-01

    The discovery of a growth hormone receptor antagonist (GHA) was initially established via expression of mutated GH genes in transgenic mice. Following this discovery, development of the compound resulted in a drug termed pegvisomant, which has been approved for use in patients with acromegaly. Pegvisomant treatment in a dose dependent manner results in normalization of IGF-1 levels in most patients. Thus, it is a very efficacious and safe drug. Since the GH/IGF-1 axis has been implicated in the progression of several types of cancers, many have suggested the use of pegvisomant as an anti-cancer therapeutic. In this manuscript, we will review the use of mouse strains that possess elevated or depressed levels of GH action for unraveling many of GH actions. Additionally, we will describe experiments in which the GHA was discovered, review results of pegvisomant's preclinical and clinical trials, and provide data suggesting pegvisomant's therapeutic value in selected types of cancer. PMID:24035867

  9. Observational clinical study of 22 adult-onset Pompe disease patients undergoing enzyme replacement therapy over 5years.

    PubMed

    Stepien, Karolina M; Hendriksz, Christian J; Roberts, Mark; Sharma, Reena

    2016-04-01

    Pompe disease is an autosomal recessive disease resulting from deficiency of the acid alpha-glucosidase (GAA). The late-onset Pompe Disease (LOPD) patients develop muscular and respiratory complications later in life. We describe a retrospective observational cohort study including 22 patients with LOPD. The cohort was assessed at baseline before Enzyme Replacement Therapy (ERT) with alglucosidase alpha (20mg/kg biweekly) was commenced and subsequently relevant information was collected at 2, 4 and 5years later. The median age of the patients at study entry was 44years (16-64years), with median disease duration of 11.5years (4-31years). At baseline, 10 patients (45%) could walk without support, 12 (55%) could walk with unilateral or bilateral support including 3/12 were wheelchair bound. Mean predicted FVC % was 55.7 (95% CI 45-66) of predicted normal at baseline and showed no significant change after 5years (54.6 (95% CI 43-66)), (all p=0.9815). Mean FVC % supine was 41.8 (95% CI 33.8-49) of predicted normal at baseline and remained significantly unchanged at 5years (48.4 (95% CI 37-59.6)), (all p=0.8680). The overnight non-invasive ventilator dependence increased by 18.2% as compared with baseline and requirement of mobility aids increased during this period by 5.2% as compared with the baseline. Mean walking distance at 6min walk test was 411.5 (95% CI 338-485) at baseline, 266.5 (95% CI 187-346) m at 2years, 238.6 (95% CI 162-315) m at 4years and 286.8 (95% CI 203-370) m at 5years (p=0.1981; ANOVA was completed only for 14 patients). A gradual decline in FVC% predicted was noted only in four cases and a decline in FVC% supine in two other. Only one patient showed a decline in both pulmonary function tests. In all remaining cases (17/22) respiratory function remains stable. In conclusion overall pulmonary function tests and mobility remained stable for 5years in majority of patients on ERT. However, in some patients they continued to decline in spite of ERT

  10. Determinants of GH-releasing hormone and GH-releasing peptide synergy in men

    PubMed Central

    Veldhuis, Johannes D.; Bowers, Cyril Y.

    2009-01-01

    Age, sex steroids, and abdominal-visceral fat (AVF) jointly affect pulsatile growth hormone (GH) secretion. Pulsatile GH secretion in turn is controlled by GH-releasing hormone (GHRH), GH-releasing peptide (GHRP), and somatostatin. Marked stimulation of pulsatile GH secretion is achieved via GHRH-GHRP synergy. Nonetheless, how key modulators of GH secretion, such as age, sex steroids, and body mass index, modify GHRH-GHRP synergy is not known. The present strategy was to 1) infuse GHRH and GHRP-2 simultaneously to evoke synergy and 2) downregulate the gonadal axis with leuprolide and then restore placebo (Pl) or testosterone (T) to clamp the sex steroid milieu. Forty-seven men [18–74 yr of age, T = 7–1,950 ng/dl, estradiol (E2) = 5–79 pg/ml, insulin-like growth factor (IGF)-I = 115–817 μg/l, AVF = 11–349 cm2] were studied. GHRH-GHRP synergy correlated negatively with age and AVF (both P < 0.001) and positively with IGF-I (P < 0.001) and IGF-binding protein (IGFBP)-3 (P = 0.031). Unstimulated basal (nonpulsatile) GH secretion correlated positively with T (P = 0.015) and E2 (P = 0.004) concentrations. Fasting pulsatile GH secretion varied negatively with age (P = 0.017) and positively with IGF-I (P = 0.002) and IGFBP-3 (P = 0.001). By stepwise forward-selection multivariate analyses, AVF, IGF-I, and IGFBP-3 together explained 60% of the variability in GHRH-GHRP synergy (P < 0.001), E2 accounted for 17% of the variability in basal GH secretion (P = 0.007), and IGF-I explained 20% of the variability in fasting pulsatile GH secretion (P = 0.002). In conclusion, a paradigm examining GHRH-GHRP synergy under a sex steroid clamp reveals highly selective control of basal, pulsatile, and synergistic peptide-driven GH secretion by AVF, E2, and IGF-I in healthy men. PMID:19240251

  11. Carnitine palmitoyltransferase II deficiency

    PubMed Central

    Roe, C R.; Yang, B-Z; Brunengraber, H; Roe, D S.; Wallace, M; Garritson, B K.

    2008-01-01

    Background: Carnitine palmitoyltransferase II (CPT II) deficiency is an important cause of recurrent rhabdomyolysis in children and adults. Current treatment includes dietary fat restriction, with increased carbohydrate intake and exercise restriction to avoid muscle pain and rhabdomyolysis. Methods: CPT II enzyme assay, DNA mutation analysis, quantitative analysis of acylcarnitines in blood and cultured fibroblasts, urinary organic acids, the standardized 36-item Short-Form Health Status survey (SF-36) version 2, and bioelectric impedance for body fat composition. Diet treatment with triheptanoin at 30% to 35% of total daily caloric intake was used for all patients. Results: Seven patients with CPT II deficiency were studied from 7 to 61 months on the triheptanoin (anaplerotic) diet. Five had previous episodes of rhabdomyolysis requiring hospitalizations and muscle pain on exertion prior to the diet (two younger patients had not had rhabdomyolysis). While on the diet, only two patients experienced mild muscle pain with exercise. During short periods of noncompliance, two patients experienced rhabdomyolysis with exercise. None experienced rhabdomyolysis or hospitalizations while on the diet. All patients returned to normal physical activities including strenuous sports. Exercise restriction was eliminated. Previously abnormal SF-36 physical composite scores returned to normal levels that persisted for the duration of the therapy in all five symptomatic patients. Conclusions: The triheptanoin diet seems to be an effective therapy for adult-onset carnitine palmitoyltransferase II deficiency. GLOSSARY ALT = alanine aminotransferase; AST = aspartate aminotransferase; ATP = adenosine triphosphate; BHP = β-hydroxypentanoate; BKP = β-ketopentanoate; BKP-CoA = β-ketopentanoyl–coenzyme A; BUN = blood urea nitrogen; CAC = citric acid cycle; CoA = coenzyme A; CPK = creatine phosphokinase; CPT II = carnitine palmitoyltransferase II; LDL = low-density lipoprotein; MCT

  12. Natural history of adult-onset eIF2B-related disorders: a multi-centric survey of 16 cases.

    PubMed

    Labauge, Pierre; Horzinski, Laetitia; Ayrignac, Xavier; Blanc, Pierre; Vukusic, Sandra; Rodriguez, Diana; Mauguiere, Francois; Peter, Laure; Goizet, Cyril; Bouhour, Francoise; Denier, Christian; Confavreux, Christian; Obadia, Michael; Blanc, Frederic; de Sèze, Jérome; Fogli, Anne; Boespflug-Tanguy, Odile

    2009-08-01

    Mutations in one of the five eukaryotic initiation factor 2B genes (EIF2B1-5) were first described in childhood ataxia with cerebral hypomyelination--vanishing white matter syndrome. The syndrome is characterized by (i) cerebellar and pyramidal signs in children aged 2-5 years; (ii) extensive cavitating leucoencephalopathy; and (iii) episodes of rapid deterioration following stress. Since then a broad clinical spectrum from congenital to adult-onset forms has been reported, leading to the concept of eIF2B-related disorders. Our aim was to describe clinical and brain magnetic resonance imaging characteristics, genetic findings and natural history of patients with adult-onset eIF2B-related disorders (after age 16). The inclusion criteria were based on the presence of eIF2B mutations and a disease onset after the age of 16 years. One patient with an asymptomatic diagnosis (age 16 years) was also included. Clinical and magnetic resonance findings were retrospectively recorded in all patients. All patients were examined to assess clinical evolution, using functional, pyramidal, cerebellar and cognitive scales. This multi-centric study included 16 patients from 14 families. A sex ratio imbalance was noted (male/female = 3/13). The mean age of onset was 31.1 years (range 16-62). Initial symptoms were neurologic (n = 11), psychiatric (n = 2) and ovarian failure (n = 2). Onset of the symptoms was linked to a precipitating factor in 13% of cases that included minor head trauma and delivery. During follow-up (mean: 11.2 years, range 2-22 years) 12.5% of the patients died. Of the 14 survivors, 62% showed a decline in their cognitive functions, and 79% were severely handicapped or bedridden. One case remained asymptomatic. Stress worsened clinical symptoms in 38% of the patients. Magnetic resonance imaging findings consist of constant cerebral atrophy, extensive cystic leucoencephalopathy (81%), corpus callosum (69%) and cerebellar (38%) T2-weighted hyperintensities. All

  13. GH safety workshop position paper: A critical appraisal of recombinant human GH therapy in children and adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Recombinant human Growth Hormone (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that 'for approved indications, GH is safe'; however, t...

  14. [A case in which the subject was affected by Listeia meningoencephalitis during administration of infliximab for steroid-dependent adult onset Still's disease].

    PubMed

    Yamamoto, Motohisa; Takahashi, Hiroki; Miyamoto, Chie; Ohara, Mikiko; Suzuki, Chisako; Naishiro, Yasuyoshi; Yamamoto, Hiroyuki; Shinomura, Yasuhisa; Nonaka, Michio; Imai, Kohzoh

    2006-06-01

    The subject was a 22-year-old woman who developed high fever and arthralgias and eruptions in the extremities around June 2005. She sought medical advice at a nearby dermatology clinic, where hepatic dysfunction was noted on blood testing. The patient was thus hospitalized the next day. Although CRP levels were significantly high, no sign of infection was observed and bone marrow cell differentiation was normal. Adult onset Still's disease was diagnosed based on the observation of persistent high fever >39 degrees C, eruptions, increased leukocytes, pharyngeal pain, splenomegaly, hepatic dysfunction, negative autoantibody results from blood testing, and high serum ferritin levels. Administration of prednisolone 30 mg/day was initiated, but proved ineffective. Steroid pulse therapy was conducted, and the subject was transferred to our medical facility for continued treatment. Attempts were made to control the disease using combined steroid and cyclosporine administration; but exacerbation of high serum ferritin levels and hepatic dysfunctions were observed, so a second course of steroid pulse therapy was conducted. Symptoms improved temporarily, but steroid levels were difficult to reduce. Cyclosporine was therefore replaced by methotrexate, and administration of infliximab was initiated. In the course of treatment, administration of a sulfamethoxazole/trimethoprim combination was initiated, but was discontinued due to suspicion of drug-induced hepatic injury. A second administration of infliximab was conducted in late August, and rapid improvements in clinical symptoms and abnormal test values was observed. However, high fever and headache developed suddenly in early September. Based on the results of spinal fluid testing, blood and spinal fluid cultures and MRI of the head, Listeria meningoencephalitis was diagnosed. Diplopia and impaired consciousness occurred during the disease course, and formation of a brain abscess was observed on imaging. However, symptoms

  15. Regular inhaled corticosteroids in adult-onset asthma and the risk for future cancer: a population-based cohort study with proper person-time analysis

    PubMed Central

    Kok, Victor C; Horng, Jorng-Tzong; Huang, Hsu-Kai; Chao, Tsung-Ming; Hong, Ya-Fang

    2015-01-01

    Background Recent studies have shown that inhaled corticosteroids (ICS) can exert anti-inflammatory effects for chronic airway diseases, and several observational studies suggest that they play a role as cancer chemopreventive agents, particularly against lung cancer. We aimed to examine whether regular ICS use was associated with a reduced risk for future malignancy in patients with newly diagnosed adult-onset asthma. Methods We used a population-based cohort study between 2001 and 2008 with appropriate person-time analysis. Participants were followed up until the first incident of cancer, death, or to the end of 2008. The Cox model was used to derive an adjusted hazard ratio (aHR) for cancer development. Kaplan–Meier cancer-free survival curves of two groups were compared. Results The exposed group of 2,117 regular ICS users and the nonexposed group of 17,732 non-ICS users were assembled. After 7,365 (mean, 3.5 years; standard deviation 2.1) and 73,789 (mean, 4.1 years; standard deviation 2.4) person-years of follow-up for the ICS users and the comparator group of non-ICS users, respectively, the aHR for overall cancer was nonsignificantly elevated at 1.33 with 95% confidence interval (CI), 1.00–1.76, P=0.0501. The Kaplan–Meier curves for overall cancer-free proportions of both groups were not significant (log-rank, P=0.065). Synergistic interaction of concurrent presence of regular ICS use was conducted using “ICS-negative and chronic obstructive pulmonary disease (COPD)-negative” as the reference. The aHR for the group of “ICS-positive, COPD-negative” did not reach statistically significant levels with aHR at 1.38 (95% CI, 0.53–3.56). There was a statistically significant synergistic interaction of concurrent presence of regular ICS use and COPD with aHR at 3.78 (95% CI, 2.10–6.81). Conclusion The protective effect of regular ICS use in the studied East Asian patients with adult-onset asthma was not detectable, contrary to reports of previous

  16. GH and Pituitary Hormone Alterations After Traumatic Brain Injury.

    PubMed

    Karaca, Züleyha; Tanrıverdi, Fatih; Ünlühızarcı, Kürşad; Kelestimur, Fahrettin

    2016-01-01

    Traumatic brain injury (TBI) is a crucially important public health problem around the world, which gives rise to increased mortality and is the leading cause of physical and psychological disability in young adults, in particular. Pituitary dysfunction due to TBI was first described 95years ago. However, until recently, only a few papers have been published in the literature and for this reason, TBI-induced hypopituitarism has been neglected for a long time. Recent studies have revealed that TBI is one of the leading causes of hypopituitarism. TBI which causes hypopituitarism may be characterized by a single head injury such as from a traffic accident or by chronic repetitive head trauma as seen in combative sports including boxing, kickboxing, and football. Vascular damage, hypoxic insult, direct trauma, genetic predisposition, autoimmunity, and neuroinflammatory changes may have a role in the development of hypopituitarism after TBI. Because of the exceptional structure of the hypothalamo-pituitary vasculature and the special anatomic location of anterior pituitary cells, GH is the most commonly lost hormone after TBI, and the frequency of isolated GHD is considerably high. TBI-induced pituitary dysfunction remains undiagnosed and therefore untreated in most patients because of the nonspecific and subtle clinical manifestations of hypopituitarism. Treatment of TBI-induced hypopituitarism depends on the deficient anterior pituitary hormones. GH replacement therapy has some beneficial effects on metabolic parameters and neurocognitive dysfunction. Patients with TBI without neuroendocrine changes and those with TBI-induced hypopituitarism share the same clinical manifestations, such as attention deficits, impulsion impairment, depression, sleep abnormalities, and cognitive disorders. For this reason, TBI-induced hypopituitarism may be neglected in TBI victims and it would be expected that underlying hypopituitarism would aggravate the clinical picture of TBI itself

  17. Sequence polymorphisms at the growth hormone GH1/GH2-N and GH2-Z gene copies and their relationship with dairy traits in domestic sheep (Ovis aries).

    PubMed

    Vacca, G M; Dettori, M L; Balia, F; Luridiana, S; Mura, M C; Carcangiu, V; Pazzola, M

    2013-09-01

    The purpose was to analyze the growth hormone GH1/GH2-N and GH2-Z gene copies and to assess their possible association with milk traits in Sarda sheep. Two hundred multiparous lactating ewes were monitored. The two gene copies were amplified separately and each was used as template for a nested PCR, to investigate single strand conformation polymorphism (SSCP) of the 5'UTR, exon-1, exon-5 and 3'UTR DNA regions. SSCP analysis revealed marked differences in the number of polymorphic patterns between the two genes. Sequencing revealed five nucleotide changes at the GH1/GH2-N gene. Five nucleotide changes occurred at the GH2-Z gene: one was located in exon-5 (c.556G > A) and resulted in a putative amino acid substitution G186S. All the nucleotide changes were copy-specific, except c.*30delT, which was common to both GH1/GH2-N and GH2-Z. Variability in the promoter regions of each gene might have consequences on the expression level, due to the involvement in potential transcription factor binding sites. Both gene copies influenced milk yield. A correlation with milk protein and casein content was also evidenced. These results may have implications that make them useful for future breeding strategies in dairy sheep breeding. PMID:23653010

  18. A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)

    SciTech Connect

    Giorgio, E.; Robyr, D.; Spielmann, M.; Ferrero, E.; Di Gregorio, E.; Imperiale, D.; Vaula, G.; Stamoulis, G.; Santoni, F.; Atzori, C.; Gasparini, L.; Ferrera, D.; Canale, C.; Guipponi, M.; Pennacchio, L. A.; Antonarakis, S. E.; Brussino, A.; Brusco, A.

    2015-02-20

    Chromosomal rearrangements with duplication of the lamin B1 (LMNB1) gene underlie autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), a rare neurological disorder in which overexpression of LMNB1 causes progressive central nervous system demyelination. However, we previously reported an ADLD family (ADLD-1-TO) without evidence of duplication or other mutation in LMNB1 despite linkage to the LMNB1 locus and lamin B1 overexpression. By custom array-CGH, we further investigated this family and report here that patients carry a large (~660 kb) heterozygous deletion that begins 66 kb upstream of the LMNB1 promoter. Lamin B1 overexpression was confirmed in further ADLD-1-TO tissues and in a postmortem brain sample, where lamin B1 was increased in the frontal lobe. Through parallel studies, we investigated both loss of genetic material and chromosomal rearrangement as possible causes of LMNB1 overexpression, and found that ADLD-1-TO plausibly results from an enhancer adoption mechanism. The deletion eliminates a genome topological domain boundary, allowing normally forbidden interactions between at least three forebrain-directed enhancers and the LMNB1 promoter, in line with the observed mainly cerebral localization of lamin B1 overexpression and myelin degeneration. Finally, this second route to LMNB1 overexpression and ADLD is a new example of the relevance of regulatory landscape modifications in determining Mendelian phenotypes.

  19. A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)

    DOE PAGESBeta

    Giorgio, E.; Robyr, D.; Spielmann, M.; Ferrero, E.; Di Gregorio, E.; Imperiale, D.; Vaula, G.; Stamoulis, G.; Santoni, F.; Atzori, C.; et al

    2015-02-20

    Chromosomal rearrangements with duplication of the lamin B1 (LMNB1) gene underlie autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), a rare neurological disorder in which overexpression of LMNB1 causes progressive central nervous system demyelination. However, we previously reported an ADLD family (ADLD-1-TO) without evidence of duplication or other mutation in LMNB1 despite linkage to the LMNB1 locus and lamin B1 overexpression. By custom array-CGH, we further investigated this family and report here that patients carry a large (~660 kb) heterozygous deletion that begins 66 kb upstream of the LMNB1 promoter. Lamin B1 overexpression was confirmed in further ADLD-1-TO tissues and in amore » postmortem brain sample, where lamin B1 was increased in the frontal lobe. Through parallel studies, we investigated both loss of genetic material and chromosomal rearrangement as possible causes of LMNB1 overexpression, and found that ADLD-1-TO plausibly results from an enhancer adoption mechanism. The deletion eliminates a genome topological domain boundary, allowing normally forbidden interactions between at least three forebrain-directed enhancers and the LMNB1 promoter, in line with the observed mainly cerebral localization of lamin B1 overexpression and myelin degeneration. Finally, this second route to LMNB1 overexpression and ADLD is a new example of the relevance of regulatory landscape modifications in determining Mendelian phenotypes.« less

  20. ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43.

    PubMed

    Arnold, Eveline S; Ling, Shuo-Chien; Huelga, Stephanie C; Lagier-Tourenne, Clotilde; Polymenidou, Magdalini; Ditsworth, Dara; Kordasiewicz, Holly B; McAlonis-Downes, Melissa; Platoshyn, Oleksandr; Parone, Philippe A; Da Cruz, Sandrine; Clutario, Kevin M; Swing, Debbie; Tessarollo, Lino; Marsala, Martin; Shaw, Christopher E; Yeo, Gene W; Cleveland, Don W

    2013-02-19

    Transactivating response region DNA binding protein (TDP-43) is the major protein component of ubiquitinated inclusions found in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions. Two ALS-causing mutants (TDP-43(Q331K) and TDP-43(M337V)), but not wild-type human TDP-43, are shown here to provoke age-dependent, mutant-dependent, progressive motor axon degeneration and motor neuron death when expressed in mice at levels and in a cell type-selective pattern similar to endogenous TDP-43. Mutant TDP-43-dependent degeneration of lower motor neurons occurs without: (i) loss of TDP-43 from the corresponding nuclei, (ii) accumulation of TDP-43 aggregates, and (iii) accumulation of insoluble TDP-43. Computational analysis using splicing-sensitive microarrays demonstrates alterations of endogenous TDP-43-dependent alternative splicing events conferred by both human wild-type and mutant TDP-43(Q331K), but with high levels of mutant TDP-43 preferentially enhancing exon exclusion of some target pre-mRNAs affecting genes involved in neurological transmission and function. Comparison with splicing alterations following TDP-43 depletion demonstrates that TDP-43(Q331K) enhances normal TDP-43 splicing function for some RNA targets but loss-of-function for others. Thus, adult-onset motor neuron disease does not require aggregation or loss of nuclear TDP-43, with ALS-linked mutants producing loss and gain of splicing function of selected RNA targets at an early disease stage. PMID:23382207

  1. An autopsied case of adult-onset bulbospinalform Alexander disease with a novel S393R mutation in the GFAP gene.

    PubMed

    Iwasaki, Yasushi; Saito, Yufuko; Mori, Keiko; Ito, Masumi; Mimuro, Maya; Aiba, Ikuko; Saito, Kozo; Mizuta, Ikuko; Yoshida, Tomokatsu; Nakagawa, Masanori; Yoshida, Mari

    2015-01-01

    A 50-year-old Japanese man with no apparent family history noticed diplopia. He gradually showed gait disturbance and dysuria. Abducens disorder of eye movement with nystagmus, tongue atrophy with fasciculation, spastic tetraparesis, and sensory disturbance were also observed. MRI showed severe atrophy of the medulla oblongata to the cervical cord ("tadpole appearance"). Tracheotomy and gastrostomy were performed 7 years after onset due to the development of bulbar palsy. Death occurred following respiratory failure after 11 years total disease duration. The brain weighed 1,380 g. The cerebrum, cerebellum, midbrain, and upper pons were preserved from atrophy, but the medulla oblongata to the cervical cord showed severe atrophy. A few Rosenthal fibers were observed in the cerebral white matter, basal ganglia, and cerebellum, whereas numerous Rosenthal fibers were observed in the medulla oblongata to the cervical cord. Myelin loss with relatively preserved axons was extensively observed from the middle of the pons to the spinal cord. The clinicopathological diagnosis was adult-onset bulbospinal-form Alexander disease. Glial fibrillary acidic protein (GFAP) gene analysis revealed a novel mutation of S393R. Expression patterns of S393R mutant GFAP using adrenal carcinoma-derived cells (SW13 cells) showed a decreased number of filamentous structures and abnormal aggregates. PMID:25828773

  2. Prader-Willi Syndrome and Growth Hormone Deficiency

    PubMed Central

    Aycan, Zehra; Baş, Veysel Nijat

    2014-01-01

    Prader-Willi syndrome (PWS) is a rare multisystem genetic disorder demonstrating great variability with changing clinical features during patient’s life. It is characterized by severe hypotonia with poor sucking and feeding difficulties in early infancy, followed by excessive eating and gradual development of morbid obesity in later infancy or early childhood. The phenotype is most probably due to hypothalamic dysfunction which is also responsible for growth hormone (GH) and thyroid-stimulating hormone (TSH) deficiencies, central adrenal insufficiency and hypogonadism. The multidimensional problems of patients with PWS can be managed with multidisciplinary approach. Reduced GH secretion, low peak GH response to stimulation, decreased spontaneous GH secretion and low serum IGF-1 levels in PWS patients have been documented in many studies. GH therapy has multiple beneficial effects on growth and body composition, motor and mental development in PWS patients. The recommended dosage for GH is 0.5-1 mg/m2/day. GH therapy should not be started in the presence of obstructive sleep apnea syndrome, adenotonsillar hypertrophy, severe obesity and diabetes mellitus. GH treatment should be considered for patients with genetically confirmed PWS in conjunction with dietary, environmental and life-style measures. PMID:24932597

  3. GH11 xylanases: Structure/function/properties relationships and applications.

    PubMed

    Paës, Gabriel; Berrin, Jean-Guy; Beaugrand, Johnny

    2012-01-01

    For technical, environmental and economical reasons, industrial demands for process-fitted enzymes have evolved drastically in the last decade. Therefore, continuous efforts are made in order to get insights into enzyme structure/function relationships to create improved biocatalysts. Xylanases are hemicellulolytic enzymes, which are responsible for the degradation of the heteroxylans constituting the lignocellulosic plant cell wall. Due to their variety, xylanases have been classified in glycoside hydrolase families GH5, GH8, GH10, GH11, GH30 and GH43 in the CAZy database. In this review, we focus on GH11 family, which is one of the best characterized GH families with bacterial and fungal members considered as true xylanases compared to the other families because of their high substrate specificity. Based on an exhaustive analysis of the sequences and 3D structures available so far, in relation with biochemical properties, we assess biochemical aspects of GH11 xylanases: structure, catalytic machinery, focus on their "thumb" loop of major importance in catalytic efficiency and substrate selectivity, inhibition, stability to pH and temperature. GH11 xylanases have for a long time been used as biotechnological tools in various industrial applications and represent in addition promising candidates for future other uses. PMID:22067746

  4. Growth hormone treatment in non-growth hormone-deficient children.

    PubMed

    Loche, Sandro; Carta, Luisanna; Ibba, Anastasia; Guzzetti, Chiara

    2014-03-01

    Until 1985 growth hormone (GH) was obtained from pituitary extracts, and was available in limited amounts only to treat severe growth hormone deficiency (GHD). With the availability of unlimited quantities of GH obtained from recombinant DNA technology, researchers started to explore new modalities to treat GHD children, as well as to treat a number of other non-GHD conditions. Although with some differences between different countries, GH treatment is indicated in children with Turner syndrome, chronic renal insufficiency, Prader-Willi syndrome, deletions/mutations of the SHOX gene, as well as in short children born small for gestational age and with idiopathic short stature. Available data from controlled trials indicate that GH treatment increases adult height in patients with Turner syndrome, in patients with chronic renal insufficiency, and in short children born small for gestational age. Patients with SHOX deficiency seem to respond to treatment similarly to Turner syndrome. GH treatment in children with idiopathic short stature produces a modest mean increase in adult height but the response in the individual patient is unpredictable. Uncontrolled studies indicate that GH treatment may be beneficial also in children with Noonan syndrome. In patients with Prader-Willi syndrome GH treatment normalizes growth and improves body composition and cognitive function. In any indication the response to GH seems correlated to the dose and the duration of treatment. GH treatment is generally safe with no major adverse effects being recorded in any condition. PMID:24926456

  5. Comparative analysis of three hyperthermophilic GH1 and GH3 family members with industrial potential.

    PubMed

    Cota, Junio; Corrêa, Thamy L R; Damásio, André R L; Diogo, José A; Hoffmam, Zaira B; Garcia, Wanius; Oliveira, Leandro C; Prade, Rolf A; Squina, Fabio M

    2015-01-25

    Beta-glucosidases (BGLs) are enzymes of great potential for several industrial processes, since they catalyze the cleavage of glucosidic bonds in cellobiose and other short cellooligosaccharides. However, features such as good stability to temperature, pH, ions and chemicals are required characteristics for industrial applications. This work aimed to provide a comparative biochemical analysis of three thermostable BGLs from Pyrococcus furiosus and Thermotoga petrophila. The genes PfBgl1 (GH1 from P. furiosus), TpBgl1 (GH1 from T. petrophila) and TpBgl3 (GH3 from T. petrophila) were cloned and proteins were expressed in Escherichia coli. The purified enzymes are hyperthermophilic, showing highest activity at temperatures above 80°C at acidic (TpBgl3 and PfBgl1) and neutral (TpBgl1) pHs. The BGLs showed greatest stability to temperature mainly at pH 6.0. Activities using a set of different substrates suggested that TpBgl3 (GH3) is more specific than GH1 family members. In addition, the influence of six monosaccharides on BGL catalysis was assayed. While PfBgl1 and TpBgl3 seemed to be weakly inhibited by monosaccharides, TpBgl1 was activated, with xylose showing the strongest activation. Under the conditions tested, TpBgl1 showed the highest inhibition constant (Ki=1100.00mM) when compared with several BGLs previously characterized. The BGLs studied have potential for industrial use, specifically the enzymes belonging to the GH1 family, due to its broad substrate specificity and weak inhibition by glucose and other saccharides. PMID:25102284

  6. Adult Growth Hormone Deficiency – Benefits, Side Effects, and Risks of Growth Hormone Replacement

    PubMed Central

    Reed, Mary L.; Merriam, George R.; Kargi, Atil Y.

    2013-01-01

    Deficiency of growth hormone (GH) in adults results in a syndrome characterized by decreased muscle mass and exercise capacity, increased visceral fat, impaired quality of life, unfavorable alterations in lipid profile and markers of cardiovascular risk, decrease in bone mass and integrity, and increased mortality. When dosed appropriately, GH replacement therapy (GHRT) is well tolerated, with a low incidence of side effects, and improves most of the alterations observed in GH deficiency (GHD); beneficial effects on mortality, cardiovascular events, and fracture rates, however, remain to be conclusively demonstrated. The potential of GH to act as a mitogen has resulted in concern over the possibility of increased de novo tumors or recurrence of pre-existing malignancies in individuals treated with GH. Though studies of adults who received GHRT in childhood have produced conflicting reports in this regard, long-term surveillance of adult GHRT has not demonstrated increased cancer risk or mortality. PMID:23761782

  7. Localization of a locus (GLC1B) for adult-onset primary open angle glaucoma to the 2cen-q13 region

    SciTech Connect

    Stoilova, D.; Trifan, O.C.; Sarfarazi, M.

    1996-08-15

    Primary open angle glaucoma (GLC1) is a common ocular disorder with a characteristic degeneration of the optic nerve and visual field defects that is often associated with an elevated intraocular pressure. The severe but rare juvenile-onset type has previously been mapped to 1q21-q31, and its genetic heterogeneity has been established. Herein, we present a new locus (GLC1B) for one form of GLC1 on chromosome 2cen-q13 with a clinical presentation of low to moderate intraocular pressure, onset in late 40s, and a good response to medical treatment. Two-point and haplotype analyses of affected and unaffected meioses in six families provided maximum linkage information with D2S417, GATA112EO3, D2S113, D2S373, and D2S274 (lod scores ranging from 3.11 to 6.48) within a region of 8.5 cM that is flanked by D2S2161 and D2S2264. Analysis of affected meioses alone revealed no recombination with an additional two markers (D2S2264 and D2S135) in a region of 11.2 cM that is flanked by D2S2161 and D2S176. Analysis of unaffected meioses identified only one healthy 86-year-old male who has inherited the entire affected haplotype and, hence, is a gene carrier for this condition. Eight additional families with similar and/or different clinical presentation did not show any linkage to this region and, therefore, provided evidence for genetic heterogeneity of adult-onset primary open angle glaucoma. 63 refs., 2 figs., 2 tabs.

  8. Functional and Structural Analyses of CYP1B1 Variants Linked to Congenital and Adult-Onset Glaucoma to Investigate the Molecular Basis of These Diseases.

    PubMed

    Banerjee, Antara; Chakraborty, Subhadip; Chakraborty, Abhijit; Chakrabarti, Saikat; Ray, Kunal

    2016-01-01

    Glaucoma, the leading cause of irreversible blindness, appears in various forms. Mutations in CYP1B1 result in primary congenital glaucoma (PCG) by an autosomal recessive mode of inheritance while it acts as a modifier locus for primary open angle glaucoma (POAG). We investigated the molecular basis of the variable phenotypes resulting from the defects in CYP1B1 by using subclones of 23 CYP1B1 mutants reported in glaucoma patients, in a cell based system by measuring the dual activity of the enzyme to metabolize both retinol and 17β-estradiol. Most variants linked to POAG showed low steroid metabolism while null or very high retinol metabolism was observed in variants identified in PCG. We examined the translational turnover rates of mutant proteins after the addition of cycloheximide and observed that the levels of enzyme activity mostly corroborated the translational turnover rate. We performed extensive normal mode analysis and molecular-dynamics-simulations-based structural analyses and observed significant variation of fluctuation in certain segmental parts of the mutant proteins, especially at the B-C and F-G loops, which were previously shown to affect the dynamic behavior and ligand entry/exit properties of the cytochrome P450 family of proteins. Our molecular study corroborates the structural analysis, and suggests that the pathologic state of the carrier of CYP1B1 mutations is determined by the allelic state of the gene. To our knowledge, this is the first attempt to dissect biological activities of CYP1B1 for correlation with congenital and adult onset glaucomas. PMID:27243976

  9. TLR4 Endogenous Ligand S100A8/A9 Levels in Adult-Onset Still’s Disease and Their Association with Disease Activity and Clinical Manifestations

    PubMed Central

    Kim, Hyoun-Ah; Han, Jae Ho; Kim, Woo-Jung; Noh, Hyun Jin; An, Jeong-Mi; Yim, Hyunee; Jung, Ju-Yang; Kim, You-Sun; Suh, Chang-Hee

    2016-01-01

    S100A8/A9 has been suggested as a marker of disease activity in patients with adult-onset Still’s disease (AOSD). We evaluated the clinical significance of S100A8/A9 as a biomarker and its pathogenic role in AOSD. Blood samples were collected prospectively from 20 AOSD patients and 20 healthy controls (HCs). Furthermore, skin and lymph node biopsy specimens of AOSD patients were investigated for S100A8/A9 expression levels via immunohistochemistry. Peripheral blood mononuclear cells (PBMCs) of active AOSD patients and HCs were investigated for S100A8/A9 cell signals. S100A8/A9, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) levels in active AOSD patients were higher than those of HCs. S100A8/A9 levels correlated positively with IL-1β, TNF-α and C-reactive protein. The inflammatory cells expressing S100A8/A9 were graded from one to three in skin and lymph node biopsies of AOSD patients. The grading for S100A8/A9 was more intense in the skin lesions with karyorrhexis, mucin deposition, and neutrophil infiltration. Like lipopolysaccharide (LPS), S100A8/A9 induced phosphorylation of p38 and c-Jun amino-terminal kinase (JNK) in PBMCs, suggesting that S100A8/A9 activates Toll-like receptor 4 signaling pathways. These findings suggest that S100A8/A9 may be involved in the inflammatory response with induction of proinflammatory cytokines and may serve as a clinicopathological marker for disease activity in AOSD. PMID:27537874

  10. Adult-Onset Deletion of β-Catenin in (10kb)Dmp1-Expressing Cells Prevents Intermittent PTH-Induced Bone Gain.

    PubMed

    Kedlaya, Rajendra; Kang, Kyung Shin; Hong, Jung Min; Bettagere, Vidya; Lim, Kyung-Eun; Horan, Daniel; Divieti-Pajevic, Paola; Robling, Alexander G

    2016-08-01

    β-Catenin (βcat) is a major downstream signaling node in canonical Wingless-related integration site (Wnt) signaling pathway, and its activity is crucial for canonical Wnt signal transduction. Wnt signaling has recently been implicated in the osteo-anabolic response to PTH, a potent calcium-regulating factor. We investigated whether βcat is essential for the anabolic action of intermittent PTH by generating male mice with adult-onset deletion of βcat in a subpopulation of bone cells (osteocytes and late-stage osteoblasts), treating them with an anabolic regimen of PTH, and measuring the skeletal responses. Male (10kb)Dmp1-CreERt2 transgenic mice that also harbored floxed loss-of-function βcat alleles (βcat(f/f)) were induced for Cre activity using tamoxifen, then injected daily with human PTH 1-34 (30 μg/kg) or vehicle for 5 weeks. Mice in which βcat was deleted showed either total lack of bone mineral density (BMD) gain, or BMD loss, and did not respond to PTH treatment. However, bone mass measurements in the trabecular compartment of the femur and spine revealed PTH-induced bone gain whether βcat was deleted or not. PTH-stimulated increases in periosteal and cancellous bone formation rates were not impaired by βcat deletion, but resorption markers and cortical porosity were significantly increased in induced mice, particularly induced mice treated with PTH. These results suggest that βcat is required for net-positive BMD effects of PTH therapy but that the anabolic effects per se of PTH treatment might not require osteocytic/osteoblastic βcat. PMID:27253995

  11. Elevated high-mobility group B1 levels in active adult-onset Still's disease associated with systemic score and skin rash.

    PubMed

    Jung, Ju-Yang; Suh, Chang-Hee; Sohn, Seonghyang; Nam, Jin-Young; Kim, Hyoun-Ah

    2016-08-01

    High-mobility group box-1 (HMGB1) is a nuclear protein, and such prototypical damage-associated molecular patterns mediate the immune response in the noninfectious inflammatory response. Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder involved in the dysregulation of innate immunity. We investigated the serum HMGB1 level in patients with AOSD and evaluated its clinical significance. Blood samples were collected from 40 patients with active AOSD and 40 healthy controls (HC). Of the patients with AOSD, follow-up samples were collected from 16 patients after a resolution of AOSD disease activity. Serum HMGB1 levels in patients with AOSD were higher than those of the HC (10.0 ± 5.85 vs. 5.15 ± 1.79 ng/mL, p < 0.001). Serum HMGB1 levels were found to be correlated with C-reactive protein (CRP) and the systemic score. The AOSD patient who had a sore throat showed a higher serum HMGB1 level than those patients who did not, and the patient with a skin rash had higher levels than the patients without. In addition, the serum HMGB1 levels were decreased after the resolution of disease activity in the AOSD patients who were followed up. The serum HMGB1 levels were elevated in AOSD patients compared to the HC and were correlated with both CRP and the systemic score. The HMGB1 levels were associated with skin rash and a sore throat in AOSD patients. After the resolution of disease activity, serum HMGB1 levels were found to have decreased. PMID:27225247

  12. Functional and Structural Analyses of CYP1B1 Variants Linked to Congenital and Adult-Onset Glaucoma to Investigate the Molecular Basis of These Diseases

    PubMed Central

    Chakrabarti, Saikat; Ray, Kunal

    2016-01-01

    Glaucoma, the leading cause of irreversible blindness, appears in various forms. Mutations in CYP1B1 result in primary congenital glaucoma (PCG) by an autosomal recessive mode of inheritance while it acts as a modifier locus for primary open angle glaucoma (POAG). We investigated the molecular basis of the variable phenotypes resulting from the defects in CYP1B1 by using subclones of 23 CYP1B1 mutants reported in glaucoma patients, in a cell based system by measuring the dual activity of the enzyme to metabolize both retinol and 17β-estradiol. Most variants linked to POAG showed low steroid metabolism while null or very high retinol metabolism was observed in variants identified in PCG. We examined the translational turnover rates of mutant proteins after the addition of cycloheximide and observed that the levels of enzyme activity mostly corroborated the translational turnover rate. We performed extensive normal mode analysis and molecular-dynamics-simulations-based structural analyses and observed significant variation of fluctuation in certain segmental parts of the mutant proteins, especially at the B-C and F-G loops, which were previously shown to affect the dynamic behavior and ligand entry/exit properties of the cytochrome P450 family of proteins. Our molecular study corroborates the structural analysis, and suggests that the pathologic state of the carrier of CYP1B1 mutations is determined by the allelic state of the gene. To our knowledge, this is the first attempt to dissect biological activities of CYP1B1 for correlation with congenital and adult onset glaucomas. PMID:27243976

  13. Impaired IGF1-GH axis and new therapeutic options in Alström Syndrome patients: a case series

    PubMed Central

    2009-01-01

    Background Defects of the primary cilium and its anchoring structure, the basal body, cause a number of human genetic disorders, collectively termed ciliopathies: primary ciliary dyskinesia, Bardet-Biedl syndrome, polycystic kidney and liver disease, nephronophthisis, Alström syndrome, Meckel-Gruber syndrome and some forms of retinal degeneration. Alström syndrome is an extremely rare, autosomal recessive genetic disorder characterized by a group of signs and symptoms including infantile onset dilated cardiomyopathy, blindness, hearing impairment/loss, obesity, diabetes, hepatic and renal dysfunction. Because adult growth hormone deficiency and Alström Syndrome share some clinical and metabolic features, we studied the GH-IGF1 axis, using MRI techniques and dynamic tests in 3 unrelated patients with Alström syndrome. Case presentation The patients were hospitalized and the growth hormone stimulatory tests were made, as well as brain MRI. Insulin provocative test revealed a severe GH deficiency in these patients, defined by a peak response to insulin-induced hypoglycemia less than 3 ng/dl and IGF1 concentrations less than – 2SDS. We didn't find multiple pituitary hormone deficiency and we noticed only a severe GH deficiency in all three patients. The MRI study of the diencephalic and pituitary region was suggestive for the diagnosis of empty sella in one patient. One patient received Recombinant-GH replacement for one year with very good results, one underwent a gastric sleeve with a satisfactory outcome, one patient died due to the progression of the cardiac myopathy. Conclusion Future studies are needed to assses if the substitution therapy with Recombinant Growth hormone is cost-effective and without risk in such patients with Alström Syndrome and severe insulin resistance, despite our good results in one patient. Also, careful clinical and genetic studies can contribute to a better understanding of the evolution after different therapeutical attempt in

  14. Recurrent encephalopathy: NAGS (N-acetylglutamate synthase) deficiency in adults.

    PubMed

    Cartagena, A; Prasad, A N; Rupar, C A; Strong, M; Tuchman, M; Ah Mew, N; Prasad, C

    2013-01-01

    N-acetyl-glutamate synthase (NAGS) deficiency is a rare autosomal recessive urea cycle disorder (UCD) that uncommonly presents in adulthood. Adult presentations of UCDs include; confusional episodes, neuropsychiatric symptoms and encephalopathy. To date, there have been no detailed neurological descriptions of an adult onset presentation of NAGS deficiency. In this review we examine the clinical presentation and management of UCDs with an emphasis on NAGS deficiency. An illustrative case is provided. Plasma ammonia levels should be measured in all adult patients with unexplained encephalopathy, as treatment can be potentially life-saving. Availability of N-carbamylglutamate (NCG; carglumic acid) has made protein restriction largely unnecessary in treatment regimens currently employed. Genetic counselling remains an essential component of management of NAGS. PMID:23250120

  15. Recurrent Encephalopathy: NAGS (N-acetylglutamate synthase) Deficiency in Adults

    PubMed Central

    Cartagena, A; Prasad, AN; Rupar, CA; Strong, M; Tuchman, M; Ah Mew, N; Prasad, C.

    2014-01-01

    Urea cycle disorders (UCDs) are a group of uncommon heterogeneous conditions that are often detected in childhood and only rarely in adults where the presentations are subtle or non specific with symptoms of confusion and encephalopathy. N-acetyl-glutamate synthase (NAGS) deficiency is a rare urea cycle disorder that uncommonly presents in adulthood. To date there has been no detailed neurological description of an adult onset presentation of NAGS deficiency. In this review we examine the clinical presentation and management of UCDs with an emphasis on NAGS deficiency. An illustrative case is provided. Plasma ammonia levels should be measured in all patients with unexplained encephalopathy as treatment can be life-saving. Management of this rare disorder includes protein restriction and adjunct pharmacologic treatment to reduce plasma ammonia levels. Genetic counselling remains an essential component of management of UCDs. PMID:23250120

  16. Phenotypic characterization of a Csf1r haploinsufficient mouse model of adult-onset leukodystrophy with axonal spheroids and pigmented glia (ALSP).

    PubMed

    Chitu, Violeta; Gokhan, Solen; Gulinello, Maria; Branch, Craig A; Patil, Madhuvati; Basu, Ranu; Stoddart, Corrina; Mehler, Mark F; Stanley, E Richard

    2015-02-01

    Mutations in the colony stimulating factor-1 receptor (CSF1R) that abrogate the expression of the affected allele or lead to the expression of mutant receptor chains devoid of kinase activity have been identified in both familial and sporadic cases of ALSP. To determine the validity of the Csf1r heterozygous mouse as a model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) we performed behavioral, radiologic, histopathologic, ultrastructural and cytokine expression studies of young and old Csf1r+/- and control Csf1r+/+ mice. Six to 8-month old Csf1r+/- mice exhibit cognitive deficits, and by 9-11 months develop sensorimotor deficits and in male mice, depression and anxiety-like behavior. MRIs of one year-old Csf1r+/- mice reveal lateral ventricle enlargement and thinning of the corpus callosum. Ultrastructural analysis of the corpus callosum uncovers dysmyelinated axons as well as neurodegeneration, evidenced by the presence of axonal spheroids. Histopathological examination of 11-week-old mice reveals increased axonal and myelin staining in the cortex, increase of neuronal cell density in layer V and increase of microglial cell densities throughout the brain, suggesting that early developmental changes contribute to disease. By 10-months of age, the neuronal cell density normalizes, oligodendrocyte precursor cells increase in layers II-III and V and microglial densities remain elevated without an increase in astrocytes. Also, the age-dependent increase in CSF-1R+ neurons in cortical layer V is reduced. Moreover, the expression of Csf2, Csf3, Il27 and Il6 family cytokines is increased, consistent with microglia-mediated inflammation. These results demonstrate that the inactivation of one Csf1r allele is sufficient to cause an ALSP-like disease in mice. The Csf1r+/- mouse is a model of ALSP that will allow the critical events for disease development to be determined and permit rapid evaluation of therapeutic approaches. Furthermore

  17. Phenotypic characterization of a Csf1r haploinsufficient mouse model of adult-onset leukodystrophy with axonal spheroids and pigmented glia (ALSP)

    PubMed Central

    Chitu, Violeta; Gokhan, Solen; Gulinello, Maria; Branch, Craig A.; Patil, Madhuvati; Basu, Ranu; Stoddart, Corrina; Mehler, Mark F.; Stanley, E. Richard

    2014-01-01

    Mutations in the colony stimulating factor-1 receptor (CSF1R) that abrogate the expression of the affected allele or lead to the expression of mutant receptor chains devoid of kinase activity have been identified in both familial and sporadic cases of ALSP. To determine the validity of the Csf1r heterozygous mouse as a model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) we performed behavioral, radiologic, histopathologic, ultrastructural and cytokine expression studies of young and old Csf1r+/− and control Csf1r+/+ mice. Six to 8-month old Csf1r+/− mice exhibit cognitive deficits, and by 9-11 months develop sensorimotor deficits and in male mice, depression and anxiety-like behavior. MRIs of one year-old Csf1r+/− mice reveal lateral ventricle enlargement and thinning of the corpus callosum. Ultrastructural analysis of the corpus callosum uncovers dysmyelinated axons as well as neurodegeneration, evidenced by the presence of axonal spheroids. Histopathological examination of 11-week-old mice reveals increased axonal and myelin staining in the cortex, increase of neuronal cell density in layer V and increase of microglial cell densities throughout the brain, suggesting that early developmental changes contribute to disease. By 10-months of age, the neuronal cell density normalizes, oligodendrocyte precursor cells increase in layers II-III and V and microglial densities remain elevated without an increase in astrocytes. Also, the age-dependent increase in CSF-1R+ neurons in cortical layer V is reduced. Moreover, the expression of Csf2, Csf3, Il27 and Il6 family cytokines is increased, consistent with microglia-mediated inflammation. These results demonstrate that the inactivation of one Csf1r allele is sufficient to cause an ALSP-like disease in mice. The Csf1r+/− mouse is a model of ALSP that will allow the critical events for disease development to be determined and permit rapid evaluation of therapeutic approaches

  18. Adult-onset cerebello-brainstem dominant form of X-linked adrenoleukodystrophy presenting as multiple system atrophy: case report and literature review.

