Background Development of pre-transplantation islet culture strategies that preserve or enhance β-cell viability would eliminate the requirement for the large numbers of islets needed to restore insulin independence in type 1 diabetes patients. We investigated whether glial cell line-derived neurotrophic factor (GDNF) could improve human islet survival and post-transplantation function in diabetic mice. Methods Human islets were cultured in medium supplemented with or without GDNF (100 ng/ml) and in vitro islet survival and function assessed by analyzing β-cell apoptosis and glucose stimulated insulin release. In vivo effects of GDNF were assessed in streptozotocin-induced diabetic nude mice transplanted under the kidney capsule with 2000 islet equivalents of human islets pre-cultured in medium supplemented with or without GDNF. Results In vitro, human islets cultured for 2–10 days in medium supplemented with GDNF showed lower β-cell death, increased Akt phosphorylation and higher glucose-induced insulin secretion than islets cultured in vehicle. Human islets pre-cultured in medium supplemented with GDNF restored more diabetic mice to normoglycemia and for a longer period after transplantation than islets cultured in vehicle. Conclusions Our study shows that GDNF has beneficial effects on human islet survival and could be used to improve islet post-transplantation survival.

Glial cell line-derived neurotrophic factor (GDNF) is a factor produced by glial cells that is required for the development of the enteric nervous system. In transgenic mice that overexpress GDNF in the pancreas, GDNF has been shown to enhance beta-cell mass and improve glucose control, but the transcriptional and cellular processes involved are not known. In this study we examined the influence of GDNF on the expression of neurogenin3 (Ngn3) and other transcription factors implicated in early beta-cell development, as well as on beta-cell proliferation during embryonic and early postnatal mouse pancreas development. Embryonic day 15.5 (E15.5) mouse pancreatic tissue when exposed to GDNF for 24 h showed higher Ngn3, pancreatic and duodenal homeobox gene 1 (Pdx1), neuroD1/beta(2), paired homeobox gene 4 (Pax4), and insulin mRNA expression than tissue exposed to vehicle only. Transgenic expression of GDNF in mouse pancreata was associated with increased numbers of Ngn3-expressing pancreatic cells and higher beta-cell mass at embryonic day 18 (E18), as well as higher beta-cell proliferation and Pdx1 expression in beta-cells at E18 and postnatal day 1. In the HIT-T15 beta-cell line, GDNF enhanced the expression of Pax6. This response was, however, blocked in the presence of Pdx1 small interfering RNA (siRNA). Chromatin immunoprecipitation studies using the HIT-T15 beta-cell line demonstrated that GDNF can influence Pdx1 gene expression by enhancing the binding of Sox9 and neuroD1/beta(2) to the Pdx1 promoter. Our data provide evidence of a mechanism by which GDNF influences beta-cell development. GDNF could be a potential therapeutic target for the treatment and prevention of diabetes.

The development of the pituitary gland is not well understood, but duplication of the gland, a rare embryonic anomaly, may shed some light on the process. Since 1880 only about 40 cases have been described. A 56-year-old woman complained of chronic bilateral upper extremity paresthesia and numbness along her first three fingers relieved by rest and exacerbated by increased activity. Magnetic resonance imaging of her head and neck showed an incidental discovery of a duplication of the pituitary infundibulum and pituitary fossa. Computed tomography of the neck showed congenital fusion of C2 with C3, C4 with C5, C1 with the occipital bone, and a duplication of the odontoid process. Her physical examination and all laboratory data were negative. Only seven patients with a pituitary duplication have ever survived beyond puberty. While all of these patients had normal mental capabilities, they also all had obvious craniofacial malformations. Unlike our patient, all other reported cases of duplicated pituitaries have been associated with abnormalities of the face or brain. Previously proposed theories for duplicated pituitary glands include failed twinning, teratogens, and an extreme form of the median cleft face syndrome. We feel that the cleft theory developed by Morton et al. best describes the cause of our patient's malformations. Such anomalous presentations will improve our understanding of how the pituitary gland develops and the order in which cranial structures develop to cause these cranial malformations.

Introduction:Hyperthyroidism is a known cause of nonspecific abnormalities in liver biochemitries; most commonly mild elevations in serum bilirubin and liver enzymes. Case Report: A case of severe cholestatic jaundice secondary to Grave's disease. The patient is a 28yearoldAfricanAmerican male who presented to the emergency room with chronic diarrhea, weight loss and jaundice. At presentation, his liver enzymes were elevated in a cholestatic pattern and his bilirubin was 21.4 mg/dL. Upon treatment with propranolol and propylthouracil, his diarrhea, pruritus, jaundice, and liver enzymes quickly improved. His bilirubin returned to normal over a period of two months. Conclusion: While severe intrahepatic cholestasis and jaundice due to hyperthyroidism is rare, the diagnosis should be considered in patients presenting with manifestations of liver disease, as appropriate treatment of hyperthyroidism results in resolution of jaundice.

We present a 24-year-old combat veteran who underwent extensive work-up for elevated aminotransferases, including liver biopsy, with no underlying pathology identified. Subsequent investigations showed elevated creatinine kinase and aldolase. The patient was later diagnosed with biopsy-proven dysferlin-deficient muscular dystrophy. Persistent transaminase elevation despite negative liver work-up should prompt clinicians to consider extrahepatic sources of enzyme elevation. Promptly correlating aminotransferase elevation with musculoskeletal pathology may present an opportunity for clinicians to detect myopathies such as muscular dystrophy in their preclinical stages.