    PubMed

    Ogaki, Kotaro; Koga, Shunsuke; Aoki, Naoya; Lin, Wenlang; Suzuki, Kinuko; Ross, Owen A; Dickson, Dennis W

    2016-02-01

    X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder and is caused by ABCD1 mutations. A cerebello-brainstem dominant form that mainly involves the cerebellum and brainstem is summarized in a review of the literature, with autopsy-confirmed cases exceedingly rare. We report a 69-year-old White man who was diagnosed with this rare disorder and describe neuropathologic, ultrastructural and genetic analyses. He did not have adrenal insufficiency or a family history of X-ALD or Addison's disease. His initial symptom was temporary loss of eyesight at age 34 years. His major symptoms were chronic and progressive gait disorder, weakness in his lower extremities and spasticity, as well as autonomic failure and cerebellar ataxia suggesting possible multiple system atrophy (MSA). He also had seizures, hearing loss and sensory disturbances. His brain MRI showed no obvious atrophy or significant white matter pathology in cerebrum, brainstem or cerebellum. He died at age 69 years with a diagnosis of MSA. Microscopic analysis showed mild, patchy myelin rarefaction with perivascular clusters of PAS-positive, CD68-positive macrophages in the white matter most prominent in the cerebellum and occipital lobe, but also affecting the optic tract and internal capsule. Electron microscopy of cerebellar white matter showed cleft-like trilamellar cytoplasmic inclusions in macrophages typical of X-ALD, which prompted genetic analysis that revealed a novel ABCD1 mutation, p.R163G. Given the relatively mild pathological findings and long disease duration, it is likely that the observed pathology was the result of a slow and indolent disease process. We described a patient who had sporadic cerebello-brainstem dominant form of X-ALD with long clinical course, mild pathological findings, and an ABCD1 p.R163G substitution. We also review a total of 34 cases of adult-onset cerebello-brainstem dominant form of X-ALD. Although rare, X-ALD should be considered in the

  19. Effects of rat growth hormone (rGH)-releasing factor and somatostatin on the release and synthesis of rGH in dispersed pituitary cells

    SciTech Connect

    Fukata, J.; Diamond, D.J.; Martin, J.B.

    1985-08-01

    The effects of rat hypothalamic GH-releasing factor (GRF) and somatostatin (SRIF) on the release and biosynthesis of rat GH were studied by RIA and quantitative immunoprecipitation using monolayer cultures of rat anterior pituitary cells. In kinetic studies, GRF stimulation of GH release appeared at the first sampling time (20-min incubation) and the effect began to diminish after 2-h incubation with GRF. On the other hand, total (cell plus medium) content of GH significantly increased only after 24-h incubation. To examine the GH-synthesizing effect of GRF more directly, newly synthesized GH labeled by (TVS)methionine during incubation with GRF was quantified by immunoprecipitation. The amount of immunoprecipitable GH increased significantly and specifically also only after 24-h incubation. When GH pools were labeled with (TVS)methionine under different schedules, the basal release of newly synthesized GH, which was labeled for 1 h immediately before chase incubation was lower during the first 15 min than stored GH which had been labeled earlier. Basal newly synthesized GH secretion exceeded stored GH secretion after 30 min. In this system, SRIF suppressed both the basal and stimulated release of GH but did not modify GH biosynthesis under either condition. Newly synthesized GH showed significant degradation during 24-h incubation; neither GRF nor SRIF affected the rate of GH degradation during the same incubation period.

  20. The GH/IGF-1 axis in ageing and longevity

    PubMed Central

    List, Edward O.; Berryman, Darlene E.; Murrey, John W.

    2014-01-01

    Secretion of growth hormone (GH), and consequently that of insulin-like growth factor 1 (IGF-1), declines over time until only low levels can be detected in individuals aged ≥60 years. This phenomenon, which is known as the ‘somatopause’, has led to recombinant human GH being widely promoted and abused as an antiageing drug, despite lack of evidence of efficacy. By contrast, several mutations that decrease the tone of the GH/IGF-1 axis are associated with extended longevity in mice. In humans, corresponding or similar mutations have been identified, but whether these mutations alter longevity has yet to be established. The powerful effect of reduced GH activity on lifespan extension in mice has generated the hypothesis that pharmaceutically inhibiting, rather than increasing, GH action might delay ageing. Moreover, mice as well as humans with reduced activity of the GH/IGF-1 axis are protected from cancer and diabetes mellitus, two major ageing-related morbidities. Here, we review data on mouse strains with alterations in the GH/IGF-1 axis and their effects on lifespan. The outcome of corresponding or similar mutations in humans is described, as well as the potential mechanisms underlying increased longevity and the therapeutic benefits and risks of medical disruption of the GH/IGF-1 axis in humans. PMID:23591370

  1. Suppression of growth hormone (GH) secretion by a selective GH-releasing hormone (GHRH) antagonist. Direct evidence for involvement of endogenous GHRH in the generation of GH pulses.

    PubMed Central

    Jaffe, C A; Friberg, R D; Barkan, A L

    1993-01-01

    To study the potential involvement of growth hormone-releasing hormone (GHRH) in the generation of growth hormone (GH) pulses in humans we have used a competitive antagonist to the GHRH receptor, (N-Ac-Tyr1,D-Arg2)GHRH(1-29)NH2(GHRH-Ant). Six healthy young men were given a bolus injection of GHRH-Ant 400 micrograms/kg body wt or vehicle at 2200 h and nocturnal GH concentrations were assessed by every 10-min blood sampling until 0800 h. Integrated total and pulsatile GH secretion were suppressed during GHRH-Ant treatment by 40 +/- 6 (SE) % and 75 +/- 5%, respectively. GHRH-Ant suppressed maximum (7.6 +/- 2.2 vs 1.8 +/- 0.5 micrograms/liter; P < 0.001) and mean (3.3 +/- 1.0 vs 1.1 +/- 0.2 micrograms/liter; P = 0.02) GH pulse amplitudes. There was no change in integrated nonpulsatile GH levels, pulse frequency, or interpulse GH concentration. GHRH-Ant 400 micrograms/kg also suppressed the GH responses to intravenous boluses of GHRH 0.33 micrograms/kg given 1, 6, 12, and 24 h later by 95, 81, 59, and 4%, respectively. In five healthy men, the responses to 10-fold larger GHRH boluses (3.3 micrograms/kg) were suppressed by 82 and 0%, 1 and 6 h after GHRH-Ant 400 micrograms/kg, respectively. These studies provide the first direct evidence that endogenous GHRH participates in the generation of spontaneous GH pulses in humans. PMID:8349808

  2. Growth hormone (GH) induces tyrosine-phosphorylated proteins in mouse L cells that express recombinant GH receptors.

    PubMed Central

    Wang, X; Xu, B; Souza, S C; Kopchick, J J

    1994-01-01

    Porcine and bovine GH receptor (GHR) cDNAs were stably expressed in mouse L cells, which normally do not possess detectable levels of mouse GHR. Expression of the GHR cDNAs resulted in specific binding of 125I-labeled GH by these cell lines. To study GHR-related signaling events in these cells, protein tyrosine phosphorylation was examined. In GH-treated cells, a tyrosine-phosphorylated protein with a molecular mass of approximately 95 kDa (pp95) was increased dramatically (approximately 100-fold) relative to non-GH-treated cells. The amount of pp95 within the cells after GH treatment was positively correlated with the number of GHRs on the cells. Tyrosine phosphorylation of pp95 could not be induced by prolactin, insulin, insulin-like growth factor I, interleukin 2, epidermal growth factor, platelet-derived growth factor, or fibroblast growth factor. Phosphorylation of pp95 was found to be a rapid event that could be observed 60 sec after GH treatment. Also, pp95 appears to exist as a complex of two proteins, i.e., pp95 and pp96. The GH-induced response by these cells may be of use in screening GH analogs for biological activity. Images PMID:7509070

  3. GH safety workshop position paper: a critical appraisal of recombinant human GH therapy in children and adults

    PubMed Central

    Allen, D B; Backeljauw, P; Bidlingmaier, M; Biller, B M K; Boguszewski, M; Burman, P; Butler, G; Chihara, K; Christiansen, J; Cianfarani, S; Clayton, P; Clemmons, D; Cohen, P; Darendeliler, F; Deal, C; Dunger, D; Erfurth, E M; Fuqua, J S; Grimberg, A; Haymond, M; Higham, C; Ho, K; Hoffman, A R; Hokken-Koelega, A; Johannsson, G; Juul, A; Kopchick, J; Lee, P; Pollak, M; Radovick, S; Robison, L; Rosenfeld, R; Ross, R J; Savendahl, L; Saenger, P; Toft Sorensen, H; Stochholm, K; Strasburger, C; Swerdlow, A; Thorner, M

    2015-01-01

    Recombinant human GH (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that ‘for approved indications, GH is safe’; however, the statement highlighted a number of areas for on-going surveillance of long-term safety, including cancer risk, impact on glucose homeostasis, and use of high dose pharmacological rhGH treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard to mortality, cancer and cardiovascular risk, and the need for long-term surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric Endocrinology (ESPE), the GRS, and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of rhGH. The ouput of the meeting is a concise position statement. PMID:26563978

  4. Exceptional Association Between Klinefelter Syndrome and Growth Hormone Deficiency

    PubMed Central

    Doubi, Sana; Amrani, Zoubida; Ouahabi, Hanan El; Boujraf, Saïd; Ajdi, Farida

    2015-01-01

    Klinefelter syndrome (KS) is characterized in adults by the combination of a tall stature, small testes, gynecomastia, and azoospermia. This case is described in a North African population of the Mediterranean region of North Africa. We report the case of a male 16 years old, of Arab ethnic origin, and diagnosed with this syndrome, who had a small height in relation to a growth hormone (GH) deficiency and a history of absence seizures (generalized myoclonic epilepsy). The patient's size was <−2.8 standard deviation (SD) with weight <−3 SD. GH deficiency was isolated and confirmed by two dynamic tests (insulin — hypoglycemia tolerance test and clonidine) with normal hypothalamic magnetic resonance imaging (MRI). GH supplementation using recombinant GH was advocated, while gonadotropin treatment was deferred. Small size in children or adolescents should not eliminate the diagnosis of Klinefelter syndrome — on the contrary, the presence of any associated sign (brain maturation, delay in puberty, aggressiveness) should encourage one to request a karyotype for the diagnosis and appropriate care of any case of KS that can be associated with GH deficiency, or which is in a variant form (isochromosome Xq, 49,XXXXY).

  5. Burden of Growth Hormone Deficiency and Excess in Children.

    PubMed

    Fideleff, Hugo L; Boquete, Hugo R; Suárez, Martha G; Azaretzky, Miriam

    2016-01-01

    Longitudinal growth results from multifactorial and complex processes that take place in the context of different genetic traits and environmental influences. Thus, in view of the difficulties in comprehension of the physiological mechanisms involved in the achievement of normal height, our ability to make a definitive diagnosis of GH impairment still remains limited. There is a myriad of controversial aspects in relation to GH deficiency, mainly related to diagnostic controversies and advances in molecular biology. This might explain the diversity in therapeutic responses and may also serve as a rationale for new "nonclassical" treatment indications for GH. It is necessary to acquire more effective tools to reach an adequate evaluation, particularly while considering the long-term implications of a correct diagnosis, the cost, and safety of treatments. On the other hand, overgrowth constitutes a heterogeneous group of different pathophysiological situations including excessive somatic and visceral growth. There are overlaps in clinical and molecular features among overgrowth syndromes, which constitute the real burden for an accurate diagnosis. In conclusion, both GH deficiency and overgrowth are a great dilemma, still not completely solved. In this chapter, we review the most burdensome aspects related to short stature, GH deficiency, and excess in children, avoiding any details about well-known issues that have been extensively discussed in the literature. PMID:26940390

  6. GH13 amylosucrases and GH70 branching sucrases, atypical enzymes in their respective families.

    PubMed

    Moulis, Claire; André, Isabelle; Remaud-Simeon, Magali

    2016-07-01

    Amylosucrases and branching sucrases are α-retaining transglucosylases found in the glycoside-hydrolase families 13 and 70, respectively, of the clan GH-H. These enzymes display unique activities in their respective families. Using sucrose as substrate and without mediation of nucleotide-activated sugars, amylosucrase catalyzes the formation of an α-(1 → 4) linked glucan that resembles amylose. In contrast, the recently discovered branching sucrases are unable to catalyze polymerization of glucosyl units as they are rather specific for dextran branching through α-(1 → 2) or α-(1 → 3) branching linkages depending on the enzyme regiospecificity. In addition, GH13 amylosucrases and GH70 branching sucrases are naturally promiscuous and can glucosylate different types of acceptor molecules including sugars, polyols, or flavonoids. Amylosucrases have been the most investigated glucansucrases, in particular to control product profiles or to successfully develop tailored α-transglucosylases able to glucosylate various molecules of interest, for example, chemically protected carbohydrates that are planned to enter in chemoenzymatic pathways. The structural traits of these atypical enzymes will be described and compared, and an overview of the potential of natural or engineered enzymes for glycodiversification and chemoenzymatic synthesis will be highlighted. PMID:27141938

  7. Expression of endogenous and exogenous growth hormone (GH) messenger (m) RNA in a GH-transgenic tilapia (Oreochromis niloticus).

    PubMed

    Caelers, Antje; Maclean, Norman; Hwang, Gyulin; Eppler, Elisabeth; Reinecke, Manfred

    2005-02-01

    We have previously produced transgenic fish from crosses between a wild-type female tilapia (Oreochromis niloticus) and a G transgenic male. This line of growth-enhanced tilapia carries a single copy of a chinook salmon (s) growth hormone (GH) gene spliced to an ocean pout antifreeze promoter (OPA-FPcsGH) co-ligated to a carp beta-actin/lacZ reporter gene construct, integrated into the tilapia genome. Because little is known about the expression sites of transgenes, we have characterised the gene expression patterns of sGH and tilapia (t)GH in transgenic tilapia using a newly established real-time PCR to measure the absolute mRNA amounts of both hormones. The sGH gene, which was expected to be expressed mainly in liver, was also found to be expressed in other organs, such as gills, heart, brain, skeletal muscle, kidney, spleen, intestine and testes. However, in pituitary no sGH mRNA but only tGH mRNA was found. Tilapia GH mRNA in wild-type pituitary amounted to 226 +/- 30 pg/microg total RNA but in transgenics only to 187 +/- 43 pg/microg total RNA. Liver exhibited the highest level of sGH mRNA (8.3 +/- 2.5 pg/microg total RNA) but the extrahepatic sites expressed considerable amounts of sGH mRNA ranging from 4.1 +/- 2.0 pg/microg total RNA in gills to 0.2 +/- 0.08 pg/microg total RNA in kidney. The widespread expression of the sGH gene is assumed to be due to the tissue specificity of the type III AFP gene promoter. It is assumed that our transgenic experiments, which in contrast to some other approaches caused no obvious organ abnormalities, mimick the GH expression during ontogeny. Because sGH mRNA is expressed both in liver and in extrahepatic sites it may not only promote secretion and release of liver-derived (endocrine) IGF-I leading to an overall growth enhancement but also stimulate IGF-I expression within the different organs in a paracrine/autocrine manner and, thus, further promote organ growth. PMID:15865052

  8. Human growth hormone (GH)-releasing factor stimulates and somatostatin inhibits the release of rat GH variants.

    PubMed

    Yokoya, S; Friesen, H G

    1986-11-01

    Two-dimensional polyacrylamide gel electrophoresis (2D PAGE) was used for the analysis of proteins secreted by male rat pituitary cells in monolayer culture in the presence of 10 nM human GH-releasing factor (hGRF) or 30 nM somatostatin (SRIF) or in the absence of these factors. More than 300 medium proteins were reproducibly detected either by fluorographic autoradiography or by silver staining. Immunoreactivity of each protein was examined after 2D PAGE followed by Western blotting and immunostaining with affinity-purified antirat GH (rGH) antibody. While there was a cluster of immunoreactive spots in the GH dimer range (40,000-50,000 mol wt), at least 16 medium proteins of mol wt 22,000 or less were also stained. Among these 16 proteins the release of 15 was stimulated and the release of 14 was inhibited by hGRF and SRIF, respectively. On the other hand, there were 3 proteins of approximate mol wt 16,000 whose secretion was regulated in a coordinate manner as rGH by the hypothalamic factors but which did not cross-react with anti-rGH antibodies. The increase or decrease in the radioactivity of each protein spot obtained from media after pituitary cells were incubated with [35S]methionine and hypothalamic factors was analyzed statistically. A pulse-chase study suggested that at least 7 of the hormonally regulated proteins, including rGH, were synthesized very rapidly. Finally, the 2D PAGE analysis of cell-free translation products of messenger RNA derived from male rat anterior pituitaries revealed the presence of about 40 rGH-immunoreactive proteins which included pre-GH. These data suggest that there are multiple forms of rGH-variants or rGH-related proteins. The biological significance(s) of all the rGH immunoreactive proteins and of the GRF- and SRIF-regulated pituitary proteins remains unclear. It is evident that a number of these proteins are synthesized and released rapidly by pituitary cells in culture. Furthermore, the presence of multiple genes for

  9. Action of three GH51 and one GH54 α-arabinofuranosidases on internally and terminally located arabinofuranosyl branches.

    PubMed

    Koutaniemi, Sanna; Tenkanen, Maija

    2016-07-10

    The action of three glycoside hydrolase family GH51 and one GH54 α-arabinofuranosidases (ABFs) was studied on polymeric arabinoxylan and arabinoxylooligosaccharides. The substrates covered all possible arabinofuranosyl (Araf) substituents, i.e., terminal and internal α(1→2) and α(1→3)-linked Araf monosubstitutions and disubstitutions. The GH51 ABFs removed nearly all mono- and disubstitutions from terminal non-reducing end xylopyranosyl (Xylp) residues, showing dual ABF-m/d activity. From internal Xylp, primarily monosubstitutions were removed, except after treatment with GH51 Aspergillus niger ABF. It degraded slowly internal disubstitutions as well, showing versatility in substrate specificity within GH51. GH54 Trichoderma reesei ABF core protein also presented dual ABF-m/d activity, slowly degrading Araf disubstitutions from both terminal and internal positions. Surprisingly, regioselectivity of the T. reesei ABF changed from α(1→3)-linked Araf on terminal Xylp to α(1→2)-linked Araf on internal Xylp on both mono- and disubstitutions. In conclusion, systematic analysis of natural substrates revealed interesting new details on the action T. reesei ABF and showed that the dual ABF-m/d activity could be more prevalent than previously thought, especially within GH51 ABFs. PMID:27142490

  10. Effect of growth hormone-releasing factor on growth hormone release in children with radiation-induced growth hormone deficiency

    SciTech Connect

    Lustig, R.H.; Schriock, E.A.; Kaplan, S.L.; Grumbach, M.M.

    1985-08-01

    Five male children who received cranial irradiation for extrahypothalamic intracranial neoplasms or leukemia and subsequently developed severe growth hormone (GH) deficiency were challenged with synthetic growth hormone-releasing factor (GRF-44), in an attempt to distinguish hypothalamic from pituitary dysfunction as a cause of their GH deficiency, and to assess the readily releasable GH reserve in the pituitary. In response to a pulse of GRF-44 (5 micrograms/kg intravenously), mean peak GH levels rose to values higher than those evoked by the pharmacologic agents L-dopa or arginine (6.4 +/- 1.3 ng/mL v 1.5 +/- 0.4 ng/mL, P less than .05). The peak GH value occurred at a mean of 26.0 minutes after administration of GRF-44. These responses were similar to those obtained in children with severe GH deficiency due to other etiologies (peak GH 6.3 +/- 1.7 ng/mL, mean 28.0 minutes). In addition, there was a trend toward an inverse relationship between peak GH response to GRF-44 and the postirradiation interval. Prolactin and somatomedin-C levels did not change significantly after the administration of a single dose of GRF-44. The results of this study support the hypothesis that cranial irradiation in children can lead to hypothalamic GRF deficiency secondary to radiation injury of hypothalamic GRF-secreting neurons. This study also lends support to the potential therapeutic usefulness of GRF-44 or an analog for GH deficiency secondary to cranial irradiation.

  11. TIMP3 Modulates GHR Abundance and GH Sensitivity.

    PubMed

    Zhang, Yue; Wang, Xiangdong; Loesch, Kimberly; May, Larry A; Davis, George E; Jiang, Jing; Frank, Stuart J

    2016-06-01

    GH receptor (GHR) binds GH at the cell surface via its extracellular domain and initiates intracellular signal transduction, resulting in important anabolic and metabolic actions. GH signaling is subject to dynamic regulation, which in part is exerted by modulation of cell surface GHR levels. Constitutive and inducible metalloprotease-mediated cleavage of GHR regulate GHR abundance and thereby modulate GH action. We previously demonstrated that GHR proteolysis is catalyzed by the TNF-α converting enzyme (TACE; ADAM17). Tissue inhibitors of metalloproteases-3 (TIMP3) is a natural specific inhibitor of TACE, although mechanisms underlying this inhibition are not yet fully understood. In the current study, we use two model cell lines to examine the relationships between cellular TACE, TIMP3 expression, GHR metalloproteolysis, and GH sensitivity. These two cell lines exhibited markedly different sensitivity to inducible GHR proteolysis, which correlated directly to their relative levels of mature TACE vs unprocessed TACE precursor and indirectly to their levels of cellular TIMP3. Our results implicate TIMP3 as a modulator of cell surface GHR abundance and the ability of GH to promote cellular signaling; these modulatory effects may be conferred by endogenous TIMP3 expression as well as exogenous TIMP3 exposure. Furthermore, our analysis suggests that TIMP3, in addition to regulating the activity of TACE, may also modulate the maturation of TACE, thereby affecting the abundance of the active form of the enzyme. PMID:27075707

  12. Aged PROP1 Deficient Dwarf Mice Maintain ACTH Production

    PubMed Central

    Bavers, David L.; Beuschlein, Felix; Mortensen, Amanda H.; Keegan, Catherine E.; Hammer, Gary D.; Camper, Sally A.

    2011-01-01

    Humans with PROP1 mutations have multiple pituitary hormone deficiencies (MPHD) that typically advance from growth insufficiency diagnosed in infancy to include more severe growth hormone (GH) deficiency and progressive reduction in other anterior pituitary hormones, eventually including adrenocorticotropic hormone (ACTH) deficiency and hypocortisolism. Congenital deficiencies of GH, prolactin, and thyroid stimulating hormone have been reported in the Prop1null (Prop1-/-) and the Ames dwarf (Prop1df/df) mouse models, but corticotroph and pituitary adrenal axis function have not been thoroughly investigated. Here we report that the C57BL6 background sensitizes mutants to a wasting phenotype that causes approximately one third to die precipitously between weaning and adulthood, while remaining homozygotes live with no signs of illness. The wasting phenotype is associated with severe hypoglycemia. Circulating ACTH and corticosterone levels are elevated in juvenile and aged Prop1 mutants, indicating activation of the pituitary-adrenal axis. Despite this, young adult Prop1 deficient mice are capable of responding to restraint stress with further elevation of ACTH and corticosterone. Low blood glucose, an expected side effect of GH deficiency, is likely responsible for the elevated corticosterone level. These studies suggest that the mouse model differs from the human patients who display progressive hormone loss and hypocortisolism. PMID:22145038

  13. Aged PROP1 deficient dwarf mice maintain ACTH production.

    PubMed

    Nasonkin, Igor O; Ward, Robert D; Bavers, David L; Beuschlein, Felix; Mortensen, Amanda H; Keegan, Catherine E; Hammer, Gary D; Camper, Sally A

    2011-01-01

    Humans with PROP1 mutations have multiple pituitary hormone deficiencies (MPHD) that typically advance from growth insufficiency diagnosed in infancy to include more severe growth hormone (GH) deficiency and progressive reduction in other anterior pituitary hormones, eventually including adrenocorticotropic hormone (ACTH) deficiency and hypocortisolism. Congenital deficiencies of GH, prolactin, and thyroid stimulating hormone have been reported in the Prop1(null) (Prop1(-/-)) and the Ames dwarf (Prop1(df/df)) mouse models, but corticotroph and pituitary adrenal axis function have not been thoroughly investigated. Here we report that the C57BL6 background sensitizes mutants to a wasting phenotype that causes approximately one third to die precipitously between weaning and adulthood, while remaining homozygotes live with no signs of illness. The wasting phenotype is associated with severe hypoglycemia. Circulating ACTH and corticosterone levels are elevated in juvenile and aged Prop1 mutants, indicating activation of the pituitary-adrenal axis. Despite this, young adult Prop1 deficient mice are capable of responding to restraint stress with further elevation of ACTH and corticosterone. Low blood glucose, an expected side effect of GH deficiency, is likely responsible for the elevated corticosterone level. These studies suggest that the mouse model differs from the human patients who display progressive hormone loss and hypocortisolism. PMID:22145038

  14. Hepatic PPARγ Is Not Essential for the Rapid Development of Steatosis After Loss of Hepatic GH Signaling, in Adult Male Mice.

    PubMed

    Kineman, Rhonda D; Majumdar, Neena; Subbaiah, Papasani V; Cordoba-Chacon, Jose

    2016-05-01

    Our group has previously reported de novo lipogenesis (DNL) and hepatic triglyceride content increases in chow-fed male mice within 7 days of hepatocyte-specific GH receptor knockdown (aLivGHRkd). Here, we report that these changes are associated with an increase in hepatic expression of peroxisome proliferator-activated receptor γ (PPARγ), consistent with previous reports showing steatosis is associated with an increase in PPARγ expression in mice with congenital loss of hepatic GH signaling. PPARγ is thought to be an important driver of steatosis by enhancing DNL, as well as increasing the uptake and esterification of extrahepatic fatty acids (FAs). In order to determine whether hepatic PPARγ is critical for the rapid development of steatosis in the aLivGHRkd mouse model, we have generated aLivGHRkd mice, with or without PPARγ (ie, adult-onset, hepatocyte-specific double knockout of GHR and PPARγ). Hepatic PPARγ was not required for the rapid increase in liver triglyceride content or FA indexes of DNL (16:0/18:2 and 16:1/16:0). However, loss of hepatic PPARγ blunted the rise in fatty acid translocase/CD36 and monoacylglycerol acyltransferase 1 expression induced by aLivGHRkd, and this was associated with a reduction in the hepatic content of 18:2. These results suggest that the major role of PPARγ is to enhance pathways critical in uptake and reesterification of extrahepatic FA. Because FAs have been reported to directly increase PPARγ expression, we speculate that in the aLivGHRkd mouse, the FA produced by DNL enhances the expression of PPARγ, which in turn increases extrahepatic FA uptake, thereby further enhancing PPARγ activity and exacerbating steatosis overtime. PMID:26950202

  15. The characterization of six auxin-induced tomato GH3 genes uncovers a member, SlGH3.4, strongly responsive to arbuscular mycorrhizal symbiosis.

    PubMed

    Liao, Dehua; Chen, Xiao; Chen, Aiqun; Wang, Huimin; Liu, Jianjian; Liu, Junli; Gu, Mian; Sun, Shubin; Xu, Guohua

    2015-04-01

    In plants, the GH3 gene family is widely considered to be involved in a broad range of plant physiological processes, through modulation of hormonal homeostasis. Multiple GH3 genes have been functionally characterized in several plant species; however, to date, limited works to study the GH3 genes in tomato have been reported. Here, we characterize the expression and regulatory profiles of six tomato GH3 genes, SlGH3.2, SlGH3.3, SlGH3.4, SlGH3.7, SlGH3.9 and SlGH3.15, in response to different phytohormone applications and arbuscular mycorrhizal (AM) fungal colonization. All six GH3 genes showed inducible responses to external IAA, and three members were significantly up-regulated in response to AM symbiosis. In particular, SlGH3.4, the transcripts of which were barely detectable under normal growth conditions, was strongly activated in the IAA-treated and AM fungal-colonized roots. A comparison of the SlGH3.4 expression in wild-type plants and M161, a mutant with a defect in AM symbiosis, confirmed that SlGH3.4 expression is highly correlated to mycorrhizal colonization. Histochemical staining demonstrated that a 2,258 bp SlGH3.4 promoter fragment could drive β-glucuronidase (GUS) expression strongly in root tips, steles and cortical cells of IAA-treated roots, but predominantly in the fungal-colonized cells of mycorrhizal roots. A truncated 654 bp promoter failed to direct GUS expression in IAA-treated roots, but maintained the symbiosis-induced activity in mycorrhizal roots. In summary, our results suggest that a mycorrhizal signaling pathway that is at least partially independent of the auxin signaling pathway has evolved for the co-regulation of the auxin- and mycorrhiza-activated GH3 genes in plants. PMID:25535196

  16. Molecular and SNP characterization of two genome specific transcription factor genes GhMyb8 and GhMyb10 in cotton species

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Two R2R3-Myb cDNAs (GhMyb8 and GhMyb10) and their corresponding genes were isolated and characterized from allotetraploid cotton (Gossypium hirsutum L. cv. DES119) fiber cells. Both GhMyb8 and GhMyb10 exhibit some conserved features shared in subgroup 4 of plant R2R3-MYB proteins, including the GIDx...

  17. The role of GH in adipose tissue: lessons from adipose-specific GH receptor gene-disrupted mice.

    PubMed

    List, Edward O; Berryman, Darlene E; Funk, Kevin; Gosney, Elahu S; Jara, Adam; Kelder, Bruce; Wang, Xinyue; Kutz, Laura; Troike, Katie; Lozier, Nicholas; Mikula, Vincent; Lubbers, Ellen R; Zhang, Han; Vesel, Clare; Junnila, Riia K; Frank, Stuart J; Masternak, Michal M; Bartke, Andrzej; Kopchick, John J

    2013-03-01

    GH receptor (GHR) gene-disrupted mice (GHR-/-) have provided countless discoveries as to the numerous actions of GH. Many of these discoveries highlight the importance of GH in adipose tissue. For example GHR-/- mice are insulin sensitive yet obese with preferential enlargement of the sc adipose depot. GHR-/- mice also have elevated levels of leptin, resistin, and adiponectin, compared with controls leading some to suggest that GH may negatively regulate certain adipokines. To help clarify the role that GH exerts specifically on adipose tissue in vivo, we selectively disrupted GHR in adipose tissue to produce Fat GHR Knockout (FaGHRKO) mice. Surprisingly, FaGHRKOs shared only a few characteristics with global GHR-/- mice. Like the GHR-/- mice, FaGHRKO mice are obese with increased total body fat and increased adipocyte size. However, FaGHRKO mice have increases in all adipose depots with no improvements in measures of glucose homeostasis. Furthermore, resistin and adiponectin levels in FaGHRKO mice are similar to controls (or slightly decreased) unlike the increased levels found in GHR-/- mice, suggesting that GH does not regulate these adipokines directly in adipose tissue in vivo. Other features of FaGHRKO mice include decreased levels of adipsin, a near-normal GH/IGF-1 axis, and minimal changes to a large assortment of circulating factors that were measured such as IGF-binding proteins. In conclusion, specific removal of GHR in adipose tissue is sufficient to increase adipose tissue and decrease circulating adipsin. However, removal of GHR in adipose tissue alone is not sufficient to increase levels of resistin or adiponectin and does not alter glucose metabolism. PMID:23349524

  18. Cloning and characterization of the first GH10 and GH11 xylanases from Rhizopus oryzae.

    PubMed

    Xiao, Zhizhuang; Grosse, Stephan; Bergeron, Hélène; Lau, Peter C K

    2014-10-01

    The only available genome sequence for Rhizopus oryzae strain 99-880 was annotated to not encode any β-1,4-endoxylanase encoding genes of the glycoside hydrolase (GH) family 10 or 11. Here, we report the identification and cloning of two such members in R. oryzae strain NRRL 29086. Strain 29086 was one of several selected fungi grown on wheat or triticale bran and screened for xylanase activity among other hydrolytic actions. Its high activity (138 U/ml) in the culture supernatant led to the identification of two activity-stained proteins, designated Xyn-1 and Xyn-2 of respective molecular masses 32,000 and 22,000. These proteins were purified to electrophoretic homogeneity and characterized. The specific activities of Xyn-1 and Xyn-2 towards birchwood xylan were 605 and 7,710 U/mg, respectively. Kinetic data showed that the lower molecular weight Xyn-2 had a higher affinity (K m=3.2 ± 0.2 g/l) towards birchwood xylan than Xyn-1 by about 4-fold. The melting temperature (T m) of the two proteins, estimated to be in the range of 49.5-53.7 °C indicated that they are rather thermostable proteins. N-terminal and internal peptide sequences were obtained by chemical digestion of the purified xylanases to facilitate cloning, expression in Escherichia coli, and sequencing of the respective gene. The cloned Rhizopus xylanases were used to demonstrate release of xylose from flax shives-derived hemicellulose as model feedstock. Overall, this study expands the catalytic toolbox of GH10 and 11 family proteins that have applications in various industrial and bioproducts settings. PMID:24760228

  19. An atypical presentation of adult-onset Still’s disease complicated by pulmonary hypertension and macrophage activation syndrome treated with immunosuppression: a case-based review of the literature

    PubMed Central

    Manson, Daniel K.; Horn, Evelyn M.; Haythe, Jennifer

    2016-01-01

    Abstract Pulmonary arterial hypertension (PAH) is a known complication of rheumatologic diseases, but it is only rarely associated with adult-onset Still’s disease (AOSD). We describe the case of a 30-year-old woman who presented in a pulmonary hypertension crisis and was found to have underlying AOSD with PAH and nonspecific interstitial pneumonia (NSIP) with a course complicated by macrophage activation syndrome (MAS). She dramatically improved with steroids, cyclosporine A, and anakinra, with total resolution of the MAS and significant improvement of her pulmonary arterial pressures. While there are only select case reports of AOSD associated with PAH, this is the first reported case of (1) AOSD complicated by both PAH and MAS and (2) AOSD complicated by biopsy-proven NSIP. Clinically, this case highlights the efficacy of immunosuppressive agents in the treatment of PAH and MAS from underlying AOSD and supports their use in this setting. PMID:27162622

  20. [GH10 Family of Glycoside Hydrolases: Structure and Evolutionary Connections].

    PubMed

    Naumoff, D G

    2016-01-01

    Evolutionary connections were analyzed for endo-β-xylanases, which possess the GH10 family catalytic domains. A homology search yielded thrice as many proteins as are available from the Carbohydrate-Active Enzymes (CAZy) database. Lateral gene transfer was shown to play an important role in evolution of bacterial proteins of the family, especially in the phyla Acidobacteria, Cyanobacteria, Planctomycetes, Spirochaetes, and Verrucomicrobia. In the case of Verrucomicrobia, 23 lateral transfers from organisms of other phyla were detected. Evolutionary relationships were observed between the GH10 family domains and domains with the TIM-barrel tertiary structure from several other glycosidase families. The GH39 family of glycoside hydrolases showed the closest relationship. Unclassified homologs were grouped into 12 novel families of putative glycoside hydrolases (GHL51-GHL62). PMID:27028821

  1. An efficient expression of Human Growth Hormone (hGH) in the milk of transgenic mice using rat {beta}-casein/hGH fusion genes

    SciTech Connect

    Lee, Chul-Sang; Yu, Dae-Yeul; Lee, Kyung-Kwang

    1996-03-01

    In order to produce human growth hormone (hGH) in the milk of transgenic mice, two expression vectors for hGH differing in their 3{prime} flanking sequences were constructed by placing the genomic sequences of hGH gene under the control of the rat {beta}-casein gene promotor. The 3{prime} flanking sequences of the expression constructs were derived from either the hGH gene (pBCN1GH) or the rat {beta}-casein gene (pBCN2GH). Transgenic lines bearing pBCN1GH expressed hGH more efficiently than those bearing pBCN2GH in the milk (19-5500 {mu}g/mL vs 0.7-2 {mu}g/mL). In particular, one of the BCN1GH lines expressed hGH as much as 5500 {plus_minus} 620 {mu}g/mL. Northern blot analysis showed that the transgene expression was specifically confined to the mammary gland and developmentally regulated like the endogeneous mouse {beta}-casein gene in the mammary gland. However, a low level of nonmammary expression was also detected with more sensitive assay methods. In conclusion, the rat {beta}-casein/hGH fusion gene could direct an efficient production of hGH in a highly tissue- and stage-specific manner in the transgenic mice and the 3{prime} flanking sequences of hGH gene had an important role for the efficient expression. 27 refs., 5 figs., 2 tabs.

  2. Internalization and synaptogenic effect of GH in retinal ganglion cells (RGCs).

    PubMed

    Fleming, Thomas; Martínez-Moreno, Carlos G; Mora, Janeth; Aizouki, Miray; Luna, Maricela; Arámburo, Carlos; Harvey, Steve

    2016-08-01

    In the chicken embryo, GH gene expression occurs in the neural retina and retinal GH promotes cell survival and induces axonal growth of retinal ganglion cells. Neuroretinal GH is therefore of functional importance before the appearance of somatotrophs and the onset of pituitary GH secretion to the peripheral plasma (at ED15-17). Endocrine actions of pituitary GH in the development and function of the chicken embryo eye are, however, unknown. This possibility has therefore been investigated in ED15 embryos and using the quail neuroretinal derived cell line (QNR/D). During this research, we studied for the first time, the coexistence of exogenous (endocrine) and local GH (autocrine/paracrine) in retinal ganglion cells (RGCs). In ovo systemic injections of Cy3-labeled GH demonstrated that GH in the embryo bloodstream was translocated into the neural retina and internalized into RGC's. Pituitary GH may therefore be functionally involved in retinal development during late embryogenesis. Cy3-labelled GH was similarly internalized into QNR/D cells after its addition into incubation media. The uptake of exogenous GH was by a receptor-mediated mechanism and maximal after 30-60min. The exogenous (endocrine) GH induced STAT5 phosphorylation and increased growth associated protein 43 (GAP43) and SNAP-25 immunoreactivity. Ex ovo intravitreal injections of Cy3-GH in ED12 embryos resulted in GH internalization and STAT5 activation. Interestingly, the CY3-labeled GH accumulated in perinuclear regions of the QNR/D cells, but was not found in the cytoplasm of neurite outgrowths, in which endogenous retinal GH is located. This suggests that exogenous (endocrine) and local (autocrine/paracrine) GH are both involved in retinal function in late embryogenesis but they co-exist in separate intracellular compartments within retinal ganglion cells. PMID:27036926

  3. 60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-GH axis: the past 60 years.

    PubMed

    Murray, P G; Higham, C E; Clayton, P E

    2015-08-01

    At the time of the publication of Geoffrey Harris's monograph on 'Neural control of the pituitary gland' 60 years ago, the pituitary was recognised to produce a growth factor, and extracts administered to children with hypopituitarism could accelerate growth. Since then our understanding of the neuroendocrinology of the GH axis has included identification of the key central components of the GH axis: GH-releasing hormone and somatostatin (SST) in the 1970s and 1980s and ghrelin in the 1990s. Characterisation of the physiological control of the axis was significantly advanced by frequent blood sampling studies in the 1980s and 1990s; the pulsatile pattern of GH secretion and the factors that influenced the frequency and amplitude of the pulses have been defined. Over the same time, spontaneously occurring and targeted mutations in the GH axis in rodents combined with the recognition of genetic causes of familial hypopituitarism demonstrated the key factors controlling pituitary development. As the understanding of the control of GH secretion advanced, developments of treatments for GH axis disorders have evolved. Administration of pituitary-derived human GH was followed by the introduction of recombinant human GH in the 1980s, and, more recently, by long-acting GH preparations. For GH excess disorders, dopamine agonists were used first followed by SST analogues, and in 2005 the GH receptor blocker pegvisomant was introduced. This review will cover the evolution of these discoveries and build a picture of our current understanding of the hypothalamo-GH axis. PMID:26040485

  4. A novel mitochondrial DNA deletion in a patient with Kearns-Sayre syndrome: a late-onset of the fatal cardiac conduction deficit and cardiomyopathy accompanying long-term rGH treatment

    PubMed Central

    2013-01-01

    Background Kearns-Sayre Syndrome (KSS) is a multisystem disorder caused by a dysfunction of the oxidative phosphorylation system within mitochondria. Mitochondrial DNA (mtDNA) rearrangements are a key molecular feature of this disease, which manifest a broad phenotypic spectrum. Case presentation Here, we present a boy with KSS whose symptoms included cardiac conduction deficit, cardiomyopathy and growth hormone (GH) deficiency. The patient showed typical symptoms for KSS from early childhood (chronic progressive external ophthalmoplegia, retinopathy, short stature). Long-range PCR analysis disclosed a 7663-base pair heteroplasmic deletion in the mtDNA encompassing nucleotides 6340–14003. At 12 years of age, GH deficiency was recognized and recombinant growth hormone (rGH) therapy was started. At 15 years of age, a complete atrioventicular block was diagnosed and the patient received a pacemaker. During the following 6 months, progressive deterioration of the left ventricle was observed and an echocardiogram showed features of dilated cardiomyopathy. The rGH treatment was then discontinued at a final height of 163 cm. Unfortunately, due to multi-organ insufficiency and inflammation, the patient died at the age of 18 years. Conclusions The response to rGH therapy in the patient was very satisfactory. The large mtDNA deletion had no apparent impact on the response to rGH. Cardiac disturbances occurred as part of the syndrome and were not related to rGH therapy; however, the progression of the disease led to death. PMID:23421922

  5. Growth hormone deficiency during young adulthood and the benefits of growth hormone replacement

    PubMed Central

    Ahmid, M; Perry, C G; Ahmed, S F

    2016-01-01

    Until quite recently, the management of children with growth hormone deficiency (GHD) had focussed on the use of recombinant human GH (rhGH) therapy to normalise final adult height. However, research over the past two decades that has demonstrated deficits in bone health and cardiac function, as well as impaired quality of life in adults with childhood-onset GHD (CO-GHD), has questioned this practice. Some of these studies suggested that there may be short-term benefits of rhGH in certain group of adolescents with GHD during transition, although the impact of GHD and replacement during the transition period has not been adequately investigated and its long-term benefits remain unclear. GH therapy remains expensive and well-designed long-term studies are needed to determine the cost effectiveness and clinical benefit of ongoing rhGH during transition and further into adulthood. In the absence of compelling data to justify widespread continuation of rhGH into adult life, there are several questions related to its use that remain unanswered. This paper reviews the effects of growth hormone deficiency on bone health, cardiovascular function, metabolic profile and quality of life during transition and young adulthood. PMID:27129699

  6. Should Patients with Trichorhinophalangeal Syndrome be Tested for Growth Hormone Deficiency?

    PubMed

    Marques, Jorge Sales; Maia, Catarina; Almeida, Raquel; Isidoro, Lara; Dias, Catarina

    2015-09-01

    Type 1 Trichorhinophalangeal syndrome (TRPS) is characterized by typical facial and skeletal abnormalities. These patients frequently exhibit short stature; however, only one case with growth hormone (GH) deficiency can be found in the literature. Our patient is a 10-year-old girl with two novel nonsense pathogenic mutations in the TRPS1 gene, both in heterozygosity: c. 1198C>T (p. Gln400X) and c.2086C>T (p. Arg696X). She has an additional GH deficiency. The patient is short in stature, with a growth velocity of 1.5 cm per year (SDS - 4.07), a bone age of 4.5 years, and she shows no response to the GH stimulation tests. According to a previous report of an identical case, catch-up growth will occur after beginning GH treatment. We believe that GH stimulation tests should be performed on patients with TRPS1 exhibiting a growth velocity below the normal range expected for their age and sex. If the result is subnormal, then GH therapy should be attempted. PMID:26540763

  7. Health Alert: Adrenal Crisis Causes Death in Some People Who Were Treated with hGH

    MedlinePlus

    ... Alternate Language URL Health Alert: Adrenal Crisis Causes Death in Some People Who Were Treated with hGH ... individuals treated with hGH looked at causes of death among recipients and found some disturbing news. Many ...

  8. Effects of Huang Bai (Phellodendri Cortex) and Three Other Herbs on GnRH and GH Levels in GT1–7 and GH3 Cells

    PubMed Central

    Lee, Sun Haeng; Kwak, Sung Chul; Kim, Dong Kwan; Park, Sang Woug; Kim, Hyun Soo; Kim, Young-Sik; Lee, Donghun; Lee, Ju Won; Lee, Chang Gon; Lee, Hae Kyung; Cho, Sung-Min; Shin, Yu Jeong; Lee, Jin Yong; Kim, Hocheol; Chang, Gyu Tae

    2016-01-01

    The present study was to evaluate the effects of Huang Bai, Zhi Mu, Mai Ya, and Xia Ku Cao on hormone using the GT1–7 and GH3 cells. The GT1–7 and GH3 cell lines were incubated with DW; DMSO; and 30, 100, or 300 μg/mL of one of the four extract solutions in serum-free media for 24 hours. The MTT assay was performed to determine the cytotoxicity of the four herbs. The GT1–7 and GH3 cells were incubated in DW, estradiol (GT1–7 only), or noncytotoxic herb solutions in serum-free medium for 24 hours. A quantitative RT-PCR and western blot were performed to measure the GnRH expression in GT1–7 cells and GH expression in GH3 cells. Huang Bai, Zhi Mu, Xia Ku Cao, and Mai Ya inhibited the GnRH mRNA expression in GT1–7 cells, whereas Huang Bai enhanced GH mRNA expression in GH3 cells. Additionally, Xia Ku Cao inhibited GnRH protein expression in GT1–7 cells and Huang Bai promoted GH protein expression in GH3 cells. The findings suggest that Huang Bai can delay puberty by inhibiting GnRH synthesis in the hypothalamus while also accelerating growth by promoting GH synthesis and secretion in the pituitary. PMID:26925153

  9. Dose dependency of time of onset of radiation-induced growth hormone deficiency

    SciTech Connect

    Clayton, P.E.; Shalet, S.M. )

    1991-02-01

    Growth hormone (GH) secretion during insulin-induced hypoglycemia was assessed on 133 occasions in 82 survivors of childhood malignant disease. All had received cranial irradiation with a dose range to the hypothalamic-pituitary axis of 27 to 47.5 Gy (estimated by a schedule of 16 fractions over 3 weeks) and had been tested on one or more occasions between 0.2 and 18.9 years after treatment. Results of one third of the GH tests were defined as normal (GH peak response, greater than 15 mU/L) within the first 5 years, in comparison with 16% after 5 years. Stepwise multiple linear regression analysis showed that dose (p = 0.007) and time from irradiation (p = 0.03), but not age at therapy, had a significant influence on peak GH responses. The late incidence of GH deficiency was similar over the whole dose range (4 of 26 GH test results normal for less than 30 Gy and 4 of 25 normal for greater than or equal to 30 Gy after 5 years), but the speed of onset over the first years was dependent on dose. We conclude that the requirement for GH replacement therapy and the timing of its introduction will be influenced by the dose of irradiation received by the hypothalamic-pituitary axis.

  10. [Benefits and risks of growth hormone in adults with growth hormone deficiency].

    PubMed

    Díez, Juan J; Cordido, Fernando

    2014-10-21

    Adult growth hormone (GH) deficiency is a well-recognized clinical syndrome with adverse health consequences. Many of these may improve after replacement therapy with recombinant GH. This treatment induces an increase in lean body mass and a decrease in fat mass. In long-term studies, bone mineral density increases and muscle strength improves. Health-related quality of life tends to increase after treatment with GH. Lipid profile and markers of cardiovascular risk also improve with therapy. Nevertheless, GH replacement therapy is not without risk. According to some studies, GH increases blood glucose, body mass index and waist circumference and may promote long-term development of diabetes and metabolic syndrome. Risk of neoplasia does not appear to be increased in adults treated with GH, but there are some high-risk subgroups. Methodological shortcomings and difficulties inherent to long-term studies prevent definitive conclusions about the relationship between GH and survival. Therefore, research in this field should remain active. PMID:24485161

  11. ARE THE METABOLIC EFFECTS OF GH AND IGF-I SEPARABLE?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    IGF-I mediates some, but not all of the metabolic actions of GH and it has both GH-like and insulin-like actions in vivo. GH and IGF-I both have a net anabolic effect in man enhancing whole body protein synthesis over a period of weeks and perhaps months. Both hormones favorably improve body compos...

  12. Control of cotton fibre elongation by a homeodomain transcription factor GhHOX3

    PubMed Central

    Shan, Chun-Min; Shangguan, Xiao-Xia; Zhao, Bo; Zhang, Xiu-Fang; Chao, Lu-men; Yang, Chang-Qing; Wang, Ling-Jian; Zhu, Hua-Yu; Zeng, Yan-Da; Guo, Wang-Zhen; Zhou, Bao-Liang; Hu, Guan-Jing; Guan, Xue-Ying; Chen, Z. Jeffrey; Wendel, Jonathan F.; Zhang, Tian-Zhen; Chen, Xiao-Ya

    2014-01-01

    Cotton fibres are unusually long, single-celled epidermal seed trichomes and a model for plant cell growth, but little is known about the regulation of fibre cell elongation. Here we report that a homeodomain-leucine zipper (HD-ZIP) transcription factor, GhHOX3, controls cotton fibre elongation. GhHOX3 genes are localized to the 12th homoeologous chromosome set of allotetraploid cotton cultivars, associated with quantitative trait loci (QTLs) for fibre length. Silencing of GhHOX3 greatly reduces (>80%) fibre length, whereas its overexpression leads to longer fibre. Combined transcriptomic and biochemical analyses identify target genes of GhHOX3 that also contain the L1-box cis-element, including two cell wall loosening protein genes GhRDL1 and GhEXPA1. GhHOX3 interacts with GhHD1, another homeodomain protein, resulting in enhanced transcriptional activity, and with cotton DELLA, GhSLR1, repressor of the growth hormone gibberellin (GA). GhSLR1 interferes with the GhHOX3–GhHD1 interaction and represses target gene transcription. Our results uncover a novel mechanism whereby a homeodomain protein transduces GA signal to promote fibre cell elongation. PMID:25413731

  13. Progressive Retinal Degeneration and Accumulation of Autofluorescent Lipopigments in Progranulin Deficient Mice

    PubMed Central

    Hafler, Brian P.; Klein, Zoe A.; Zhou, Z. Jimmy; Strittmatter, Stephen M.

    2014-01-01

    Prior investigations have shown that patients with neuronal ceroid lipofuscinosis (NCL) develop neurodegeneration characterized by vision loss, motor dysfunction, seizures, and often early death. Neuropathological analysis of patients with NCL shows accumulation of intracellular autofluorescent storage material, lipopigment, throughout neurons in the central nervous system including in the retina. A recent study of a sibling pair with adult onset NCL and retinal degeneration showed linkage to the region of the progranulin (GRN) locus and a homozygous mutation was demonstrated in GRN. In particular, the sibling pair with a mutation in GRN developed retinal degeneration and optic atrophy. This locus for this form of adult onset neuronal ceroid lipofuscinosis was designated neuronal ceroid lipofuscinosis-11 (CLN11). Based on these clinical observations, we wished to determine whether Grn-null mice develop accumulation of autofluorescent particles and retinal degeneration. Retinas of both wild-type and Progranulin deficient mice were examined by immunostaining and autofluorescence. Accumulation of autofluorescent material was present in Progranulin deficient mice at 12 months. Degeneration of multiple classes of neurons including photoreceptors and retinal ganglion cells was noted in mice at 12 and 18 months. Our data shows that Grn−/− mice develop degenerative pathology similar to features of human CLN11. PMID:25234724

  14. GREG cells, a dysferlin-deficient myogenic mouse cell line

    SciTech Connect

    Humphrey, Glen W.; Mekhedov, Elena; Blank, Paul S.; Morree, Antoine de; Pekkurnaz, Gulcin; Nagaraju, Kanneboyina; Zimmerberg, Joshua

    2012-01-15

    The dysferlinopathies (e.g. LGMD2b, Myoshi myopathy) are progressive, adult-onset muscle wasting syndromes caused by mutations in the gene coding for dysferlin. Dysferlin is a large ({approx} 200 kDa) membrane-anchored protein, required for maintenance of plasmalemmal integrity in muscle fibers. To facilitate analysis of dysferlin function in muscle cells, we have established a dysferlin-deficient myogenic cell line (GREG cells) from the A/J mouse, a genetic model for dysferlinopathy. GREG cells have no detectable dysferlin expression, but proliferate normally in growth medium and fuse into functional myotubes in differentiation medium. GREG myotubes exhibit deficiencies in plasma membrane repair, as measured by laser wounding in the presence of FM1-43 dye. Under the wounding conditions used, the majority ({approx} 66%) of GREG myotubes lack membrane repair capacity, while no membrane repair deficiency was observed in dysferlin-normal C2C12 myotubes, assayed under the same conditions. We discuss the possibility that the observed heterogeneity in membrane resealing represents genetic compensation for dysferlin deficiency.

  15. Abalation of Ghrelin receptor in leptin-deficient mice has paradoxical effects on glucose homeostasis compared to Ghrelin-abalated Leptin-deficient mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ghrelin is produced predominantly in stomach and is known to be the endogenous ligand of the growth hormone secretagogue receptor (GHSR). Ghrelin is a GH stimulator and an orexigenic hormone. In contrast, leptin is an anorexic hormone, and leptin-deficient ob/ob mice are obese and diabetic. To study...

  16. Structural-Functional Analysis Reveals a Specific Domain Organization in Family GH20 Hexosaminidases

    PubMed Central

    Val-Cid, Cristina; Biarnés, Xevi; Faijes, Magda; Planas, Antoni

    2015-01-01

    Hexosaminidases are involved in important biological processes catalyzing the hydrolysis of N-acetyl-hexosaminyl residues in glycosaminoglycans and glycoconjugates. The GH20 enzymes present diverse domain organizations for which we propose two minimal model architectures: Model A containing at least a non-catalytic GH20b domain and the catalytic one (GH20) always accompanied with an extra α-helix (GH20b-GH20-α), and Model B with only the catalytic GH20 domain. The large Bifidobacterium bifidum lacto-N-biosidase was used as a model protein to evaluate the minimal functional unit due to its interest and structural complexity. By expressing different truncated forms of this enzyme, we show that Model A architectures cannot be reduced to Model B. In particular, there are two structural requirements general to GH20 enzymes with Model A architecture. First, the non-catalytic domain GH20b at the N-terminus of the catalytic GH20 domain is required for expression and seems to stabilize it. Second, the substrate-binding cavity at the GH20 domain always involves a remote element provided by a long loop from the catalytic domain itself or, when this loop is short, by an element from another domain of the multidomain structure or from the dimeric partner. Particularly, the lacto-N-biosidase requires GH20b and the lectin-like domain at the N- and C-termini of the catalytic GH20 domain to be fully soluble and functional. The lectin domain provides this remote element to the active site. We demonstrate restoration of activity of the inactive GH20b-GH20-α construct (model A architecture) by a complementation assay with the lectin-like domain. The engineering of minimal functional units of multidomain GH20 enzymes must consider these structural requirements. PMID:26024355

  17. Iron deficiency.

    PubMed

    Scrimshaw, N S

    1991-10-01

    The world's leading nutritional problem is iron deficiency. 66% of children and women aged 15-44 years in developing countries have it. Further, 10-20% of women of childbearing age in developed countries are anemic. Iron deficiency is identified with often irreversible impairment of a child's learning ability. It is also associated with low capacity for adults to work which reduces productivity. In addition, it impairs the immune system which reduces the body's ability to fight infection. Iron deficiency also lowers the metabolic rate and the body temperature when exposed to cold. Hemoglobin contains nearly 73% of the body's iron. This iron is always being recycled as more red blood cells are made. The rest of the needed iron does important tasks for the body, such as binds to molecules that are reservoirs of oxygen for muscle cells. This iron comes from our diet, especially meat. Even though some plants, such as spinach, are high in iron, the body can only absorb 1.4-7% of the iron in plants whereas it can absorb 20% of the iron in red meat. In many developing countries, the common vegetarian diets contribute to high rates of iron deficiency. Parasitic diseases and abnormal uterine bleeding also promote iron deficiency. Iron therapy in anemic children can often, but not always, improve behavior and cognitive performance. Iron deficiency during pregnancy often contributes to maternal and perinatal mortality. Yet treatment, if given to a child in time, can lead to normal growth and hinder infections. However, excess iron can be damaging. Too much supplemental iron in a malnourished child promotes fatal infections since the excess iron is available for the pathogens use. Many countries do not have an effective system for diagnosing, treating, and preventing iron deficiency. Therefore a concerted international effort is needed to eliminate iron deficiency in the world. PMID:1745900

  18. GPR101 Mutations are not a Frequent Cause of Congenital Isolated Growth Hormone Deficiency.

    PubMed

    Castinetti, F; Daly, A F; Stratakis, C A; Caberg, J-H; Castermans, E; Trivellin, G; Rostomyan, L; Saveanu, A; Jullien, N; Reynaud, R; Barlier, A; Bours, V; Brue, T; Beckers, A

    2016-06-01

    Patients with Xq26.3 microduplication present with X-linked acrogigantism (X-LAG) syndrome, an early-childhood form of gigantism due to marked growth hormone (GH) hypersecretion from mixed GH-PRL adenomas and hyperplasia. The microduplication includes GPR101, which is upregulated in patients' tumor tissue. The GPR101 gene codes for an orphan G protein coupled receptor that is normally highly expressed in the hypothalamus. Our aim was to determine whether GPR101 loss of function mutations or deletions could be involved in patients with congenital isolated GH deficiency (GHD). Taking advantage of the cohort of patients from the GENHYPOPIT network, we studied 41 patients with unexplained isolated GHD. All patients had Sanger sequencing of the GPR101 gene and array comparative genome hybridization (aCGH) to look for deletions. Functional studies (cell culture with GH secretion measurements, cAMP response) were performed. One novel GPR101 variant, c.589 G>T (p.V197L), was seen in the heterozygous state in a patient with isolated GHD. In silico analysis suggested that this variant could be deleterious. Functional studies did not show any significant difference in comparison with wild type for GH secretion and cAMP response. No truncating, frameshift, or small insertion-deletion (indel) GPR101 mutations were seen in the 41 patients. No deletion or other copy number variation at chromosome Xq26.3 was found on aCGH. We found a novel GPR101 variant of unknown significance, in a patient with isolated GH deficiency. Our study did not identify GPR101 abnormalities as a frequent cause of GH deficiency. PMID:26797872

  19. Structure-function relationships of family GH70 glucansucrase and 4,6-α-glucanotransferase enzymes, and their evolutionary relationships with family GH13 enzymes.

    PubMed

    Meng, Xiangfeng; Gangoiti, Joana; Bai, Yuxiang; Pijning, Tjaard; Van Leeuwen, Sander S; Dijkhuizen, Lubbert

    2016-07-01

    Lactic acid bacteria (LAB) are known to produce large amounts of α-glucan exopolysaccharides. Family GH70 glucansucrase (GS) enzymes catalyze the synthesis of these α-glucans from sucrose. The elucidation of the crystal structures of representative GS enzymes has advanced our understanding of their reaction mechanism, especially structural features determining their linkage specificity. In addition, with the increase of genome sequencing, more and more GS enzymes are identified and characterized. Together, such knowledge may promote the synthesis of α-glucans with desired structures and properties from sucrose. In the meantime, two new GH70 subfamilies (GTFB- and GTFC-like) have been identified as 4,6-α-glucanotransferases (4,6-α-GTs) that represent novel evolutionary intermediates between the family GH13 and "classical GH70 enzymes". These enzymes are not active on sucrose; instead, they use (α1 → 4) glucans (i.e. malto-oligosaccharides and starch) as substrates to synthesize novel α-glucans by introducing linear chains of (α1 → 6) linkages. All these GH70 enzymes are very interesting biocatalysts and hold strong potential for applications in the food, medicine and cosmetic industries. In this review, we summarize the microbiological distribution and the structure-function relationships of family GH70 enzymes, introduce the two newly identified GH70 subfamilies, and discuss evolutionary relationships between family GH70 and GH13 enzymes. PMID:27155661

  20. Effects of growth hormone therapeutic supplementation on hematopoietic stem/progenitor cells in children with growth hormone deficiency: focus on proliferation and differentiation capabilities.

    PubMed

    Kawa, M P; Stecewicz, I; Piecyk, K; Pius-Sadowska, E; Paczkowska, E; Rogińska, D; Sobuś, A; Łuczkowska, K; Gawrych, E; Petriczko, E; Walczak, M; Machaliński, B

    2015-09-01

    We investigated the direct effects of growth hormone (GH) replacement therapy (GH-RT) on hematopoiesis in children with GH deficiency (GHD) with the special emphasis on proliferation and cell cycle regulation. Peripheral blood (PB) was collected from sixty control individuals and forty GHD children before GH-RT and in 3rd and 6th month of GH-RT to measure hematological parameters and isolate CD34(+)-enriched hematopoietic progenitor cells (HPCs). Selected parameters of PB were analyzed by hematological analyzer. Moreover, collected HPCs were used to analyze GH receptor (GHR) and IGF1 expression, clonogenicity, and cell cycle activity. Finally, global gene expression profile of collected HPCs was analyzed using genome-wide RNA microarrays. GHD resulted in a decrease in several hematological parameters related to RBCs and significantly diminished clonogenicity of erythroid progenies. In contrast, GH-RT stimulated increases in clonogenic growth of erythroid lineage and RBC counts as well as significant up-regulation of cell cycle-propagating genes, including MAP2K1, cyclins D1/E1, PCNA, and IGF1. Likewise, GH-RT significantly modified GHR expression in isolated HPCs and augmented systemic IGF1 levels. Global gene expression analysis revealed significantly higher expression of genes associated with cell cycle, proliferation, and differentiation in HPCs from GH-treated subjects. (i) GH-RT significantly augments cell cycle progression in HPCs and increases clonogenicity of erythroid progenitors; (ii) GHR expression in HPCs is modulated by GH status; (iii) molecular mechanisms by which GH influences hematopoiesis might provide a basis for designing therapeutic interventions for hematological complications related to GHD. PMID:25920498

  1. Sequential Exercise in Triathletes: Variations in GH and Water Loss

    PubMed Central

    Galy, Olivier; Chamari, Karim; Peyreigne, Christelle; Mercier, Jacques; Hue, Olivier

    2014-01-01

    Growth hormone (GH) may stimulate water loss during exercise by activating sweating. This study investigated GH secretion and water loss during sequential cycling and running, taking postural changes into account. The two exercise segments had similar durations and were performed at the same relative intensity to determine their respective contributions to water loss and the plasma volume variation noted in such trials. Eight elite triathletes first performed an incremental cycle test to assess maximal oxygen consumption. Then, the triathletes performed one of two trials in randomized order: constant submaximal cycling followed by treadmill running (C1-R2) or an inversed succession of running followed by cycling (R1-C2). Each segment of both trials was performed for 20 minutes at ∼75% of maximal oxygen consumption. The second trial, reversing the segment order of the first trial, took place two weeks later. During cycling, the triathletes used their own bicycles equipped with a profiled handlebar. Blood sampling (for GH concentrations, plasma viscosity and plasma volume variation) was conducted at rest and after each segment while water loss was estimated from the post- and pre-measures. GH increases were significantly lower in R2 than C2 (72.2±50.1 vs. 164.0±157 ng.ml−1.min−1, respectively; P<0.05). Water loss was significantly lower after C1-R2 than R1-C2 (1105±163 and 1235±153 ml, respectively; P<0.05). Plasma volume variation was significantly negative in C1 and R1 (−6.15±2.0 and −3.16±5.0%, respectively; P<0.05), not significant in C2, and significantly positive for seven subjects in R2 (4.05±3.1%). We concluded that the lower GH increases in R2 may have contributed to the smaller reduction in plasma volume by reducing sweating. Moreover, this lower GH response could be explained by the postural change during the transition from cycling to running. We recommend to pay particular attention to their hydration status during R1 which could limit a

  2. Sequential exercise in triathletes: variations in GH and water loss.

    PubMed

    Galy, Olivier; Chamari, Karim; Peyreigne, Christelle; Mercier, Jacques; Hue, Olivier

    2014-01-01

    Growth hormone (GH) may stimulate water loss during exercise by activating sweating. This study investigated GH secretion and water loss during sequential cycling and running, taking postural changes into account. The two exercise segments had similar durations and were performed at the same relative intensity to determine their respective contributions to water loss and the plasma volume variation noted in such trials. Eight elite triathletes first performed an incremental cycle test to assess maximal oxygen consumption. Then, the triathletes performed one of two trials in randomized order: constant submaximal cycling followed by treadmill running (C1-R2) or an inversed succession of running followed by cycling (R1-C2). Each segment of both trials was performed for 20 minutes at ∼75% of maximal oxygen consumption. The second trial, reversing the segment order of the first trial, took place two weeks later. During cycling, the triathletes used their own bicycles equipped with a profiled handlebar. Blood sampling (for GH concentrations, plasma viscosity and plasma volume variation) was conducted at rest and after each segment while water loss was estimated from the post- and pre-measures. GH increases were significantly lower in R2 than C2 (72.2±50.1 vs. 164.0±157 ng x ml(-1) x min(-1), respectively; P<0.05). Water loss was significantly lower after C1-R2 than R1-C2 (1105±163 and 1235±153 ml, respectively; P<0.05). Plasma volume variation was significantly negative in C1 and R1 (-6.15±2.0 and -3.16±5.0%, respectively; P<0.05), not significant in C2, and significantly positive for seven subjects in R2 (4.05±3.1%). We concluded that the lower GH increases in R2 may have contributed to the smaller reduction in plasma volume by reducing sweating. Moreover, this lower GH response could be explained by the postural change during the transition from cycling to running. We recommend to pay particular attention to their hydration status during R1 which could limit a

  3. Growth hormone deficiency and cerebral palsy

    PubMed Central

    Devesa, Jesús; Casteleiro, Nerea; Rodicio, Cristina; López, Natalia; Reimunde, Pedro

    2010-01-01

    Cerebral palsy (CP) is a catastrophic acquired disease, occurring during development of the fetal or infant brain. It mainly affects the motor control centres of the developing brain, but can also affect cognitive functions, and is usually accompanied by a cohort of symptoms including lack of communication, epilepsy, and alterations in behavior. Most children with cerebral palsy exhibit a short stature, progressively declining from birth to puberty. We tested here whether this lack of normal growth might be due to an impaired or deficient growth hormone (GH) secretion. Our study sample comprised 46 CP children, of which 28 were male and 18 were female, aged between 3 and 11 years. Data obtained show that 70% of these children lack normal GH secretion. We conclude that GH replacement therapy should be implemented early for CP children, not only to allow them to achieve a normal height, but also because of the known neurotrophic effects of the hormone, perhaps allowing for the correction of some of the common disabilities experienced by CP children. PMID:20856687

  4. The GH/IGF-1 System in Critical Illness

    PubMed Central

    Elijah, Itoro; Branski, Ludwik K.; Finnerty, Celeste F.; Herndon, David N.

    2013-01-01

    The Growth Hormone and Insulin-like Growth Factor-1 axis plays a pivotal role in critical illness, with a derangement leading to profound changes in metabolism. Protein wasting with skeletal muscle loss, delayed wound healing, and impaired recovery of organ systems are some of the most feared consequences. The use of human recombinant Growth Hormone (rhGH) and Insulin-like Growth Factor-1 (IGF-1) - alone and in combination - has been studied extensively in preclinical and clinical trials. This article reviews the current knowlegde and clinical practice of the use of rhGh and IGF-1 in critically ill patients, with a special focus on the trauma and burns patient population. PMID:21925076

  5. Structure and regulation of expression of the mouse GH receptor.

    PubMed

    Talamantes, F; Ortiz, R

    2002-10-01

    GH-binding protein (GHBP) in the mouse consists of a ligand-binding domain, which is identical to the extracellular portion of the GH receptor (GHR), and a hydrophilic C-terminal domain, in place of the transmembrane and intracellular domains of the GHR. The two proteins are encoded by separate mRNAs which are derived from a single gene by alternative splicing. Determination of the gestational profiles of GHR and GHBP mRNA expression in mouse liver and placenta shows that in the liver, the 1.4 kb mRNA corresponding to the mouse GHBP increases approximately 20-fold between non-pregnant and late pregnant mice, whereas the relative increase in the expression of the 4.2 kb mouse GHR was 8-fold. The rise in the steady-state levels of both mRNAs began on day 9 of gestation. Mouse GHBP mRNA levels continue to rise until day 15 of pregnancy, while GHR mRNA abundance reaches a plateau by day 13. By elucidating the temporal changes in GHR and GHBP mRNA abundance during pregnancy and lactation in multiple maternal tissues and by assessing the ontogeny of these mRNAs in fetal and early postnatal mouse liver, our studies have demonstrated that the alternative splicing of mouse GHR/GHBP mRNA precursor is regulated in a tissue-, developmental stage- and physiological state-specific manner. In vitro studies using hepatocytes in culture have begun to elucidate the hormonal factor(s) involved in the gestation control of the expression of GHR and GHBP. Treatment of hepatocytes with GH or estradiol (E2) alone did not have any effect on the cellular concentrations of GHBP and GHR. However, the combination of E2 and GH up-regulated the cellular concentrations of GHBP and GHR 2- to 3-fold. GHBP and GHR mRNA concentrations were also up-regulated 2- to 3-fold. ICI 182-780, a competitive inhibitor of E2 for the estrogen receptor (ER), at different concentrations inhibited the E2- and GH-induced stimulation of GHBP and GHR. Furthermore, ER concentrations increased 5- to 7-fold in hepatocytes

  6. Enhanced spontaneous locomotor activity in bovine GH transgenic mice involves peripheral mechanisms.

    PubMed

    Bohlooly-Y, M; Olsson, B; Gritli-Linde, A; Brusehed, O; Isaksson, O G; Ohlsson, C; Söderpalm, B; Törnell, J; Ola, B

    2001-10-01

    Clinical and experimental studies indicate a role for GH in mechanisms related to anhedonia/hedonia, psychic energy, and reward. Recently we showed that transgenic mice with general overexpression of bovine GH display increased spontaneous locomotor activity. In the present study, we investigated whether this behavioral change is owing to a direct action of GH in the central nervous system or to peripheral GH actions. A transgenic construct, containing the glial fibrillary acidic protein promoter directing specific expression of bovine GH to the central nervous system, was designed. The central nervous system-specific expression of bovine GH in the glial fibrillary acidic protein-bovine GH transgenic mice was confirmed, but no effect on spontaneous locomotor activity was observed. Serum bovine GH levels were increased in glial fibrillary acidic protein-bovine GH transgenic mice but clearly lower than in transgenic mice with general overexpression of bovine GH. In contrast to the transgenic mice with general overexpression of bovine GH, glial fibrillary acidic protein-bovine GH mice did not display any difference in serum IGF-I levels. The levels of free T(3) and the conversion of the free T(4) to free T(3) were only increased in transgenic mice with general overexpression of bovine GH, but serum corticosterone levels were similarly increased in both transgenic models. These results suggest that free T(3) and/or IGF-I, affecting dopamine and serotonin systems in the central nervous system, may mediate the enhanced locomotor activity observed in transgenic mice with general overexpression of bovine GH. PMID:11564723

  7. Molecular evolution of GH in primates: characterisation of the GH genes from slow loris and marmoset defines an episode of rapid evolutionary change.

    PubMed

    Wallis, O C; Zhang, Y P; Wallis, M

    2001-06-01

    Pituitary growth hormone (GH), like several other protein hormones, shows an unusual episodic pattern of molecular evolution in which sustained bursts of rapid change are imposed on long periods of very slow evolution (near-stasis). A marked period of rapid change occurred in the evolution of GH in primates or a primate ancestor, and gave rise to the species specificity that is characteristic of human GH. We have defined more precisely the position of this burst by cloning and sequencing the GH genes for a prosimian, the slow loris (Nycticebus pygmaeus) and a New World monkey, marmoset (Callithrix jacchus). Slow loris GH is very similar in sequence to pig GH, demonstrating that the period of rapid change occurred during primate evolution, after the separation of lines leading to prosimians and higher primates. The putative marmoset GH is similar in sequence to human GH, demonstrating that the accelerated evolution occurred before divergence of New World monkeys and Old World monkeys/apes. The burst of change was confined largely to coding sequence for mature GH, and is not marked in other components of the gene sequence including signal peptide, 5' upstream region and introns. A number of factors support the idea that this episode of rapid change was due to positive adaptive selection. Thus (1) there is no apparent loss of function of GH in man compared with non-primates, (2) after the episode of rapid change the rate of evolution fell towards the slow basal level that is seen for most mammalian GHs, (3) the accelerated rate of substitution for the exons of the GH gene significantly exceeds that for introns, and (4) the amino acids contributing to the hydrophobic core of GH are strongly conserved when higher primate and other GH sequences are compared, and for coding sequences other than that coding for hydrophobic core residues the rate of substitution for non-synonymous sites (K(A)) is significantly greater than that for synonymous sites (K(S)). In slow loris, as

  8. Caenorhabditis elegans dnj-14, the orthologue of the DNAJC5 gene mutated in adult onset neuronal ceroid lipofuscinosis, provides a new platform for neuroprotective drug screening and identifies a SIR-2.1-independent action of resveratrol.

    PubMed

    Kashyap, Sudhanva S; Johnson, James R; McCue, Hannah V; Chen, Xi; Edmonds, Matthew J; Ayala, Mimieveshiofuo; Graham, Margaret E; Jenn, Robert C; Barclay, Jeff W; Burgoyne, Robert D; Morgan, Alan

    2014-11-15

    Adult onset neuronal lipofuscinosis (ANCL) is a human neurodegenerative disorder characterized by progressive neuronal dysfunction and premature death. Recently, the mutations that cause ANCL were mapped to the DNAJC5 gene, which encodes cysteine string protein alpha. We show here that mutating dnj-14, the Caenorhabditis elegans orthologue of DNAJC5, results in shortened lifespan and a small impairment of locomotion and neurotransmission. Mutant dnj-14 worms also exhibited age-dependent neurodegeneration of sensory neurons, which was preceded by severe progressive chemosensory defects. A focussed chemical screen revealed that resveratrol could ameliorate dnj-14 mutant phenotypes, an effect mimicked by the cAMP phosphodiesterase inhibitor, rolipram. In contrast to other worm neurodegeneration models, activation of the Sirtuin, SIR-2.1, was not required, as sir-2.1; dnj-14 double mutants showed full lifespan rescue by resveratrol. The Sirtuin-independent neuroprotective action of resveratrol revealed here suggests potential therapeutic applications for ANCL and possibly other human neurodegenerative diseases. PMID:24947438

  9. Genotypic and phenotypic features of citrin deficiency: five-year experience in a Chinese pediatric center.

    PubMed

    Song, Yuan-Zong; Deng, Mei; Chen, Feng-Ping; Wen, Fang; Guo, Li; Cao, Shui-Liang; Gong, Jian; Xu, Hao; Jiang, Guang-Yu; Zhong, Le; Kobayashi, Keiko; Saheki, Takeyori; Wang, Zi-Neng

    2011-07-01

    Citrin is a liver-type aspartate/glutamate carrier (AGC) encoded by the gene SLC25A13. Two phenotypes for human citrin deficiency have been described, namely the adult-onset citrullinemia type II (CTLN2) and the neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). However, citrin deficiency currently remains a perplexing and poorly recognized disorder. In particular, description of post-NICCD clinical presentations before CTLN2 onset is rather limited. Analysis of SLC25A13 mutations, identification of dysmorphic erythrocytes, hepatobiliary scintigraphic imaging and investigation of post-NICCD clinical presentations were performed in a citrin-deficient cohort comprised of 51 cases of children diagnosed with citrin deficiency in a Chinese pediatric center. Twelve SLC25A13 mutations were detected in this cohort, including the novel V411M and G283X mutations. Among the 51 citrin-deficient subjects, 7 cases had echinocytosis, which was associated with more severe biochemical abnormalities. Delayed hepatic discharge and bile duct/bowel visualization were common scintigraphic findings. Moreover, 9 of the 34 post-NICCD cases demonstrated concurrent failure to thrive and dyslipidemia, constituting a clinical phenotype different from NICCD and CTLN2. The novel mutations, echinocytosis, hepatobiliary scintigraphic features and the novel clinical phenotype in this study expanded the genotypic and phenotypic spectrum of citrin deficiency, and challenge the traditionally-assumed 'apparently healthy' period after the NICCD state for this disease entity. PMID:21424115

  10. The Emerging Role of IGF-1 Deficiency in Cardiovascular Aging: Recent Advances

    PubMed Central

    Csiszar, Anna

    2012-01-01

    This review focuses on cardiovascular protective effects of insulin-like growth factor (IGF)-1, provides a landscape of molecular mechanisms involved in cardiovascular alterations in patients and animal models with congenital and adult-onset IGF-1 deficiency, and explores the link between age-related IGF-1 deficiency and the molecular, cellular, and functional changes that occur in the cardiovascular system during aging. Microvascular protection conferred by endocrine and paracrine IGF-1 signaling, its implications for the pathophysiology of cardiac failure and vascular cognitive impairment, and the role of impaired cellular stress resistance in cardiovascular aging considered here are based on emerging knowledge of the effects of IGF-1 on Nrf2-driven antioxidant response. PMID:22451468

  11. Borjeson-Forssman-Lehmann syndrome and multiple pituitary hormone deficiency.

    PubMed

    Birrell, G; Lampe, A; Richmond, S; Bruce, S N; Gécz, J; Lower, K; Wright, M; Cheetham, T D

    2003-12-01

    We describe two brothers with Borjeson-Forssman-Lehmann syndrome and the 22A-->T (Lys8X) PHF6 mutation, who presented with the symptoms and signs of multiple pituitary hormone deficiency. Biochemical investigations and radiology confirmed growth hormone (GH), thyroid stimulating hormone (TSH) and adrenocorticotrophic hormone (ACTH) as well as gonadotrophin deficiency. They were also found to have optic nerve hypoplasia. This family suggests that the BFL gene product may play an important role in midline neuro-development including the hypothalamo-pituitary axis. PMID:14714754

  12. A novel NAP member GhNAP is involved in leaf senescence in Gossypium hirsutum

    PubMed Central

    Fan, Kai; Bibi, Noreen; Gan, Susheng; Li, Feng; Yuan, Shuna; Ni, Mi; Wang, Ming; Shen, Hao; Wang, Xuede

    2015-01-01

    Premature leaf senescence has a negative influence on the yield and quality of cotton, and several genes have been found to regulate leaf senescence. Howeer, many underlying transcription factors are yet to be identified. In this study, a NAP-like transcription factor (GhNAP) was isolated from Gossypium hirsutum. GhNAP has the typical NAC structure and a conserved novel subdomain in its divergent transcription activation region (TAR). GhNAP was demonstrated to be a nuclear protein, and it showed transcriptional activation activity in yeast. Furthermore, the expression of GhNAP was closely associated with leaf senescence. GhNAP could rescue the delayed-senescence phenotype of the atnap null mutant. Overexpression of GhNAP could cause precocious senescence in Arabidopsis. However, down-regulation of GhNAP delayed leaf senescence in cotton, and affected cotton yield and its fibre quality. Moreover, the expression of GhNAP can be induced by abscisic acid (ABA), and the delayed leaf senescence phenotype in GhNAPi plants might be caused by the decreased ABA level and reduced expression level of ABA-responsive genes. All of the results suggested that GhNAP could regulate the leaf senescence via the ABA-mediated pathways and was further related to the yield and quality in cotton. PMID:25991739

  13. Low doses of estradiol partly inhibit release of GH in sheep without affecting basal levels.

    PubMed

    Hudmon, A; Davenport, G; Coleman, E S; Sartin, J L

    2009-10-01

    Estradiol increases basal growth hormone (GH) concentrations in sheep and cattle. This study sought to determine the effects of estradiol on GH-releasing hormone (GRH)-stimulated GH release in sheep. Growth hormone secretory characteristics, the GH response to GRH, and steady-state GH mRNA concentrations were determined in castrated male lambs treated with 2 different doses of estradiol 17-beta for a 28-d experimental period. Although no differences between treatments in mean GH, basal GH, or GH pulse number were observed after 28 d of estradiol treatment, GH pulse amplitude was greater (P < 0.05) in the 2.00-cm implant-treated animals than in the control and 0.75-cm implant group. The effect of estradiol treatment on GRH-stimulated GH release revealed differences between the control and estradiol-treated animals (P < 0.05). The 15-min GH responses to 0.075 microg/kg hGRH in the control, 0.75-cm, and 2.00-cm implant groups, respectively, were 76 +/- 10, 22.6 +/- 2.1, and 43.6 +/- 15.0 ng/mL. Growth hormone mRNA content was determined for pituitary glands from the different treatment groups, and no differences in steady-state GH mRNA levels were observed. There were no differences in the mean plasma concentrations of IGF-I, cortisol, T(3), or T(4) from weekly samples. Growth hormone release from cultured ovine pituitary cells from control sheep was not affected by estradiol after 72 h or in a subsequent 3-h incubation with estradiol combined with GRH. These data suggest that estradiol has differing actions on basal and GRH-stimulated GH concentrations in plasma, but the increase in pulse amplitude does not represent an increased pituitary sensitivity to GRH. PMID:19616401

  14. Excessive Growth Hormone Expression in Male GH Transgenic Mice Adversely Alters Bone Architecture and Mechanical Strength

    PubMed Central

    Lim, S. V.; Marenzana, M.; Hopkinson, M.; List, E. O.; Kopchick, J. J.; Pereira, M.; Javaheri, B.; Roux, J. P.; Chavassieux, P.; Korbonits, M.

    2015-01-01

    Patients with acromegaly have a higher prevalence of vertebral fractures despite normal bone mineral density (BMD), suggesting that GH overexpression has adverse effects on skeletal architecture and strength. We used giant bovine GH (bGH) transgenic mice to analyze the effects of high serum GH levels on BMD, architecture, and mechanical strength. Five-month-old hemizygous male bGH mice were compared with age- and sex-matched nontransgenic littermates controls (NT; n=16/group). Bone architecture and BMD were analyzed in tibia and lumbar vertebrae using microcomputed tomography. Femora were tested to failure using three-point bending and bone cellular activity determined by bone histomorphometry. bGH transgenic mice displayed significant increases in body weight and bone lengths. bGH tibia showed decreases in trabecular bone volume fraction, thickness, and number compared with NT ones, whereas trabecular pattern factor and structure model index were significantly increased, indicating deterioration in bone structure. Although cortical tissue perimeter was increased in transgenic mice, cortical thickness was reduced. bGH mice showed similar trabecular BMD but reduced trabecular thickness in lumbar vertebra relative to controls. Cortical BMD and thickness were significantly reduced in bGH lumbar vertebra. Mechanical testing of femora confirmed that bGH femora have decreased intrinsic mechanical properties compared with NT ones. Bone turnover is increased in favor of bone resorption in bGH tibia and vertebra compared with controls, and serum PTH levels is also enhanced in bGH mice. These data collectively suggest that high serum GH levels negatively affect bone architecture and quality at multiple skeletal sites. PMID:25646711

  15. Neuroprotection by GH against excitotoxic-induced cell death in retinal ganglion cells.

    PubMed

    Martínez-Moreno, Carlos G; Ávila-Mendoza, José; Wu, Yilun; Arellanes-Licea, Elvira Del Carmen; Louie, Marcela; Luna, Maricela; Arámburo, Carlos; Harvey, Steve

    2016-08-01

    Retinal growth hormone (GH) has been shown to promote cell survival in retinal ganglion cells (RGCs) during developmental waves of apoptosis during chicken embryonic development. The possibility that it might also against excitotoxicity-induced cell death was therefore examined in the present study, which utilized quail-derived QNR/D cells as an in vitro RGC model. QNR/D cell death was induced by glutamate in the presence of BSO (buthionine sulfoxamide) (an enhancer of oxidative stress), but this was significantly reduced (P<0.01) in the presence of exogenous recombinant chicken GH (rcGH). Similarly, QNR/D cells that had been prior transfected with a GH plasmid to overexpress secreted and non-secreted GH. This treatment reduced the number of TUNEL-labeled cells and blocked their release of lactate dehydrogenase (LDH). In a further experiment with dissected neuroretinal explants from ED (embryonic day) 10 embryos, rcGH treatment of the explants also reduced (P<0.01) the number of glutamate-BSO-induced apoptotic cells and blocked the explant release of LDH. This neuroprotective action was likely mediated by increased STAT5 phosphorylation and increased bcl-2 production, as induced by exogenous rcGH treatment and the media from GH-overexpressing QNR/D cells. As rcGH treatment and GH-overexpression cells also increased the content of IGF-1 and IGF-1 mRNA this neuroprotective action of GH is likely to be mediated, at least partially, through an IGF-1 mechanism. This possibility is supported by the fact that the siRNA knockdown of GH or IGF-1 significantly reduced QNR/D cell viability, as did the immunoneutralization of IGF-1. GH is therefore neuroprotective against excitotoxicity-induced RGC cell death by anti-apoptotic actions involving IGF-1 stimulation. PMID:27129619

  16. Fetal programming, epigenetics, and adult onset disease.

    PubMed

    Lane, Robert H

    2014-12-01

    How early life events program adult disease is undergoing a transition from the broad field of maternal malnutrition to the current relevant issues of food deserts and prematurity. Although many adult diseases and morbidities associate with various early life events and programming, the morbidities of insulin resistance, cardiovascular disease, and obesity seem to be common end points of many early life events despite potential confounders. PMID:25459776

  17. Unusual sequelae of adult-onset dermatomyositis

    PubMed Central

    Naffaa, Mohammad Ebrahim; Bishara, Rema; Braun-Moscovici, Yolanda; Balbir-Gurman, Alexandra

    2014-01-01

    A 44-year-old woman diagnosed with dermatomyositis 5 years ago based on progressive proximal muscle weakness, elevated creatine kinase, typical findings on electromyography and muscle biopsy. Despite the treatment, in contrast to improvement in her muscle symptoms, the heliotrope rash of her eyelids persisted. After several years, the patient developed multiple limited skin retraction lesions with hyperpigmentation on both lower limbs. Palpation of these lesions revealed dry, cold and very firm skin on both thighs and calves, particularly in the distal areas. X-ray and ultrasound imaging of the calves showed multiple subcutaneous calcifications in the distal muscles. PMID:25085949

  18. Alpha-1 Antitrypsin Deficiency

    MedlinePlus

    ... Liver Disease Information > Alpha-1 Antitrypsin Deficiency Alpha-1 Antitrypsin Deficiency Explore this section to learn more about alpha-1 antitrypsin deficiency, including a description of the disorder ...

  19. GH, IGF-I and binding proteins in altered nutritional states.

    PubMed

    Ross, R J

    2000-06-01

    Nutritional state has profound actions at all levels of the GH/IGF-I axis and growth hormone has potent effects on nutritional state. The growth promoting effects of GH on linear height in children has long been recognised and, more recently, the important action of GH in maintaining adult body composition have been appreciated. The strong anabolic actions of GH have made it a drug of abuse among athletes and, of interest, clinicians, as a potent anti-catabolic therapy. In this review we consider the effects of nutrition on the GH/IGF-I axis and then discuss its potential use as an anti-catabolic agent. We also note the recent study in critically ill patients which has been associated with a poor outcome using high dose GH therapy. PMID:10997619

  20. The R3-MYB Gene GhCPC Negatively Regulates Cotton Fiber Elongation

    PubMed Central

    Liu, Bingliang; Zhu, Yichao; Zhang, Tianzhen

    2015-01-01

    Cotton (Gossypium spp.) fibers are single-cell trichomes that arise from the outer epidermal layer of seed coat. Here, we isolated a R3-MYB gene GhCPC, identified by cDNA microarray analysis. The only conserved R3 motif and different expression between TM-1 and fuzzless-lintless mutants suggested that it might be a negative regulator in fiber development. Transgenic evidence showed that GhCPC overexpression not only delayed fiber initiation but also led to significant decreases in fiber length. Interestingly, Yeast two-hybrid analysis revealed an interaction complex, in which GhCPC and GhTTG1/4 separately interacted with GhMYC1. In transgenic plants, Q-PCR analysis showed that GhHOX3 (GL2) and GhRDL1 were significantly down regulated in −1–5 DPA ovules and fibers. In addition, Yeast one-hybrid analysis demonstrated that GhMYC1 could bind to the E-box cis-elements and the promoter of GhHOX3. These results suggested that GhHOX3 (GL2) might be downstream gene of the regulatory complex. Also, overexpression of GhCPC in tobacco led to differential loss of pigmentation. Taken together, the results suggested that GhCPC might negatively regulate cotton fiber initiation and early elongation by a potential CPC-MYC1-TTG1/4 complex. Although the fibers were shorter in transgenic cotton lines than in the wild type, no significant difference was detected in stem or leaf trichomes, even in cotton mutants (five naked seed or fuzzless), suggesting that fiber and trichome development might be regulated by two sets of genes sharing a similar model. PMID:25646816

  1. GH/IGF-I Transgene Expression on Muscle Homeostasis

    NASA Technical Reports Server (NTRS)

    Schwartz, Robert J.

    1999-01-01

    We propose to test the hypothesis that the growth hormone/ insulin like growth factor-I axis through autocrine/paracrine mechanisms may provide long term muscle homeostasis under conditions of prolonged weightlessness. As a key alternative to hormone replacement therapy, ectopic production of hGH, growth hormone releasing hormone (GHRH), and IGF-I will be studied for its potential on muscle mass impact in transgenic mice under simulated microgravity. Expression of either hGH or IGF-I would provide a chronic source of a growth-promoting protein whose biosynthesis or secretion is shut down in space. Muscle expression of the IGF-I transgene has demonstrated about a 20% increase in hind limb muscle mass over control nontransgenic litter mates. These recent experiments, also establish the utility of hind-limb suspension in mice as a workable model to study atrophy in weight bearing muscles. Thus, transgenic mice will be used in hind-limb suspension models to determine the role of GH/IGF-I on maintenance of muscle mass and whether concentric exercises might act in synergy with hormone treatment. As a means to engineer and ensure long-term protein production that would be workable in humans, gene therapy technology will be used by to monitor muscle mass preservation during hind-limb suspension, after direct intramuscular injection of a genetically engineered muscle-specific vector expressing GHRH. Effects of this gene-based therapy will be assessed in both fast twitch (medial gastrocnemius) and slow twitch muscle (soleus). End-points include muscle size, ultrastructure, fiber type, and contractile function, in normal animals, hind limb suspension, and reambutation.

  2. Screening for dopa-responsive dystonia in patients with Scans Without Evidence of Dopaminergic Deficiency (SWEDD).

    PubMed

    De Rosa, Anna; Carducci, Claudia; Carducci, Carla; Peluso, Silvio; Lieto, Maria; Mazzella, Andrea; Saccà, Francesco; Brescia Morra, Vincenzo; Pappatà, Sabina; Leuzzi, Vincenzo; De Michele, Giuseppe

    2014-11-01

    The clinical diagnosis of Parkinson's Disease (PD) is not supported by Single Photon Emission Computed Tomography (SPECT) using dopamine transporter radioligand in 4-15 % of patients. It has been hypothesized that this phenomenon, named "Scans Without Evidence of Dopaminergic Deficiency" (SWEDD), may be an adult-onset dystonia. We investigated the hypothesis that these patients might be affected by Dopa-Responsive Dystonia (DRD). We enrolled eleven unrelated patients (8 F and 3 M) with clinical parkinsonism and normal [(123)I]FP-CIT SPECT. The GTP-cyclohydrolase1 (GCH1) gene was sequenced in all patients; urine biopterin and neopterin analysis was carried out in nine and oral phenylalanine (Phe) loading in seven. Neurological examination showed bradykinesia and resting/postural tremor in all patients, and rigidity in ten, suggesting a clinical diagnosis of PD. We detected mild dystonic signs in eight cases. In particular, five of them presented cranial dyskinesias. No mutation of the GCH1 gene was found. The results of the urine biopterin and neopterin analysis and the oral Phe loading did not reveal biochemical abnormalities suggestive of reduced GCH1 activity. We confirm that some clinical features, namely the presence of focal or segmental dystonia, suggest an adult-onset dystonia in SWEDD cases. However, we exclude DRD caused by GCH1 gene mutations in the present series. PMID:25182701

  3. Tripartite neuroendocrine activation of the human growth hormone (GH) axis in women by continuous 24-hour GH-releasing peptide infusion: pulsatile, entropic, and nyctohemeral mechanisms.

    PubMed

    Shah, N; Evans, W S; Bowers, C Y; Veldhuis, J D

    1999-06-01

    Despite the discovery of potent GH-releasing peptides (GHRPs) more than 15 yr ago and the recent cloning of human, rat, and pig GHRP receptors in the hypothalamus and pituitary gland, the neuroregulatory mechanisms of action of GHRP agonists on the human hypothalamo-somatotroph unit are not well delineated. To gain such clinical insights, we evaluated the ultradian (pulsatile), entropic (pattern orderliness), and nyctohemeral GH secretory responses during continuous 24-h i.v. infusion of saline vs. the most potent clinically available hexapeptide, GHRP-2 (1 microg/kg x h) in estrogen-unreplaced (mean serum estradiol, 12 +/- 2.4 pg/mL) postmenopausal women (n = 7) in a paired, randomized design. Blood was sampled every 10 min for 24 h during infusions and was assayed by ultrasensitive GH chemiluminescence assay. Pulsatile GH secretion was quantitated by deconvolution analysis, orderliness of GH release patterns by the approximate entropy statistic, and 24-h GH rhythmicity by cosinor analysis. Statistical analysis revealed that GHRP-2 elicited a 7.7-fold increase in (24-h) mean serum (+/-SEM) GH concentrations, viz. from 0.32 +/- 0.042 (saline) to 2.4 +/- 0.34 microg/L (GHRP-2; P = 0.0006). This occurred via markedly stimulated pulsatile GH release, namely a 7.1-fold augmentation of GH secretory burst mass: 0.87 +/- 0.18 (control) vs. 6.3 +/- 1.3 microg/L (GHRP-2; P = 0.0038). Enhanced GH pulse mass reflected a commensurate 10-fold (P = 0.023) rise in GH secretory burst amplitude [maximal GH secretory rate (micrograms per L/min) attained within a secretory pulse] with no prolongation in event duration. GH burst frequency, interpulse interval, and calculated GH half-life were all invariant of GHRP-2 treatment. Concurrently, as detected in the ultrasensitive GH assay, GHRP-2 augmented deconvolution-estimated interpulse (basal) GH secretion by 4.5-fold (P = 0.025). The approximate entropy of 24-h serum GH concentration profiles rose significantly during GHRP-2 infusion

  4. Difference in growth hormone response to growth hormone-releasing hormone (GHRH) testing following GHRH subacute treatment in normal aging and growth hormone-deficient adults: possible perspectives for therapeutic use of GHRH or its analogs in elderly subjects?

    PubMed

    Iovino, M; Triggiani, V; Giagulli, V A; Iovine, N; Licchelli, B; Resta, F; Sabbà, C; Tafaro, E; Solimando, A; Tommasicchio, A; Guastamacchia, E

    2011-06-01

    The somatotroph axis function shows a decline in the elderly (somatopause). In particular growth hormone (GH) response to GH-releasing hormone (GHRH) is reduced in aged man but less than that observed in GH-deficient adults (GHDAs). Plasma GH response to GHRH (1 µg/kg BW) was significantly lower in four GHDAs than in seven healthy aged men 30, 60, and 90 min after acute GHRH administration. To verify whether a priming regimen might be able to increase the reduced GH response to GHRH, both healthy aged men and GHDA patients underwent repetitive administration of GHRH (100 µg GHRH intravenously as a single morning dose, every 2 days for 12 days). After the GHRH-priming regimen, plasma GH values 30, 60, and 90 min after the acute GHRH test were significantly higher than values at the corresponding time points before priming regimen in healthy aged men but not in GHDA patients. These findings confirmed that somatotroph cells become less sensitive to GHRH with normal aging and demonstrate that repetitive administration of GHRH restores the attenuated response only in healthy aged men but not in GHDA patients. This could support the possible use of GHRH or its analogs instead of recombinant human GH in elderly patients with the advantage of preserving the endogenous pulses of GH with the secretion of the different isoforms of GH. However, concerns arise about the possible role of these molecules in tumorigenesis and tumor growth promotion. PMID:20843274

  5. Genetic and protein biomarkers in blood for the improved detection of GH abuse.

    PubMed

    Ferro, P; Ventura, R; Pérez-Mañá, C; Farré, M; Segura, J

    2016-09-01

    Human Growth Hormone (hGH, somatotropin) is one of the relevant forbidden substances to be detected in sport drug testing. Since the appearance of recombinant hGH (rhGH) in the 80's, its expansion and availability through the black market have increased, so the detection of its abuse continues to be a challenge at present. New techniques or biomarkers that are robust, reliable, sensitive and allowing a large detection time window are welcome. rhGH produces an increase of insulin-like growth factor 1 (IGF-1). FN1 (fibronectin 1) and RAB31 (member of RAS oncogene family) genes have been suggested as two potential biomarkers for IGF-1 abuse. Following this line, in the present study some genetic and proteomic approaches have been performed with fourteen healthy male subjects treated with rhGH (which produces increase of IGF-1 concentrations) to study FN1 gene, FN1 protein, RAB31 gene and RAB31 protein as potential biomarkers for rhGH abuse. The results showed that both, RAB31 and FN1 genes and FN1 protein could be potential biomarkers for rhGH administration. Preliminary assessments of gender, age, acute sport activities and GHRP-2 (pralmorelin, a rhGH releasing peptide) influence suggest they are not relevant confounding factors. Thus, the selected markers present high sensitivity and a larger detection window for rhGH detection than IGF-1 itself. PMID:27243825

  6. Osmoregulatory actions of the GH/IGF axis in non-salmonid teleosts

    USGS Publications Warehouse

    Mancera, J.M.; McCormick, S.D.

    1998-01-01

    Salmonid fishes provided the first findings on the influence of the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis on osmoregulation in teleost fishes. Recent studies on non-salmonid species, however, indicate that this physiological action of the GH/IGF-I axis is not restricted to salmonids or anadromous fishes. GH-producing cells in the pituitary of fish acclimated to different salinities show different degrees of activation depending on the species studied. Plasma GH levels either increase or do not change after transfer of fish from freshwater to seawater. Treatment with GH or IGF-I increases salinity tolerance and/or increases gill Na+,K+-ATPase activity of killifish (Fundulus heteroclitus), tilapia (Oreochromis mossambicus and Oreochromis niloticus) and striped bass (Morone saxatilis). As in salmonids, a positive interaction between GH and cortisol for improving hypoosmoregulatory capacity has been described in tilapia (O. mossambicus). Research on the osmoregulatory role of the GH/IGF-I axis is derived from a small number of teleost species. The study of more species with different osmoregulary patterns will be necessary to fully clarify the osmoregulatory role of GH/IGF-I axis in fish. The available data does suggest, however, that the influence of the GH/IGF-I axis on osmoregulation may be a common feature of euryhalinity in teleosts. Copyright (C) 1998 Elsevier Science Inc.

  7. Growth hormone activity in mitochondria depends on GH receptor Box 1 and involves caveolar pathway targeting

    SciTech Connect

    Perret-Vivancos, Cecile; Abbate, Aude; Ardail, Dominique; Raccurt, Mireille; Usson, Yves; Lobie, Peter E.; Morel, Gerard . E-mail: gerard.morel@univ-lyon1.fr

    2006-02-01

    Growth hormone (GH) binding to its receptor (GHR) initiates GH-dependent signal transduction and internalization pathways to generate the biological effects. The precise role and way of action of GH on mitochondrial function are not yet fully understood. We show here that GH can stimulate cellular oxygen consumption in CHO cells transfected with cDNA coding for the full-length GHR. By using different GHR cDNA constructs, we succeeded in determining the different parts of the GHR implicated in the mitochondrial response to GH. Polarography and two-photon excitation fluorescence microscopy analysis showed that the Box 1 of the GHR intracellular domain was required for an activation of the mitochondrial respiration in response to a GH exposure. However, confocal laser scanning microscopy demonstrated that cells lacking the GHR Box 1 could efficiently internalize the hormone. We demonstrated that internalization mediated either by clathrin-coated pits or by caveolae was able to regulate GH mitochondrial effect: these two pathways are both essential to obtain the GH stimulatory action on mitochondrial function. Moreover, electron microscopic and biochemical approaches allowed us to identify the caveolar pathway as essential for targeting GH and GHR to mitochondria.

  8. Structure of the GH1 domain of guanylate kinase-associated protein from Rattus norvegicus

    SciTech Connect

    Tong, Junsen; Yang, Huiseon; Eom, Soo Hyun; Chun, ChangJu; Im, Young Jun

    2014-09-12

    Graphical abstract: - Highlights: • The crystal structure of GKAP homology domain 1 (GH1) was determined. • GKAP GH1 is a three-helix bundle connected by short flexible loops. • The predicted helix α4 associates weakly with the helix α3, suggesting dynamic nature of the GH1 domain. - Abstract: Guanylate-kinase-associated protein (GKAP) is a scaffolding protein that links NMDA receptor-PSD-95 to Shank–Homer complexes by protein–protein interactions at the synaptic junction. GKAP family proteins are characterized by the presence of a C-terminal conserved GKAP homology domain 1 (GH1) of unknown structure and function. In this study, crystal structure of the GH1 domain of GKAP from Rattus norvegicus was determined in fusion with an N-terminal maltose-binding protein at 2.0 Å resolution. The structure of GKAP GH1 displays a three-helix bundle connected by short flexible loops. The predicted helix α4 which was not visible in the crystal structure associates weakly with the helix α3 suggesting dynamic nature of the GH1 domain. The strict conservation of GH1 domain across GKAP family members and the lack of a catalytic active site required for enzyme activity imply that the GH1 domain might serve as a protein–protein interaction module for the synaptic protein clustering.

  9. Pulsatile characteristics of spontaneous growth hormone (GH) concentration profiles in boys evaluated by an ultrasensitive immunoradiometric assay: Evidence for ultradian periodicity of GH secretion

    SciTech Connect

    Goji, Katsumi )

    1993-03-01

    To investigate underlying ultradian periodicities in spontaneous circulating GH concentrations, blood samples were drawn from 15 normal short boys every 20 min over a 24-h period, and plasma GH concentrations were measured using an ultrasensitive immunoradiometric assay. The limit of detection for the GH assay was 0.01 [mu]g/L. The GH time series were analyzed using the Cluster program, Ultra program, cosinor analysis, and autocorrelation analysis. Plasma GH concentrations in 1,095 samples derived from 15 normal short boys were all within the detectable range of the assay and ranged from 0.07-52.2 [mu]g/L. Thirty-six percent of the GH values in the 1,095 samples from 15 normal short boys were below 1 [mu]g/L, and 82% of them occurred during the diurnal awakening period. Cluster analysis disclosed a total of 176 peaks in 15 normal short boys, with a mean [+-] SEM number of significant GH peaks of 12.1 [+-] 0.5/24 h. Twelve percent of the 176 peaks were below 1 [mu]g/L, and 95% of them occurred during the diurnal awakening period. In addition, Cluster analysis disclosed 161 interpulse intervals in total, with a mean [+-] SEM interval of 116.5 [+-] 4.3 min. The GH interpulse interval did not show a significant 24-h rhythm, whereas the GH peak height increased significantly at night. An independent discrete peak detection in program, Ultra, identified 12.6 [+-] 0.5 GH peaks/24 h. This result was in good agreement with that from analysis by the Cluster program (P = NS). Autocorrelation analysis revealed that GH time series were significantly autocorrelated in 9 of the 15 boys, with maximal autocorrelation coefficients at 115.5 min, on the average. The mean autocorrelation coefficient for a group of 15 normal short boys was significantly positive at a 100-min lag. These findings suggest that there could be a regularly occurring periodicity of approximately 100-120 min in the human GH time series. 18 refs., 4 figs., 1 tab.

  10. Seed-specific expression of a lysine-rich protein gene, GhLRP, from cotton significantly increases the lysine content in maize seeds.

    PubMed

    Yue, Jing; Li, Cong; Zhao, Qian; Zhu, Dengyun; Yu, Jingjuan

    2014-01-01

    Maize seed storage proteins are a major source of human and livestock consumption. However, these proteins have poor nutritional value, because they are deficient in lysine and tryptophan. Much research has been done to elevate the lysine content by reducing zein content or regulating the activities of key enzymes in lysine metabolism. Using the naturally lysine-rich protein genes, sb401 and SBgLR, from potato, we previously increased the lysine and protein contents of maize seeds. Here, we examined another natural lysine-rich protein gene, GhLRP, from cotton, which increased the lysine content of transgenic maize seeds at levels varying from 16.2% to 65.0% relative to the wild-type. The total protein content was not distinctly different, except in the six transgenic lines. The lipid and starch levels did not differ substantially in Gossypium hirsutum L. lysine-rich protein (GhLRP) transgenic kernels when compared to wild-type. The agronomic characteristics of all the transgenic maize were also normal. GhLRP is a high-lysine protein candidate gene for increasing the lysine content of maize. This study provided a valuable model system for improving maize lysine content. PMID:24681583

  11. Divalent metal activation of a GH43 β-xylosidase.

    PubMed

    Lee, Charles C; Braker, Jay D; Grigorescu, Arabela A; Wagschal, Kurt; Jordan, Douglas B

    2013-02-01

    Depolymerization of xylan, a major fraction of lignocellulosic biomass, releases xylose which can be converted into transportation fuels and chemical feedstocks. A requisite enzyme for the breakdown of xylan is β-xylosidase. A gene encoding the 324-amino acid β-xylosidase, RS223-BX, was cloned from an anaerobic mixed microbial culture. This glycoside hydrolase belongs to family 43. Unlike other GH43 enzymes, RS223-BX can be strongly activated by exogenously supplied Ca(2+), Co(2+), Fe(2+), Mg(2+), Mn(2+) and Ni(2+) (e.g., 28-fold by Mg(2+)) and it is inhibited by Cu(2+) or Zn(2+). Sedimentation equilibrium centrifugation experiments indicated that the divalent metal cations mediate multimerization of the enzyme from a dimeric to a tetrameric state, which have equal catalytic activity on an active-site basis. Compared to the determined active sites of other GH43 β-xylosidases, the predicted active site of RS223-BX contains two additional amino acids with carboxylated side chains that provide potential sites for divalent metal cations to reside. Thus, the divalent metal cations likely occupy the active site and participate in the catalytic mechanism. RS223-BX accepts as substrate xylobiose, arabinobiose, 4-nitrophenyl-β-D-xylopyranoside, and 4-nitrophenyl-α-L-arabinofuranoside. Additionally, the enzyme has good pH and temperature stabilities and a large K(i) for D-glucose (1.3 M), favorable properties for performance in saccharification reactors. PMID:23273276

  12. Identification of novel GH-regulated genes in C2C12 cells.

    PubMed

    Resmini, E; Morte, B; Sorianello, E; Gallardo, E; de Luna, N; Illa, I; Zorzano, A; Bernal, J; Webb, S M

    2011-12-01

    Growth hormone (GH) is the main regulator of longitudinal growth before puberty, and treatment with human recombinant (rh) GH can increase muscle strength. Nevertheless, molecular mechanisms responsible remain mostly unknown. Many physiological effects of GH require hormone-mediated changes in gene expression. In an attempt to gain insight into the mechanism of GH action in muscle cells we evaluated the effects of rhGH on gene expression profile in a murine skeletal muscle cell line C2C12. The objective of the work was to identify changes in gene expression in the murine skeletal muscle cell line C2C12 after rGH treatment using microarray assays. C2C12 murine skeletal muscle cell cultures were differentiated during 4 days. After 16 h growing in serum-free medium, C2C12 myotubes were stimulated during 6 h with 500 ng/ml rhGH. Four independent sets of experiments were performed to identify GH-regulated genes. Total RNA was isolated and subjected to analysis. To validate changes candidate genes were analyzed by real-time quantitative polymerase chain reaction. One hundred and fifty-four differentially expressed genes were identified; 90 upregulated and 64 downregulated. Many had not been previously identified as GH-responsive. Real-time PCR in biological replicates confirmed the effect of rGH on 15 genes: Cish, Serpina3g, Socs2, Bmp4, Tnfrsf11b, Rgs2, Tgfbr3, Ugdh, Npy1r, Gbp6, Tgfbi, Tgtp, Btc, Clec3b, and Bcl6. This study shows modifications in the gene expression profile of the C2C12 cell line after rhGH exposure. In vitro and gene function analysis revealed genes involved in skeletal and muscle system as well as cardiovascular system development and function. PMID:22072432

  13. Expression and functional characterization of intrafollicular GH-IGF system in the zebrafish ovary.

    PubMed

    Zhou, Rui; Yu, Susana Man Ying; Ge, Wei

    2016-06-01

    The somatotrophic axis plays important roles in influencing reproduction. All key members of this axis including growth hormone (GH, gh), GH receptors (ghra and ghrb), insulin-like growth factors (IGFs, igf1, igf2 and igf3) and IGF receptors (igf1ra and igf1rb) were detected in the zebrafish ovary. GH was exclusively expressed in the full-grown oocytes, while its receptors were detectable in both the follicle cells and oocytes. The IGFs and their receptors were all expressed in both compartments except igf3, which was expressed in the follicle cells only. During folliculogenesis, there was a sharp decrease of gh expression at follicle activation; however, the expression of its receptors increased significantly. The expression profiles of igf1, igf2a, and igf2b were similar to that of fshr, whereas igf3 expression was close to lhcgr, suggesting differential roles for different forms of IGFs in follicle development. To examine if the ovarian GH-IGF system is regulated by gonadotropins (e.g., hCG) and GH, we performed in vitro experiments using cultured zebrafish follicle cells. The expression of igf1 and igf1ra, but not others, was down-regulated by hCG (LH analog), whereas recombinant zebrafish GH stimulated igf1 expression. In addition, GH also increased the expression of activin βA subunit (inhbaa). In agreement with this, the stimulatory effect of GH but not IGF-I on oocyte maturation could be abolished by follistatin. In conclusion, the present study revealed an intrafollicular network involving GH-IGF mini-axis in the zebrafish ovary; however, it might not work in the same way as that of the systemic somatotrophic axis. PMID:26654745

  14. Response to long-term growth hormone therapy in patients affected by RASopathies and growth hormone deficiency: Patterns of growth, puberty and final height data.

    PubMed

    Tamburrino, Federica; Gibertoni, Dino; Rossi, Cesare; Scarano, Emanuela; Perri, Annamaria; Montanari, Francesca; Fantini, Maria Pia; Pession, Andrea; Tartaglia, Marco; Mazzanti, Laura

    2015-11-01

    RASopathies are developmental disorders caused by heterozygous germline mutations in genes encoding proteins in the RAS-MAPK signaling pathway. Reduced growth is a common feature. Several studies generated data on growth, final height (FH), and height velocity (HV) after growth hormone (GH) treatment in patients with these disorders, particularly in Noonan syndrome, the most common RASopathy. These studies, however, refer to heterogeneous cohorts in terms of molecular information, GH status, age at start and length of therapy, and GH dosage. This work reports growth data in 88 patients affected by RASopathies with molecularly confirmed diagnosis, together with statistics on body proportions, pubertal pattern, and FH in 33, including 16 treated with GH therapy for proven GH deficiency. Thirty-three patients showed GH deficiency after pharmacological tests, and were GH-treated for an average period of 6.8 ± 4.8 years. Before starting therapy, HV was -2.6 ± 1.3 SDS, and mean basal IGF1 levels were -2.0 ± 1.1 SDS. Long-term GH therapy, starting early during childhood, resulted in a positive height response compared with untreated patients (1.3 SDS in terms of height-gain), normalizing FH for Ranke standards but not for general population and Target Height. Pubertal timing negatively affected pubertal growth spurt and FH, with IGF1 standardized score increased from -2.43 to -0.27 SDS. During GH treatment, no significant change in bone age velocity, body proportions, or cardiovascular function was observed. PMID:26227443

  15. PGK deficiency.

    PubMed

    Beutler, Ernest

    2007-01-01

    Phosphoglycerate kinase (PGK) deficiency is one of the relatively uncommon causes of hereditary non-spherocytic haemolytic anaemia (HNSHA). The gene encoding the erythrocyte enzyme PGK1, is X-linked. Mutations of this gene may cause chronic haemolysis with or without mental retardation and they may cause myopathies, often with episodes of myoglobinuria, or a combination of these clinical manifestations. Twenty-six families have been described and in 20 of these the mutations are known. The reason for different clinical manifestations of mutations of the same gene remains unknown. PMID:17222195

  16. Lymphocyte subset distribution and natural killer activity in growth hormone deficiency before and during short-term treatment with growth hormone releasing hormone.

    PubMed

    Kiess, W; Malozowski, S; Gelato, M; Butenand, O; Doerr, H; Crisp, B; Eisl, E; Maluish, A; Belohradsky, B H

    1988-07-01

    Natural killer (NK) cell activity was assessed in the peripheral blood of 20 patients with growth hormone (GH) deficiency due to a hypothalamic deficit of GH-releasing hormone (GHRH). All patients failed to respond to at least two provocative tests of GH secretion (GH below 7 ng/ml) but responded to a single GHRH iv bolus injection (1 microgram/kg body wt). In 14 of the 20 patients (20 determinations), lymphocyte subsets were also measured; in all patients the distribution of lymphocyte subsets was within the normal range. More importantly, NK cell activity in the 20 patients was significantly lower than in controls (P less than 0.01). To assess the in vivo effect of GH and GHRH on NK activity and lymphocyte subset distribution, immunologic tests were performed (i) before and after a single iv bolus injection of GHRH (1 microgram/kg body wt) in six patients; (ii) before and after 3 weeks of GHRH treatment (3-9 micrograms/kg body wt, one to four times daily) in five patients; and (iii) after 6 weeks of GH treatment (5 IU sc every alternate day) in one patient. Neither NK activity nor the distribution of lymphocyte subsets was altered during short-term GHRH administration. In conclusion, low NK activity is found in GH-deficient patients, and short-term administration of GH or GHRH fails to restore this immunological abnormality. This result suggests that the hypothalamus may be a regulator of NK activity in the human and that patients with hypothalamic deficiencies should be monitored for the development of discrete immunodeficiencies. PMID:3133146

  17. STAT5B deficiency: Impacts on human growth and immunity.

    PubMed

    Hwa, Vivian

    2016-06-01

    Growth hormone (GH) promotes postnatal human growth primarily by regulating insulin-like growth factor (IGF)-I production through activation of the GH receptor (GHR)-signal transducer and activator of transcription (STAT)-5B signaling cascade. The critical importance of STAT5B in human IGF-I production was confirmed with the identification of the first homozygous, autosomal recessive, STAT5B mutation in a young female patient who phenotypically resembled patients with classical growth hormone insensitivity (GHI) syndrome (Laron syndrome) due to mutations in the GHR gene, presenting with severe postnatal growth failure and marked IGF-I deficiency. Of note, the closely related STAT5A, which shares >95% amino acid identity with STAT5B, could not compensate for loss of functional STAT5B. To date, 7 homozygous, inactivating, STAT5B mutations in 10 patients have been reported. STAT5B deficient patients, unlike patients deficient in GHR, can also present with a novel, potentially fatal, primary immunodeficiency, which can manifest as chronic pulmonary disease. STAT5B deficiency may be underestimated in endocrine, immunology and pulmonary clinics. PMID:26703237

  18. Autocrine/paracrine proliferative effect of ovarian GH and IGF-I in chicken granulosa cell cultures.

    PubMed

    Ahumada-Solórzano, S Marisela; Martínez-Moreno, Carlos G; Carranza, Martha; Ávila-Mendoza, José; Luna-Acosta, José Luis; Harvey, Steve; Luna, Maricela; Arámburo, Carlos

    2016-08-01

    It is known that growth hormone (GH) and its receptor (GHR) are expressed in granulosa cells (GC) and thecal cells during the follicular development in the hen ovary, which suggests GH is involved in autocrine/paracrine actions in the female reproductive system. In this work, we show that the knockdown of local ovarian GH with a specific cGH siRNA in GC cultures significantly decreased both cGH mRNA expression and GH secretion to the media, and also reduced their proliferative rate. Thus, we analyzed the effect of ovarian GH and recombinant chicken GH (rcGH) on the proliferation of pre-hierarchical GCs in primary cultures. Incubation of GCs with either rcGH or conditioned media, containing predominantly a 15-kDa GH isoform, showed that both significantly increased proliferation as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, proliferating cell nuclear antigen (PCNA) quantification and ((3)H)-thymidine incorporation ((3)H-T) assays in a dose response fashion. Both, locally produced GH and rcGH also induced the phosphorylation of Erk1/2 in GC cultures. Furthermore, GH increased IGF-I synthesis and its release into the GC culture incubation media. These results suggest that GH may act through local IGF-I to induce GC proliferation, since IGF-I immunoneutralization completely abolished the GH-induced proliferative effect. These data suggest that GH and IGF-I may play a role as autocrine/paracrine regulators during the follicular development in the hen ovary at the pre-hierarchical stage. PMID:27174747

  19. LysGH15 kills Staphylococcus aureus without being affected by the humoral immune response or inducing inflammation.

    PubMed

    Zhang, Lei; Li, Dong; Li, Xinwei; Hu, Liyuan; Cheng, Mengjun; Xia, Feifei; Gong, Pengjuan; Wang, Bin; Ge, Jinli; Zhang, Hao; Cai, Ruopeng; Wang, Yanmei; Sun, Changjiang; Feng, Xin; Lei, Liancheng; Han, Wenyu; Gu, Jingmin

    2016-01-01

    The lysin LysGH15, derived from the staphylococcal phage GH15, exhibits a wide lytic spectrum and highly efficient lytic activity against methicillin-resistant Staphylococcus aureus (MRSA). Here, we found that LysGH15 did not induce resistance in MRSA or methicillin-sensitive S. aureus (MSSA) strains after repeated treatment. Although LysGH15 triggered the generation of LysGH15-specific antibodies in mice, these antibodies did not block lytic activity in vitro (nor the binding capacity of LysGH15). More importantly, when the antibody titre was highest in mice immunized with LysGH15, a single intravenous injection of LysGH15 was sufficient to protect mice against lethal infection with MRSA. These results indicated that LysGH15-specific antibodies did not affect the killing efficiency of LysGH15 against MRSA in vitro or in vivo. LysGH15 also reduced pro-inflammatory cytokines in mice with lethal infections. Furthermore, a high-dose LysGH15 injection did not cause significant adverse effects or pathological changes in the main organs of treated animals. These results provide further evidence for the administration of LysGH15 as an alternative strategy for the treatment of infections caused by MRSA. PMID:27385518

  20. LysGH15 kills Staphylococcus aureus without being affected by the humoral immune response or inducing inflammation

    PubMed Central

    Zhang, Lei; Li, Dong; Li, Xinwei; Hu, Liyuan; Cheng, Mengjun; Xia, Feifei; Gong, Pengjuan; Wang, Bin; Ge, Jinli; Zhang, Hao; Cai, Ruopeng; Wang, Yanmei; Sun, Changjiang; Feng, Xin; Lei, Liancheng; Han, Wenyu; Gu, Jingmin

    2016-01-01

    The lysin LysGH15, derived from the staphylococcal phage GH15, exhibits a wide lytic spectrum and highly efficient lytic activity against methicillin-resistant Staphylococcus aureus (MRSA). Here, we found that LysGH15 did not induce resistance in MRSA or methicillin-sensitive S. aureus (MSSA) strains after repeated treatment. Although LysGH15 triggered the generation of LysGH15-specific antibodies in mice, these antibodies did not block lytic activity in vitro (nor the binding capacity of LysGH15). More importantly, when the antibody titre was highest in mice immunized with LysGH15, a single intravenous injection of LysGH15 was sufficient to protect mice against lethal infection with MRSA. These results indicated that LysGH15-specific antibodies did not affect the killing efficiency of LysGH15 against MRSA in vitro or in vivo. LysGH15 also reduced pro-inflammatory cytokines in mice with lethal infections. Furthermore, a high-dose LysGH15 injection did not cause significant adverse effects or pathological changes in the main organs of treated animals. These results provide further evidence for the administration of LysGH15 as an alternative strategy for the treatment of infections caused by MRSA. PMID:27385518

  1. Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency in Korean Infants

    PubMed Central

    Ko, Jae Sung; Song, Jung Han; Park, Sung Sup

    2007-01-01

    Citrin is a liver-type mitochondrial aspartate-glutamate carrier encoded by the SLC25A13 gene, and its deficiency causes adult-onset type II citrullinemia and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). Here, the authors investigated clinical findings in Korean infants with NICCD and performed mutation analysis on the SLC25A13 gene. Of 47 patients with neonatal cholestasis, three infants had multiple aminoacidemia (involving citrulline, methionine, and arginine) and galactosemia, and thus were diagnosed as having NICCD. Two of these three showed failure to thrive. The laboratory findings showed hypoproteinemia and hyperammonemia, and liver biopsies revealed micro-macrovesicular fatty liver and cholestasis. The three patients each harbored compound heterozygous 1,638-1,660 dup/ S225X mutation, compound heterozygous 851del4/S225X mutation, and heterozygous 1,638-1,660 dup mutation, respectively. With nutritional manipulation, liver functions were normalized and catch-up growth was achieved. NICCD should be considered in the differential diagnosis of cholestatic jaundice in Korean infants. PMID:18162705

  2. Association of Turner Syndrome and Growth Hormone Deficiency: A Review.

    PubMed

    Marques, Jorge Sales; Aires, Sónia

    2015-09-01

    Turner syndrome (TS) is an important cause of short stature in girls. Patients with TS most often do not have growth hormone deficiency (GHD). Testing GH secretion is not indicated despite the presence of short stature. In the last 20 years only three cases were reported with this association in Pubmed. We describe a case of an 11 year old girl with short stature and karyotype confirmed TS: 45,X(16)46,X,i(X)(ql0)(13). Because her growth velocity was low (-3 SD), we evaluated the GH response with stimulating tests and the results were under the normal range. These findings were compatible with GHD. It is important to check for GHD in patients with TS whenever the growth velocity is low for age and sex. PMID:26540761

  3. Effects of fulvestrant on biological activity and Wnt expression in rat GH3 cells☆

    PubMed Central

    Bai, Jiwei; Wang, Yan; Li, Chuzhong; Zhang, Yazhuo

    2012-01-01

    The present study investigated the influence of anti-estrogen treatment (fulvestrant) on pituitary adenoma cell line GH3 biological activity, the estrogen receptor α pathway, the WnT pathway, and mechanisms of decreased Wnt inhibitory factor-1 expression in GH3 cells. Results showed that fulvestrant suppressed GH3 cell proliferation and reduced hormone secretion in a dose-dependent manner. Estrogen receptor α and Wnt4 expression decreased, but Wnt inhibitory factor-1 expression increased in a dose-dependent manner following fulvestrant treatment, and β-catenin expression remained unchanged. Inhibitors of DNA methylation and histone modification upregulated Wnt inhibitory factor-1 expression. Results suggested that fulvestrant suppressed biological activity of GH3 cells via the estrogen receptor α and Wnt pathways. These results suggested that decreased Wnt inhibitory factor-1 expression in GH3 cells played a role in epigenetic mechanisms. Anti-estrogen therapies could provide novel treatments for growth hormone adenomas. PMID:25806070

  4. Effects of Double Transgenesis of Somatotrophic Axis (GH/GHR) on Skeletal Muscle Growth of Zebrafish (Danio rerio).

    PubMed

    Silva, Ana Cecilia Gomes; Almeida, Daniela Volcan; Nornberg, Bruna Felix; Figueiredo, Marcio Azevedo; Romano, Luis Alberto; Marins, Luis Fernando

    2015-12-01

    Transgenic fish for growth hormone (GH) has been considered as a potential technological improvement in aquaculture. In this study, a double-transgenic zebrafish was used to evaluate the effect of GH and its receptor (GHR) on muscle growth. Double transgenics reached the same length of GH transgenic, but with significantly less weight, featuring an unbalanced growth. The condition factor of GH/GHR-transgenic fish was lower than the other genotypes. Histological analysis showed a decrease in the percentage of thick muscle fibers in GH/GHR genotype of ∼ 80% in comparison to GH-transgenic line. The analysis of gene expression showed a significant decrease in genes related to muscle growth in GH/GHR genotype. It seems that concomitant overexpression of GH and GHR resulted in a strong decrease of the somatotrophic axis intracellular signaling by diminishing its principal transcription factor signal transducer and activator of transcription 5.1 (STAT5.1). PMID:26574627

  5. Climacteric in untreated isolated growth hormone deficiency

    PubMed Central

    Menezes, Menilson; Salvatori, Roberto; Oliveira, Carla R.P.; Pereira, Rossana M.C.; Souza, Anita H.O.; Nobrega, Luciana M.A.; Cruz, Edla do A.C.; Menezes, Marcos; Alves, Érica O.; Aguiar-Oliveira, Manuel H.

    2008-01-01

    Objective To study the time, intensity of symptoms, hormonal profile, and related morbidity of climacteric in women with untreated isolated growth hormone (GH) deficiency (IGHD). Design Women belonging to a large Brazilian kindred with IGHD due to a homozygous mutation in the GH-releasing hormone receptor gene were studied. None of them had ever received GH replacement therapy. A two-step protocol was performed. In the first case-control experiment, aimed to determine the age at climacteric, we compared eight women with IGHD and 32 normal women between 37 and 55 years of age. In the second cross-sectional experiment, aimed to determine the severity of climacteric symptoms, seven women with IGHD (aged 47-65 y) were compared with 13 controls (aged 44-65 y). The Kupperman Index scores, serum follicle-stimulating hormone, luteinizing hormone, prolactin, and estradiol levels were determined, and pelvic and mammary ultrasonography, mammography, and colpocytology were performed. Results The number of women with follicle-stimulating hormone above 20 mIU/mL was higher in women with IGHD than controls. Kupperman’s Index was not different between the two groups. Menarche had been delayed and parity was lower in women with IGHD. Hormonal profile was similar, but prolactin was lower in women with IGHD. Uterine volume was smaller in women with IGHD, and endometrial thickness and ovarian volume were similar in the two groups. No difference in breast images or in colpocytology was observed between the two groups. Conclusions Menarche was delayed and the beginning of climacteric is anticipated in untreated lifetime IGHD, but menopausal symptoms and hormonal profile resemble the normal climacteric. PMID:18223507

  6. Elevated systolic blood pressure in male GH transgenic mice is age dependent.

    PubMed

    Jara, Adam; Benner, Chance M; Sim, Don; Liu, Xingbo; List, Edward O; Householder, Lara A; Berryman, Darlene E; Kopchick, John J

    2014-03-01

    Acromegaly is associated with an increased incidence of cardiovascular disease. Transgenic mice expressing bovine GH (bGH) gene have previously been used to examine the effects of chronic GH stimulation on cardiovascular function. Results concerning systolic blood pressure (SBP) in bGH mice are conflicting. We hypothesized that these discrepancies may be the result of the various ages of the mice used in previous studies. In the current study, SBP was assessed monthly in male bGH mice from 3-12 months of age. Factors known to alter blood pressure were assessed during this time and included: levels of brain natriuretic peptide (BNP) and glucose homeostasis markers, and renal levels of angiotensin-converting enzyme 2 and endothelial nitric oxide synthase. Beginning at 6 months of age bGH had increased SBP compared with wild-type controls, which remained elevated through 12 months of age. Despite having increased blood pressure and cardiac BNP mRNA, bGH mice had decreased circulating levels of BNP. Additionally, bGH mice had an age-dependent decline in insulin levels. For example, they were hyperinsulinemic at 3 months, but by 11 months of age were hypoinsulinemic relative to wild-type controls. This decrease in insulin was accompanied by improved glucose tolerance at 11 months. Finally, both angiotensin-converting enzyme 2 and endothelial nitric oxide synthase expression were severely depressed in kidneys of 11-month-old bGH mice. These results indicate that elevated SBP in bGH mice is dependent on age, independent of insulin resistance, and related to alterations in both the natriuretic peptide and renin-angiotensin systems. PMID:24424040

  7. Molecular Engineering of Fungal GH5 and GH26 Beta-(1,4)-Mannanases toward Improvement of Enzyme Activity

    PubMed Central

    Couturier, Marie; Féliu, Julia; Bozonnet, Sophie; Roussel, Alain; Berrin, Jean-Guy

    2013-01-01

    Microbial mannanases are biotechnologically important enzymes since they target the hydrolysis of hemicellulosic polysaccharides of softwood biomass into simple molecules like manno-oligosaccharides and mannose. In this study, we have implemented a strategy of molecular engineering in the yeast Yarrowia lipolytica to improve the specific activity of two fungal endo-mannanases, PaMan5A and PaMan26A, which belong to the glycoside hydrolase (GH) families GH5 and GH26, respectively. Following random mutagenesis and two steps of high-throughput enzymatic screening, we identified several PaMan5A and PaMan26A mutants that displayed improved kinetic constants for the hydrolysis of galactomannan. Examination of the three-dimensional structures of PaMan5A and PaMan26A revealed which of the mutated residues are potentially important for enzyme function. Among them, the PaMan5A-G311S single mutant, which displayed an impressive 8.2-fold increase in kcat/KM due to a significant decrease of KM, is located within the core of the enzyme. The PaMan5A-K139R/Y223H double mutant revealed modification of hydrolysis products probably in relation to an amino-acid substitution located nearby one of the positive subsites. The PaMan26A-P140L/D416G double mutant yielded a 30% increase in kcat/KM compared to the parental enzyme. It displayed a mutation in the linker region (P140L) that may confer more flexibility to the linker and another mutation (D416G) located at the entrance of the catalytic cleft that may promote the entrance of the substrate into the active site. Taken together, these results show that the directed evolution strategy implemented in this study was very pertinent since a straightforward round of random mutagenesis yielded significantly improved variants, in terms of catalytic efiiciency (kcat/KM). PMID:24278180

  8. Pharmacokinetics and pharmacodynamics of recombinant human growth hormone by subcutaneous jet- or needle-injection in patients with growth hormone deficiency.

    PubMed

    Houdijk, E C; Herdes, E; Delemarre-Van de Waal, H A

    1997-12-01

    Eighteen growth hormone (GH) deficient children and adolescents (11 6/12-20 9/12 y) participated in a randomized open, two-period (4 weeks) cross-over study to evaluate the pharmacokinetics and pharmacodynamics of recombinant human growth hormone (rhGH) administered daily, either by subcutaneous jet-injection or conventional needle-injection. Plasma growth hormone (GH), insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), glucose, insulin, HbAlc and serum-free fatty acids (FFA) levels were analysed repeatedly. GH absorption characteristics, expressed as AUC(0-infinity), Cmax and Tmax ratio (%) jet-injected over needle-injected were similar in both groups. IGF-I and IGFBP-3 plasma levels were identical in both groups. Serum FFA concentrations were comparable after GH administration with either injection device. Surprisingly nocturnal blood glucose decreased to asymptomatic hypoglycaemic levels in all patients. The results of this study showed equal responses concerning absorption and bioavailability of growth hormone administered daily for 4 weeks by either a jet- or a needle-injection device in GH-deficient children and adolescents. PMID:9475305

  9. Cello-oligosaccharide oxidation reveals differences between two lytic polysaccharide monooxygenases (family GH61) from Podospora anserina.

    PubMed

    Bey, Mathieu; Zhou, Simeng; Poidevin, Laetitia; Henrissat, Bernard; Coutinho, Pedro M; Berrin, Jean-Guy; Sigoillot, Jean-Claude

    2013-01-01

    The genome of the coprophilic ascomycete Podospora anserina encodes 33 different genes encoding copper-dependent lytic polysaccharide monooxygenases (LPMOs) from glycoside hydrolase family 61 (GH61). In this study, two of these enzymes (P. anserina GH61A [PaGH61A] and PaGH61B), which both harbored a family 1 carbohydrate binding module, were successfully produced in Pichia pastoris. Synergistic cooperation between PaGH61A or PaGH61B with the cellobiose dehydrogenase (CDH) of Pycnoporus cinnabarinus on cellulose resulted in the formation of oxidized and nonoxidized cello-oligosaccharides. A striking difference between PaGH61A and PaGH61B was observed through the identification of the products, among which were doubly and triply oxidized cellodextrins, which were released only by the combination of PaGH61B with CDH. The mass spectrometry fragmentation patterns of these oxidized products could be consistent with oxidation at the C-6 position with a geminal diol group. The different properties of PaGH61A and PaGH61B and their effect on the interaction with CDH are discussed in regard to the proposed in vivo function of the CDH/GH61 enzyme system in oxidative cellulose hydrolysis. PMID:23124232

  10. Cello-Oligosaccharide Oxidation Reveals Differences between Two Lytic Polysaccharide Monooxygenases (Family GH61) from Podospora anserina

    PubMed Central

    Bey, Mathieu; Zhou, Simeng; Poidevin, Laetitia; Henrissat, Bernard; Coutinho, Pedro M.; Sigoillot, Jean-Claude

    2013-01-01

    The genome of the coprophilic ascomycete Podospora anserina encodes 33 different genes encoding copper-dependent lytic polysaccharide monooxygenases (LPMOs) from glycoside hydrolase family 61 (GH61). In this study, two of these enzymes (P. anserina GH61A [PaGH61A] and PaGH61B), which both harbored a family 1 carbohydrate binding module, were successfully produced in Pichia pastoris. Synergistic cooperation between PaGH61A or PaGH61B with the cellobiose dehydrogenase (CDH) of Pycnoporus cinnabarinus on cellulose resulted in the formation of oxidized and nonoxidized cello-oligosaccharides. A striking difference between PaGH61A and PaGH61B was observed through the identification of the products, among which were doubly and triply oxidized cellodextrins, which were released only by the combination of PaGH61B with CDH. The mass spectrometry fragmentation patterns of these oxidized products could be consistent with oxidation at the C-6 position with a geminal diol group. The different properties of PaGH61A and PaGH61B and their effect on the interaction with CDH are discussed in regard to the proposed in vivo function of the CDH/GH61 enzyme system in oxidative cellulose hydrolysis. PMID:23124232

  11. Controversies in the diagnosis and management of growth hormone deficiency in childhood and adolescence.

    PubMed

    Murray, P G; Dattani, M T; Clayton, P E

    2016-01-01

    Growth hormone deficiency (GHD) is a rare but important cause of short stature in childhood with a prevalence of 1 in 4000. The diagnosis is currently based on an assessment of auxology along with supporting evidence from biochemical and neuroradiological studies. There are significant controversies in the diagnosis and management of GHD. Growth hormone (GH) stimulation tests continue to play a key role in GHD diagnosis but the measured GH concentration can vary significantly with stimulation test and GH assay used, creating difficulties for diagnostic accuracy. Such issues along with the use of adjunct biochemical markers such as IGF-I and IGFBP-3 for the diagnosis of GHD, will be discussed in this review. Additionally, the treatment of GHD remains a source of much debate; there is no consensus on the best mechanism for determining the starting dose of GH in patients with GHD. Weight and prediction based models will be discussed along with different mechanisms for dose adjustment during treatment (auxology or IGF-I targeting approaches). At the end of growth and childhood treatment, many subjects diagnosed with isolated GHD re-test normal. It is not clear if this represents a form of transient GHD or a false positive diagnosis during childhood. Given the difficulties inherent in the diagnosis of GHD, an early reassessment of the diagnosis in those who respond poorly to GH is to be recommended. PMID:26153506

  12. Multiple endocrinopathies (growth hormone deficiency, autoimmune hypothyroidism and diabetes mellitus) in Kearns-Sayre syndrome.

    PubMed

    Berio, A; Piazzi, A

    2013-01-01

    Kearns-Sayre syndrome is characterized by onset before 20 years, chronic progressive external opthalmoplegia, pigmentary retinal degeneration, and ataxia (and/or hearth block, and/or high protein content in the cerebrospinal fluid) in the presence of mtDNA rearrangements. Multiple endocrine dysfunction associated with this syndrome was rarely reported. In this paper, the Authors report on a female patient with Kearns-Sayre syndrome with large heteroplasmic mtDNA deletion, absence of cytochrome c oxidase in many muscle fibers, partial GH deficiency, hypothyroidism and subsequently insulin dependent diabetes mellitus (IDDM). Anti-thyroid peroxidase and antithyreoglobulin antibodies were present in high titer in serum while anti-islet cell antibodies were absent. The patient developed thyroiditis with Hashimoto encephalopathy. The presence of GH deficiency, autoimmune thyroiditis with hypothyroidism and IDDM distinguishes this case from others and confirms the association of Kearns-Sayre syndrome with multiple endocrine dysfunction. Hashimoto encephalopathy and anti-thyroideal antibodies suggest that in this patient, predisposed by a genetic factor (a mitochondrial deletion) anti-thyroideal antibodies may have contributed to the hypothyroidism and, by interfering with cerebral mitochondrial function, may have caused the encephalopathy. GH deficiency and IDDM can be attributed to oxidative phosphorylation deficiency but the autoimmunity may also have played a role in the production of glandular insufficiencies. It seems important to search for endocrine autoimmunity in every case of KSS. PMID:23947115

  13. Microarchitecture, but Not Bone Mechanical Properties, Is Rescued with Growth Hormone Treatment in a Mouse Model of Growth Hormone Deficiency

    PubMed Central

    Kristensen, Erika; Hallgrímsson, Benedikt; Morck, Douglas W.; Boyd, Steven K.

    2012-01-01

    Growth hormone (GH) deficiency is related to an increased fracture risk although it is not clear if this is due to compromised bone quality or a small bone size. We investigated the relationship between bone macrostructure, microarchitecture and mechanical properties in a GH-deficient (GHD) mouse model undergoing GH treatment commencing at an early (prepubertal) or late (postpubertal) time point. Microcomputed tomography images of the femur and L4 vertebra were obtained to quantify macrostructure and vertebral trabecular microarchitecture, and mechanical properties were determined using finite element analyses. In the GHD animals, bone macrostructure was 25 to 43% smaller as compared to the GH-sufficient (GHS) controls (P < 0.001). GHD animals had 20% and 19% reductions in bone volume ratio (BV/TV) and trabecular thickness (Tb.Th), respectively. Whole bone mechanical properties of the GHD mice were lower at the femur and vertebra (67% and 45% resp.) than the GHS controls (P < 0.001). Both early and late GH treatment partially recovered the bone macrostructure (15 to 32 % smaller than GHS controls) and the whole bone mechanical properties (24 to 43% larger than GHD animals) although there remained a sustained 27–52% net deficit compared to normal mice (P < 0.05). Importantly, early treatment with GH led to a recovery of BV/TV and Tb.Th with a concomitant improvement of trabecular mechanical properties. Therefore, the results suggest that GH treatment should start early, and that measurements of microarchitecture should be considered in the management of GHD. PMID:22505889

  14. GH binding to liver in young and old female rats: relation to somatomedin-C secretion

    SciTech Connect

    Takahashi, S.; Meites, J.

    1987-11-01

    Age-related changes in binding of /sup 125/I-bovine GH to liver membrane fractions were measured in female Long-Evans rats 2, 6, 12, and 20 months of age. Specific GH binding did not change between 2 and 6 months of age but increased significantly at 12 and 20 months of age. Scatchard analyses showed that the plots were curvilinear and consisted of high- and low-affinity binding sites. The age-related increases in binding sites were mainly due to an increase in number of low-affinity binding sites. Serum somatomedim-C (SM-C) levels in 20-month-old rats were about half those in the 6-month-old rats. Twice daily injections of ovine GH (2 mg/kg body wt) for 7 days depressed liver GH binding and increased serum SM-C levels in 19-month-old female rats, but had no effect on GH binding in 2-month-old female rats. These results suggest that the increase in liver GH binding sites and the decrease in SM-C secretion are associated with our previously reported decrease in GH secretion in old female rats.

  15. Specific expression of a beta-tubulin gene (GhTub1) in developing cotton fibers.

    PubMed

    Li, Yuanli; Sun, Jie; Li, Chunhong; Zhu, Yongqing; Xia, Guixian

    2003-06-01

    A cDNA library was constructed using poly (A)(+) RNA isolated from -1-15 DPA fibers of upland cotton (Gossypium hirsutum). The cDNA encoding a beta-tubulin isoform (designated as GhTub1) was identified through EST search. Northern blot analysis using 3'-UTR of the cDNA as a gene-specific probe was performed to investigate the expression levels of GhTub1 in various organs and in the developing fibers. The results showed that GhTub1 gene was specifically expressed in cotton fiber cells. During fiber development, GhTub1 transcripts accumulated highly at the stage of cell rapid elongation with the highest expression appearing at the time when fiber expansion reaches the peak rate. To probe the in vivo function of GhTub1, its cDNA was cloned in the yeast expression vector pREP1 and transformed into the fission yeast Schizosaccharomyces pombe. Overexpression of GhTub1 in yeast cells caused severe changes in the cell morphology. These results suggest that GhTub1 may play a role in the polar elongation of cotton fibers. To our knowledge, this is the first report on the fiber-specific transcript accumulation of a cotton beta-tubulin gene. PMID:18763138

  16. Enhanced lignocellulosic biomass hydrolysis by oxidative lytic polysaccharide monooxygenases (LPMOs) GH61 from Gloeophyllum trabeum.

    PubMed

    Jung, Sera; Song, Younho; Kim, Ho Myeong; Bae, Hyeun-Jong

    2015-09-01

    Lignocellulose is a renewable resource that is extremely abundant, and the complete enzymatic hydrolysis of lignocellulose requires a cocktail containing a variety of enzyme groups that act synergistically. The hydrolysis efficiency can be improved by introducing glycoside hydrolase 61 (GH61), a new enzyme that belongs to the auxiliary activity family 9 (AA9). GH61was isolated from Gloeophyllum trabeum and cleaves the glycosidic bonds on the cellulose surface via oxidation of various carbons. In this study, we investigated the properties of GH61. GtGH61 alone did not exhibit any notable activity, but the synergistic activity of GtGH61 with xylanase (GtXyl10G) or cellulase (GtCel5B) showed efficient bioconversion rates of 56 and 174% in pretreated kenaf (Hibiscus cannabinus L.) and oak (Quercus spp.), respectively. Furthermore, the GtGH61 activity was strongly accelerated in the presence of cobalt Co(2+). Enzyme cocktails (GtXyl10G, GtCel5B, and GtGH61) increased the amount of sugar released by 7 and 6% for pretreated oak and kenaf, respectively, and the addition of Co(2+) stimulated bioconversion by 12 and 11% in pretreated oak and kenaf, respectively. PMID:26138398

  17. Does the GH/IGF-1 axis contribute to skeletal sexual dimorphism? Evidence from mouse studies.

    PubMed

    Liu, Zhongbo; Mohan, Subburaman; Yakar, Shoshana

    2016-04-01

    The contribution of the gonadotropic axis to skeletal sexual dimorphism (SSD) was clarified in recent years. Studies with animal models of estrogen receptor (ER) or androgen receptor (AR) null mice, as well as mice with bone cell-specific ablation of ER or AR, revealed that both hormones play major roles in skeletal acquisition, and that estrogen regulates skeletal accrual in both sexes. The growth hormone (GH) and its downstream effector, the insulin-like growth factor-1 (IGF-1) are also major determinants of peak bone mass during puberty and young adulthood, and play important roles in maintaining bone integrity during aging. A few studies in both humans and animal models suggest that in addition to the differences in sex steroid actions on bone, sex-specific effects of GH and IGF-1 play essential roles in SSD. However, the contributions of the somatotropic (GH/IGF-1) axis to SSD are controversial and data is difficult to interpret. GH/IGF-1 are pleotropic hormones that act in an endocrine and autocrine/paracrine fashion on multiple tissues, affecting body composition as well as metabolism. Thus, understanding the contribution of the somatotropic axis to SSD requires the use of mouse models that will differentiate between these two modes of action. Elucidation of the relative contribution of GH/IGF-1 axis to SSD is significant because GH is approved for the treatment of normal children with short stature and children with congenital growth disorders. Thus, if the GH/IGF-1 axis determines SSD, treatment with GH may be tailored according to sex. In the following review, we give an overview of the roles of sex steroids in determining SSD and how they may interact with the GH/IGF-1 axis in bone. We summarize several mouse models with impaired somatotropic axis and speculate on the possible contribution of that axis to SSD. PMID:26843472

  18. Mechanisms Involved in Glucocorticoid Induction of Pituitary GH Expression During Embryonic Development

    PubMed Central

    Ellestad, Laura E.; Puckett, Stefanie A.

    2015-01-01

    Glucocorticoid hormones are involved in functional differentiation of GH-producing somatotrophs. Glucocorticoid treatment prematurely induces GH expression in mammals and birds in a process requiring protein synthesis and Rat sarcoma (Ras) signaling. The objective of this study was to investigate mechanisms through which glucocorticoids initiate GH expression during embryogenesis, taking advantage of the unique properties of chicken embryos as a developmental model. We determined that stimulation of GH expression occurred through transcriptional activation of GH, rather than enhancement of mRNA stability, and this process requires histone deacetylase activity. Through pharmacological inhibition, we identified the ERK1/2 pathway as a likely downstream Ras effector necessary for glucocorticoid stimulation of GH. However, we also found that chronic activation of ERK1/2 activity with a constitutively active mutant or stimulatory ligand reduced initiation of GH expression by glucocorticoid treatment. Corticosterone treatment of cultured embryonic pituitary cells increased ERK1/2 activity in an apparent cyclical manner, with a rapid increase within 5 minutes, followed by a reduction to near-basal levels at 3 hours, and a subsequent increase again at 6 hours. Therefore, we conclude that ERK1/2 signaling must be strictly controlled for maximal glucocorticoid induction of GH to occur. These results are the first in any species to demonstrate that Ras- and ERK1/2-mediated transcriptional events requiring histone deacetylase activity are involved in glucocorticoid induction of pituitary GH during embryonic development. This report increases our understanding of the molecular mechanisms underlying glucocorticoid recruitment of somatotrophs during embryogenesis and should provide insight into glucocorticoid-induced developmental changes in other tissues and cell types. PMID:25560830

  19. Growth hormone deficiency due to traumatic brain injury in a patient with X-linked congenital adrenal hypoplasia.

    PubMed

    Engiz, Ozlem; Ozön, Alev; Riepe, Felix; Alikaşifoğlu, Ayfer; Gönç, Nazli; Kandemir, Nurgün

    2010-01-01

    X-linked adrenal hypoplasia congenita (AHC) is characterized by primary adrenal insufficiency and is frequently associated with hypogonadotropic hypogonadism (HH). The production of other pituitary hormones (adrenocorticotropic hormone [ACTH], growth hormone [GH], thyroid-stimulating hormone [TSH], and prolactin [PRL]) is usually normal. Mutations of the DAX-1 gene have been reported in patients with AHC and HH. We present a 13-year-old male patient with AHC caused by a nonsense mutation in the DAX-1 gene who developed GH deficiency following head trauma. He showed signs of adrenal insufficiency at the age of 23 months, and glucocorticoid and mineralocorticoid treatment was started. His parents reported head trauma due to a traffic accident at the age of 21 months. Adrenal computed tomography revealed hypoplasia of the left and agenesis of the right adrenal gland. Decreased growth rate was noted at the age of 12.5 years while receiving hydrocortisone 15 mg/m2/day. His height was 139.9 cm (-1.46 SD), body weight was 54.9 kg, pubic hair was Tanner stage 1, and testis size was 3 ml. His bone age was 7 years. His gonadotropin (follicle-stimulating hormone [FSH], luteinizing hormone [LH]) and testosterone levels were prepubertal. The evaluation of GH/insulin-like growth factor-1 (IGF-1) secretion at the age of 13 years revealed GH deficiency. Pituitary magnetic resonance imaging demonstrated a hypoplastic hypophysis (< 2.5 mm) and a normal infundibulum. GH treatment (0.73 IU/kg/week) was started. This paper reports a patient with genetically confirmed AHC demonstrating GH deficiency possibly due to a previous head trauma. Complete pituitary evaluation should be performed in any child who has survived severe traumatic brain injury. PMID:20718192

  20. Altered pituitary growth hormone (GH) regulation in streptozotocin-diabetic rats: a combined defect of hypothalamic somatostatin and GH-releasing factor.

    PubMed

    Olchovsky, D; Bruno, J F; Wood, T L; Gelato, M C; Leidy, J W; Gilbert, J M; Berelowitz, M

    1990-01-01

    Diabetes mellitus in the rat is associated with loss of pulsatile GH secretion. An interplay between hypothalamic GH-releasing factor (GRF) and inhibitory factor [somatostatin (SRIF)] secretion is thought to account for episodic pituitary GH release. An increase in SRIF tone/action or a decrease in GRF release/response in diabetic rats could account for the suppressed GH levels. Pituitaries from streptozotocin-diabetic rats contained less GH than controls (15.9 +/- 2.5 vs. 29.5 +/- 4.6 micrograms/mg; P less than 0.05) despite normal somatotrope representation, as demonstrated using immunofluorescence studies. Basal GH secretion from monolayer culture of dispersed anterior pituitary (AP) cells from diabetic rats was proportionately decreased (150 +/- 10 vs. 103 +/- 10 ng/10(5) cells; P less than 0.005). GRF (10(-11)-10(-8) M)-induced release of GH from AP cells was decreased in diabetic rats (maximum response to 10(-8) M GRF, 401 +/- 60 vs. 618 +/- 41 ng/10(5) cells; P less than 0.01); however, sensitivity to GRF was unchanged (EC50, 79 +/- 41 vs. 128 +/- 67 pM). By contrast, SRIF (10(-7)-10(-10)-induced inhibition of GRF (10(-8) M)-mediated GH release was impaired in AP cells of diabetic rats compared to that in controls (IC50, 112 +/- 33 vs. 55 +/- 31 pM; P less than 0.05) associated with a decrease in AP plasma membrane SRIF receptor concentration (63.4 +/- 15.6 vs. 160.3 +/- 13.7 fmol/mg protein; P less than 0.05), with no change in affinity. These findings are consistent with chronic exposure to increased hypothalamic SRIF influence. GH synthesis has been shown to be independent of SRIF regulation; however, insulin-like growth factor-I and GRF inhibit and stimulate GH synthesis, respectively. In diabetic rats insulin-like growth factor-I levels were decreased, appropriate to low GH status, in serum (290 +/- 66 vs. 1662 +/- 92 ng/ml; P less than 0.001) and hypothalamus (6.8 +/- 1.0 vs. 13.0 +/- 0.4 pg/mg wet wt; P less than 0.001) and, thus, did not seem to

  1. GH16 and GH81 family β-(1,3)-glucanases in Aspergillus fumigatus are essential for conidial cell wall morphogenesis.

    PubMed

    Mouyna, Isabelle; Aimanianda, Vishukumar; Hartl, Lukas; Prevost, Marie-Christine; Sismeiro, Odile; Dillies, Marie-Agnès; Jagla, Bernd; Legendre, Rachel; Coppee, Jean-Yves; Latgé, Jean-Paul

    2016-09-01

    The fungal cell wall is a rigid structure because of fibrillar and branched β-(1,3)-glucan linked to chitin. Softening of the cell wall is an essential phenomenon during fungal morphogenesis, wherein rigid cell wall structures are cleaved by glycosylhydrolases. During the search for glycosylhydrolases acting on β-(1,3)-glucan, we identified seven genes in the Aspergillus fumigatus genome coding for potential endo-β-(1,3)-glucanase. ENG1 (previously characterized and named ENGL1, Mouyna et al., ), belongs to the Glycoside-Hydrolase 81 (GH81) family, while ENG2 to ENG7, to GH16 family. ENG1 and four GH16 genes (ENG2-5) were expressed in the resting conidia as well as during germination, suggesting an essential role during A. fumigatus morphogenesis. Here, we report the effect of sequential deletion of AfENG2-5 (GH16) followed by AfENG1 (GH81) deletion in the Δeng2,3,4,5 mutant. The Δeng1,2,3,4,5 mutant showed conidial defects, with linear chains of conidia unable to separate while the germination rate was not affected. These results show, for the first time in a filamentous fungus, that endo β-(1,3)-glucanases are essential for proper conidial cell wall assembly and thus segregation of conidia during conidiation. PMID:27306610

  2. Netherton Syndrome in a Neonate with Possible Growth Hormone Deficiency and Transient Hyperaldosteronism.

    PubMed

    Ilias, Chatziioannidis; Evgenia, Babatseva; Aikaterini, Patsatsi; Asimina, Galli-Tsinopoulou; Constantina, Sarri; Maria, Lithoxopoulou; George, Mitsiakos; Paraskevi, Karagianni; Christos, Tsakalidis; Zissis, Mamuris; Nikolaos, Nikolaidis

    2015-01-01

    Netherton syndrome, a rare autosomal recessive genetic disorder, is classified as an ichthyosiform syndrome. In this report we present the case of a neonate with erythroderma shortly after birth, accompanied by severe hypernatremia, recurrent infections, transient hyperaldosteronism, and signs of growth hormone (GH) deficiency. DNA molecular analysis in the SPINK5 gene revealed heterozygosity in our index patient for 238insG and 2468delA frameshift mutations in exons 4 and 26, respectively, in the maternal allele and 1431-12G>A splice-site mutation in intron 15 in the paternal allele as well as the missense variation E420K in homozygous state. Combination of the identified mutations along with transient hyperaldosteronism and possible GH deficiency have not been described before. Accordingly, the importance of early multidisciplinary approach is highlighted, in order to reach accurate diagnosis, initiate prompt treatment, and ensure survival with fewer disease complications. PMID:26229701

  3. Netherton Syndrome in a Neonate with Possible Growth Hormone Deficiency and Transient Hyperaldosteronism

    PubMed Central

    Ilias, Chatziioannidis; Evgenia, Babatseva; Aikaterini, Patsatsi; Asimina, Galli-Tsinopoulou; Constantina, Sarri; Maria, Lithoxopoulou; George, Mitsiakos; Paraskevi, Karagianni; Christos, Tsakalidis; Zissis, Mamuris; Nikolaos, Nikolaidis

    2015-01-01

    Netherton syndrome, a rare autosomal recessive genetic disorder, is classified as an ichthyosiform syndrome. In this report we present the case of a neonate with erythroderma shortly after birth, accompanied by severe hypernatremia, recurrent infections, transient hyperaldosteronism, and signs of growth hormone (GH) deficiency. DNA molecular analysis in the SPINK5 gene revealed heterozygosity in our index patient for 238insG and 2468delA frameshift mutations in exons 4 and 26, respectively, in the maternal allele and 1431-12G>A splice-site mutation in intron 15 in the paternal allele as well as the missense variation E420K in homozygous state. Combination of the identified mutations along with transient hyperaldosteronism and possible GH deficiency have not been described before. Accordingly, the importance of early multidisciplinary approach is highlighted, in order to reach accurate diagnosis, initiate prompt treatment, and ensure survival with fewer disease complications. PMID:26229701

  4. pKa Modulation of the Acid/Base Catalyst within GH32 and GH68: A Role in Substrate/Inhibitor Specificity?

    PubMed Central

    Yuan, Shuguang; Le Roy, Katrien; Venken, Tom; Lammens, Willem; Van den Ende, Wim; De Maeyer, Marc

    2012-01-01

    Glycoside hydrolases of families 32 (GH32) and 68 (GH68) belong to clan GH-J, containing hydrolytic enzymes (sucrose/fructans as donor substrates) and fructosyltransferases (sucrose/fructans as donor and acceptor substrates). In GH32 members, some of the sugar substrates can also function as inhibitors, this regulatory aspect further adding to the complexity in enzyme functionalities within this family. Although 3D structural information becomes increasingly available within this clan and huge progress has been made on structure-function relationships, it is not clear why some sugars bind as inhibitors without being catalyzed. Conserved aspartate and glutamate residues are well known to act as nucleophile and acid/bases within this clan. Based on the available 3D structures of enzymes and enzyme-ligand complexes as well as docking simulations, we calculated the pKa of the acid-base before and after substrate binding. The obtained results strongly suggest that most GH-J members show an acid-base catalyst that is not sufficiently protonated before ligand entrance, while the acid-base can be fully protonated when a substrate, but not an inhibitor, enters the catalytic pocket. This provides a new mechanistic insight aiming at understanding the complex substrate and inhibitor specificities observed within the GH-J clan. Moreover, besides the effect of substrate entrance on its own, we strongly suggest that a highly conserved arginine residue (in the RDP motif) rather than the previously proposed Tyr motif (not conserved) provides the proton to increase the pKa of the acid-base catalyst. PMID:22662155

  5. Dense calcification in a GH-secreting pituitary macroadenoma

    PubMed Central

    Ibrahim, Ramez; Kalhan, Atul; Lammie, Alistair; Kotonya, Christine; Nannapanenni, Ravindra; Rees, Aled

    2014-01-01

    Summary A 30-year-old female presented with a history of secondary amenorrhoea, acromegalic features and progressive visual deterioration. She had elevated serum IGF1 levels and unsuppressed GH levels after an oral glucose tolerance test. Magnetic resonance imaging revealed a heterogeneously enhancing space-occupying lesion with atypical extensive calcification within the sellar and suprasellar areas. Owing to the extent of calcification, the tumour was a surgical challenge. Postoperatively, there was clinical, radiological and biochemical evidence of residual disease, which required treatment with a somatostatin analogue and radiotherapy. Mutational analysis of the aryl hydrocarbon receptor-interacting protein (AIP) gene was negative. This case confirms the relatively rare occurrence of calcification within a pituitary macroadenoma and its associated management problems. The presentation, biochemical, radiological and pathological findings are discussed in the context of the relevant literature. Learning points Calcification of pituitary tumours is relatively rare.Recognising calcification in pituitary adenomas on preoperative imaging is important in surgical decision-making.Gross total resection can be difficult to achieve in the presence of extensive calcification and dictates further management and follow-up to achieve disease control. PMID:24683483

  6. Substrate-specific transcription of the enigmatic GH61 family of the pathogenic white-rot fungus Heterobasidion irregulare during growth on lignocellulose.

    PubMed

    Yakovlev, Igor; Vaaje-Kolstad, Gustav; Hietala, Ari M; Stefańczyk, Emil; Solheim, Halvor; Fossdal, Carl Gunnar

    2012-08-01

    The GH61 represents the most enigmatic Glycoside Hydrolase family (GH) regarding enzymatic activity and importance in cellulose degradation. Heterobasidion irregulare is a necrotizing pathogen and white-rot fungus that causes enormous damages in conifer forests. The genome of H. irregulare allowed identification of ten HiGH61 genes. qRT-PCR analysis separate the HiGH61 members into two groups; one that show up regulation on lignocellulosic substrates (HiGH61A, HiGH61B, HiGH61D, HiGH61G, HiGH61H, and HiGH61I) and a second showing either down-regulation or constitutive expression (HiGH61C, HiGH61E, HiGH61F, and HiGH61J). HiGH61H showed up to 17,000-fold increase on spruce heartwood suggesting a pivotal role in cellulose decomposition during saprotrophic growth. Sequence analysis of these genes reveals that all GH61s except HiGH61G possess the conserved metal-binding motif essential for activity. The sequences also divide into groups having either an insert near the N terminus or an insert near the second catalytic histidine, which may represent extensions of the substrate-binding surface. Three of the HiGH61s encode cellulose-binding modules (CBM1). Interestingly, HiGH61H and HiGH61I having CBM1s are up-regulated on pure cellulose. There was a common substrate-specific induction patterns of the HiGH61s with several reference cellulolytic and hemicellulolytic GHs, this taken together with their low transcript levels on media lacking lignocellulose, reflect the concerted nature of cell wall polymer degradation. PMID:22718248

  7. Structural Basis for Prereceptor Modulation of Plant Hormones by GH3 Proteins

    SciTech Connect

    Westfall, Corey S.; Zubieta, Chloe; Herrmann, Jonathan; Kapp, Ulrike; Nanao, Max H.; Jez, Joseph M.

    2013-04-08

    Acyl acid amido synthetases of the GH3 family act as critical prereceptor modulators of plant hormone action; however, the molecular basis for their hormone selectivity is unclear. Here, we report the crystal structures of benzoate-specific Arabidopsis thaliana AtGH3.12/PBS3 and jasmonic acid-specific AtGH3.11/JAR1. These structures, combined with biochemical analysis, define features for the conjugation of amino acids to diverse acyl acid substrates and highlight the importance of conformational changes in the carboxyl-terminal domain for catalysis. We also identify residues forming the acyl acid binding site across the GH3 family and residues critical for amino acid recognition. Our results demonstrate how a highly adaptable three-dimensional scaffold is used for the evolution of promiscuous activity across an enzyme family for modulation of plant signaling molecules.

  8. A recurring dominant negative mutation causes autosomal dominant growth hormone deficiency - a clinical research center study

    SciTech Connect

    Cogan, J.D.; Prince, M.; Phillips, J.

    1995-12-01

    Familial isolated GH deficiency type II (IGHD-II) is an autosomal dominant disorder that has been previously shown in some patients to be caused by heterogeneous GH gene defects that affect GH messenger RNA (mRNA) splicing. We report here our findings of multiple G{r_arrow}A transitions of the first base of the donor splice site of IVS 3 (+1G{r_arrow}A) in IGHD II subjects from three nonrelated kindreds from Sweden, North America, and South Africa. This + 1G{r_arrow}A substitution creates an NlaIII site that was used to demonstrate that all affected individuals in all three families were heterozygous for the mutation. To determine the effect of this mutation of GH mRNA processing, HeLa cells were transfected with expression plasmids containing normal or mutant +1G{r_arrow}A alleles, and complementary DNAs from the resulting GH mRNAs were sequenced. The mutation was found to destroy the GH IVS3 donor splice site, causing skipping of exon 3 and loss of the codons for amino acids 32-71 of the mature GH peptide from the mutant GH mRNA. Our finding of exon 3 skipping in transcripts of the +1G{r_arrow}A mutant allele is identical to our previous report of a different sixth base transition (+6T{r_arrow}C) mutation of the IVS 3 donor splice site that also causes IGHD II. Microsatellite analysis of an affected subjects` DNA from each of the three nonrelated kindreds indicates that the +1G{r_arrow}A mutation arose independently in each family. Finding that neither grandparent has the mutation in the first family suggests that it arose de novo in that family. Our data indicate that (1) +1G{r_arrow}A IVS 3 mutations perturb GH mRNA splicing and cause IGHD II; and (2) these mutations can present as de novo GHD cases. 13 refs., 4 figs., 1 tab.

  9. Transcriptome analysis of the mammary gland from GH transgenic goats during involution.

    PubMed

    Lin, Jian; Bao, Ze Kun; Zhang, Qiang; Hu, Wei Wei; Yu, Qing Hua; Yang, Qian

    2015-07-10

    Mammary glands are organs for milk production in female mammals. Growth hormone (GH) is known to affect the growth and development of the mammary gland, as well as to increase milk production in dairy goats. This study performed a comprehensive expression profiling of genes expressed in the mammary gland of early involution GH transgenic (n=4) and non-transgenic goats (n=4) by RNA sequencing. RNA was extracted from mammary gland tissues collected at day 3 of involution. Gene expression analysis was conducted by Illumina RNA sequencing and sequence reads were assembled and analyzed using TopHat. FPKM (fragments per kilobase of exon per million) values were analyzed for differentially expressed genes using the Cufflinks package. Gene ontology analysis of differentially expressed genes was categorized using agriGO, while KEGG pathway analysis was performed with the online KEGG automatic annotation server. Our results revealed that 75% of NCBI goat annotated genes were expressed during early involution. A total of 18,323 genes were expressed during early involution in GH transgenic goats, compared with 18,196 expressed genes during early involution of non-transgenic goats. In these expressed genes, the majority (17,589) were ubiquitously expressed in GH transgenic and non-transgenic goats. However, there were 745 differentially expressed genes, 421 of which were upregulated and 324 were downregulated in GH transgenic goats. GO and KEGG pathway analysis showed that these genes were involved in mammary gland physiology, including cell adhesion molecules, ECM-receptor interaction, Jak-STAT signaling pathway, and fat metabolism. Our results demonstrated that the GH receptor was strongly affected in GH transgenic goats, which may activate the IGF-1/Stat3 signaling pathway. Overall, our study provided a global view of the transcriptome during involution of GH transgenic and non-transgenic goats, which increases our understanding of the biology of involution in the goat. PMID

  10. Adiponectin in mice with altered GH action: links to insulin sensitivity and longevity?

    PubMed

    Lubbers, Ellen R; List, Edward O; Jara, Adam; Sackman-Sala, Lucila; Cordoba-Chacon, Jose; Gahete, Manuel D; Kineman, Rhonda D; Boparai, Ravneet; Bartke, Andrzej; Kopchick, John J; Berryman, Darlene E

    2013-03-01

    Adiponectin is positively correlated with longevity and negatively correlated with many obesity-related diseases. While there are several circulating forms of adiponectin, the high-molecular-weight (HMW) version has been suggested to have the predominant bioactivity. Adiponectin gene expression and cognate serum protein levels are of particular interest in mice with altered GH signaling as these mice exhibit extremes in obesity that are positively associated with insulin sensitivity and lifespan as opposed to the typical negative association of these factors. While a few studies have reported total adiponectin levels in young adult mice with altered GH signaling, much remains unresolved, including changes in adiponectin levels with advancing age, proportion of total adiponectin in the HMW form, adipose depot of origin, and differential effects of GH vs IGF1. Therefore, the purpose of this study was to address these issues using assorted mouse lines with altered GH signaling. Our results show that adiponectin is generally negatively associated with GH activity, regardless of age. Further, the amount of HMW adiponectin is consistently linked with the level of total adiponectin and not necessarily with previously reported lifespan or insulin sensitivity of these mice. Interestingly, circulating adiponectin levels correlated strongly with inguinal fat mass, implying that the effects of GH on adiponectin are depot specific. Interestingly, rbGH, but not IGF1, decreased circulating total and HMW adiponectin levels. Taken together, these results fill important gaps in the literature related to GH and adiponectin and question the frequently reported associations of total and HMW adiponectin with insulin sensitivity and longevity. PMID:23261955

  11. Effects of dietary genistein on GH/IGF-I axis of Nile tilapia Oreochromis niloticus

    NASA Astrophysics Data System (ADS)

    Chen, Dong; Wang, Wei; Ru, Shaoguo

    2016-01-01

    There is considerable concern that isoflavones, such as genistein in fish feed composed of soybean protein, aff ects somatic growth in fish. Our previous works demonstrated that 30 and 300 μg/g dietary genistein had no significant eff ect on growth performance in Nile tilapia (Oreochromis niloticus), but the higher level of genistein (3 000 μg/g) significantly depressed growth. This study was conducted to further examine the eff ects of dietary genistein on the endocrine disruption on growth hormone/insulin-like growth factor-I (GH/IGF-I) axis in Nile tilapia (O. niloticus). Juvenile fish were fed by hand twice daily to satiation with one of four isonitrogenous and isoenergetic diets, each containing either 0, 30, 300 or 3 000 μg/g genistein. Following an 8-week feeding period, plasma GH and IGF-I levels were investigated by radioimmunoassay and gene expression levels of gh, ghrelin, gnrhs, ghr, npy, npyrs, pacap, ghrs, igf-I, igf-Ir, and igfbp3 were examined by real-time PCR. The results show that no significant change in plasma GH and IGF-I levels in fish fed with diets containing 30 μg/g and 300 μg/g genistein. mRNA expression of genes along the GH/IGF-I axis remained unaff ected, except for igf-Ir, which was stimulated by the 300 μg/g genistein diet. While in fish fed the 3 000 μg/g genistein diet, the plasma GH and IGF-I levels decreased, and mRNA expression of gh, ghr2, npyr1, igf-I, and igf-Ir were also significantly depressed. In contrast, npy and igfbp3 mRNA expression were enhanced. This study provides convincing evidence for growth impediment by genistein by disturbing the GH/IGF-I axis in Nile tilapia O. niloticus.

  12. Effects of dietary genistein on GH/IGF-I axis of Nile tilapia Oreochromis niloticus

    NASA Astrophysics Data System (ADS)

    Chen, Dong; Wang, Wei; Ru, Shaoguo

    2016-09-01

    There is considerable concern that isoflavones, such as genistein in fish feed composed of soybean protein, aff ects somatic growth in fish. Our previous works demonstrated that 30 and 300 μg/g dietary genistein had no significant eff ect on growth performance in Nile tilapia ( Oreochromis niloticus), but the higher level of genistein (3 000 μg/g) significantly depressed growth. This study was conducted to further examine the eff ects of dietary genistein on the endocrine disruption on growth hormone/insulin-like growth factor-I (GH/IGF-I) axis in Nile tilapia ( O. niloticus). Juvenile fish were fed by hand twice daily to satiation with one of four isonitrogenous and isoenergetic diets, each containing either 0, 30, 300 or 3 000 μg/g genistein. Following an 8-week feeding period, plasma GH and IGF-I levels were investigated by radioimmunoassay and gene expression levels of gh, ghrelin, gnrhs, ghr, npy, npyrs, pacap, ghrs, i gf-I, igf-Ir, and igfbp3 were examined by real-time PCR. The results show that no significant change in plasma GH and IGF-I levels in fish fed with diets containing 30 μg/g and 300 μg/g genistein. mRNA expression of genes along the GH/IGF-I axis remained unaff ected, except for igf-Ir, which was stimulated by the 300 μg/g genistein diet. While in fish fed the 3 000 μg/g genistein diet, the plasma GH and IGF-I levels decreased, and mRNA expression of gh, ghr2, npyr1, igf-I, and igf-Ir were also significantly depressed. In contrast, npy and igfbp3 mRNA expression were enhanced. This study provides convincing evidence for growth impediment by genistein by disturbing the GH/IGF-I axis in Nile tilapia O. niloticus.

  13. Development of a Transnasal Delivery System for Recombinant Human Growth Hormone (rhGH): Effects of the Concentration and Molecular Weight of Poly-L-arginine on the Nasal Absorption of rhGH in Rats.

    PubMed

    Kawashima, Ryo; Uchida, Masaki; Yamaki, Tsutomu; Ohtake, Kazuo; Hatanaka, Tomomi; Uchida, Hiroyuki; Ueda, Hideo; Kobayashi, Jun; Morimoto, Yasunori; Natsume, Hideshi

    2016-01-01

    A novel system for delivering recombinant human growth hormone (rhGH) that is noninvasive and has a simple method of administration is strongly desired to improve the compliance of children. The aim of this study was to investigate the potential for the intranasal (i.n.) co-administration of rhGH with poly-L-arginine (PLA) as a novel delivery system by evaluating the effects of the concentration and molecular weight of PLA on the nasal absorption of rhGH. The influence of the formation of insoluble aggregates and a soluble complex in the dosage formulation on nasal rhGH absorption was also evaluated by size-exclusion chromatography and ultrafiltration. PLA enhanced the nasal absorption of rhGH at each concentration and molecular weight examined. Nasal rhGH absorption increased dramatically when the PLA concentration was 1.0 % (w/v) due to the improved solubility of rhGH in the formulation. A delay in rhGH absorption was observed when the molecular weight of PLA was increased. This appeared to be because the increase in molecular weight caused the formation of a soluble complex. It seems that the PLA concentration affects the absorption-enhancing effect on rhGH, while the molecular weight of PLA affects the time when the maximum plasma rhGH concentration was reached (Tmax) of rhGH after i.n. administration, mainly because of the interactions among rhGH, PLA, and additives. Therefore, the transnasal rhGH delivery system using PLA is considered to be a promising alternative to subcutaneous (s.c.) injection if these interactions are sufficiently controlled. PMID:26725528

  14. Dynamic Analysis of GH Receptor Conformational Changes by Split Luciferase Complementation

    PubMed Central

    Liu, Ying; Berry, Philip A.; Zhang, Yue; Jiang, Jing; Lobie, Peter E.; Paulmurugan, Ramasamy; Langenheim, John F.; Chen, Wen Y.; Zinn, Kurt R.

    2014-01-01

    The transmembrane GH receptor (GHR) exists at least in part as a preformed homodimer on the cell surface. Structural and biochemical studies suggest that GH binds GHR in a 1:2 stoichiometry to effect acute GHR conformational changes that trigger the activation of the receptor-associated tyrosine kinase, Janus kinase 2 (JAK2), and downstream signaling. Despite information about GHR-GHR association derived from elegant fluorescence resonance energy transfer/bioluminescence resonance energy transfer studies, an assessment of the dynamics of GH-induced GHR conformational changes has been lacking. To this end, we used a split luciferase complementation assay that allowed detection in living cells of specific ligand-independent GHR-GHR interaction. Furthermore, GH treatment acutely augmented complementation of enzyme activity between GHRs fused, respectively, to N- and C-terminal fragments of firefly luciferase. Analysis of the temporal pattern of GH-induced complementation changes, pharmacological manipulation, genetic alteration of JAK2 levels, and truncation of the GHR intracellular domain (ICD) tail suggested that GH acutely enhances proximity of the GHR homodimer partners independent of the presence of JAK2, phosphorylation of GHR-luciferase chimeras, or an intact ICD. However, subsequent reduction of complementation requires JAK2 kinase activity and the ICD tail. This conclusion is in contrast to existing models of the GHR activation process. PMID:25188449

  15. Identification and characterization of the GhHsp20 gene family in Gossypium hirsutum.

    PubMed

    Ma, Wei; Zhao, Ting; Li, Jie; Liu, Bingliang; Fang, Lei; Hu, Yan; Zhang, Tianzhen

    2016-01-01

    In higher plants, Heat Shock Protein 20 (Hsp20) plays crucial roles in growth, development and responses to abiotic stresses. In this study, 94 GhHsp20 genes were identified in G. hirsutum, and these genes were phylogenetically clustered into 14 subfamilies. Out of these, 73 paralogous gene pairs remained in conserved positions on segmental duplicated blocks and only 14 genes clustered into seven tandem duplication event regions. Transcriptome analysis showed that 82 GhHsp20 genes were expressed in at least one tested tissues, indicating that the GhHsp20 genes were involved in physiological and developmental processes of cotton. Further, expression profiles under abiotic stress exhibited that two-thirds of the GhHsp20 genes were responsive to heat stress, while 15 genes were induced by multiple stresses. In addition, qRT-PCR confirmed that 16 GhHsp20 genes were hot-induced, and eight genes were up-regulated under multiple abiotic stresses and stress-related phytohormone treatments. Taken together, our results presented here would be helpful in laying the foundation for understanding the complex mechanisms of GhHsp20 mediated developmental processes and abiotic stress signaling transduction pathways in cotton. PMID:27580529

  16. Dwarfism and increased adiposity in the gh1 mutant zebrafish vizzini.

    PubMed

    McMenamin, Sarah K; Minchin, James E N; Gordon, Tiffany N; Rawls, John F; Parichy, David M

    2013-04-01

    Somatic growth and adipogenesis are closely associated with the development of obesity in humans. In this study, we identify a zebrafish mutant, vizzini, that exhibits both a severe defect in somatic growth and increased accumulation of adipose tissue. Positional cloning of vizzini revealed a premature stop codon in gh1. Although the effects of GH are largely through igfs in mammals, we found no decrease in the expression of igf transcripts in gh1 mutants during larval development. As development progressed, however, we found overall growth to be progressively retarded and the attainment of specific developmental stages to occur at abnormally small body sizes relative to wild type. Moreover, both subcutaneous (sc) and visceral adipose tissues underwent precocious development in vizzini mutants, and at maturity, the sizes of different fat deposits were greatly expanded relative to wild type. In vivo confocal imaging of sc adipose tissue (SAT) expansion revealed that vizzini mutants exhibit extreme enlargement of adipocyte lipid droplets without a corresponding increase in lipid droplet number. These findings suggest that GH1 signaling restricts SAT hypertrophy in zebrafish. Finally, nutrient deprivation of vizzini mutants revealed that SAT mobilization was greatly diminished during caloric restriction, further implicating GH1 signaling in adipose tissue homeostasis. Overall, the zebrafish gh1 mutant, vizzini, exhibits decreased somatic growth, increased adipose tissue accumulation, and disrupted adipose plasticity after nutrient deprivation and represents a novel model to investigate the in vivo dynamics of vertebrate obesity. PMID:23456361

  17. GhWRKY68 Reduces Resistance to Salt and Drought in Transgenic Nicotiana benthamiana

    PubMed Central

    Jia, Haihong; Wang, Chen; Wang, Fang; Liu, Shuchang; Li, Guilin; Guo, Xingqi

    2015-01-01

    The WRKY transcription factors modulate numerous physiological processes, including plant growth, development and responses to various environmental stresses. Currently, our understanding of the functions of the majority of the WRKY family members and their possible roles in signalling crosstalk is limited. In particular, very few WRKYs have been identified and characterised from an economically important crop, cotton. In this study, we characterised a novel group IIc WRKY gene, GhWRKY68, which is induced by different abiotic stresses and multiple defence-related signalling molecules. The β-glucuronidase activity driven by the GhWRKY68 promoter was enhanced after exposure to drought, salt, abscisic acid (ABA) and H2O2. The overexpression of GhWRKY68 in Nicotiana benthamiana reduced resistance to drought and salt and affected several physiological indices. GhWRKY68 may mediate salt and drought responses by modulating ABA content and enhancing the transcript levels of ABA-responsive genes. GhWRKY68-overexpressing plants exhibited reduced tolerance to oxidative stress after drought and salt stress treatments, which correlated with the accumulation of reactive oxygen species (ROS), reduced enzyme activities, elevated malondialdehyde (MDA) content and altered ROS-related gene expression. These results indicate that GhWRKY68 is a transcription factor that responds to drought and salt stresses by regulating ABA signalling and modulating cellular ROS. PMID:25793865

  18. Evolutionary history of the GH3 family of acyl adenylases in rosids.

    PubMed

    Okrent, Rachel A; Wildermuth, Mary C

    2011-08-01

    GH3 amino acid conjugases have been identified in many plant and bacterial species. The evolution of GH3 genes in plant species is explored using the sequenced rosids Arabidopsis, papaya, poplar, and grape. Analysis of the sequenced non-rosid eudicots monkey flower and columbine, the monocots maize and rice, as well as spikemoss and moss is included to provide further insight into the origin of GH3 clades. Comparison of co-linear genes in regions surrounding GH3 genes between species helps reconstruct the evolutionary history of the family. Combining analysis of synteny with phylogenetics, gene expression and functional data redefines the Group III GH3 genes, of which AtGH3.12/PBS3, a regulator of stress-induced salicylic acid metabolism and plant defense, is a member. Contrary to previous reports that restrict PBS3 to Arabidopsis and its close relatives, PBS3 syntelogs are identified in poplar, grape, columbine, maize and rice suggesting descent from a common ancestral chromosome dating to before the eudicot/monocot split. In addition, the clade containing PBS3 has undergone a unique expansion in Arabidopsis, with expression patterns for these genes consistent with specialized and evolving stress-responsive functions. PMID:21594748

  19. Identification and characterization of the GhHsp20 gene family in Gossypium hirsutum

    PubMed Central

    Ma, Wei; Zhao, Ting; Li, Jie; Liu, Bingliang; Fang, Lei; Hu, Yan; Zhang, Tianzhen

    2016-01-01

    In higher plants, Heat Shock Protein 20 (Hsp20) plays crucial roles in growth, development and responses to abiotic stresses. In this study, 94 GhHsp20 genes were identified in G. hirsutum, and these genes were phylogenetically clustered into 14 subfamilies. Out of these, 73 paralogous gene pairs remained in conserved positions on segmental duplicated blocks and only 14 genes clustered into seven tandem duplication event regions. Transcriptome analysis showed that 82 GhHsp20 genes were expressed in at least one tested tissues, indicating that the GhHsp20 genes were involved in physiological and developmental processes of cotton. Further, expression profiles under abiotic stress exhibited that two-thirds of the GhHsp20 genes were responsive to heat stress, while 15 genes were induced by multiple stresses. In addition, qRT-PCR confirmed that 16 GhHsp20 genes were hot-induced, and eight genes were up-regulated under multiple abiotic stresses and stress-related phytohormone treatments. Taken together, our results presented here would be helpful in laying the foundation for understanding the complex mechanisms of GhHsp20 mediated developmental processes and abiotic stress signaling transduction pathways in cotton. PMID:27580529

  20. Human GnRH Deficiency: A Unique Disease Model to Unravel the Ontogeny of GnRH Neurons

    PubMed Central

    Balasubramanian, Ravikumar; Dwyer, Andrew; Seminara, Stephanie B.; Pitteloud, Nelly; Kaiser, Ursula B.; Crowley, William F.

    2010-01-01

    Evolutionary survival of a species is largely a function of its reproductive fitness. In mammals, a sparsely populated and widely dispersed network of hypothalamic neurons, the gonadotropin-releasing hormone (GnRH) neurons, serve as the pilot light of reproduction via coordinated secretion of GnRH. Since it first description, human GnRH deficiency has been recognized both clinically and genetically as a heterogeneous disease. A spectrum of different reproductive phenotypes comprised of congenital GnRH deficiency with anosmia (Kallmann syndrome), congenital GnRH deficiency with normal olfaction (normosmic idiopathic hypogonadotropic hypogonadism), and adult-onset hypogonadotropic hypogonadism has been described. In the last two decades, several genes and pathways which govern GnRH ontogeny have been discovered by studying humans with GnRH deficiency. More importantly, detailed study of these patients has highlighted the emerging theme of oligogenicity and genotypic synergism, and also expanded the phenotypic diversity with the documentation of reversal of GnRH deficiency later in adulthood in some patients. The underlying genetic defect has also helped understand the associated nonreproductive phenotypes seen in some of these patients. These insights now provide practicing clinicians with targeted genetic diagnostic strategies and also impact on clinical management. PMID:20606386

  1. Mutation Update and Review of Severe Methylenetetrahydrofolate Reductase Deficiency.

    PubMed

    Froese, D Sean; Huemer, Martina; Suormala, Terttu; Burda, Patricie; Coelho, David; Guéant, Jean-Louis; Landolt, Markus A; Kožich, Viktor; Fowler, Brian; Baumgartner, Matthias R

    2016-05-01

    Severe 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is caused by mutations in the MTHFR gene and results in hyperhomocysteinemia and varying severity of disease, ranging from neonatal lethal to adult onset. Including those described here, 109 MTHFR mutations have been reported in 171 families, consisting of 70 missense mutations, 17 that primarily affect splicing, 11 nonsense mutations, seven small deletions, two no-stop mutations, one small duplication, and one large duplication. Only 36% of mutations recur in unrelated families, indicating that most are "private." The most common mutation is c.1530A>G (numbered from NM_005957.4, p.Lys510 = ) causing a splicing defect, found in 13 families; the most common missense mutation is c.1129C>T (p.Arg377Cys) identified in 10 families. To increase disease understanding, we report enzymatic activity, detected mutations, and clinical onset information (early, <1 year; or late, >1 year) for all published patients available, demonstrating that patients with early onset have less residual enzyme activity than those presenting later. We also review animal models, diagnostic approaches, clinical presentations, and treatment options. This is the first large review of mutations in MTHFR, highlighting the wide spectrum of disease-causing mutations. PMID:26872964

  2. Sequence and Bioinformatic Analysis of Family 1 Glycoside Hydrolase (GH) 1 Gene from the Oomycete Pythium myriotylum Drechsler.

    PubMed

    Nair, R Aswati; Geethu, C; Sangwan, Amit; Pillai, P Padmesh

    2015-06-01

    The oomycetous phytopathogen Pythium myriotylum secretes cellulases for growth/nutrition of the necrotroph. Cellulases are multi-enzyme system classified into different glycoside hydrolase (GH) families. The present study deals with identification and characterization of GH gene sequence from P. myriotylum by a PCR strategy using consensus primers. Cloning of the full-length gene sequence using genome walker strategy resulted in identification of 1230-bp P. myriotylum GH gene sequence, designated as PmGH1. Analysis revealed that PmGH1 encodes a predicted cytoplasmic 421 amino acid protein with an apparent molecular weight of 46.77 kDa and a theoretical pI of 8.11. Tertiary structure of the deduced amino acid sequence showed typical (α/β)8 barrel folding of family 1 GHs. Sequence characterization of PmGH1 identified the conserved active site residues, viz., Glu 181 and Glu 399, that function as acid-base catalyst and catalytically active nucleophile, respectively. Binding sites for N-acetyl-D-glucosamine (NAG) were revealed in the PmGH1 3D structure with Glu181 and Glu399 positioned on either side to form a catalytic pair. Phylogenetic analysis indicated a closer affiliation of PmGH1 with sequences of GH1 family. Results presented are first attempts providing novel insights into the evolutionary and functional perspectives of the identified P. myriotylum GH. PMID:25877398

  3. Glycoside Hydrolase (GH) 45 and 5 Candidate Cellulases in Aphelenchoides besseyi Isolated from Bird’s-Nest Fern

    PubMed Central

    Tsay, Tung-Tsuan; Tsai, Isheng J.; Chen, Peichen J.

    2016-01-01

    Five Aphelenchoides besseyi isolates collected from bird’s-nest ferns or rice possess different parasitic capacities in bird’s-nest fern. Two different glycoside hydrolase (GH) 45 genes were identified in the fern isolates, and only one was found in the rice isolates. A Abe GH5-1 gene containing an SCP-like family domain was found only in the fern isolates. Abe GH5-1 gene has five introns suggesting a eukaryotic origin. A maximum likelihood phylogeny revealed that Abe GH5-1 is part of the nematode monophyletic group that can be clearly distinguished from those of other eukaryotic and bacterial GH5 sequences with high bootstrap support values. The fern A. besseyi isolates were the first parasitic plant nematode found to possess both GH5 and GH45 genes. Surveying the genome of the five A. besseyi isolates by Southern blotting using an 834 bp probe targeting the GH5 domain suggests the presence of at least two copies in the fern-origin isolates but none in the rice-origin isolates. The in situ hybridization shows that the Abe GH5-1 gene is expressed in the nematode ovary and testis. Our study provides insights into the diversity of GH in isolates of plant parasitic nematodes of different host origins. PMID:27391812

  4. Glycoside Hydrolase (GH) 45 and 5 Candidate Cellulases in Aphelenchoides besseyi Isolated from Bird's-Nest Fern.

    PubMed

    Wu, Guan-Long; Kuo, Tzu-Hao; Tsay, Tung-Tsuan; Tsai, Isheng J; Chen, Peichen J

    2016-01-01

    Five Aphelenchoides besseyi isolates collected from bird's-nest ferns or rice possess different parasitic capacities in bird's-nest fern. Two different glycoside hydrolase (GH) 45 genes were identified in the fern isolates, and only one was found in the rice isolates. A Abe GH5-1 gene containing an SCP-like family domain was found only in the fern isolates. Abe GH5-1 gene has five introns suggesting a eukaryotic origin. A maximum likelihood phylogeny revealed that Abe GH5-1 is part of the nematode monophyletic group that can be clearly distinguished from those of other eukaryotic and bacterial GH5 sequences with high bootstrap support values. The fern A. besseyi isolates were the first parasitic plant nematode found to possess both GH5 and GH45 genes. Surveying the genome of the five A. besseyi isolates by Southern blotting using an 834 bp probe targeting the GH5 domain suggests the presence of at least two copies in the fern-origin isolates but none in the rice-origin isolates. The in situ hybridization shows that the Abe GH5-1 gene is expressed in the nematode ovary and testis. Our study provides insights into the diversity of GH in isolates of plant parasitic nematodes of different host origins. PMID:27391812

  5. No differences in metabolic outcomes between nadir GH 0.4 and 1.0 ng/mL during OGTT in surgically cured acromegalic patients (observational study).

    PubMed

    Ku, Cheol Ryong; Choe, Eun Yeong; Hong, Jae Won; Kim, Eui Hyun; Park, Se Hee; Kim, Sun Ho; Lee, Eun Jig

    2016-06-01

    Metabolic impairment is the common cause for mortality in acromegalic patients. In this study, long-term improvements of metabolic parameters were evaluated according to 2 different remission criteria.This was an observational cohort study before and up to 1 year after transsphenoidal adenomectomy (TSA). Participants were 187 patients with acromegaly. At 6 months after TSA, remitted patients with age- and sex-matched normalized IGF-1 were divided into 2 groups: remission 1 (R1), nadir growth hormone (GH) below 0.4 ng/mL; and remission 2 (R2), nadir GH between 0.4 and 1.0 ng/mL in oral glucose tolerance test (OGTT). Metabolic parameters during serial OGTTs were evaluated for 12 months. Remission was achieved in 157 (R1-136; R2-21) patients. Immediate postoperative metabolic parameters including body weight, body mass index, glucose, insulin, and free fatty acid in OGTT were all significantly improved in R1 and R2. HOMA-%β and HOMA-IR scores also improved in both R1 and R2. These improvements persisted for duration (12 months) of this study. However, no difference was present in metabolic parameters between R1 and R2. Although the patients with preoperative adrenal insufficiency presented significantly increased HOMA scores before TSA, there was no difference between classifications of deficient pituitary axes and changes of metabolic parameters after TSA. Remitted patients exhibited rapid restoration of metabolic parameters immediate postoperative period. Long-term improvements in metabolic parameters were not different between the 2 different nadir GH cut-offs, 0.4 and 1.0 ng/mL. PMID:27310957

  6. Optimization of a GO2/GH2 Impinging Injector Element

    NASA Technical Reports Server (NTRS)

    Tucker, P. Kevin; Shyy, Wei; Vaidyanathan, Rajkumar

    2001-01-01

    An injector optimization methodology, method i, is used to investigate optimal design points for a gaseous oxygen/gaseous hydrogen (GO2/GH2) impinging injector element. The unlike impinging element, a fuel-oxidizer- fuel (F-O-F) triplet, is optimized in terms of design variables such as fuel pressure drop, (Delta)P(sub f), oxidizer pressure drop, (Delta)P(sub o), combustor length, L(sub comb), and impingement half-angle, alpha, for a given mixture ratio and chamber pressure. Dependent variables such as energy release efficiency, ERE, wall heat flux, Q(sub w), injector heat flux, Q(sub inj), relative combustor weight, W(sub rel), and relative injector cost, C(sub rel), are calculated and then correlated with the design variables. An empirical design methodology is used to generate these responses for 163 combinations of input variables. Method i is then used to generate response surfaces for each dependent variable. Desirability functions based on dependent variable constraints are created and used to facilitate development of composite response surfaces representing some, or all, of the five dependent variables in terms of the input variables. Three examples illustrating the utility and flexibility of method i are discussed in detail. First, joint response surfaces are constructed by sequentially adding dependent variables. Optimum designs are identified after addition of each variable and the effect each variable has on the design is shown. This stepwise demonstration also highlights the importance of including variables such as weight and cost early in the design process. Secondly, using the composite response surface which includes all five dependent variables, unequal weights are assigned to emphasize certain variables relative to others. Here, method i is used to enable objective trade studies on design issues such as component life and thrust to weight ratio. Finally, specific variable weights are further increased to illustrate the high marginal cost of

  7. Biochemical and kinetic characterization of GH43 β-D-xylosidase/α-L-arabinofuranosidase and GH30 α-L-arabinofuranosidase/β-D -xylosidase from rumen metagenome.

    PubMed

    Zhou, Jungang; Bao, Lei; Chang, Lei; Zhou, Yufei; Lu, Hong

    2012-01-01

    The present study focuses on characterization of two hemicellulases, RuXyn1 and RuXyn2, from rumen bacterial metagenome and their capabilities for degradation of xylans. Glycosyl hydrolase (GH) family 43 β-D -xylosidase/α-L -arabinofuranosidase RuXyn1 can hydrolyze p-nitrophenyl-β-D -xylopyranoside (pNPX), p-nitrophenyl-α-L -arabinofuranoside (pNPA), and xylo-oligosaccharide substrates, while GH30 1,5-α-L -arabinofuranosidase/β-D -xylosidase RuXyn2, the first α-L -arabinofuranosidase assigned to this GH family, shows activities towards 1,5-α-L -arabinobiose and pNPX substrates but no activity for pNPA. Kinetic analysis for aryl-glycosides revealed that RuXyn2 had higher catalytic efficiency than RuXyn1 toward pNPX substrate. RuXyn1 shows high synergism with endoxylanase, elevating by 73% the reducing sugars released from brichwood xylans, and converted most intermediate xylo-oligosaccharide hydrolysate into xylose. The high xylose conversion capability of RuXyn1 suggests it has potential applications in enzymatic production of xylose and improvement of hemicellulose saccharification for production of biofuels. RuXyn2 shows no obviously synergistic effect in the endoxylanase-coupled assay for enzymatic saccharification of xylan. Further cosmid DNA sequencing revealed a neighboring putative GH43 α-L -arabinofuranosidase RuAra1 and two putative GH3 β-xylosidase/arabinosidases, RuXyn3 and RuXyn5, downstream of RuXyn2, indicating that this hemicellulase gene cluster may be responsible for production of end-product, xylose and arabinose, from hemicellulose biomass. PMID:21720773

  8. First Structural Insights into α-l-Arabinofuranosidases from the Two GH62 Glycoside Hydrolase Subfamilies*

    PubMed Central

    Siguier, Béatrice; Haon, Mireille; Nahoum, Virginie; Marcellin, Marlène; Burlet-Schiltz, Odile; Coutinho, Pedro M.; Henrissat, Bernard; Mourey, Lionel; O'Donohue, Michael J.; Berrin, Jean-Guy; Tranier, Samuel; Dumon, Claire

    2014-01-01

    α-l-Arabinofuranosidases are glycoside hydrolases that specifically hydrolyze non-reducing residues from arabinose-containing polysaccharides. In the case of arabinoxylans, which are the main components of hemicellulose, they are part of microbial xylanolytic systems and are necessary for complete breakdown of arabinoxylans. Glycoside hydrolase family 62 (GH62) is currently a small family of α-l-arabinofuranosidases that contains only bacterial and fungal members. Little is known about the GH62 mechanism of action, because only a few members have been biochemically characterized and no three-dimensional structure is available. Here, we present the first crystal structures of two fungal GH62 α-l-arabinofuranosidases from the basidiomycete Ustilago maydis (UmAbf62A) and ascomycete Podospora anserina (PaAbf62A). Both enzymes are able to efficiently remove the α-l-arabinosyl substituents from arabinoxylan. The overall three-dimensional structure of UmAbf62A and PaAbf62A reveals a five-bladed β-propeller fold that confirms their predicted classification into clan GH-F together with GH43 α-l-arabinofuranosidases. Crystallographic structures of the complexes with arabinose and cellotriose reveal the important role of subsites +1 and +2 for sugar binding. Intriguingly, we observed that PaAbf62A was inhibited by cello-oligosaccharides and displayed binding affinity to cellulose although no activity was observed on a range of cellulosic substrates. Bioinformatic analyses showed that UmAbf62A and PaAbf62A belong to two distinct subfamilies within the GH62 family. The results presented here provide a framework to better investigate the structure-function relationships within the GH62 family. PMID:24394409

  9. Evolution, substrate specificity and subfamily classification of glycoside hydrolase family 5 (GH5)

    PubMed Central

    2012-01-01

    Background The large Glycoside Hydrolase family 5 (GH5) groups together a wide range of enzymes acting on β-linked oligo- and polysaccharides, and glycoconjugates from a large spectrum of organisms. The long and complex evolution of this family of enzymes and its broad sequence diversity limits functional prediction. With the objective of improving the differentiation of enzyme specificities in a knowledge-based context, and to obtain new evolutionary insights, we present here a new, robust subfamily classification of family GH5. Results About 80% of the current sequences were assigned into 51 subfamilies in a global analysis of all publicly available GH5 sequences and associated biochemical data. Examination of subfamilies with catalytically-active members revealed that one third are monospecific (containing a single enzyme activity), although new functions may be discovered with biochemical characterization in the future. Furthermore, twenty subfamilies presently have no characterization whatsoever and many others have only limited structural and biochemical data. Mapping of functional knowledge onto the GH5 phylogenetic tree revealed that the sequence space of this historical and industrially important family is far from well dispersed, highlighting targets in need of further study. The analysis also uncovered a number of GH5 proteins which have lost their catalytic machinery, indicating evolution towards novel functions. Conclusion Overall, the subfamily division of GH5 provides an actively curated resource for large-scale protein sequence annotation for glycogenomics; the subfamily assignments are openly accessible via the Carbohydrate-Active Enzyme database at http://www.cazy.org/GH5.html. PMID:22992189

  10. [Influence of prolonged treatment with octreotide on GH, IGF I, insulin, ACTH, cortisol, T3, T4 and TSH secretion in a case of congenital chylothorax].

    PubMed

    Bagnoli, F; Badii, S; Conte, M L; Toti, M S; De Felice, C; Bellieni, C V; Borlini, G; Tomasini, B; Zani, S

    2010-08-01

    Congenital chylothorax is a rare condition characterized by the accumulation of lymph fluid in the pleural space that causes respiratory and circulatory dysfunctions, immune deficiencies, hypoalbuminemia, electrolyte imbalance and alterations of the coagulation. Mortality rates are elevated and can rise to 50%. Therapy consists in conservative treatment based on thoracic drainage combined with total parenteral nutrition or use of low-fat high-protein diet supplemented with medium chain triglycerides. In case of failure surgical intervention may be considered. During the last years some authors have experienced the use of octreotide with doubtful results. In no case the drug impact on insulin, GH and cortisol secretion in neonatal age has been investigated and only in one case the effect on thyroid hormones has been assessed. We report the case of a 36-week baby with congenital chylothorax treated with octreotide for 42 days. The drug was well tolerated but hormonal level measurements showed a deep depression of insulin secretion unaccompanied by alterations of glucose levels. Levels of GH and TSH showed only a transitory decrease. ACTH and cortisol remained normal. At 5 months, the measurements of hormonal levels did not show significant alterations. It is not possible to determine if such a drug played an essential role in the solution of the pleural effusion, but it is important to emphasize that a prolonged treatment with octreotide has not caused, in our case, persistent hormonal alterations. PMID:20940674

  11. Growth hormone (GH) treatment acts on the endocrine and autocrine/paracrine GH/IGF-axis and on TNF-α expression in bony fish pituitary and immune organs.

    PubMed

    Shved, N; Berishvili, G; Mazel, P; Baroiller, J-F; Eppler, Elisabeth

    2011-12-01

    There exist indications that the growth hormone (GH)/insulin-like growth factor (IGF) axis may play a role in fish immune regulation, and that interactions occur via tumour necrosis factor (TNF)-α at least in mammals, but no systematic data exist on potential changes in GH, IGF-I, IGF-II, GH receptor (GHR) and TNF-α expression after GH treatment. Thus, we investigated in the Nile tilapia the influence of GH injections by real-time qPCR at different levels of the GH/IGF-axis (brain, pituitary, peripheral organs) with special emphasis on the immune organs head kidney and spleen. Endocrine IGF-I served as positive control for GH treatment efficiency. Basal TNF-α gene expression was detected in all organs investigated with the expression being most pronounced in brain. Two consecutive intraperitoneal injections of bream GH elevated liver IGF-I mRNA and plasma IGF-I concentration. Also liver IGF-II mRNA and TNF-α were increased while the GHR was downregulated. In brain, no change occurred in the expression levels of all genes investigated. GH gene expression was exclusively detected in the pituitary where the GH injections elevated both GH and IGF-I gene expression. In the head kidney, GH upregulated IGF-I mRNA to an even higher extent than liver IGF-I while IGF-II and GHR gene expressions were not affected. Also in the spleen, no change occurred in GHR mRNA, however, IGF-I and IGF-II mRNAs were increased. In correlation, in situ hybridisation showed a markedly higher amount of IGF-I mRNA in head kidney and spleen after GH injection. In both immune tissues, TNF-α gene expression showed a trend to decrease after GH treatment. The stimulation of IGF-I and also partially of IGF-II expression in the fish immune organs by GH indicates a local role of the IGFs in immune organ regulation while the differential changes in TNF-α support the in mammals postulated interactions with the GH/IGF-axis which demand for further investigations. PMID:21903170

  12. Arginine induces GH gene expression by activating NOS/NO signaling in rat isolated hemi-pituitaries

    PubMed Central

    Olinto, S.C.F.; Adrião, M.G.; Castro-Barbosa, T.; Goulart-Silva, F.; Nunes, M.T.

    2012-01-01

    The amino acid arginine (Arg) is a recognized secretagogue of growth hormone (GH), and has been shown to induce GH gene expression. Arg is the natural precursor of nitric oxide (NO), which is known to mediate many of the effects of Arg, such as GH secretion. Arg was also shown to increase calcium influx in pituitary cells, which might contribute to its effects on GH secretion. Although the mechanisms involved in the effects of Arg on GH secretion are well established, little is known about them regarding the control of GH gene expression. We investigated whether the NO pathway and/or calcium are involved in the effects of Arg on GH gene expression in rat isolated pituitaries. To this end, pituitaries from approximately 170 male Wistar rats (∼250 g) were removed, divided into two halves, pooled (three hemi-pituitaries) and incubated or not with Arg, as well as with different pharmacological agents. Arg (71 mM), the NO donor sodium nitroprusside (SNP, 1 and 0.1 mM) and a cyclic guanosine monophosphate (cGMP) analogue (8-Br-cGMP, 1 mM) increased GH mRNA expression 60 min later. The NO acceptor hemoglobin (0.3 µM) blunted the effect of SNP, and the combined treatment with Arg and L-NAME (an NO synthase (NOS) inhibitor, 55 mM) abolished the stimulatory effect of Arg on GH gene expression. The calcium channel inhibitor nifedipine (3 µM) also abolished Arg-induced GH gene expression. The present study shows that Arg directly induces GH gene expression in hemi-pituitaries isolated from rats, excluding interference from somatostatinergic neurons, which are supposed to be inhibited by Arg. Moreover, the data demonstrate that the NOS/NO signaling pathway and calcium mediate the Arg effects on GH gene expression. PMID:22641416

  13. Efficacy and Safety of Sustained-Release Recombinant Human Growth Hormone in Korean Adults with Growth Hormone Deficiency

    PubMed Central

    Kim, Youngsook; Hong, Jae Won; Chung, Yoon-Sok; Kim, Sung-Woon; Cho, Yong-Wook; Kim, Jin Hwa; Kim, Byung-Joon

    2014-01-01

    Purpose The administration of recombinant human growth hormone in adults with growth hormone deficiency has been known to improve metabolic impairment and quality of life. Patients, however, have to tolerate daily injections of growth hormone. The efficacy, safety, and compliance of weekly administered sustained-release recombinant human growth hormone (SR-rhGH, Declage™) supplement in patients with growth hormone deficiency were evaluated. Materials and Methods This trial is 12-week prospective, single-arm, open-label trial. Men and women aged ≥20 years with diagnosed growth hormone deficiency (caused by pituitary tumor, trauma and other pituitary diseases) were eligible for this study. Each subject was given 2 mg (6 IU) of SR-rhGH once a week, subcutaneously for 12 weeks. Efficacy and safety at baseline and within 30 days after the 12th injection were assessed and compared. Score of Assessment of Growth Hormone Deficiency in Adults (AGHDA score) for quality of life and serum IGF-1 level. Results The IGF-1 level of 108.67±74.03 ng/mL was increased to 129.01±68.37 ng/mL (p=0.0111) and the AGHDA QoL score was decreased from 9.80±6.51 to 7.55±5.76 (p<0.0001) at week 12 compared with those at baseline. Adverse events included pain, swelling, erythema, and warmth sensation at the administration site, but many adverse events gradually disappeared during the investigation. Conclusion Weekly administered SR-rhGH for 12 weeks effectively increased IGF-1 level and improved the quality of life in patients with GH deficiency without serious adverse events. PMID:24954335

  14. Folate-deficiency anemia

    MedlinePlus

    ... medlineplus.gov/ency/article/000551.htm Folate-deficiency anemia To use the sharing features on this page, please enable JavaScript. Folate-deficiency anemia is a decrease in red blood cells (anemia) ...

  15. Alpha-1 Antitrypsin Deficiency

    MedlinePlus

    ... from the NHLBI on Twitter. What Is Alpha-1 Antitrypsin Deficiency? Alpha-1 antitrypsin (an-tee-TRIP-sin) deficiency, or AAT ... as it relates to lung disease. Overview Alpha-1 antitrypsin, also called AAT, is a protein made ...

  16. A polymorphism in the leptin receptor gene at position 223 is associated with growth hormone replacement therapy responsiveness in idiopathic short stature and growth hormone deficiency patients.

    PubMed

    Su, Pen-Hua; Yang, Shun-Fa; Yu, Ju-Shan; Chen, Suh-Jen; Chen, Jia-Yuh

    2012-12-01

    We hypothesized that responses to growth hormone (GH) therapy by idiopathic short stature (ISS) and growth hormone deficiency (GHD) patients were associated with single nucleotide polymorphisms (SNPs) in the leptin (LEP) and leptin receptor (LEPR) genes. We retrospectively enrolled ISS (n = 32) and GHD (n = 38) patients and forty healthy age-and gender-matched children. They were genotyped for the LEP promoter at nt.-2548, and LEPR K109R and LEPR Q223R polymorphisms. Clinical and laboratory variables were determined before and after 2 years of GH treatment. ISS patients with G/A or A/A genotypes of the LEPR Q223R SNP had a significantly higher height velocity (cm/y) than ISS patients with the G/G genotype at 2 years after GH treatment. For GHD patients, G/A or A/A genotype of the LEPR K109R SNP was associated with higher body weight, higher BMI, and higher weight velocity than patients with the G/G genotype before GH treatment, but not after GH treatment. G/A or A/A genotype of the LEPR Q223R SNP was associated with a significantly higher body weight, higher height velocity before treatment, but not after GH treatment. G/A or A/A genotype of the LEPR Q223R SNP was associated with a significantly higher weight velocity before treatment, but a significantly lower weight velocity was found at 2 years after GH treatment. These results suggest LEPR Q223R SNP (rs1137101) is associated with outcomes of GH replacement therapy in ISS and GHD patients. PMID:23009903

  17. A mechanism of glucose tolerance and stimulation of GH1 β-glucosidases

    PubMed Central

    Yang, Yang; Zhang, Xinxin; Yin, Qiang; Fang, Wei; Fang, Zemin; Wang, Xiaotang; Zhang, Xuecheng; Xiao, Yazhong

    2015-01-01

    β-Glucosidases are enzymes that hydrolyze β-glycosidic bonds to release non-reducing terminal glucosyl residues from glycosides and oligosaccharides, and thus have significant application potential in industries. However, most β-glucosidases are feedback inhibited by the glucose product, which restricts their application. Remarkably, some β-glucosidases of the glycoside hydrolase (GH) 1 family are tolerant to or even stimulated by glucose. Elucidation of the mechanisms of glucose tolerance and stimulation of the GH1 β-glucosidases will be crucial to improve their application through enzyme engineering. In this study, by comparing the primary and tertiary structures of two GH1 β-glucosidases with distinct glucose dependence, some putative glucose-dependence relevant sites were mutated to investigate their exact roles. Both biochemical and structural characterization of the mutants suggested that some sites at the entrance and middle of the substrate channel regulate the effects of glucose, and the relative binding affinity/preference of these sites to glucose modulates the glucose dependence. A mechanism was therefore proposed to interpret the glucose dependence of GH1 β-glucosidases. This research provides fresh insight into our current understanding of the properties and mechanisms of GH1 β-glycosidases and related enzymes that modulate their activity via feedback control mechanism. PMID:26603650

  18. In silico Identification and Taxonomic Distribution of Plant Class C GH9 Endoglucanases

    PubMed Central

    Kundu, Siddhartha; Sharma, Rita

    2016-01-01

    The glycoside hydrolase 9 superfamily, mainly comprising the endoglucanases, is represented in all three domains of life. The current division of GH9 enzymes, into three subclasses, namely A, B, and C, is centered on parameters derived from sequence information alone. However, this classification is ambiguous, and is limited by the paralogous ancestry of classes B and C endoglucanases, and paucity of biochemical and structural data. Here, we extend this classification schema to putative GH9 endoglucanases present in green plants, with an emphasis on identifying novel members of the class C subset. These enzymes cleave the β(1 → 4) linkage between non-terminal adjacent D-glucopyranose residues, in both, amorphous and crystalline regions of cellulose. We utilized non redundant plant GH9 enzymes with characterized molecular data, as the training set to construct Hidden Markov Models (HMMs) and train an Artificial Neural Network (ANN). The parameters that were used for predicting dominant enzyme function, were derived from this training set, and subsequently refined on 147 sequences with available expression data. Our knowledge-based approach, can ascribe differential endoglucanase activity (A, B, or C) to a query sequence with high confidence, and was used to construct a local repository of class C GH9 endoglucanases (GH9C = 241) from 32 sequenced green plants. PMID:27570528

  19. A mechanism of glucose tolerance and stimulation of GH1 β-glucosidases.

    PubMed

    Yang, Yang; Zhang, Xinxin; Yin, Qiang; Fang, Wei; Fang, Zemin; Wang, Xiaotang; Zhang, Xuecheng; Xiao, Yazhong

    2015-01-01

    β-Glucosidases are enzymes that hydrolyze β-glycosidic bonds to release non-reducing terminal glucosyl residues from glycosides and oligosaccharides, and thus have significant application potential in industries. However, most β-glucosidases are feedback inhibited by the glucose product, which restricts their application. Remarkably, some β-glucosidases of the glycoside hydrolase (GH) 1 family are tolerant to or even stimulated by glucose. Elucidation of the mechanisms of glucose tolerance and stimulation of the GH1 β-glucosidases will be crucial to improve their application through enzyme engineering. In this study, by comparing the primary and tertiary structures of two GH1 β-glucosidases with distinct glucose dependence, some putative glucose-dependence relevant sites were mutated to investigate their exact roles. Both biochemical and structural characterization of the mutants suggested that some sites at the entrance and middle of the substrate channel regulate the effects of glucose, and the relative binding affinity/preference of these sites to glucose modulates the glucose dependence. A mechanism was therefore proposed to interpret the glucose dependence of GH1 β-glucosidases. This research provides fresh insight into our current understanding of the properties and mechanisms of GH1 β-glycosidases and related enzymes that modulate their activity via feedback control mechanism. PMID:26603650

  20. Identification of GH10 xylanases in strains 2 and Mz5 of Pseudobutyrivibrio xylanivorans.

    PubMed

    Grilli, Diego J; Kopečný, Jan; Mrázek, Jakub; Marinšek-Logar, Romana; Paez Lama, Sebastián; Escudero, Miguel Sosa; Arenas, Graciela N

    2014-11-01

    Genes encoding glycosyl hydrolase family 11 (GH11) xylanases and xylanases have been identified from Pseudobutyrivibrio xylanivorans. In contrast, little is known about the diversity and distribution of the GH10 xylanase in strains of P. xylanivorans. Xylanase and associated activities of P. xylanivorans have been characterized in detail in the type strain, Mz5. The aim of the present study was to identify GH10 xylanase genes in strains 2 and Mz5 of P. xylanivorans. In addition, we evaluated degradation and utilization of xylan by P. xylanivorans 2 isolated from rumen of Creole goats. After a 12-h culture, P. xylanivorans 2 was able to utilize up to 53% of the total pentose content present in birchwood xylan (BWX) and to utilize up to 62% of a ethanol-acetic acid-soluble fraction prepared from BWX. This is the first report describing the presence of GH10 xylanase-encoding genes in P. xylanivorans. Strain 2 and Mz5 contained xylanases which were related to GH10 xylanase of Butyrivibrio sp. Identifying xylanase-encoding genes and activity of these enzymes are a step toward understanding possible functional role of P. xylanivorans in the rumen ecosystem and contribute to providing an improved choice of enzymes for improving fiber digestion in ruminant animals, agricultural biomass utilization for biofuel production, and other industries. PMID:24942109

  1. In silico Identification and Taxonomic Distribution of Plant Class C GH9 Endoglucanases.

    PubMed

    Kundu, Siddhartha; Sharma, Rita

    2016-01-01

    The glycoside hydrolase 9 superfamily, mainly comprising the endoglucanases, is represented in all three domains of life. The current division of GH9 enzymes, into three subclasses, namely A, B, and C, is centered on parameters derived from sequence information alone. However, this classification is ambiguous, and is limited by the paralogous ancestry of classes B and C endoglucanases, and paucity of biochemical and structural data. Here, we extend this classification schema to putative GH9 endoglucanases present in green plants, with an emphasis on identifying novel members of the class C subset. These enzymes cleave the β(1 → 4) linkage between non-terminal adjacent D-glucopyranose residues, in both, amorphous and crystalline regions of cellulose. We utilized non redundant plant GH9 enzymes with characterized molecular data, as the training set to construct Hidden Markov Models (HMMs) and train an Artificial Neural Network (ANN). The parameters that were used for predicting dominant enzyme function, were derived from this training set, and subsequently refined on 147 sequences with available expression data. Our knowledge-based approach, can ascribe differential endoglucanase activity (A, B, or C) to a query sequence with high confidence, and was used to construct a local repository of class C GH9 endoglucanases (GH9C = 241) from 32 sequenced green plants. PMID:27570528

  2. Expression and Characterization of Hyperthermostable Exo-polygalacturonase TtGH28 from Thermotoga thermophilus.

    PubMed

    Wagschal, Kurt; Rose Stoller, J; Chan, Victor J; Lee, Charles C; Grigorescu, Arabela A; Jordan, Douglas B

    2016-07-01

    D-galacturonic acid is a potential platform chemical comprising the principal component of pectin in the citrus processing waste stream. Several enzyme activities are required for the enzymatic production of galacturonic acid from pectin, including exo- and endo-polygalacturonases. The gene TtGH28 encoding a putative GH28 polygalacturonase from Pseudothermotoga thermarum DSM 5069 (Theth_0397, NCBI# AEH50492.1) was synthesized, expressed in Escherichia coli, and characterized. Alignment of the amino acid sequence of gene product TtGH28 with other GH28 proteins whose structures and details of their catalytic mechanism have been elucidated shows that three catalytic Asp residues and several other key active site residues are strictly conserved. Purified TtGH28 was dimeric and hyperthermostable, with K t (0.5)  = 86.3 °C. Kinetic parameters for activity on digalacturonic acid, trigalacturonic acid, and polygalacturonic acid were obtained. No substrate inhibition was observed for polygalacturonate, while the K si values for the oligogalacturonides were in the low mM range, and K i for product galacturonic acid was in the low μM range. Kinetic modeling of the progress of reaction showed that the enzyme is both fully exo- and fully non-processional. PMID:27209035

  3. Pharmacological activation of the GABAergic system does not affect GH and PRL release in acromegaly.

    PubMed

    Orio, F; Iovino, M; Monteleone, P; Agrusta, M; Steardo, L; Lombardi, G

    1988-11-01

    An extensive hypothalamic neurotransmitter impairment has been proposed in acromegaly. However, at the moment, the hypothalamic GABAergic system has been little investigated in this disorder. Since GABA has been shown to modulate growth hormone (GH) and prolactin (PRL) secretion in human subjects, it seemed reasonable to investigate hypothalamic GABAergic functioning through the assessment of basal GH and PRL responses to pharmacological activation of this system. 800 mg of sodium valproate (SV), a drug with GABA facilitating properties, were administered orally to 7 acromegalic patients and 9 healthy volunteers. Blood samples were collected before and after the drug administration for the measurement of plasma GH and PRL levels. SV induced a clear-cut rise in basal GH and a decrease in basal PRL in healthy subjects, but it did not induce any change in the basal levels of these hormones in acromegalics. These results suggest that the response of GH and PRL to SV in acromegaly is qualitatively different from normal controls. PMID:2850985

  4. DOCK8 Deficiency

    MedlinePlus

    ... on ClinicalTrials.gov . Related Links Primary Immune Deficiency Diseases (PIDDs) Immune System ​​​​​​​ Javascript Error Your browser JavaScript is turned ... Scientists Identify Genetic Cause of Previously Undefined Primary Immune Deficiency Disease Signs and Symptoms DOCK8 deficiency causes persistent skin ...

  5. Carnitine Deficiency and Pregnancy

    PubMed Central

    de Bruyn, Anouk; Jacquemyn, Yves; Kinget, Kristof; Eyskens, François

    2015-01-01

    We present two cases of carnitine deficiency in pregnancy. In our first case, systematic screening revealed L-carnitine deficiency in the first born of an asymptomatic mother. In the course of her second pregnancy, maternal carnitine levels showed a deficiency as well. In a second case, a mother known with carnitine deficiency under supplementation was followed throughout her pregnancy. Both pregnancies had an uneventful outcome. Because carnitine deficiency can have serious complications, supplementation with carnitine is advised. This supplementation should be continued throughout pregnancy according to plasma concentrations. PMID:26113999

  6. Carnitine Deficiency and Pregnancy.

    PubMed

    de Bruyn, Anouk; Jacquemyn, Yves; Kinget, Kristof; Eyskens, François

    2015-01-01

    We present two cases of carnitine deficiency in pregnancy. In our first case, systematic screening revealed L-carnitine deficiency in the first born of an asymptomatic mother. In the course of her second pregnancy, maternal carnitine levels showed a deficiency as well. In a second case, a mother known with carnitine deficiency under supplementation was followed throughout her pregnancy. Both pregnancies had an uneventful outcome. Because carnitine deficiency can have serious complications, supplementation with carnitine is advised. This supplementation should be continued throughout pregnancy according to plasma concentrations. PMID:26113999

  7. An evolutionary analysis of the GH57 amylopullulanases based on the DOMON_glucodextranase_like domains.

    PubMed

    Jiao, Yu-Liang; Wang, Shu-Jun; Lv, Ming-Sheng; Fang, Yao-Wei; Liu, Shu

    2013-03-01

    Thermostable amylopullulanase (TAPU) is valuable in starch saccharification industry for its capability to catalyze both α-1,4 and α-1,6 glucosidic bonds under the industrial starch liquefication condition. The majority of TAPUs belong to glycoside hydrolase family 57 (GH57). In this study, we performed a phylogenetic analysis of GH57 amylopullulanase (APU) based on the highly conserved DOMON_glucodextranase_like (DDL) domain and classified APUs according to their multidomain architectures, phylogenetic analysis and enzymatic characters. This study revealed that amylopullulanase, pullulanase, andα-amylase had passed through a long joint evolution process, in which DDL played an important role. The phylogenetic analysis of DDL domain showed that the GH57 APU is directly sharing a common ancestor with pullulanase, and the DDL domains in some species undergo evolution scenarios such as domain duplication and recombination. PMID:22733591

  8. Direct stimulation of bone mass by increased GH signalling in the osteoblasts of Socs2−/− mice

    PubMed Central

    Dobie, R; MacRae, V E; Huesa, C; van't Hof, R; Ahmed, S F; Farquharson, C

    2014-01-01

    The suppressor of cytokine signalling (Socs2 −/−)-knockout mouse is characterised by an overgrowth phenotype due to enhanced GH signalling. The objective of this study was to define the Socs2 −/− bone phenotype and determine whether GH promotes bone mass via IGF1-dependent mechanisms. Despite no elevation in systemic IGF1 levels, increased body weight in 4-week-old Socs2 −/− mice following GH treatment was associated with increased cortical bone area (Ct.Ar) (P<0.01). Furthermore, detailed bone analysis of male and female juvenile and adult Socs2 −/− mice revealed an altered cortical and trabecular phenotype consistent with the known anabolic effects of GH. Indeed, male Socs2 −/− mice had increased Ct.Ar (P<0.05) and thickness associated with increased strength. Despite this, there was no elevation in hepatic Igf1 expression, suggesting that the anabolic bone phenotype was the result of increased local GH action. Mechanistic studies showed that in osteoblasts and bone of Socs2 −/− mice, STAT5 phosphorylation was significantly increased in response to GH. Conversely, overexpression of SOCS2 decreased GH-induced STAT5 signalling. Although an increase in Igf1 expression was observed in Socs2 −/− osteoblasts following GH, it was not evident in vivo. Igf1 expression levels were not elevated in response to GH in 4-week-old mice and no alterations in expression was observed in bone samples of 6-week-old Socs2 −/− mice. These studies emphasise the critical role of SOCS2 in controlling the local GH anabolic bone effects. We provide compelling evidence implicating SOCS2 in the regulation of GH osteoblast signalling and ultimately bone accrual, which maybe via mechanisms that are independent of IGF1 production in vivo. PMID:25074853

  9. Male Bovine GH Transgenic Mice Have Decreased Adiposity With an Adipose Depot-Specific Increase in Immune Cell Populations

    PubMed Central

    Benencia, Fabian; Harshman, Stephanie; Duran-Ortiz, Silvana; Lubbers, Ellen R.; List, Edward O.; Householder, Lara; Al-Naeeli, Mawadda; Liang, Xiaoyu; Welch, Lonnie; Kopchick, John J.

    2015-01-01

    White adipose tissue (WAT) is composed of mature adipocytes and a stromal vascular fraction (SVF), which contains a variety of cells, including immune cells that vary among the different WAT depots. Growth hormone (GH) impacts immune function and adiposity in an adipose depot-specific manner. However, its effects on WAT immune cell populations remain unstudied. Bovine GH transgenic (bGH) mice are commonly used to study the in vivo effects of GH. These giant mice have an excess of GH action, impaired glucose metabolism, decreased adiposity, increased lean mass, and a shortened lifespan. Therefore, the purpose of this study was to characterize the WAT depot-specific differences in immune cell populations in the presence of excess GH in vivo. Three WAT depots were assessed: inguinal (sc), epididymal (EPI), and mesenteric (MES). Subcutaneous and MES bGH WAT depots showed a significantly higher number of total SVF cells, yet only MES bGH WAT had higher leukocyte counts compared with control samples. By means of flow cytometry analysis of the SVF, we detected greater macrophage and regulatory T-cell infiltration in sc and MES bGH WAT depots compared with controls. However, no differences were observed in the EPI WAT depot. RNA-sequencing confirmed significant alterations in pathways related to T-cell infiltration and activation in the sc depot with fewer significant changes in the EPI bGH WAT depot. These findings collectively point to a previously unrecognized role for GH in influencing the distribution of WAT immune cell populations in a depot-specific manner. PMID:25521584

  10. Effects of Hypergravity Rearing on Growth Hormone (GH) Secretion In Preweanling Rats

    NASA Technical Reports Server (NTRS)

    Baer, L. A.; Chowdhury, J. H.; Wade, C. E.; Ronca, A. E.; Dalton, Bonnie (Technical Monitor)

    2002-01-01

    We previously reported that rat pups reared at 1.5-g, 1.75 or 2.0-g hypergravity weigh 6-15% less than 1.0-g controls. To account for these findings. we measured the lactational hormones, prolaction (Prl) and oxytocin (OT), in the pups' mothers. Gravity related differences in Prl were not observed whereas OT of lactating dams was significantly reduced relative to controls. Milk transfer from dam to pup was not impaired in hypergravity-reared litters tested at 1-g. Together, these findings suggest that impaired lactation and milk transfer do not account for reduced body masses of postnatal rats reared in hypergravity. In the present study, we analyzed growth hormone (GH) secretion and maternal licking in pups reared in hypergravity and in 1.0-g controls. Recent reports using dwarfing phenotypes in mouse mutants have provided evidence for postnatal dependence on GH and insulin-like growth factors (IGFs). Beginning on Gestational day (G)11 of the rats' 22 day pregnancy, rat dams and their litters were exposed to either 1.5-g, 1.75-g or 2.0-g. On Postnatal day (P)10, we measured plasma GH using enzyme immunoassay (EIA). Contrary to our hypothesis, GH was significantly elevated in pups reared at 2.0-g relative to 1.0-g controls. Pup-oriented behaviors of the hypergravity dams were also changed, possibly accounting for the increase in pup GH. GH alone does not appear to play a role in reduced body weights of hypergravity-reared pups.

  11. Characterization of African bat henipavirus GH-M74a glycoproteins.

    PubMed

    Weis, Michael; Behner, Laura; Hoffmann, Markus; Krüger, Nadine; Herrler, Georg; Drosten, Christian; Drexler, Jan Felix; Dietzel, Erik; Maisner, Andrea

    2014-03-01

    In recent years, novel henipavirus-related sequences have been identified in bats in Africa. To evaluate the potential of African bat henipaviruses to spread in non-bat mammalian cells, we compared the biological functions of the surface glycoproteins G and F of the prototype African henipavirus GH-M74a with those of the glycoproteins of Nipah virus (NiV), a well-characterized pathogenic member of the henipavirus genus. Glycoproteins are central determinants for virus tropism, as efficient binding of henipavirus G proteins to cellular ephrin receptors and functional expression of fusion-competent F proteins are indispensable prerequisites for virus entry and cell-to-cell spread. In this study, we analysed the ability of the GH-M74a G and F proteins to cause cell-to-cell fusion in mammalian cell types readily permissive to NiV or Hendra virus infections. Except for limited syncytium formation in a bat cell line derived from Hypsignathus monstrosus, HypNi/1.1 cells, we did not observe any fusion. The highly restricted fusion activity was predominantly due to the F protein. Whilst GH-M74a G protein was found to interact with the main henipavirus receptor ephrin-B2 and induced syncytia upon co-expression with heterotypic NiV F protein, GH-M74a F protein did not cause evident fusion in the presence of heterotypic NiV G protein. Pulse-chase and surface biotinylation analyses revealed delayed F cleavage kinetics with a reduced expression of cleaved and fusion-active GH-M74a F protein on the cell surface. Thus, the F protein of GH-M74a showed a functional defect that is most likely caused by impaired trafficking leading to less efficient proteolytic activation and surface expression. PMID:24296468

  12. Fatty Liver Index Associates with Relative Sarcopenia and GH/ IGF- 1 Status in Obese Subjects

    PubMed Central

    Gnessi, Lucio; Mariani, Stefania; Lenzi, Andrea; Donini, Lorenzo Maria

    2016-01-01

    Introduction Recently the association between hepatic steatosis and sarcopenia has been described. GH/IGF-1 axis has been postulated to play a role in linking fatty liver and low muscle mass. The aim of our study was to explore the association between fatty liver index, sarcopenic obesity, insulin sensitivity, and GH/IGF-1 status. Methods 427 subjects [age: 45.65±13.94 years, BMI: 36.92±6.43 kg/m2] were enrolled. Participants were divided into three groups: fatty liver index (FLI) <20, 20≥FLI<60, and FLI≥60. Body composition was assessed by DXA. The truncal fat mass (TrFM) to appendicular skeletal muscle (ASM) ratio was used as an indicator of sarcopenic obesity. ISI-Matsuda index was used. Results BMI, fat mass, and the TrFM/ASM ratio were higher in subjects with FLI≥60. GH, IGF-1 and ISI-Matsuda were lower in the high FLI group (all p<0.05). A significantly positive correlation between FLI and TrFM/ ASM ratio (r = 0.221, p<0.001) was found, whereas FLI levels were negatively correlated with ISI- Matsuda (r = -0.335, p<0.001), GH (r = -0.200, p = 0.006), and IGF- 1 levels (r = -0.157, p = 0.028). Stepwise linear regression analysis showed that GH levels were significantly negatively correlated with FLI, while the TrFM/ ASM ratio was positively associated with FLI, after adjustment for age, BMI, total fat mass, truncal fat mass, fat- free mass, and ISI- Matsuda. Conclusions Impairment of GH/IGF-1 axis seems to be associated to the risk of the development of sarcopenic obesity and ectopic fat deposition in the liver. Metabolic and hormonal derangements as determinants of ectopic fat deposition and body composition deserve to be evaluated in obese subjects. PMID:26741958

  13. Phylogenetic analysis of β-xylanase SRXL1 of Sporisorium reilianum and its relationship with families (GH10 and GH11) of Ascomycetes and Basidiomycetes

    PubMed Central

    Álvarez-Cervantes, Jorge; Díaz-Godínez, Gerardo; Mercado-Flores, Yuridia; Gupta, Vijai Kumar; Anducho-Reyes, Miguel Angel

    2016-01-01

    In this paper, the amino acid sequence of the β-xylanase SRXL1 of Sporisorium reilianum, which is a pathogenic fungus of maize was used as a model protein to find its phylogenetic relationship with other xylanases of Ascomycetes and Basidiomycetes and the information obtained allowed to establish a hypothesis of monophyly and of biological role. 84 amino acid sequences of β-xylanase obtained from the GenBank database was used. Groupings analysis of higher-level in the Pfam database allowed to determine that the proteins under study were classified into the GH10 and GH11 families, based on the regions of highly conserved amino acids, 233–318 and 180–193 respectively, where glutamate residues are responsible for the catalysis. PMID:27040368

  14. Three-dimensional structure of RBcel1, a metagenome-derived psychrotolerant family GH5 endoglucanase

    PubMed Central

    Delsaute, Maud; Berlemont, Renaud; Dehareng, Dominique; Van Elder, Dany; Galleni, Moreno; Bauvois, Cédric

    2013-01-01

    RBcel1 is an endoglucanase belonging to glycoside hydrolase family 5 subfamily 5 (GH5_5) that was recently identified from a soil metagenome library from the Antarctic. Unlike its closest structural homologue (Cel5A from Thermoascus aurantiacus), this enzyme was reported to be able to catalyze transglycosylation reactions and has putatively been implicated in the bacterial cellulose-synthesis process. Here, the structure of RBcel1 at 1.4 Å resolution, solved by molecular replacement, is reported. The structure and putative substrate-binding site are described and compared with those of other GH5_5 subfamily members. PMID:23908022

  15. [Advances in studying microbial GH13 starch debranching enzyme--a review].

    PubMed

    Duan, Xuguo; Wu, Jing

    2013-07-01

    Pullulanase and isoamylase belong to the GH13 family (glycoside hydrolase family 13) with similar sequence, catalytic mechanism and three-dimensional fold ((beta/alpha)8-barrel structure). Starch debranching enzymes can hydrolyze the alpha-1,6-glucosidic bonds at the branch sites of starch, and improve raw material utilization and production efficiency in the starch industry. In this review, the substrate specificity, protein structure, advances and new trends in the study of microbial GH13 starch debranching enzyme were systematically introduced. In addition, some opinions on the research status and prospect for starch debranching enzyme were discussed. PMID:24195371

  16. GH, IGF-I and GH receptors mRNA expression in response to growth impairment following a food deprivation period in individually housed cichlid fish Cichlasoma dimerus.

    PubMed

    Delgadin, Tomás Horacio; Pérez Sirkin, Daniela Irina; Di Yorio, María Paula; Arranz, Silvia Eda; Vissio, Paula Gabriela

    2015-02-01

    Cichlasoma dimerus is a social cichlid fish capable of growing at high rates under laboratory conditions, but knowledge on somatic growth regulation is still unclear. Growth hormone (GH)/insulin-like growth factor I (IGF-I) axis is the key regulator of somatic growth in vertebrates. Two types of growth hormone receptors have been described in teleost fish, named GH receptor type 1 (GHR1) and type 2 (GHR2). In addition, isoforms of these receptors lacking part of the intracellular region have been described. The aim of this study was to evaluate the somatic growth, liver histology and changes in the GH/IGF-I axis after 4 weeks of food deprivation in C. dimerus. Four-week fasted fish showed reductions in specific growth rates in body weight (p < 0.001) and standard length (p < 0.001). Additionally, the hepatosomatic index (p < 0.001) and hepatocyte area (p < 0.001) decreased in fasted fish, while no changes in glucose levels were detected in plasma. The starvation protocol failed to induce changes in GH mRNA levels in the pituitary and IGF-I mRNA levels in liver. In contrast, IGF-I mRNA levels in muscle decreased in fasted fish (p = 0.002). On the other hand, GHR2 (detected with primer sets designed over the extracellular and intracellular region) was upregulated by starvation both in liver and muscle (p < 0.05), while GHR1 remained unchanged. These results show that a fasting period reduced somatic growth both in length and body weight concomitantly with alterations on liver and muscle GHR2 and muscle IGF-I mRNA expression. PMID:25351458

  17. Distinct Roles for Carbohydrate-Binding Modules of Glycoside Hydrolase 10 (GH10) and GH11 Xylanases from Caldicellulosiruptor sp. Strain F32 in Thermostability and Catalytic Efficiency

    PubMed Central

    Meng, Dong-Dong; Ying, Yu; Chen, Xiao-Hua; Lu, Ming; Ning, Kang; Wang, Lu-Shan

    2015-01-01

    Xylanases are crucial for lignocellulosic biomass deconstruction and generally contain noncatalytic carbohydrate-binding modules (CBMs) accessing recalcitrant polymers. Understanding how multimodular enzymes assemble can benefit protein engineering by aiming at accommodating various environmental conditions. Two multimodular xylanases, XynA and XynB, which belong to glycoside hydrolase families 11 (GH11) and GH10, respectively, have been identified from Caldicellulosiruptor sp. strain F32. In this study, both xylanases and their truncated mutants were overexpressed in Escherichia coli, purified, and characterized. GH11 XynATM1 lacking CBM exhibited a considerable improvement in specific activity (215.8 U nmol−1 versus 94.7 U nmol−1) and thermal stability (half-life of 48 h versus 5.5 h at 75°C) compared with those of XynA. However, GH10 XynB showed higher enzyme activity and thermostability than its truncated mutant without CBM. Site-directed mutagenesis of N-terminal amino acids resulted in a mutant, XynATM1-M, with 50% residual activity improvement at 75°C for 48 h, revealing that the disordered region influenced protein thermostability negatively. The thermal stability of both xylanases and their truncated mutants were consistent with their melting temperature (Tm), which was determined by using differential scanning calorimetry. Through homology modeling and cross-linking analysis, we demonstrated that for XynB, the resistance against thermoinactivation generally was enhanced through improving both domain properties and interdomain interactions, whereas for XynA, no interdomain interactions were observed. Optimized intramolecular interactions can accelerate thermostability, which provided microbes a powerful evolutionary strategy to assemble catalysts that are adapted to various ecological conditions. PMID:25576604

  18. Creatine deficiency syndromes.

    PubMed

    Schulze, Andreas

    2003-02-01

    Since the first description of a creatine deficiency syndrome, the guanidinoacetate methyltransferase (GAMT) deficiency, in 1994, the two further suspected creatine deficiency syndromes--the creatine transporter (CrT1) defect and the arginine:glycine amidinotransferase (AGAT) deficiency were disclosed. GAMT and AGAT deficiency have autosomal-recessive traits, whereas the CrT1 defect is a X-linked disorder. All patients reveal developmental delay/regression, mental retardation, and severe disturbance of their expressive and cognitive speech. The common feature of all creatine deficiency syndromes is the severe depletion of creatine/phosphocreatine in the brain. Only the GAMT deficiency is in addition characterized by accumulation of guanidinoacetic acid in brain and body fluids. Guanidinoacetic acid seems to be responsible for intractable seizures and the movement disorder, both exclusively found in GAMT deficiency. Treatment with oral creatine supplementation is in part successful in GAMT and AGAT deficiency, whereas in CrT1 defect it is not able to replenish creatine in the brain. Treatment of combined arginine restriction and ornithine substitution in GAMT deficiency is capable to decrease guanidinoacetic acid permanently and improves the clinical outcome. The lack of the creatine/phosphocreatine signal in the patient's brain by means of in vivo proton magnetic resonance spectroscopy is the common finding and the diagnostic clue in all three diseases. In AGAT deficiency guanidinoacetic acid is decreased, whereas creatine in blood was found to be normal. On the other hand the CrT1 defect is characterized by an increased concentration of creatine in blood and urine whereas guanidinoacetic acid concentration is normal. The increasing number of patients detected very recently suffering from a creatine deficiency syndrome and the unfavorable outcome highlights the need of further attempts in early recognition of affected individuals and in optimizing its treatment

  19. Lack of association of progestin-induced cystic endometrial hyperplasia with GH gene expression in the canine uterus.

    PubMed

    Kooistra, H S; Okkens, A C; Mol, J A; van Garderen, E; Kirpensteijn, J; Rijnberk, A

    1997-01-01

    Growth hormone (GH) is produced in progestin-induced hyperplastic ductular mammary epithelia in dogs. Progestins also induce the development of cystic endometrial hyperplasia (CEH) in this species. The study reported here investigated whether GH gene expression could also be demonstrated in progestin-induced hyperplastic epithelium in the canine uterus. Eight beagle bitches were treated with 10 mg medroxyprogesterone acetate (MPA) kg-1 body mass s.c. at intervals of 3 weeks, for a total of five times in four dogs (group I) and for a total of 13 times in the other four dogs (group II). Blood samples were collected twice during each 3 week period for measurement of plasma concentrations of GH, insulin-like growth factor I (IGF-I) and IGF-II. At the end of the series of injections uterine tissue was obtained by ovario-hysterectomy. Histological examination confirmed that CEH was present in all uteri after MPA treatment; the changes in the dogs of group I were less marked than those in group II. Immunohistochemical examination of the uterine tissues showed that immunoreactive(i) GH was present in a number of uteri with CEH. iGH was usually located in the cytoplasm of glandular epithelial cells. However, reverse transcriptase PCR using GH-specific primers failed to demonstrate mRNA encoding GH in the uterine tissue of all dogs. It is concluded that local production of GH is not involved in progestin-induced hyperplasia of uterine epithelial cells in dogs. PMID:9404306

  20. Overexpression of a cotton annexin gene, GhAnn1, enhances drought and salt stress tolerance in transgenic cotton.

    PubMed

    Zhang, Feng; Li, Shufen; Yang, Shuming; Wang, Like; Guo, Wangzhen

    2015-01-01

    Plant annexins are members of a diverse, multigene protein family that has been associated with a variety of cellular processes and responses to abiotic stresses. GhAnn1, which encodes a putative annexin protein, was isolated from a cotton (Gossypium hirsutum L. acc 7235) cDNA library. Tissue-specific expression showed that GhAnn1 is expressed at differential levels in all tissues examined and strongly induced by various phytohormones and abiotic stress. In vivo and in vitro subcellular localization suggested that GhAnn1 is located in the plasma membrane. In response to drought and salt stress, transgenic cotton plants overexpressing GhAnn1 showed significantly higher germination rates, longer roots, and more vigorous growth than wild-type plants. In addition, plants overexpressing GhAnn1 had higher total chlorophyll content, lower lipid peroxidation levels, increased peroxidase activities, and higher levels of proline and soluble sugars, all of which contributed to increased salt and drought stress tolerance. However, transgenic cotton plants in which the expression of GhAnn1 was suppressed showed the opposite results compared to the overexpressing plants. These findings demonstrated that GhAnn1 plays an important role in the abiotic stress response, and that overexpression of GhAnn1 in transgenic cotton improves salt and drought tolerance. PMID:25330941

  1. Rhabdomyolysis and Cardiomyopathy in a 20-Year-Old Patient with CPT II Deficiency

    PubMed Central

    Vavlukis, M.; Eftimov, A.; Zafirovska, P.; Caparovska, E.; Pocesta, B.; Kedev, S.; Dimovski, A. J.

    2014-01-01

    Aim. To raise the awareness of adult-onset carnitite palmitoyltransferase II deficiency (CPT II) by describing clinical, biochemical, and genetic features of the disease occurring in early adulthood. Method. Review of the case characteristics and literature review. Results. We report on a 20-year-old man presenting with dyspnea, fatigue, fever, and myoglobinuria. This was the second episode with such symptoms (the previous one being three years earlier). The symptoms occurred after intense physical work, followed by a viral infection resulting in fever treated with NSAIDs. Massive rhabdomyolysis was diagnosed, resulting in acute renal failure necessitating plasmapheresis and hemodialysis, acute hepatic lesion, and respiratory insufficiency. Additionally, our patient had cardiomyopathy with volume overload. After a detailed workup, CPT II deficiency was suspected. We did a sequencing analysis for exons 1, 3, and 4 of the CPT II gene and found that the patient was homozygote for Ser 113 Leu mutation in exon 3 of the CPT II gene. The patient recovery was complete except for the cardiomiopathy with mildly impaired systolic function. Conclusion. Whenever a patient suffers recurrent episodes of myalgia, followed by myoglobinuria due to rhabdomyolysis, we should always consider the possibility of this rare condition. The definitive diagnose of this condition is achieved by genetic testing. PMID:24563797

  2. Mild pituitary phenotype in 3- and 12-month-old Aip-deficient male mice.

    PubMed

    Lecoq, Anne-Lise; Zizzari, Philippe; Hage, Mirella; Decourtye, Lyvianne; Adam, Clovis; Viengchareun, Say; Veldhuis, Johannes D; Geoffroy, Valérie; Lombès, Marc; Tolle, Virginie; Guillou, Anne; Karhu, Auli; Kappeler, Laurent; Chanson, Philippe; Kamenický, Peter

    2016-10-01

    Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene predispose humans to pituitary adenomas, particularly of the somatotroph lineage. Mice with global heterozygous inactivation of Aip (Aip(+/-)) also develop pituitary adenomas but differ from AIP-mutated patients by the high penetrance of pituitary disease. The endocrine phenotype of these mice is unknown. The aim of this study was to determine the endocrine phenotype of Aip(+/-) mice by assessing the somatic growth, ultradian pattern of GH secretion and IGF1 concentrations of longitudinally followed male mice at 3 and 12 months of age. As the early stages of pituitary tumorigenesis are controversial, we also studied the pituitary histology and somatotroph cell proliferation in these mice. Aip(+/-) mice did not develop gigantism but exhibited a leaner phenotype than wild-type mice. Analysis of GH pulsatility by deconvolution in 12-month-old Aip(+/-) mice showed a mild increase in total GH secretion, a conserved GH pulsatility pattern, but a normal IGF1 concentration. No pituitary adenomas were detected up to 12 months of age. An increased ex vivo response to GHRH of pituitary explants from 3-month-old Aip(+/-) mice, together with areas of enlarged acini identified on reticulin staining in the pituitary of some Aip(+/-) mice, was suggestive of somatotroph hyperplasia. Global heterozygous Aip deficiency in mice is accompanied by subtle increase in GH secretion, which does not result in gigantism. The absence of pituitary adenomas in 12-month-old Aip(+/-) mice in our experimental conditions demonstrates the important phenotypic variability of this congenic mouse model. PMID:27621108

  3. Growth Hormone Deficiency in a Child with Neurofibromatosis-Noonan Syndrome.

    PubMed

    Vurallı, Doğuş; Gönç, Nazlı; Vidaud, Dominique; Özön, Alev; Alikaşifoğlu, Ayfer; Kandemir, Nurgün

    2016-03-01

    Neurofibromatosis-Noonan syndrome (NFNS) is a distinct entity which shows the features of both NF1 (neurofibromatosis 1) and Noonan syndrome (NS). While growth hormone deficiency (GHD) has been relatively frequently identified in NF1 and NS patients, there is limited experience in NFNS cases. The literature includes only one case report of a NFNS patient having GHD and that report primarily focuses on the dermatological lesions that accompany the syndrome and not on growth hormone (GH) treatment. Here, we present a 13-year-old girl who had clinical features of NFNS with a mutation in the NF1 gene. The case is the first NFNS patient reported in the literature who was diagnosed to have GHD and who received GH treatment until reaching final height. The findings in this patient show that short stature is a feature of NFNS and can be caused by GHD. Patients with NFNS who show poor growth should be evaluated for GHD. PMID:26758488

  4. Growth Hormone Deficiency in a Child with Neurofibromatosis-Noonan Syndrome

    PubMed Central

    Vurallı, Doğuş; Gönç, Nazlı; Vidaud, Dominique; Özön, Alev; Alikaşifoğlu, Ayfer; Kandemir, Nurgün

    2016-01-01

    Neurofibromatosis-Noonan syndrome (NFNS) is a distinct entity which shows the features of both NF1 (neurofibromatosis 1) and Noonan syndrome (NS). While growth hormone deficiency (GHD) has been relatively frequently identified in NF1 and NS patients, there is limited experience in NFNS cases. The literature includes only one case report of a NFNS patient having GHD and that report primarily focuses on the dermatological lesions that accompany the syndrome and not on growth hormone (GH) treatment. Here, we present a 13-year-old girl who had clinical features of NFNS with a mutation in the NF1 gene. The case is the first NFNS patient reported in the literature who was diagnosed to have GHD and who received GH treatment until reaching final height. The findings in this patient show that short stature is a feature of NFNS and can be caused by GHD. Patients with NFNS who show poor growth should be evaluated for GHD. PMID:26758488

  5. α1-Antitrypsin Deficiency.

    PubMed

    Hatipoğlu, Umur; Stoller, James K

    2016-09-01

    α1-Antitrypsin deficiency is an autosomal codominant condition that predisposes to emphysema and cirrhosis. The condition is common but grossly under-recognized. Identifying patients' α1-antitrypsin deficiency has important management implications (ie, smoking cessation, genetic and occupational counseling, and specific treatment with the infusion of pooled human plasma α1-antitrypsin). The weight of evidence suggests that augmentation therapy slows the progression of emphysema in individuals with severe α1-antitrypsin deficiency. PMID:27514595

  6. Increased linear bone growth by GH in the absence of SOCS2 is independent of IGF‐1

    PubMed Central

    Dobie, Ross; Ahmed, Syed F.; Staines, Katherine A.; Pass, Chloe; Jasim, Seema; MacRae, Vicky E.

    2015-01-01

    Growth hormone (GH) signaling is essential for postnatal linear bone growth, but the relative importance of GHs actions on the liver and/or growth plate cartilage remains unclear. The importance of liver derived insulin like‐growth factor‐1 (IGF‐1) for endochondral growth has recently been challenged. Here, we investigate linear growth in Suppressor of Cytokine Signaling‐2 (SOCS2) knockout mice, which have enhanced growth despite normal systemic GH/IGF‐1 levels. Wild‐type embryonic ex vivo metatarsals failed to exhibit increased linear growth in response to GH, but displayed increased Socs2 transcript levels (P < 0.01). In the absence of SOCS2, GH treatment enhanced metatarsal linear growth over a 12 day period. Despite this increase, IGF‐1 transcript and protein levels were not increased in response to GH. In accordance with these data, IGF‐1 levels were unchanged in GH‐challenged postnatal Socs2‐/‐ conditioned medium despite metatarsals showing enhanced linear growth. Growth‐plate Igf1 mRNA levels were not elevated in juvenile Socs2‐/‐ mice. GH did however elevate IGF‐binding protein 3 levels in conditioned medium from GH challenged metatarsals and this was more apparent in Socs2‐/‐ metatarsals. GH did not enhance the growth of Socs2‐/‐ metatarsals when the IGF receptor was inhibited, suggesting that IGF receptor mediated mechanisms are required. IGF‐2 may be responsible as IGF‐2 promoted metatarsal growth and Igf2 expression was elevated in Socs2‐/‐ (but not WT) metatarsals in response to GH. These studies emphasise the critical importance of SOCS2 in regulating GHs ability to promote bone growth. Also, GH appears to act directly on the metatarsals of Socs2‐/‐ mice, promoting growth via a mechanism that is independent of IGF‐1. J. Cell. Physiol. 9999: 2796–2806, 2015. © 2015 Wiley Periodicals, Inc. PMID:25833299

  7. GH1-family 6-P-β-glucosidases from human microbiome lactic acid bacteria

    PubMed Central

    Michalska, Karolina; Tan, Kemin; Li, Hui; Hatzos-Skintges, Catherine; Bearden, Jessica; Babnigg, Gyorgy; Joachimiak, Andrzej

    2013-01-01

    In lactic acid bacteria and other bacteria, carbohydrate uptake is mostly governed by phosphoenolpyruvate-dependent phosphotransferase systems (PTSs). PTS-dependent translocation through the cell membrane is coupled with phosphorylation of the incoming sugar. After translocation through the bacterial membrane, the β-glycosidic bond in 6′-­P-­β-glucoside is cleaved, releasing 6-P-β-glucose and the respective aglycon. This reaction is catalyzed by 6-P-β-glucosidases, which belong to two glycoside hydrolase (GH) families: GH1 and GH4. Here, the high-resolution crystal structures of GH1 6-P-β-glucosidases from Lactobacillus plantarum (LpPbg1) and Streptococcus mutans (SmBgl) and their complexes with ligands are reported. Both enzymes show hydrolytic activity towards 6′-P-β-glucosides. The LpPbg1 structure has been determined in an apo form as well as in a complex with phosphate and a glucose molecule corresponding to the aglycon molecule. The S. mutans homolog contains a sulfate ion in the phosphate-dedicated subcavity. SmBgl was also crystallized in the presence of the reaction product 6-P-β-glucose. For a mutated variant of the S. mutans enzyme (E375Q), the structure of a 6′-P-salicin complex has also been determined. The presence of natural ligands enabled the definition of the structural elements that are responsible for substrate recognition during catalysis. PMID:23519420

  8. Interaction of Pseudomonas putida ATCC 12633 and Bacteriophage gh-1 in Berea Sandstone Rock.

    PubMed

    Chang, P L; Yen, T F

    1985-12-01

    Measurements of the passage of Pseudomonas putida ATCC 12633 and a phage-resistant mutant through Berea sandstone rock were made. When bacteriophage gh-1 was adsorbed within the rock matrix, a reduction in the passage of the susceptible but not the resistant cells through the rock was observed. PMID:16346956

  9. Interaction of Pseudomonas putida ATCC 12633 and Bacteriophage gh-1 in Berea Sandstone Rock

    PubMed Central

    Chang, Philip Lee; Yen, Teh Fu

    1985-01-01

    Measurements of the passage of Pseudomonas putida ATCC 12633 and a phage-resistant mutant through Berea sandstone rock were made. When bacteriophage gh-1 was adsorbed within the rock matrix, a reduction in the passage of the susceptible but not the resistant cells through the rock was observed. PMID:16346956

  10. Biochemical characterization of a GH43 ß-xylosidase from Bacteroides ovatus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Divalent-metal-activated, glycoside hydrolase (GH43) ß-xylosidases have been found to have high kcat/Km for xylooligosaccharides and may demonstrate high efficacy in industrial reactors digesting hemicellulose. By searching an amino acid database, we found an enzyme that is 81% identical in amino ac...

  11. IGF-I modulation of GH and LH secretion in the pig

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Three experiments (EXP) were conducted to determine the role of IGF-I in modulating GH and LH secretion. In EXP I, prepuberal gilts, 65 ± 6 kg body weight (BW) and 140 days of age received intracerebroventricular (ICV) injections of saline (n = 4), 25µg (n = 4) or 75µg (n = 4) IGF-I and jugular blo...

  12. GH-Producing Pituitary Adenoma and Concomitant Rathke's Cleft Cyst: A Case Report and Short Review.

    PubMed

    Tamura, Ryota; Takahashi, Satoshi; Emoto, Katsura; Nagashima, Hideaki; Toda, Masahiro; Yoshida, Kazunari

    2015-01-01

    Concomitant pituitary adenoma (PA) and Rathke's cleft cyst (RCC) are rare. In some cases, such PA is known to produce pituitary hormones. A 53-year-old man was admitted to our hospital with a diagnosis of lacunar infarction in the left basal ganglia. Magnetic resonance imaging (MRI) incidentally showed a suprasellar mass with radiographic features of RCC. When he consulted with a neurosurgical outpatient clinic, acromegaly was suspected based on his appearance. A diagnosis of growth hormone- (GH-) producing PA was confirmed from hormonal examinations and additional MRI. Retrospectively, initial MR images also showed intrasellar mass that is compatible with the diagnosis of PA other than suprasellar RCC. The patient underwent endonasal-endoscopic removal of the PA. Since we judged that the RCC of the patient was asymptomatic, only the PA was completely removed. The postoperative course of the patient was uneventful and GH levels gradually normalized. Only 40 cases of PA with concomitant RCC have been reported to date, including 13 cases of GH-producing PA. In those 13 cases, RCC tended to be located in the sella turcica, and suprasellar RCC like this case appears rare. In a few cases, concomitant RCCs were fenestrated, but GH levels normalized postoperatively as in the cases without RCC fenestration. If radiographic imaging shows typical RCC, and PA is not obvious at first glance, the possibility of concomitant PA still needs to be considered. In terms of treatment, removal of the RCC is not needed to achieve hormone normalization. PMID:25883817

  13. Food intake and appetite control in a GH-transgenic zebrafish.

    PubMed

    Dalmolin, Camila; Almeida, Daniela Volcan; Figueiredo, Marcio Azevedo; Marins, Luis Fernando

    2015-10-01

    The biological actions of growth hormone (GH) are pleiotropic, including growth promotion, energy mobilization, gonadal development, appetite, and social behavior. The regulatory network for GH is complex and includes many central and peripheral endocrine factors as well as that from the environment. It is known that GH transgenesis results in increased growth, food intake, and consequent metabolic rates in fishes. However, the manner in which GH transgenesis alters the energetic metabolism in fishes has not been well explored. In order to elucidate these consequences, we examined the effect of GH overexpression on appetite control mechanisms in a transgenic zebrafish (Danio rerio) model. To this, we analyzed feeding behavior and the expression of the main appetite-related genes in two different feeding periods (fed and fasting) in non-transgenic (NT) and transgenic (T) zebrafish as well as glycaemic parameters of them. Our initial results have shown that NT males and females present the same feeding behavior and expression of main appetite-controlling genes; therefore, the data of both sexes were properly grouped. Following grouped data analyses, we compared the same parameters in NT and T animals. Feeding behavior results have shown that T animals eat significantly more and faster than NT siblings. Gene expression results pointed out that gastrointestinal (GT) cholecystokinin has a substantial contribution to the communication between peripheral and central control of food intake. Brain genes expression analyses revealed that T animals have a down-regulation of two strong and opposite peptides related to food intake: the anorexigenic proopiomelanocortin (pomc) and the orexigenic neuropeptide Y (npy). The down-regulation of pomc in T when compared with NT is an expected result, since the decrease in an anorexigenic factor might keep the transgenic fish hungry. The down-regulation of npy seemed to be contradictory at first, but if we consider the GH's capacity to

  14. The conserved Phe GH5 of importance for hemoglobin intersubunit contact is mutated in gadoid fish

    PubMed Central

    2014-01-01

    Background Functionality of the tetrameric hemoglobin molecule seems to be determined by a few amino acids located in key positions. Oxygen binding encompasses structural changes at the interfaces between the α1β2 and α2β1 dimers, but also subunit interactions are important for the oxygen binding affinity and stability. The latter packing contacts include the conserved Arg B12 interacting with Phe GH5, which is replaced by Leu and Tyr in the αA and αD chains, respectively, of birds and reptiles. Results Searching all known hemoglobins from a variety of gnathostome species (jawed vertebrates) revealed the almost invariant Arg B12 coded by the AGG triplet positioned at an exon-intron boundary. Rare substitutions of Arg B12 in the gnathostome β globins were found in pig, tree shrew and scaled reptiles. Phe GH5 is also highly conserved in the β globins, except for the Leu replacement in the β1 globin of five marine gadoid species, gilthead seabream and the Comoran coelacanth, while Cys and Ile were found in burbot and yellow croaker, respectively. Atlantic cod β1 globin showed a Leu/Met polymorphism at position GH5 dominated by the Met variant in northwest-Atlantic populations that was rarely found in northeast-Atlantic cod. Site-specific analyses identified six consensus codons under positive selection, including 122β(GH5), indicating that the amino acid changes identified at this position may offer an adaptive advantage. In fact, computational mutation analysis showed that the replacement of Phe GH5 with Leu or Cys decreased the number of van der Waals contacts essentially in the deoxy form that probably causes a slight increase in the oxygen binding affinity. Conclusions The almost invariant Arg B12 and the AGG codon seem to be important for the packing contacts and pre-mRNA processing, respectively, but the rare mutations identified might be beneficial. The Leu122β1(GH5)Met and Met55β1(D6)Val polymorphisms in Atlantic cod hemoglobin modify the

  15. Comparative pharmacokinetics and pharmacodynamics of a PEGylated recombinant human growth hormone and daily recombinant human growth hormone in growth hormone-deficient children

    PubMed Central

    Hou, Ling; Chen, Zhi-hang; Liu, Dong; Cheng, Yuan-guo; Luo, Xiao-ping

    2016-01-01

    Objective Recombinant human growth hormone (rhGH) replacement therapy in children generally requires daily subcutaneous (sc) injections, which may be inconvenient for patients. Jintrolong® is a PEGylated rhGH with the purpose of weekly sc injections. The aim of the current study was to examine the pharmacokinetics, pharmacodynamics, safety, and tolerability of multiple sc doses of Jintrolong® vs daily doses of rhGH. Design and methods Twelve children with growth hormone deficiency participated in this single-center, open-label, crossover Phase I trial. All subjects received daily sc injections of rhGH at 0.0286 mg/kg/d for 7 days, followed by a 4-week washout period and six weekly doses of Jintrolong® at 0.2 mg/kg/w. Results In comparison with rhGH, sc injection of Jintrolong® produced a noticeably higher Cmax, significantly longer half-life (t1/2), and slower plasma clearance, signifying a profile suitable for long-term treatment. The ratio of the area under the concentration vs time curve (AUC) after the seventh and first injections (AUC(0–∞)7th/AUC(0–∞)1st) of rhGH was 1.02, while the AUC(0–∞)6th/AUC(0–∞)1st of Jintrolong ® was 1.03, indicating no accumulation of circulating growth hormone. There was no significant difference in the change in insulin-like growth factor-1 expression produced by 7 days of sc rhGH and weekly Jintrolong® injections. There were no severe adverse events during the trial. Conclusion The elimination rate of Jintrolong® was slower than that of sc rhGH. No progressive serum accumulation of Jintrolong® was found. The changes in insulin-like growth factor-1 expression produced by rhGH and Jintrolong® were comparable, indicating similar pharmacodynamics. Our results demonstrate that Jintrolong® is suitable for long-term growth hormone treatment in children with growth hormone deficiency. PMID:26719670

  16. Reduced susceptibility to azoxymethane-induced aberrant crypt foci formation and colon cancer in growth hormone deficient rats

    PubMed Central

    Carroll, Robert E.; Goodlad, Robert A.; Poole, Aleksandra J.; Tyner, Angela L.; Robey, R. Brooks; Swanson, Steven M.; Unterman, Terry G.

    2010-01-01

    Objectives To evaluate the role of GH in colon carcinogenesis, we examined the formation of aberrant crypt foci (ACFs) and tumor development in wild type (WT) and GH-deficient, spontaneous dwarf rats (SDRs) exposed to the carcinogen azoxymethane (AOM). Design ACF were quantified by stereomicroscopy and tumor number and weights were recorded for each animal. Cell proliferation was measured by vincristine metaphase arrest, flow cytometry, and bromode-oxyuridine (BrdU) incorporation. Apoptosis was measured by TUNEL staining and cleaved caspase-3 immunohistochemistry. IGF-I was measured by radioimmunoassay (RIA). Hexokinase activity was measured by spectrophotometric assay. PARP cleavage, and IGF-IR, and p27kip/cip expression were measured by Western blotting. Results ACFs detected by stereomicroscopy were markedly reduced (~85%) in SDRs vs. WT rats at 10, 25, and 28 weeks after AOM. Tumor incidence, number, and weight also were reduced in SDR vs. WT animals. AOM treatment increased cell proliferation in the distal colon (where tumors occur) of WT rats but not SDRs, and these changes corresponded to increased ACF and tumor formation. Apoptosis rates were similar in AOM-treated WT and SDRs. Alterations in serum IGF-I levels may contribute to differences in the proliferative response to AOM and decreased ACF formation in SDR vs. WT rats. Conclusions We conclude that early neoplastic lesions (ACFs) were reduced in GH-deficient animals. This effect corresponds with differences in AOM-induced proliferation, but not apoptosis. These data indicate that GH is required for the full effect of AOM on colon ACF and tumor development, and that the SDR rat is a promising model for studies regarding the role of GH/IGF system in the initiation and promotion of colon cancer. PMID:19406679

  17. Candidate gene analysis of GH1 for effects on growth and carcass composition of cattle.

    PubMed

    Taylor, J F; Coutinho, L L; Herring, K L; Gallagher, D S; Brenneman, R A; Burney, N; Sanders, J O; Turner, J W; Smith, S B; Miller, R K; Savell, J W; Davis, S K

    1998-06-01

    We present an approach to evaluate the support for candidate genes as quantitative trait loci (QTLs) within the context of genome-wide map-based cloning strategies. To establish candidacy, a bacterial artificial chromosome (BAC) clone containing a putative candidate gene is physically assigned to an anchored linkage map to localise the gene relative to an identified QTL effect. Microsatellite loci derived from BAC clones containing an established candidate gene are integrated into the linkage map facilitating the evaluation by interval analysis of the statistical support for QTL identity. Permutation analysis is employed to determine experiment-wise statistical support. The approach is illustrated for the growth hormone 1 (GH1) gene and growth and carcass phenotypes in cattle. Polymerase chain reaction (PCR) primers which amplify a 441 bp fragment of GH1 were used to systematically screen a bovine BAC library comprising 60,000 clones and with a 95% probability of containing a single copy sequence. The presence of GH1 in BAC-110R2C3 was confirmed by sequence analysis of the PCR product from this clone and by the physical assignment of BAC110R2C3 to bovine chromosome 19 (BTA19) band 22 by fluorescence in situ hybridisation (FISH). Microsatellite KHGH1 was isolated from BAC110R2C3 and scored in 529 reciprocal backcross and F2 fullsib progeny from 41 resource families derived from Angus (Bos taurus) and Brahman (Bos indicus). The microsatellite KHGH1 was incorporated into a framework genetic map of BTA19 comprising 12 microsatellite loci, the erythrocyte antigen T and a GH1-TaqI restriction fragment length polymorphism (RFLP). Interval analysis localised effects of taurus vs. indicus alleles on subcutaneous fat and the percentage of either extractable fat from the Iongissimus dorsi muscle to the region of BTA19 harbouring GH1. PMID:9720178

  18. The multimodal management of GH-secreting pituitary adenomas: predictive factors, strategies and outcomes.

    PubMed

    Buliman, A; Tataranu, L G; Ciubotaru, V; Cazac, T L; Dumitrache, C

    2016-01-01

    Object. The aim of this study was to analyze a series of 28 patients with acromegaly who underwent a multimodal surgical, medical and radiosurgical therapy, with a special attention to the advantages, complications, and predictive factors of a successful outcome. Methods. 28 consecutive cases of GH-secreting pituitary adenomas, who underwent transsphenoidal endoscopic or microscopic surgery, between 1 January 2014 and 31 December 2014 were retrospectively reviewed. Tumors were classified according to the diameter, measured on MRI, as micro- or macroadenomas, and parasellar (cavernous sinus) tumor extension was analyzed based on the Knosp grading score. The mean follow-up period was of 18.4 months. Criteria justifying the complete hormonal remission were preoperative basal serum GH < 2.5 μg/ L, preoperative nadirGH < 1 ng/ L after OGTT and normal preoperative IGF-I levels age and sex-matched. Results. An overall complete hormonal remission rate was achieved in 64.3% of the patients. The remission rate was higher in patients with microadenomas (77.8%) than in those with macroadenomas (57.9%). A number of predictive factors, which might have interfered with the hormonal remission rate from a statistical, clinical and paraclinical point of view, were identified: tumor size (r = 0.625), preoperative GH serum levels (r = -0.517), cavernous sinus extension was quantified according to Knosp grading score (r = 0.469) and the degree of tumor subtotal resection (r = 0.598). Conclusions. Favorable hormonal and visual remission rates can be achieved after transsphenoidal resection of GH-secreting pituitary adenomas; however, the management remains challenging, the increased surgical experience being important for higher cure rates. If a biochemical hormonal cure is not achieved postoperatively, adjuvant medical or radio surgical therapy can be recommended. PMID:27453753

  19. A study of the mechanism of laser welding defects in low thermal expansion superalloy GH909

    SciTech Connect

    Yan, Fei; Wang, Chunming Wang, Yajun; Hu, Xiyuan; Wang, Tianjiao; Li, Jianmin; Li, Guozhu

    2013-04-15

    In this paper, we describe experimental laser welding of low-thermal-expansion superalloy GH909. The main welding defects of GH909 by laser in the weld are liquation cracks and porosities, including hydrogen and carbon monoxide porosity. The forming mechanism of laser welding defects was investigated. This investigation was conducted using an optical microscope, scanning electron microscope, energy diffraction spectrum, X-ray diffractometer and other methodologies. The results demonstrated that porosities appearing in the central weld were related to incomplete removal of oxide film on the surface of the welding samples. The porosities produced by these bubbles were formed as a result of residual hydrogen or oxygenium in the weld. These elements failed to escape from the weld since laser welding has both a rapid welding speed and cooling rate. The emerging crack in the heat affected zone is a liquation crack and extends along the grain boundary as a result of composition segregation. Laves–Ni{sub 2}Ti phase with low melting point is a harmful phase, and the stress causes grain boundaries to liquefy, migrate and even crack. Removing the oxides on the surface of the samples before welding and carefully controlling technological parameters can reduce welding defects and improve formation of the GH909 alloy weld. - Highlights: ► It is a new process for the forming of GH909 alloy via laser welding. ► The forming mechanism of laser welding defects in GH909 has been studied. ► It may be a means to improve the efficiency of aircraft engine production.

  20. Iodine-deficiency disorders.

    PubMed

    Zimmermann, Michael B; Jooste, Pieter L; Pandav, Chandrakant S

    2008-10-01

    2 billion individuals worldwide have insufficient iodine intake, with those in south Asia and sub-Saharan Africa particularly affected. Iodine deficiency has many adverse effects on growth and development. These effects are due to inadequate production of thyroid hormone and are termed iodine-deficiency disorders. Iodine deficiency is the most common cause of preventable mental impairment worldwide. Assessment methods include urinary iodine concentration, goitre, newborn thyroid-stimulating hormone, and blood thyroglobulin. In nearly all countries, the best strategy to control iodine deficiency is iodisation of salt, which is one of the most cost-effective ways to contribute to economic and social development. When iodisation of salt is not possible, iodine supplements can be given to susceptible groups. Introduction of iodised salt to regions of chronic iodine-deficiency disorders might transiently increase the proportion of thyroid disorders, but overall the small risks of iodine excess are far outweighed by the substantial risks of iodine deficiency. International efforts to control iodine-deficiency disorders are slowing, and reaching the third of the worldwide population that remains deficient poses major challenges. PMID:18676011

  1. Vitamin deficiencies and excesses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Vitamins are essential nutrients that must be supplied exogenously either as part of a well balanced diet or as supplements. Deficiency states are uncommon in developed countries except, perhaps, among some food insecure families. In contrast, deficiency states are quite common in many developing ...

  2. Testosterone deficiency myopathy.

    PubMed Central

    Orrell, R W; Woodrow, D F; Barrett, M C; Press, M; Dick, D J; Rowe, R C; Lane, R J

    1995-01-01

    Testosterone is recognized to have a positive effect on nitrogen balance and muscle development in hypogonadal men, but significantly myopathy secondary to testosterone deficiency has been reported only rarely. We describe a patient who presented with a myopathy associated with testosterone deficiency, and who demonstrated a significant functional and myometric response to treatment. PMID:7562829

  3. MENTAL DEFICIENCY. SECOND EDITION.

    ERIC Educational Resources Information Center

    HILLIARD, L.T.; KIRMAN, BRIAN H.

    REVISED TO INCLUDE LEGISLATIVE AND ADMINISTRATIVE PROCEDURES NEW IN BRITAIN SINCE THE 1957 EDITION, THE TEXT INCLUDES RECENT ADVANCES IN ETIOLOGY, PATHOLOGY, AND TREATMENT OF MENTAL DEFICIENCY. CONSIDERATION OF THE BACKGROUND OF MENTAL DEFICIENCY INCLUDES HISTORICAL AND LEGAL ASPECTS, THE SOCIAL BACKGROUND OF MENTAL DEFECT, PRENATAL CAUSES OF…

  4. Cerebral Folate Deficiency

    ERIC Educational Resources Information Center

    Gordon, Neil

    2009-01-01

    Cerebral folate deficiency (CFD) is associated with low levels of 5-methyltetrahydrofolate in the cerebrospinal fluid (CSF) with normal folate levels in the plasma and red blood cells. The onset of symptoms caused by the deficiency of folates in the brain is at around 4 to 6 months of age. This is followed by delayed development, with deceleration…

  5. Iron deficiency anemia

    MedlinePlus

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

  6. Factor X deficiency

    MedlinePlus

    Factor X (ten) deficiency is a disorder caused by a lack of a protein called factor X in the blood. It leads to problems with ... or are not functioning like they should. Factor X is one such coagulation factor. Factor X deficiency ...

  7. Iron induced nickel deficiency

    Technology Transfer Automated Retrieval System (TEKTRAN)

    It is increasingly apparent that economic loss due to nickel (Ni) deficiency likely occurs in horticultural and agronomic crops. While most soils contain sufficient Ni to meet crop requirements, situations of Ni deficiency can arise due to antagonistic interactions with other metals. This study asse...

  8. G6PD Deficiency

    MedlinePlus

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

  9. A novel GH secretagogue, A233, exhibits enhanced growth activity and innate immune system stimulation in teleosts fish.

    PubMed

    Martinez, Rebeca; Ubieta, Kenia; Herrera, Fidel; Forellat, Alina; Morales, Reynold; de la Nuez, Ania; Rodriguez, Rolando; Reyes, Osvaldo; Oliva, Ayme; Estrada, Mario P

    2012-09-01

    In teleosts fish, secretion of GH is regulated by several hypothalamic factors that are influenced by the physiological state of the animal. There is an interaction between immune and endocrine systems through hormones and cytokines. GH in fish is involved in many physiological processes that are not overtly growth related, such as saltwater osmoregulation, antifreeze synthesis, and the regulation of sexual maturation and immune functions. This study was conducted to characterize a decapeptide compound A233 (GKFDLSPEHQ) designed by molecular modeling to evaluate its function as a GH secretagogue (GHS). In pituitary cell culture, the peptide A233 induces GH secretion and it is also able to increase superoxide production in tilapia head-kidney leukocyte cultures. This effect is blocked by preincubation with the GHS receptor antagonist [d-Lys(3)]-GHRP6. Immunoneutralization of GH by addition of anti-tilapia GH monoclonal antibody blocked the stimulatory effect of A233 on superoxide production. These experiments propose a GH-mediated mechanism for the action of A233. The in vivo biological action of the decapeptide was also demonstrated for growth stimulation in goldfish and tilapia larvae (P<0.001). Superoxide dismutase levels, antiprotease activity, and lectin titer were enhanced in tilapia larvae treated with this novel molecule. The decapeptide A233 designed by molecular modeling is able to function as a GHS in teleosts and enhance parameters of the innate immune system in the fish larvae. PMID:22707376

  10. Delayed germination of Arabidopsis seeds under chilling stress by overexpressing an abiotic stress inducible GhTPS11.

    PubMed

    Wang, Cai-Li; Zhang, Shi-Cai; Qi, Sheng-Dong; Zheng, Cheng-Chao; Wu, Chang-Ai

    2016-01-10

    Trehalose-6-phosphate synthase (TPS) plays an important role in metabolic regulation and stress responses in a variety of organisms. However information about cotton TPS is poor. Here a cotton TPS gene GhTPS11 was isolated and characterized. Expression analysis revealed that GhTPS11 was induced in 20-day old cotton seedlings by heat drought and high salt stresses as well as GA and ABA. Moreover GhTPS11 was induced by chilling stress and mannitol while was depressed by sucrose. Tissue expression analysis indicated that GhTPS11 expressed higher in leaves than in stems and roots of 20-day old cotton seedlings. The GhTPS11 overexpressing Arabidopsis seeds germinated slower than the wild-type (WT) under chilling stress. Trehalose-6-phosphate (T6P) and trehalose contents were evidently higher in GhTPS11 overexpressing lines 3, 5, and 22 than in WT under normal germination condition as well as chilling stress. Further analysis demonstrated that the expression of ICE1 CBF3 and RCI2A was induced lower whereas that of CBF1 and CBF2 was induced higher under chilling stress in the GhTPS11 overexpressing seeds than WT respectively. These results suggested that GhTPS11 encoded a stress-responsive TPS protein and functioned in chilling stress during seed germination. Perhaps the chilling stress sensitivity of transgenic Arabidopsis seeds was caused by the expression changes of at least some chilling-related genes such as ICE1 CBFs and RCI2A other than HOS1. So this article provided the useful information for GhTPS11 usage for crop molecular breeding. PMID:26325072

  11. Cardiac-Specific Disruption of GH Receptor Alters Glucose Homeostasis While Maintaining Normal Cardiac Performance in Adult Male Mice.

    PubMed

    Jara, Adam; Liu, Xingbo; Sim, Don; Benner, Chance M; Duran-Ortiz, Silvana; Qian, Yanrong; List, Edward O; Berryman, Darlene E; Kim, Jason K; Kopchick, John J

    2016-05-01

    GH is considered necessary for the proper development and maintenance of several tissues, including the heart. Studies conducted in both GH receptor null and bovine GH transgenic mice have demonstrated specific cardiac structural and functional changes. In each of these mouse lines, however, GH-induced signaling is altered systemically, being decreased in GH receptor null mice and increased in bovine GH transgenic mice. Therefore, to clarify the direct effects GH has on cardiac tissue, we developed a tamoxifen-inducible, cardiac-specific GHR disrupted (iC-GHRKO) mouse line. Cardiac GH receptor was disrupted in 4-month-old iC-GHRKO mice to avoid developmental effects due to perinatal GHR gene disruption. Surprisingly, iC-GHRKO mice showed no difference vs controls in baseline or postdobutamine stress test echocardiography measurements, nor did iC-GHRKO mice show differences in longitudinal systolic blood pressure measurements. Interestingly, iC-GHRKO mice had decreased fat mass and improved insulin sensitivity at 6.5 months of age. By 12.5 months of age, however, iC-GHRKO mice no longer had significant decreases in fat mass and had developed glucose intolerance and insulin resistance. Furthermore, investigation via immunoblot analysis demonstrated that iC-GHRKO mice had appreciably decreased insulin stimulated Akt phosphorylation, specifically in heart and liver, but not in epididymal white adipose tissue. These changes were accompanied by a decrease in circulating IGF-1 levels in 12.5-month-old iC-GHRKO mice. These data indicate that whereas the disruption of cardiomyocyte GH-induced signaling in adult mice does not affect cardiac function, it does play a role in systemic glucose homeostasis, in part through modulation of circulating IGF-1. PMID:27035649

  12. GH51 Arabinofuranosidase and Its Role in the Methylglucuronoarabinoxylan Utilization System in Paenibacillus sp. Strain JDR-2

    PubMed Central

    Sawhney, Neha

    2014-01-01

    Methylglucuronoarabinoxylan (MeGAXn) from agricultural residues and energy crops is a significant yet underutilized biomass resource for production of biofuels and chemicals. Mild thermochemical pretreatment of bagasse yields MeGAXn requiring saccharifying enzymes for conversion to fermentable sugars. A xylanolytic bacterium, Paenibacillus sp. strain JDR-2, produces an extracellular cell-associated GH10 endoxylanse (XynA1) which efficiently depolymerizes methylglucuronoxylan (MeGXn) from hardwoods coupled with assimilation of oligosaccharides for further processing by intracellular GH67 α-glucuronidase, GH10 endoxylanase, and GH43 β-xylosidase. This process has been ascribed to genes that comprise a xylan utilization regulon that encodes XynA1 and includes a gene cluster encoding transcriptional regulators, ABC transporters, and intracellular enzymes that convert assimilated oligosaccharides to fermentable sugars. Here we show that Paenibacillus sp. JDR-2 utilized MeGAXn without accumulation of oligosaccharides in the medium. The Paenibacillus sp. JDR-2 growth rate on MeGAXn was 3.1-fold greater than that on oligosaccharides generated from MeGAXn by XynA1. Candidate genes encoding GH51 arabinofuranosidases with potential roles were identified. Following growth on MeGAXn, quantitative reverse transcription-PCR identified a cluster of genes encoding a GH51 arabinofuranosidase (AbfB) and transcriptional regulators which were coordinately expressed along with the genes comprising the xylan utilization regulon. The action of XynA1 on MeGAXn generated arabinoxylobiose, arabinoxylotriose, xylobiose, xylotriose, and methylglucuronoxylotriose. Recombinant AbfB processed arabinoxylooligosaccharides to xylooligosaccharides and arabinose. MeGAXn processing by Paenibacillus sp. JDR-2 may be achieved by extracellular depolymerization by XynA1 coupled to assimilation of oligosaccharides and further processing by intracellular enzymes, including AbfB. Paenibacillus sp. JDR-2

  13. A LONGER INTERVAL WITHOUT GROWTH HORMONE REPLACEMENT AND FEMALE GENDER ARE ASSOCIATED WITH LOWER BONE MINERAL DENSITY IN ADULTS WITH CHILDHOOD ONSET GROWTH HORMONE DEFICIENCY - A KIMS DATABASE ANALYSIS

    PubMed Central

    Tritos, Nicholas A; Hamrahian, Amir H; King, Donna; Greenspan, Susan L; Cook, David M; Jönsson, Peter J; Wajnrajch, Michael P; Koltowska – Häggstrom, Maria; Biller, Beverly MK

    2016-01-01

    Objective Childhood onset growth hormone deficiency (COGHD) is associated with low bone mineral density (BMD). Adults with persistent COGHD may be at risk for insufficient bone accrual or bone loss during adulthood. The purpose of this study was to identify BMD predictors and characterize the effects of GH replacement on BMD in COGHD adults with persistent GHD. Design Retrospective analysis of the KIMS database. Methods Variables predicting standardized BMD (sBMD) were identified. The effect of GH replacement (3 years) on BMD was examined. Results 314 COGHD adults (148 women, 166 men; 62 non-naïve, 178 semi-naïve, and 74 true naïve, depending on length and timing of previous GH replacement), who had BMD measured in lumbar spine (LS) and femoral neck (FN) at study entry. In semi-naïve subjects, a longer gap in GH replacement between childhood and adulthood was predictive of lower sBMD in the FN (r= −0.18, P=0.038). Thyrotropin deficiency predicted lower sBMD in the LS (r= −0.16,P=0.052). In true naïve patients, a longer gap between onset of pituitary disease and study entry (r= −0.35,P=0.012) and female gender (r= −0.27,P=0.043) independently predicted lower sBMD in the FN. There were no differences in BMD increases between non-naïve, semi-naïve and true naïve subjects on GH replacement. Conclusions In semi-naïve subjects a longer interval off GH replacement was associated with lower sBMD in the FN. Among true naïve patients, a longer gap between the onset of pituitary disease and GH replacement, and female gender predicted lower sBMD in the FN. PMID:22711759

  14. Glucose-6-phosphate dehydrogenase deficiency

    MedlinePlus

    G-6-PD deficiency; Hemolytic anemia due to G6PD deficiency; Anemia - hemolytic due to G6PD deficiency ... Churchill Livingston; 2008:chap 45. Golan DER. Hemolytic anemias: red cell membrane and metabolic defects. In: Goldman ...

  15. Exome sequencing reveals two novel compound heterozygous XYLT1 mutations in a Polish patient with Desbuquois dysplasia type 2 and growth hormone deficiency.

    PubMed

    Jamsheer, Aleksander; Olech, Ewelina M; Kozłowski, Kazimierz; Niedziela, Marek; Sowińska-Seidler, Anna; Obara-Moszyńska, Monika; Latos-Bieleńska, Anna; Karczewski, Marek; Zemojtel, Tomasz

    2016-07-01

    Desbuquois dysplasia type 2 (DBQD2) is a rare recessively inherited skeletal genetic disorder characterized by severe prenatal and postnatal growth retardation, generalized joint laxity with dislocation of large joints and facial dysmorphism. The condition was recently described to result from autosomal recessive mutations in XYLT1, encoding the enzyme xylosyltransferase-1. In this paper, we report on a Polish patient with DBQD2 who presented with severe short stature of prenatal onset, joint laxity, psychomotor retardation and multiple radiological abnormalities including short metacarpals, advanced bone age and exaggerated trochanters. Endocrinological examinations revealed that sleep-induced growth hormone (GH) release and GH peak in clonidine- and glucagon-induced provocative tests as well as insulin-like growth factor 1 (IGF-1) and IGF-binding protein-3 levels were all markedly decreased, confirming deficiency of GH secretion. Bone age, unlikely to GH deficiency, was significantly advanced. To establish the diagnosis at a molecular level, we performed whole-exome sequencing and bioinformatic analysis in the index patient, which revealed compound heterozygous XYLT1 mutations: c.595C>T(p.Gln199*) and c.1651C>T(p.Arg551Cys), both of which are novel. Sanger sequencing showed that the former mutation was inherited from the healthy mother, whereas the latter one most probably occurred de novo. Our study describes the first case of DBQD2 resulting from compound heterozygous XYLT1 mutation, expands the mutational spectrum of the disease and provides evidence that the severe growth retardation and microsomia observed in DBQD2 patients may result not only from the skeletal dysplasia itself but also from GH and IGF-1 deficiency. PMID:27030147

  16. Betaine deficiency in maize

    SciTech Connect

    Lerma, C. ); Rich, P.J.; Ju, G.C.; Yang, Wenju; Rhodes, D. ); Hanson, A.D. )

    1991-04-01

    Maize (Zea mays L.) is a betaine-accumulating species, but certain maize genotypes lack betaine almost completely; a single recessive gene has been implicated as the cause of this deficiency. This study was undertaken to determine whether betaine deficiency in diverse maize germplasm is conditioned by the same genetic locus, and to define the biochemical lesion(s) involved. Complementation tests indicated that all 13 deficient genotypes tested shared a common locus. One maize population (P77) was found to be segregating for betaine deficiency, and true breeding individuals were used to produce related lines with and without betaine. Leaf tissue of both betaine-positive and betaine-deficient lines readily converted supplied betaine aldehyde to betaine, but only the betaine-containing line was able to oxidize supplied choline to betaine. This locates the lesion in betaine-deficient plants at the choline {r arrow} betaine aldehyde step of betaine synthesis. Consistent with this location, betaine-deficient plants were shown to have no detectable endogenous pool of betaine aldehyde.

  17. Congenital limb deficiency disorders.

    PubMed

    Wilcox, William R; Coulter, Colleen P; Schmitz, Michael L

    2015-06-01

    Congenital limb deficiency disorders (LDDs) are birth defects characterized by the aplasia or hypoplasia of bones of the limbs. Limb deficiencies are classified as transverse, those due to intrauterine disruptions of previously normal limbs, or longitudinal, those that are isolated or associated with certain syndromes as well as chromosomal anomalies. Consultation with a medical geneticist is advisable. Long-term care should occur in a specialized limb deficiency center with expertise in orthopedics, prosthetics, and occupational and physical therapy and provide emotional support and contact with other families. With appropriate care, most children with LDDs can lead productive lives. PMID:26042905

  18. Iron deficiency anemia

    PubMed Central

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

    2012-01-01

    Iron is essential to virtually all living organisms and is integral to multiple metabolic functions. The most important function is oxygen transport in hemoglobin. Iron deficiency anemia in dogs and cats is usually caused by chronic blood loss and can be discovered incidentally as animals may have adapted to the anemia. Severe iron deficiency is characterized by a microcytic, hypochromic, potentially severe anemia with a variable regenerative response. Iron metabolism and homeostasis will be reviewed, followed by a discussion of diagnostic testing and therapeutic recommendations for dogs and cats with iron deficiency anemia. PMID:22942439

  19. Thiamine deficiency and delirium.

    PubMed

    Osiezagha, Kenneth; Ali, Shahid; Freeman, C; Barker, Narviar C; Jabeen, Shagufta; Maitra, Sarbani; Olagbemiro, Yetunde; Richie, William; Bailey, Rahn K

    2013-04-01

    Thiamine is an essential vitamin that plays an important role in cellular production of energy from ingested food and enhances normal neuronal actives. Deficiency of this vitamin leads to a very serious clinical condition known as delirium. Studies performed in the United States and other parts of the world have established the link between thiamine deficiency and delirium. This literature review examines the physiology, pathophysiology, predisposing factors, clinical manifestations (e.g., Wernicke's encephalopathy, Wernicke-Korsakoff syndrome, structural and functional brain injuries) and diagnosis of thiamine deficiency and delirium. Current treatment practices are also discussed that may improve patient outcome, which ultimately may result in a reduction in healthcare costs. PMID:23696956

  20. Human conditions of insulin-like growth factor-I (IGF-I) deficiency

    PubMed Central

    2012-01-01

    Insulin-like growth factor I (IGF-I) is a polypeptide hormone produced mainly by the liver in response to the endocrine GH stimulus, but it is also secreted by multiple tissues for autocrine/paracrine purposes. IGF-I is partly responsible for systemic GH activities although it possesses a wide number of own properties (anabolic, antioxidant, anti-inflammatory and cytoprotective actions). IGF-I is a closely regulated hormone. Consequently, its logical therapeutical applications seems to be limited to restore physiological circulating levels in order to recover the clinical consequences of IGF-I deficiency, conditions where, despite continuous discrepancies, IGF-I treatment has never been related to oncogenesis. Currently the best characterized conditions of IGF-I deficiency are Laron Syndrome, in children; liver cirrhosis, in adults; aging including age-related-cardiovascular and neurological diseases; and more recently, intrauterine growth restriction. The aim of this review is to summarize the increasing list of roles of IGF-I, both in physiological and pathological conditions, underlying that its potential therapeutical options seem to be limited to those proven states of local or systemic IGF-I deficiency as a replacement treatment, rather than increasing its level upper the normal range. PMID:23148873

  1. Five-dimensional supergravity and the hyperbolic Kac Moody algebra GH2

    NASA Astrophysics Data System (ADS)

    Mizoguchi, Shun'ya; Mohri, Kenji; Yamada, Yasuhiko

    2006-05-01

    Motivated by the recent analysis of the E10 sigma model for the study of M-theory, we study a one-dimensional sigma model associated with the hyperbolic Kac Moody algebra GH2 and its link to D=5, {\\cal N}=2 pure supergravity, which closely resembles in many ways D = 11 supergravity. The bosonic equations of motion and the Bianchi identity for D = 5 pure supergravity match the equations of the level ell <= 3 truncation of the GH2 sigma model up to higher level terms, just as they do for the D = 11 case. We also compute low level root and outer multiplicities in the A3 decomposition, and indeed find singlets at ell = 4k, k = 2, 3, ... corresponding to the scaling of ERk+1 terms, although the missing singlet at ell = 4 remains a puzzle.

  2. Dissociation of body growth and adipose deposition effects of growth hormone in oMt1a-oGH transgenic mice.

    PubMed

    Oberbauer, A M; Stiglich, C; Murray, J D; Keen, C L; Fong, D L; Smith, L B; Cushwa, S

    2004-01-01

    Chronic highly elevated expression of a growth hormone (GH) transgene enhances overall body growth with minimal adipose accretion, while moderate levels of circulating GH fail to enhance body growth yet promote adipose deposition. These findings suggest that the growth response to GH can be dissociated from adipose effects. This hypothesis was tested in the oMtla-oGH transgenic mouse model by titrating circulating GH levels through variable induction of transgene expression. Circulating GH levels in female transgenics were approximately 49, 132, and 750 ng/ml in response to the transgene stimulus at 0, 15, and 25 mM zinc sulfate, respectively. The highest level of circulating GH generated the largest body weight with the smallest fat accrual while the intermediate GH level generated a body weight equivalent to that for the highest GH but the heaviest gonadal fat pads. The lowest GH levels did not increase body size but did enlarge fat depots. Animals exposed to the highest level of GH had an extended growth phase relative to lower GH levels and the nontransgenic controls. In contrast, the duration of the growth phase for the 0 and 15 mM zinc stimulated transgenics was abbreviated relative to the growth phase of the control animals. The two highest levels of circulating GH increased all forms of the GH receptor, IGF-I, and hepatic lipoprotein lipase mRNA. The growth differential observed for the 0 vs. the 15 mM zinc stimulated transgenics may reflect the preferential increase in the full length GH receptor mRNA and the induction of the smaller IGF-I transcripts with the higher circulating GH while the lipid accrual paralleled the disproportionate induction of the truncated GH receptor mRNA form. Liver and bone content of zinc, manganese, copper, and iron primarily reflected dietary zinc supplementation and did not appear to play a role in the differential growth response. The dissociation of GH effects on growth and adipogenesis as a function of circulating GH

  3. Familial lipoprotein lipase deficiency

    MedlinePlus

    ... and white-colored blood vessels in the retinas Pancreatitis that keeps returning Yellowing of the eyes and ... discuss your diet needs with a registered dietitian. Pancreatitis that is related to lipoprotein lipase deficiency responds ...

  4. Growth hormone deficiency - children

    MedlinePlus

    ... the same age. The child will have normal intelligence in most cases. In older children, puberty may ... hormones cause the body to make. Tests can measure these growth factors. Accurate growth hormone deficiency testing ...

  5. Vitamin D Deficiency

    MedlinePlus

    ... deficiency can lead to a loss of bone density (size and strength), broken bones (fractures), muscle weakness, ... get too much calcium in their blood or urine. Careful monitoring of blood vitamin D levels will ...

  6. Factor V deficiency

    MedlinePlus

    ... as many as 20 different proteins in blood plasma. These proteins are called blood coagulation factors. Factor ... You will be given fresh blood plasma or fresh frozen plasma infusions ... These treatments will correct the deficiency temporarily.

  7. Folate-deficiency anemia

    MedlinePlus

    Folate-deficiency anemia is a decrease in red blood cells (anemia) due to a lack of folate. Folate is a type ... B vitamin. It is also called folic acid. Anemia is a condition in which the body does ...

  8. Expression profile of IGF paralog genes in liver and muscle of a GH-transgenic zebrafish.

    PubMed

    Nornberg, Bruna Felix; Figueiredo, Marcio Azevedo; Marins, Luis Fernando

    2016-01-15

    The objective of this study was to investigate the relationship between IGFs produced in the liver and skeletal muscle with muscle hypertrophy previously observed in a line of GH-transgenic zebrafish. In this sense, we evaluated the expression of genes related to the IGF system in liver and muscle of transgenics, as well as the main intracellular signaling pathways used by GH/IGF axis. Our results showed an increase in expression of igf1a, igf2a, and igf2b genes in the liver. Moreover, there was a decrease in the expression of igf1ra and an increase in muscle igf2r of transgenics, indicating a negative response of muscle tissue with respect to excess circulating IGFs. Muscle IGFs expression analyses revealed a significant increase only for igf2b, accompanied by a parallel induction of igfbp5a gene. The presence of IGFBP5a may potentiate the IGF2 action in muscle cells differentiation. Regarding JAK/STAT-related genes, we observed an alteration in the expression profile of both stat3 and stat5a in transgenic fish liver. No changes were observed in the muscle, suggesting that both tissues respond differently to GH-transgenesis. Western blotting analyses indicated an imbalance between the phosphorylation levels of the proliferative (MEK/ERK) and hypertrophic (PI3K/Akt) pathways, in favor of the latter. In summary, the results of this study suggest that the hypertrophy caused by GH-transgenesis in zebrafish may be due to circulating IGFs produced by the liver, with an important participation of muscle IGF2b. This group of IGFs appears to be favoring the hypertrophic intracellular pathway in muscle tissue of transgenic zebrafish. PMID:26718079

  9. Growth Hormone Inhibits Hepatic De Novo Lipogenesis in Adult Mice.

    PubMed

    Cordoba-Chacon, Jose; Majumdar, Neena; List, Edward O; Diaz-Ruiz, Alberto; Frank, Stuart J; Manzano, Anna; Bartrons, Ramon; Puchowicz, Michelle; Kopchick, John J; Kineman, Rhonda D

    2015-09-01

    Patients with nonalcoholic fatty liver disease (NAFLD) are reported to have low growth hormone (GH) production and/or hepatic GH resistance. GH replacement can resolve the fatty liver condition in diet-induced obese rodents and in GH-deficient patients. However, it remains to be determined whether this inhibitory action of GH is due to direct regulation of hepatic lipid metabolism. Therefore, an adult-onset, hepatocyte-specific, GH receptor (GHR) knockdown (aLivGHRkd) mouse was developed to model hepatic GH resistance in humans that may occur after sexual maturation. Just 7 days after aLivGHRkd, hepatic de novo lipogenesis (DNL) was increased in male and female chow-fed mice, compared with GHR-intact littermate controls. However, hepatosteatosis developed only in male and ovariectomized female aLivGHRkd mice. The increase in DNL observed in aLivGHRkd mice was not associated with hyperactivation of the pathway by which insulin is classically considered to regulate DNL. However, glucokinase mRNA and protein levels as well as fructose-2,6-bisphosphate levels were increased in aLivGHRkd mice, suggesting that enhanced glycolysis drives DNL in the GH-resistant liver. These results demonstrate that hepatic GH actions normally serve to inhibit DNL, where loss of this inhibitory signal may explain, in part, the inappropriate increase in hepatic DNL observed in NAFLD patients. PMID:26015548

  10. Microgravity associated changes in pituitary growth hormone (GH) cells prepared from rats flown on Space Lab 3

    NASA Technical Reports Server (NTRS)

    Hymer, W. C.; Farrington, M.; Hayes, C.; Grindeland, R.; Fast, T.

    1985-01-01

    The effect of microgravity on the release of pituitary growth hormone (GH) in rats is studied. The pituitary glands from six adult rats exposed to microgravity are analyzed for in vitro and in vivo changes in pituitary growth hormone cells. The GH cell functions in the somatotrophs of flight rats are compared to a control group. The two assay procedures employed in the experiment are described. It is observed that intracellular levels of GH are two to three times greater in the flight rats than in the control group; however, the amount of GH released from the somatotrophs is 1.11 + or - 0.4 micrograms for the flight rats and 1.85 + or - 1.3 micrograms for the control rats.

  11. Clinical significance of complement deficiencies.

    PubMed

    Pettigrew, H David; Teuber, Suzanne S; Gershwin, M Eric

    2009-09-01

    The complement system is composed of more than 30 serum and membrane-bound proteins, all of which are needed for normal function of complement in innate and adaptive immunity. Historically, deficiencies within the complement system have been suspected when young children have had recurrent and difficult-to-control infections. As our understanding of the complement system has increased, many other diseases have been attributed to deficiencies within the complement system. Generally, complement deficiencies within the classical pathway lead to increased susceptibility to encapsulated bacterial infections as well as a syndrome resembling systemic lupus erythematosus. Complement deficiencies within the mannose-binding lectin pathway generally lead to increased bacterial infections, and deficiencies within the alternative pathway usually lead to an increased frequency of Neisseria infections. However, factor H deficiency can lead to membranoproliferative glomerulonephritis and hemolytic uremic syndrome. Finally, deficiencies within the terminal complement pathway lead to an increased incidence of Neisseria infections. Two other notable complement-associated deficiencies are complement receptor 3 and 4 deficiency, which result from a deficiency of CD18, a disease known as leukocyte adhesion deficiency type 1, and CD59 deficiency, which causes paroxysmal nocturnal hemoglobinuria. Most inherited deficiencies of the complement system are autosomal recessive, but properidin deficiency is X-linked recessive, deficiency of C1 inhibitor is autosomal dominant, and mannose-binding lectin and factor I deficiencies are autosomal co-dominant. The diversity of clinical manifestations of complement deficiencies reflects the complexity of the complement system. PMID:19758139

  12. Resolving the growth-promoting and metabolic effects of growth hormone: Differential regulation of GH-IGF-I system components.

    PubMed

    Norbeck, Lindsey A; Kittilson, Jeffrey D; Sheridan, Mark A

    2007-05-01

    Growth hormone regulates numerous processes in vertebrates including growth promotion and lipid mobilization. During periods of food deprivation, growth is arrested yet lipid depletion is promoted. In this study, we used rainbow trout on different nutritional regimens to examine the regulation of growth hormone (GH)-insulin-like growth factor-I (IGF-I) system elements in order to resolve the growth-promoting and lipid catabolic actions of GH. Fish fasted for 2 or 6 weeks displayed significantly reduced growth compared to their fed counterparts despite elevated plasma GH, while refeeding for 2 weeks following 4 weeks of fasting partially restored growth and lowered plasma GH. Fish fasted for 6 weeks also exhausted their mesenteric adipose tissue reserves. Sensitivity to GH in the liver was reduced in fasting fish as evidenced by reduced expression of GH receptor type 1 (GHR 1) and GHR 2 mRNAs and by reduced (125)I-GH binding capacity. Expression of GHR 1 and GHR 2 mRNAs also was reduced in the gill of fasted fish. In adipose tissue, however, sensitivity to GH, as indicated by GHR 1 expression and by (125)I-GH binding capacity, increased after 6 weeks of fasting in concert with the observed lipid depletion. Fasting-associated growth retardation was accompanied by reduced expression of total IGF-I mRNA in the liver, adipose and gill, and by reduced plasma levels of IGF-I. Sensitivity to IGF-I was reduced in the gill of fasted fish as indicated by reduced expression of type 1 IGF-I receptor (IGFR 1A and IGFR 1B) mRNAs. By contrast, fasting did not affect expression of IGFR 1 mRNAs or (125)I-IGF-I binding in skeletal muscle and increased expression of IGFR 1 mRNAs and (125)I-IGF-I binding in cardiac muscle. These results indicate that nutritional state differentially regulates GH-IGF-I system components in a tissue-specific manner and that such alterations disable the growth-promoting actions of GH and promote the lipid-mobilizing actions of the hormone. PMID:17376444

  13. A structural overview of GH61 proteins - fungal cellulose degrading polysaccharide monooxygenases.

    PubMed

    Lo Leggio, Leila; Welner, Ditte; De Maria, Leonardo

    2012-01-01

    Recent years have witnessed a spurt of activities in the elucidation of the molecular function of a class of proteins with great potential in biomass degradation. GH61 proteins are of fungal origin and were originally classified in family 61 of the glycoside hydrolases. From the beginning they were strongly suspected to be involved in cellulose degradation because of their expression profiles, despite very low detectable endoglucanase activities. A major breakthrough came from structure determination of the first members, establishing the presence of a divalent metal binding site and a similarity to bacterial proteins involved in chitin degradation. A second breakthrough came from the identification of cellulase boosting activity dependent on the integrity of the metal binding site. Finally very recently GH61 proteins were demonstrated to oxidatively cleave crystalline cellulose in a Cu and reductant dependant manner. This mini-review in particular focuses on the contribution that structure elucidation has made in the understanding of GH61 molecular function and reviews the currently known structures and the challenges remaining ahead for exploiting this new class of enzymes to the full. PMID:24688660

  14. GH-releasing peptide-2 does not stimulate arginine vasopressin secretion in healthy men.

    PubMed

    Kamoi, Kyuzi; Minagawa, Shinichi; Kimura, Keita; Ishizawa, Masahiro; Ohara, Nobumasa; Uemura, Yasuyuki; Tsuchiya, Junpei

    2010-01-01

    Ghrelin has a stimulating effect on arginine vasopressin (AVP). However, it is not known whether GHRP-2, a synthetic ghrelin receptor agonist, also has a stimulating effect on AVP release in men. To determine whether the GHRP-2 test is useful for assessing AVP secretion, blood ACTH, GH, FSH, LH, PRL, TSH and AVP levels, as well as glucose, osmolality, sodium and hematocrit, were measured before and 15, 30, 45 and 60 min after an intravenous bolus of 100 microg GHRP-2 in 10 healthy men with and without fasting. Blood pressure was measured at 15-min intervals. AVP secretion was not stimulated by the GHRP-2 test with and without fasting. There were no significant differences in hematocrit, blood pressure and plasma osmolality before and after GFRP-2 injection, although significant (p<0.001) peak blood GH, and ACTH and PRL levels were observed 30 and 15 min after GHRP-2 injection with and without fasting, respectively, and the maximal peaks were significantly (p<0.05) higher with fasting than without fasting. These results suggest that AVP secretion is not stimulated by the GHRP-2 test both with and without fasting, though GH, ACTH and PRL levels were higher with than without fasting. PMID:19907099

  15. A structural overview of GH61 proteins – fungal cellulose degrading polysaccharide monooxygenases

    PubMed Central

    Leggio, Leila Lo; Welner, Ditte; De Maria, Leonardo

    2012-01-01

    Recent years have witnessed a spurt of activities in the elucidation of the molecular function of a class of proteins with great potential in biomass degradation. GH61 proteins are of fungal origin and were originally classified in family 61 of the glycoside hydrolases. From the beginning they were strongly suspected to be involved in cellulose degradation because of their expression profiles, despite very low detectable endoglucanase activities. A major breakthrough came from structure determination of the first members, establishing the presence of a divalent metal binding site and a similarity to bacterial proteins involved in chitin degradation. A second breakthrough came from the identification of cellulase boosting activity dependent on the integrity of the metal binding site. Finally very recently GH61 proteins were demonstrated to oxidatively cleave crystalline cellulose in a Cu and reductant dependant manner. This mini-review in particular focuses on the contribution that structure elucidation has made in the understanding of GH61 molecular function and reviews the currently known structures and the challenges remaining ahead for exploiting this new class of enzymes to the full. PMID:24688660

  16. Structural analysis of the GH43 enzyme Xsa43E from Butyrivibrio proteoclasticus

    PubMed Central

    Till, M.; Goldstone, D.; Card, G.; Attwood, G. T.; Moon, C. D.; Arcus, V. L.

    2014-01-01

    The rumen of dairy cattle can be thought of as a large, stable fermentation vat and as such it houses a large and diverse community of microorganisms. The bacterium Butyrivibrio proteoclasticus is a representative of a significant component of this microbial community. It is a xylan-degrading organism whose genome encodes a large number of open reading frames annotated as fibre-degrading enzymes. This suite of enzymes is essential for the organism to utilize the plant material within the rumen as a fuel source, facilitating its survival in this competitive environment. Xsa43E, a GH43 enzyme from B. proteoclasticus, has been structurally and functionally characterized. Here, the structure of selenomethionine-derived Xsa43E determined to 1.3 Å resolution using single-wavelength anomalous diffraction is reported. Xsa43E possesses the characteristic five-bladed β-propeller domain seen in all GH43 enzymes. GH43 enzymes can have a range of functions, and the functional characterization of Xsa43E shows it to be an arabinofuranosidase capable of cleaving arabinose side chains from short segments of xylan. Full functional and structural characterization of xylan-degrading enzymes will aid in creating an enzyme cocktail that can be used to completely degrade plant material into simple sugars. These molecules have a range of applications as starting materials for many industrial processes, including renewable alternatives to fossil fuels. PMID:25195890

  17. GhPSY, a phytoene synthase gene, is related to the red plant phenotype in upland cotton (Gossypium hirsutum L.).

    PubMed

    Cai, Caiping; Zhang, Xueying; Niu, Erli; Zhao, Liang; Li, Nina; Wang, Liman; Ding, Linyun; Guo, Wangzhen

    2014-08-01

    Carotenoids are important accessory pigments in plants that are essential for photosynthesis. Phytoene synthase (PSY), a rate-controlling enzyme in the carotenoid biosynthesis pathway, has been widely characterized in rice, maize, and sorghum, but at present there are no reports describing this enzyme in cotton. In this study, GhPSY was identified as a candidate gene for the red plant phenotype via a combined strategy using: (1) molecular marker data for loci closely linked to R1; (2) the whole-genome scaffold sequence from Gossypium raimondii; (3) gene expression patterns in cotton accessions expressing the red plant and green plant phenotypes; and (4) the significant correlation between a single nucleotide polymorphisms (SNP) in GhPSY and leaf phenotypes of progeny in the (Sub16 × T586) F2 segregating population. GhPSY was relatively highly expressed in leaves, and the protein was localized to the plastid where it appeared to be mostly attached to the surface of thylakoid membranes. GhPSY mRNA was expressed at a significantly higher level in T586 and SL1-7-1 red plants than TM-1 and Hai7124 green plants. SNP analysis in the GhPSY locus showed co-segregation with the red and green plant phenotypes in the (Sub16 × T586) F2 segregating population. A phylogenetic analysis showed that GhPSY belongs to the PSY2 subfamily, which is related to photosynthesis in photosynthetic tissues. Using a reverse genetics approach based on Tobacco rattle virus-induced gene silencing, we showed that the knockdown of GhPSY caused a highly uniform bleaching of the red color in newly-emerged leaves in both T586 and SL1-7-1 plants with a red plant phenotype. These findings indicate that GhPSY is important for engineering the carotenoid metabolic pathway in pigment production. PMID:24718783

  18. Cotton GhMYB7 is predominantly expressed in developing fibers and regulates secondary cell wall biosynthesis in transgenic Arabidopsis.

    PubMed

    Huang, Junfeng; Chen, Feng; Wu, Siyu; Li, Juan; Xu, Wenliang

    2016-02-01

    The secondary cell wall in mature cotton fibers contains over 90% cellulose with low quantities of xylan and lignin. However, little is known regarding the regulation of secondary cell wall biosynthesis in cotton fibers. In this study, we characterized an R2R3-MYB transcription factor, GhMYB7, in cotton. GhMYB7 is expressed at a high level in developing fibers and encodes a MYB protein that is targeted to the cell nucleus and has transcriptional activation activity. Ectopic expression of GhMYB7 in Arabidopsis resulted in small, curled, dark green leaves and also led to shorter inflorescence stems. A cross-sectional assay of basal stems revealed that cell wall thickness of vessels and interfascicular fibers was higher in transgenic lines overexpressing GhMYB7 than in the wild type. Constitutive expression of GhMYB7 in Arabidopsis activated the expression of a suite of secondary cell wall biosynthesis-related genes (including some secondary cell wall-associated transcription factors), leading to the ectopic deposition of cellulose and lignin. The ectopic deposition of secondary cell walls may have been initiated before the cessation of cell expansion. Moreover, GhMYB7 was capable of binding to the promoter regions of AtSND1 and AtCesA4, suggesting that GhMYB7 may function upstream of NAC transcription factors. Collectively, these findings suggest that GhMYB7 is a potential transcriptional activator, which may participate in regulating secondary cell wall biosynthesis of cotton fibers. PMID:26803299

  19. A Solanum torvum GH3 β-glucosidase expressed in Pichia pastoris catalyzes the hydrolysis of furostanol glycoside.

    PubMed

    Suthangkornkul, Rungarun; Sriworanun, Pornpisut; Nakai, Hiroyuki; Okuyama, Masayuki; Svasti, Jisnuson; Kimura, Atsuo; Senapin, Saengchan; Arthan, Dumrongkiet

    2016-07-01

    Plant β-glucosidases are usually members of the glucosyl hydrolase 1 (GH1) or 3 (GH3) families. Previously, a β-glucosidase (torvosidase) was purified from Solanum torvum leaves that specifically catalyzed hydrolysis of two furostanol 26-O-β-glucosides, torvosides A and H. Furostanol glycoside 26-O-β-glucosides have been reported as natural substrates of some plant GH1 enzymes. However, torvosidase was classified as a GH3 β-glucosidase, but could not hydrolyze β-oligoglucosides, the natural substrates of GH3 enzymes. Here, the full-length cDNA encoding S. torvum β-glucosidase (SBgl3) was isolated by the rapid amplification of cDNA ends method. The 1887bp ORF encoded 629 amino acids and showed high homology to other plant GH3 β-glucosidases. Internal peptide sequences of purified native Sbgl3 determined by LC-MS/MS matched the deduced amino acid sequence of the Sbgl3 cDNA, suggesting that it encoded the natural enzyme. Recombinant SBgl3 with a polyhistidine tag (SBgl3His) was successfully expressed in Pichia pastoris. The purified SBgl3His showed the same substrate specificity as natural SBgl3, hydrolyzing torvoside A with much higher catalytic efficiency than other substrates. It also had similar biochemical properties and kinetic parameters to the natural enzyme, with slight differences, possibly attributable to post-translational glycosylation. Quantitative real-time PCR (qRT-PCR) showed that SBgl3 was highly expressed in leaves and germinated seeds, suggesting a role in leaf and seedling development. To our knowledge, a recombinant GH3 β-glucosidase that hydrolyzes furostanol 26-O-β-glucosides, has not been previously reported in contrast to substrates of GH1 enzymes. PMID:27055587

  20. Cloning and biochemical characterization of indole-3-acetic acid-amino acid synthetase PsGH3 from pea.

    PubMed

    Ostrowski, Maciej; Mierek-Adamska, Agnieszka; Porowińska, Dorota; Goc, Anna; Jakubowska, Anna

    2016-10-01

    Phytohormone conjugation is one of the mechanisms that maintains a proper hormonal homeostasis and that is necessary for the realization of physiological responses. Gretchen Hagen 3 (GH3) acyl acid amido synthetases convert indole-3-acetic acid (IAA) to IAA-amino acid conjugates by ATP-dependent reactions. IAA-aspartate (IAA-Asp) exists as a predominant amide conjugate of auxin in pea tissues and acts as an intermediate during IAA catabolism. Here we report a novel recombinant indole-3-acetic acid-amido synthetase in Pisum sativum. In silico analysis shows that amino acid sequence of PsGH3 has the highest homology to Medicago truncatula GH3.3. The recombinant His-tag-PsGH3 fusion protein has been obtained in E. coli cells and is a soluble monomeric polypeptide with molecular mass of 69.18 kDa. The PsGH3 was purified using Ni(2+)-affinity chromatography and native PAGE. Kinetic analysis indicates that the enzyme strongly prefers IAA and L-aspartate as substrates for conjugation revealing Km(ATP) = 0.49 mM, Km(L-Asp) = 2.2 mM, and Km(IAA) = 0.28 mM. Diadenosine pentaphosphate (Ap5A) competes with ATP for catalytic site and diminishes the PsGH3 affinity toward ATP approximately 1.11-fold indicating Ki = 8.5 μM. L-Tryptophan acts as an inhibitor of IAA-amido synthesizing activity by competition with L-aspartate. Inorganic pyrophosphatase (PPase) hydrolyzing pyrophosphate to two phosphate ions, potentiates IAA-Asp synthetase activity of PsGH3. Our results demonstrate that PsGH3 is a novel enzyme that is involved in auxin metabolism in pea seeds. PMID:27235647

  1. The GH-IGF-SST system in hepatocellular carcinoma: biological and molecular pathogenetic mechanisms and therapeutic targets

    PubMed Central

    2014-01-01

    Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide. Different signalling pathways have been identified to be implicated in the pathogenesis of HCC; among these, GH, IGF and somatostatin (SST) pathways have emerged as some of the major pathways implicated in the development of HCC. Physiologically, GH-IGF-SST system plays a crucial role in liver growth and development since GH induces IGF1 and IGF2 secretion and the expression of their receptors, involved in hepatocytes cell proliferation, differentiation and metabolism. On the other hand, somatostatin receptors (SSTRs) are exclusively present on the biliary tract. Importantly, the GH-IGF-SST system components have been indicated as regulators of hepatocarcinogenesis. Reduction of GH binding affinity to GH receptor, decreased serum IGF1 and increased serum IGF2 production, overexpression of IGF1 receptor, loss of function of IGF2 receptor and appearance of SSTRs are frequently observed in human HCC. In particular, recently, many studies have evaluated the correlation between increased levels of IGF1 receptors and liver diseases and the oncogenic role of IGF2 and its involvement in angiogenesis, migration and, consequently, in tumour progression. SST directly or indirectly influences tumour growth and development through the inhibition of cell proliferation and secretion and induction of apoptosis, even though SST role in hepatocarcinogenesis is still opened to argument. This review addresses the present evidences suggesting a role of the GH-IGF-SST system in the development and progression of HCC, and describes the therapeutic perspectives, based on the targeting of GH-IGF-SST system, which have been hypothesised and experimented in HCC. PMID:25225571

  2. Environmental Stresses of Field Growth Allow Cinnamyl Alcohol Dehydrogenase-Deficient Nicotiana attenuata Plants to Compensate for their Structural Deficiencies1[C][W][OA

    PubMed Central

    Kaur, Harleen; Shaker, Kamel; Heinzel, Nicolas; Ralph, John; Gális, Ivan; Baldwin, Ian T.

    2012-01-01

    The organized lignocellulosic assemblies of cell walls provide the structural integrity required for the large statures of terrestrial plants. Silencing two CINNAMYL ALCOHOL DEHYDROGENASE (CAD) genes in Nicotiana attenuata produced plants (ir-CAD) with thin, red-pigmented stems, low CAD and sinapyl alcohol dehydrogenase activity, low lignin contents, and rubbery, structurally unstable stems when grown in the glasshouse (GH). However, when planted into their native desert habitat, ir-CAD plants produced robust stems that survived wind storms as well as the wild-type plants. Despite efficient silencing of NaCAD transcripts and enzymatic activity, field-grown ir-CAD plants had delayed and restricted spread of red stem pigmentation, a color change reflecting blocked lignification by CAD silencing, and attained wild-type-comparable total lignin contents. The rubbery GH phenotype was largely restored when field-grown ir-CAD plants were protected from wind, herbivore attack, and ultraviolet B exposure and grown in restricted rooting volumes; conversely, it was lost when ir-CAD plants were experimentally exposed to wind, ultraviolet B, and grown in large pots in growth chambers. Transcript and liquid chromatography-electrospray ionization-time-of-flight analysis revealed that these environmental stresses enhanced the accumulation of various phenylpropanoids in stems of field-grown plants; gas chromatography-mass spectrometry and nuclear magnetic resonance analysis revealed that the lignin of field-grown ir-CAD plants had GH-grown comparable levels of sinapaldehyde and syringaldehyde cross-linked into their lignins. Additionally, field-grown ir-CAD plants had short, thick stems with normal xylem element traits, which collectively enabled field-grown ir-CAD plants to compensate for the structural deficiencies associated with CAD silencing. Environmental stresses play an essential role in regulating lignin biosynthesis in lignin-deficient plants. PMID:22645069

  3. Growth hormone deficiency and antipituitary antibodies in a patient with common variable immunodeficiency.

    PubMed

    Delvecchio, M; De Bellis, A; De Mattia, D; Cavallo, L; Martire, B

    2009-09-01

    Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and T-lymphocytes dysfunction. Autoimmune diseases are frequent. A 10.7-yr-old female, diagnosed with CVID when 7 yr old, was referred because of short stature. She was pre-pubertal and short (height -2.86 SD score) with delayed bone age. Her intestinal absorption, routine biochemistry, heart, renal, liver, and thyroid functions were normal. Two stimulation tests for GH showed a maximum peak of 1.9 ng/ml (IGF-1: 154 ng/ml, 147-832). When the patient was 13 yr old (height -4.23 SD score, telarche and pubarche stage 2, bone age 6.25 yr), GH treatment was initiated. Despite poor compliance, the growth velocity showed improvement. Anti-thyrogobulin, anti-thyroperoxidase, anti-21-hydroxylase, and anti-tyrosine-phosphate antibodies were negative while anti- pituitary antibodies (APA) were positive. For the first time, the presence of APA (previously associated with GH deficiency in non-CVID subjects) is reported in a CVID patient. The possibility of an autoimmune involvement of the pituitary gland was previously debated for CVID patients, but had never been demonstrated. This case suggests that in CVID, the pituitary gland can be targeted by autoantibodies and thus a more comprehensive follow-up of these patients should be performed. PMID:19509479

  4. Regulation of skeletal growth and mineral acquisition by the GH/IGF-1 axis: Lessons from mouse models.

    PubMed

    Yakar, Shoshana; Isaksson, Olle

    2016-06-01

    The growth hormone (GH) and its downstream mediator, the insulin-like growth factor-1 (IGF-1), construct a pleotropic axis affecting growth, metabolism, and organ function. Serum levels of GH/IGF-1 rise during pubertal growth and associate with peak bone acquisition, while during aging their levels decline and associate with bone loss. The GH/IGF-1 axis was extensively studied in numerous biological systems including rodent models and cell cultures. Both hormones act in an endocrine and autocrine/paracrine fashion and understanding their distinct and overlapping contributions to skeletal acquisition is still a matter of debate. GH and IGF-1 exert their effects on osteogenic cells via binding to their cognate receptor, leading to activation of an array of genes that mediate cellular differentiation and function. Both hormones interact with other skeletal regulators, such as sex-steroids, thyroid hormone, and parathyroid hormone, to facilitate skeletal growth and metabolism. In this review we summarized several rodent models of the GH/IGF-1 axis and described key experiments that shed new light on the regulation of skeletal growth by the GH/IGF-1 axis. PMID:26432542

  5. Cloning and characterization of a novel Gladiolus hybridus AFP family gene (GhAFP-like) related to corm dormancy.

    PubMed

    Wu, Jian; Seng, Shanshan; Carianopol, Carina; Sui, Juanjuan; Yang, Qiuyan; Zhang, Fengqin; Jiang, Huiru; He, Junna; Yi, Mingfang

    2016-02-26

    Abscisic acid (ABA) is an important phytohormone controlling seed dormancy. AFPs (ABA INSENSITIVE FIVE BINDING PROTEINS) are reported to be negative regulators of the ABA signaling pathway. The involvement of AFPs in dormant vegetative organs remains poorly understood. Here, we isolated and characterized a novel AFP family member from Gladiolus dormant cormels, GhAFP-like, containing three conserved domains of the AFP family. Quantitative PCR analysis revealed that GhAFP-like was expressed in dormant organs and its expression was down-regulated along with corm storage. GhAFP-like was verified to be a nuclear-localized protein. Overexpressing GhAFP-like in Arabidopsis thaliana not only showed weaker seed dormancy with insensitivity to ABA, but also changed the expression of some ABA related genes. In addition, a primary root elongation assay showed GhAFP-like may involve in auxin signaling response. The results in this study indicate that GhAFP-like acts as a negative regulator in ABA signaling and is related to dormancy. PMID:26826388

  6. Distribution and linkage disequilibrium analysis of polymorphisms of GH1 gene in different populations of pigs associated with body size.

    PubMed

    Cheng, Yunyun; Liu, Songcai; Su, Dan; Lu, Chao; Zhang, Xin; Wu, Qingyan; Li, Siming; Fu, Haoyu; Yu, Hao; Hao, Linlin

    2016-03-01

    Growth hormone (GH) has been considered as a candidate gene for growth and body size in pigs. In this study, polymorphisms of the GH1 gene were evaluated for associations with body size traits in 190 pig individuals. Seventeen single-nucleotide polymorphisms (SNPs) were identified in GH1 gene of the large pig breeds and miniature pig breeds using direct sequencing and genotyped by allele-specific PCR approach. Notably, six (g.237A>G, g.283T>C, g.309A>G, g.318A>G, g.540A>G and g.544A>G) of them were significantly associated with body size, of which three loci (g.283T>C, g.309A>G, g.318A>G) located in the signal-peptide coding region of GH1 gene compose a CGG haplotype for large pigs and TAA haplotype for miniature pigs (P <0.001), two loci (g.540A>G and g.544A>G) located in the second intron of GH1 gene compose a GG haplotype for large pigs and AA haplotype for miniature pigs (P < 0.001). Our results demonstrate that these SNPs in GH1 gene are associated with the body size of pigs providing genetic basis for pig breeding with the improved economic benefits. PMID:27019435

  7. Small interfering RNAs from bidirectional transcripts of GhMML3_A12 regulate cotton fiber development.

    PubMed

    Wan, Qun; Guan, Xueying; Yang, Nannan; Wu, Huaitong; Pan, Mengqiao; Liu, Bingliang; Fang, Lei; Yang, Shouping; Hu, Yan; Ye, Wenxue; Zhang, Hua; Ma, Peiyong; Chen, Jiedan; Wang, Qiong; Mei, Gaofu; Cai, Caiping; Yang, Donglei; Wang, Jiawei; Guo, Wangzhen; Zhang, Wenhua; Chen, Xiaoya; Zhang, Tianzhen

    2016-06-01

    Natural antisense transcripts (NATs) are commonly observed in eukaryotic genomes, but only a limited number of such genes have been identified as being involved in gene regulation in plants. In this research, we investigated the function of small RNA derived from a NAT in fiber cell development. Using a map-based cloning strategy for the first time in tetraploid cotton, we cloned a naked seed mutant gene (N1 ) encoding a MYBMIXTA-like transcription factor 3 (MML3)/GhMYB25-like in chromosome A12, GhMML3_A12, that is associated with fuzz fiber development. The extremely low expression of GhMML3_A12 in N1 is associated with NAT production, driven by its 3' antisense promoter, as indicated by the promoter-driven histochemical staining assay. In addition, small RNA deep sequencing analysis suggested that the bidirectional transcriptions of GhMML3_A12 form double-stranded RNAs and generate 21-22 nt small RNAs. Therefore, in a fiber-specific manner, small RNA derived from the GhMML3_A12 locus can mediate GhMML3_A12 mRNA self-cleavage and result in the production of naked seeds followed by lint fiber inhibition in N1 plants. The present research reports the first observation of gene-mediated NATs and siRNA directly controlling fiber development in cotton. PMID:26832840

  8. VERMILION-DEFICIENCY.

    PubMed

    Bridges, C B

    1919-07-20

    In May, 1916, a culture of Drosophila melanogaster showed that a new sex-linked lethal had arisen. The linkage relations indicated that the position of the lethal was in the neighborhood of the sex-linked recessive "vermilion," whose locus in the X chromosome is at 33.0. When females heterozygous for the lethal were outcrossed to vermilion males, all the daughters that received the lethal-bearing chromosome showed vermilion eye-color, though, from the pedigree, vermilion was known to be absent from the ancestry of the mother. The lethal action and the unexpected appearance of vermilion both suggested that this was another instance of the phenomenon called "deficiency;" that is, the loss or "inactivation" of the genes of a section of the X chromosome. The lethal action would then be due to the deficient region including one or more genes necessary for the life of the individual. The appearance of vermilion in females carrying only one vermilion gene would be explainable on the ground that the deficient-bearing females are virtually haploid for the region including the vermilion locus. Linkage tests showed that the amount of crossing over in the neighborhood of the deficiency was cut down by about five units. Part of this may be attributed to the actual length of the "deficient" region, within which it is probable that no crossing over occurs, and part (probably most) to an alteration in the synaptic relations in the regions immediately adjacent. In more remote regions there was no disturbance or perhaps a slight rise in the frequency of crossing over. Both the local fall and the possible rise in more distant regions would seem to argue that a "pucker" at synapsis had been caused by an actual shortening of the deficient chromosome. That the deficient region extends to the left of the locus of vermilion was indicated by a test in which it was observed that the presence of an extra piece of chromosome including the loci for vermilion and sable ("vermilion

  9. Iron deficiency in Europe.

    PubMed

    Hercberg, S; Preziosi, P; Galan, P

    2001-04-01

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

  10. Role of the GH/IGF-1 axis in lifespan and healthspan: lessons from animal models

    PubMed Central

    Berryman, Darlene E.; Christiansen, Jens Sandahl; Johannsson, Gudmundur; Thorner, Michael O.

    2009-01-01

    Animal models are fundamentally important in our quest to understand the genetic, epigenetic, and environmental factors that contribute to human aging. In comparison to humans, relatively short-lived mammals are useful models as they allow for rapid assessment of both genetic manipulation and environmental intervention as related to longevity. These models also allow for the study of clinically relevant pathologies as a function of aging. Data associated with more distant species offers additional insight and critical consideration of the basic physiological processes and molecular mechanisms that influence lifespan. Consistently, two interventions, caloric restriction and repression of the growth hormone (GH)/insulin like growth factor-1/insulin axis, have been shown to increase lifespan in both invertebrates and vertebrate animal model systems. Caloric restriction (CR) is a nutrition intervention that robustly extends lifespan whether it is started early or later in life. Likewise, genes involved in the GH/IGF-1 signaling pathways can lengthen lifespan in vertebrates and invertebrates, implying evolutionary conservation of the molecular mechanisms. Specifically, insulin and insulin-like growth factor 1 (IGF-1)-like signaling and its downstream intracellular signaling molecules have been shown to be associated with lifespan in fruit flies and nematodes. More recently, mammalian models with reduced growth hormone (GH) and/or IGF-1 signaling have also been shown to have extended lifespans as compared to control siblings. Importantly, this research has also shown that these genetic alterations can keep the animals healthy and disease-free for longer periods and can alleviate specific age-related pathologies similar to what is observed for CR individuals. Thus, these mutations may not only extend lifespan but may also improve healthspan, the general health and quality of life of an organism as it ages. In this review, we will provide an overview of how the

  11. Dual Regulation Role of GH3.5 in Salicylic Acid and Auxin Signaling during Arabidopsis-Pseudomonas syringae Interaction1[W][OA

    PubMed Central

    Zhang, Zhongqin; Li, Qun; Li, Zhimiao; Staswick, Paul E.; Wang, Muyang; Zhu, Ying; He, Zuhua

    2007-01-01

    Salicylic acid (SA) plays a central role in plant disease resistance, and emerging evidence indicates that auxin, an essential plant hormone in regulating plant growth and development, is involved in plant disease susceptibility. GH3.5, a member of the GH3 family of early auxin-responsive genes in Arabidopsis (Arabidopsis thaliana), encodes a protein possessing in vitro adenylation activity on both indole-3-acetic acid (IAA) and SA. Here, we show that GH3.5 acts as a bifunctional modulator in both SA and auxin signaling during pathogen infection. Overexpression of the GH3.5 gene in an activation-tagged mutant gh3.5-1D led to elevated accumulation of SA and increased expression of PR-1 in local and systemic tissues in response to avirulent pathogens. In contrast, two T-DNA insertional mutations of GH3.5 partially compromised the systemic acquired resistance associated with diminished PR-1 expression in systemic tissues. The gh3.5-1D mutant also accumulated high levels of free IAA after pathogen infection and impaired different resistance-gene-mediated resistance, which was also observed in the GH3.6 activation-tagged mutant dfl1-D that impacted the auxin pathway, indicating an important role of GH3.5/GH3.6 in disease susceptibility. Furthermore, microarray analysis showed that the SA and auxin pathways were simultaneously augmented in gh3.5-1D after infection with an avirulent pathogen. The SA pathway was amplified by GH3.5 through inducing SA-responsive genes and basal defense components, whereas the auxin pathway was derepressed through up-regulating IAA biosynthesis and down-regulating auxin repressor genes. Taken together, our data reveal novel regulatory functions of GH3.5 in the plant-pathogen interaction. PMID:17704230

  12. A new animal model for evaluation of long-term growth rate over one month by rhGH/PLGA microcapsule formulations.

    PubMed

    Takada, Shigeyuki; Kurokawa, Tomofumi; Misaki, Masafumi; Taira, Keiko; Yamagata, Yutaka

    2003-07-01

    A new animal model to evaluate the long-term growth rate produced by a sustained-release formulation of recombinant human growth hormone (rhGH) over one month was developed and the usefulness of our microcapsule formulations was demonstrated in this model. Long-term pharmacological effects by subcutaneous injection of microcapsules for sustained release of rhGH were evaluated in hypophysectomized (Hpx) rats treated with immunosuppressive agent along with hormone supplement. Copoly(DL-lactic/glycolic)acid (PLGA) microcapsules for sustained release of rhGH, a two-week sustained-release formulation (rhGH-SR-2W) and a one-month sustained-release formulation (rhGH-SR-1M), were prepared by a solid-in-oil-in-water emulsion solvent evaporation technique. Body-weight gain, body-length gain and serum levels of rat insulin-like growth factor-I (rIGF-I) induced by subcutaneous injection of rhGH-SR were compared with those by daily injections of rhGH solution in Hpx rats for 35 days. Serum IGF-I levels in Hpx rats after the injection of rhGH-SR2W microcapsules were higher than those after daily injections of rhGH solution. Body-length gain, a new parameter, after single injection of rhGH-SR-1M microcapsules demonstrated the higher growth rate than that after daily injections of rhGH solution for 35 days. Thus, single injection of rhGH-SR microcapsules demonstrated long-term pharmacological effects greater than those by daily injections of rhGH solution in a newly developed model, immunosuppressed Hpx rats. PMID:12906752

  13. Growth hormone deficiency predicts cardiovascular risk in young adults treated for acute lymphoblastic leukemia in childhood.

    PubMed

    Link, Katarina; Moëll, Christian; Garwicz, Stanislaw; Cavallin-Ståhl, Eva; Björk, Jonas; Thilén, Ulf; Ahrén, Bo; Erfurth, Eva Marie

    2004-10-01

    Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, and until recently prophylactic cranial radiotherapy (CRT) was important for achieving long-term survival. Hypothalamic-pituitary hormone insufficiency is a well-recognized consequence of CRT for childhood cancer. Another problem is increased cardiovascular risk, which has been shown in long-term survivors of other childhood cancers. In the only previously reported study on cardiovascular risk after childhood ALL, obesity and dyslipidemia were recorded in a small subgroup treated with CRT, compared with patients treated with chemotherapy. The mechanisms behind the increase in cardiovascular risk in survivors of childhood cancer are not clarified. The aim of the present study was to elucidate mechanisms of increased cardiovascular risk in former childhood ALL patients. A group of 44 ALL survivors (23 males, median age 25 yr, range 19-32 yr at the time of study) treated with CRT (median 24 Gy, 18-30 Gy) at a median age of 5 yr (1-18 yr) and chemotherapy were investigated for prevalence of GH deficiency and cardiovascular risk factors. Comparison was made with controls randomly selected from the general population and individually matched for sex, age, smoking habits, and residence. All patients and controls underwent a GHRH-arginine test, and patients with a peak GH 3.9 microg/liter or greater were further investigated with an additional insulin tolerance test. Significantly higher plasma levels of insulin (P = 0.002), blood glucose (P = 0.01), and serum levels of low-density lipoprotein cholesterol, apolipoprotein (Apo) B, triglycerides, fibrinogen, and leptin (all P

  14. Iron deficiency anaemia.

    PubMed

    Lopez, Anthony; Cacoub, Patrice; Macdougall, Iain C; Peyrin-Biroulet, Laurent

    2016-02-27

    Anaemia affects roughly a third of the world's population; half the cases are due to iron deficiency. It is a major and global public health problem that affects maternal and child mortality, physical performance, and referral to health-care professionals. Children aged 0-5 years, women of childbearing age, and pregnant women are particularly at risk. Several chronic diseases are frequently associated with iron deficiency anaemia--notably chronic kidney disease, chronic heart failure, cancer, and inflammatory bowel disease. Measurement of serum ferritin, transferrin saturation, serum soluble transferrin receptors, and the serum soluble transferrin receptors-ferritin index are more accurate than classic red cell indices in the diagnosis of iron deficiency anaemia. In addition to the search for and treatment of the cause of iron deficiency, treatment strategies encompass prevention, including food fortification and iron supplementation. Oral iron is usually recommended as first-line therapy, but the most recent intravenous iron formulations, which have been available for nearly a decade, seem to replenish iron stores safely and effectively. Hepcidin has a key role in iron homoeostasis and could be a future diagnostic and therapeutic target. In this Seminar, we discuss the clinical presentation, epidemiology, pathophysiology, diagnosis, and acute management of iron deficiency anaemia, and outstanding research questions for treatment. PMID:26314490

  15. Nonparallel changes of growth hormone (GH) and insulin-like growth factor-I, insulin-like growth factor binding protein-3, and GH-binding protein, after craniospinal irradiation and chemotherapy

    SciTech Connect

    Nivot, S.; Adan, L.; Souberbielle, J.; Rappaport, R.; Brauner, R.; Benelli, C.; Clot, J.P.; Saucet, C.; Zucker, J.M.

    1994-03-01

    The authors studied the GH-insulin-like growth factor-I (IGF-I) axis serially over 24-36 months in six patients with medulloblastoma who underwent surgical removal of the tumor followed by craniospinal irradiation therapy for 6 weeks and then chemotherapy for 42 weeks. Eighteen and 24 months after beginning irradiation there was a decline in the peak GH secretory response to acute stimulation with arginine/insulin hypoglycemia. Six months after irradiation and during chemotherapy there was a transient decline in IGF-I, IGF binding protein-3 (IGFBP-3), and GH-BP values (respective mean values of 56.1 {+-} 9.0 ng/mL, 1.1 {+-} 0.2 {mu}g/mL, and 7.6 {+-} 3.3% of radioactivity as compared to time 0 values: 139 {+-} 15 ng/mL, 2.2 {+-} 0.2 {mu}g/mL, and 20.0 {+-} 4.0%, P < 0.001), although provoked GH secretion was normal at this time. The IGF-I, IGFBP-3, and GH-BP returned to pretreatment ranges by 12-36 months after initiation of the study. There was also a decline in body mass index and serum protein values at 6 months after irradiation in ligand and immunoblot analysis there was a decline in IGFBP-3 and an abnormal electrophoretic mobility of IGFBP-2 that were both normalized at 36 months. In one patient they observed a high level of IGFBP-3 proteolysis at this time. This study demonstrates that before the decrease of GH secretion in patients receiving cranial irradiation there is a transient phase of GH insensitivity that may be characteristic of the acute therapeutic phase including the chemotherapy. This partial insensitivity may explain the early growth retardation observed in these patients. 28 refs., 4 figs., 1 tab.

  16. ANO10 mutations cause ataxia and coenzyme Q₁₀ deficiency.

    PubMed

    Balreira, Andrea; Boczonadi, Veronika; Barca, Emanuele; Pyle, Angela; Bansagi, Boglarka; Appleton, Marie; Graham, Claire; Hargreaves, Iain P; Rasic, Vedrana Milic; Lochmüller, Hanns; Griffin, Helen; Taylor, Robert W; Naini, Ali; Chinnery, Patrick F; Hirano, Michio; Quinzii, Catarina M; Horvath, Rita

    2014-11-01

    Inherited ataxias are heterogeneous disorders affecting both children and adults, with over 40 different causative genes, making molecular genetic diagnosis challenging. Although recent advances in next-generation sequencing have significantly improved mutation detection, few treatments exist for patients with inherited ataxia. In two patients with adult-onset cerebellar ataxia and coenzyme Q10 (CoQ10) deficiency in muscle, whole exome sequencing revealed mutations in ANO10, which encodes anoctamin 10, a member of a family of putative calcium-activated chloride channels, and the causative gene for autosomal recessive spinocerebellar ataxia-10 (SCAR10). Both patients presented with slowly progressive ataxia and dysarthria leading to severe disability in the sixth decade. Epilepsy and learning difficulties were also present in one patient, while retinal degeneration and cataract were present in the other. The detection of mutations in ANO10 in our patients indicate that ANO10 defects cause secondary low CoQ10 and SCAR10 patients may benefit from CoQ10 supplementation. PMID:25182700

  17. Prospective study of the development of growth hormone deficiency in children given cranial irradiation, and its relation to statural growth

    SciTech Connect

    Brauner, R.; Rappaport, R.; Prevot, C.; Czernichow, P.; Zucker, J.M.; Bataini, P.; Lemerle, J.; Sarrazin, D.; Guyda, H.J.

    1989-02-01

    Although GH deficiency (GHD) is the most frequent hormonal abnormality that occurs after cranial radiation, the natural course of this complication and its relationship to growth in children are not known. Therefore, we undertook a 2-yr prospective study of 16 children, aged 1.7-15 yr at the time of treatment, who received cranial (31-42 Gy (1 Gy = 100 rads)) and spinal radiation for medulloblastoma or ependymoma (group I). Their growth was compared to that of 11 children given similar doses of cranial radiation only (group II). The mean plasma GH response to arginine-insulin test (AITT) was 9.1 +/- 1.5 (+/- SE) micrograms/L in group I and 8.5 +/- 1.8 micrograms/L in group II (P = NS). After 2 yr, 16 of the 27 children had a peak plasma GH value below 8 micrograms/L after AITT, and 10 children had a peak response less than 5 micrograms/L. In addition, in group I, AITT and sleep-related GH secretion were compared; at the 2 yr follow-up only 3 of 13 children had discrepant results. At the 2 yr follow-up children treated by cranial and spinal radiation had a mean height of -1.46 +/- 0.40 SD below the normal mean. In contrast, the children given only cranial radiation had a mean height of -0.15 +/- 0.18 SD; P less than 0.02. Therefore, most of the growth retardation appeared to be due to lack of spinal growth. GHD is thus an early complication of cranial radiation in these children, and no significant growth retardation can be attributed to GHD during the first 2 yr. These data contribute to the organization of follow-up in irradiated children in order to decide when human GH treatment is necessary.

  18. Antepartum ornithine transcarbamylase deficiency.

    PubMed

    Nakajima, Hitoshi; Sasaki, Yosuke; Maeda, Tadashi; Takeda, Masako; Hara, Noriko; Nakanishi, Kazushige; Urita, Yoshihisa; Hattori, Risa; Miura, Ken; Taniguchi, Tomoko

    2014-01-01

    Ornithine transcarbamylase deficiency (OTCD) is the most common type urea cycle enzyme deficiencies. This syndrome results from a deficiency of the mitochondrial enzyme ornithine transcarbamylase, which catalyzes the conversion of ornithine and carbamoyl phosphate to citrullin. Our case was a 28-year-old female diagnosed with OTCD following neurocognitive deficit during her first pregnancy. Although hyperammonemia was suspected as the cause of the patient's mental changes, there was no evidence of chronic liver disease. Plasma amino acid and urine organic acid analysis revealed OTCD. After combined modality treatment with arginine, sodium benzoate and hemodialysis, the patient's plasma ammonia level stabilized and her mental status returned to normal. At last she recovered without any damage left. PMID:25759629

  19. Transient neonatal zinc deficiency.

    PubMed

    Krieger, I; Alpern, B E; Cunnane, S C

    1986-06-01

    We report an infant who developed clinical manifestations of zinc deficiency during the first month of life although the diet was adequate for zinc and no other causes could be ascertained. The diagnosis was confirmed by low plasma-zinc concentrations and a positive response to zinc treatment. The fatty acid profile of plasma phospholipids was typical of zinc deficiency (ie, arachidonic acid was markedly decreased). The transient nature of this disorder was evident when no relapse occurred