Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocin-induced diabetic rats.

Recent studies into the physiology of the incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have added stimulation of beta-cell growth, differentiation, and cell survival to well-documented, potent insulinotropic effects. Unfortunately, the therapeutic potential of these hormones is limited by their rapid enzymatic inactivation in vivo by dipeptidyl peptidase IV (DP IV). Inhibition of DP IV, so as to enhance circulating incretin levels, has proved effective in the treatment of type 2 diabetes both in humans and in animal models, stimulating improvements in glucose tolerance, insulin sensitivity, and beta-cell function. We hypothesized that enhancement of the cytoprotective and beta-cell regenerative effects of GIP and GLP-1 might extend the therapeutic potential of DP IV inhibitors to include type 1 diabetes. For testing this hypothesis, male Wistar rats, exposed to a single dose of streptozotocin (STZ; 50 mg/kg), were treated twice daily with the DP IV inhibitor P32/98 for 7 weeks. Relative to STZ-injected controls, P32/98-treated animals displayed increased weight gain (230%) and nutrient intake, decreased fed blood glucose ( approximately 26 vs. approximately 20 mmol/l, respectively), and a return of plasma insulin values toward normal (0.07 vs. 0.12 nmol/l, respectively). Marked improvements in oral glucose tolerance, suggesting enhanced insulin secretory capacity, were corroborated by pancreas perfusion and insulin content measurements that revealed two- to eightfold increases in both secretory function and insulin content after 7 weeks of treatment. Immunohistochemical analyses of pancreatic sections showed marked increases in the number of small islets (+35%) and total beta-cells (+120%) and in the islet beta-cell fraction (12% control vs. 24% treated) in the treated animals, suggesting that DP IV inhibitor treatment enhanced islet neogenesis, beta-cell survival, and insulin biosynthesis. In vitro studies using a beta-(INS-1) cell line showed a dose-dependent prevention of STZ-induced apoptotic cell-death by both GIP and GLP-1, supporting a role for the incretins in eliciting the in vivo results. These novel findings provide evidence to support the potential utility of DP IV inhibitors in the treatment of type 1 and possibly late-stage type 2 diabetes.

Congenital myopathy with cap-like structures and nemaline rods: case report and literature review.

BACKGROUND: Cap myopathy is a rare congenital myopathy characterized by cap structures located at the periphery of the muscle fiber. Cap structures consist of disarranged thin filaments with enlarged Z discs. The clinical presentation and natural history of cap myopathy is variable and overlaps with other congenital myopathies. METHODS: We describe a 10-year-old boy with cap myopathy and contrast him with 20 other individuals reported in the literature. RESULTS: Our patient presented at birth with hypotonia and weakness and subsequently developed respiratory failure in infancy. He is ambulatory but has increasing fatigue and requires a wheelchair by midafternoon. His muscle biopsy at 3 months revealed a nemaline myopathy and secondary fiber-type disproportion with type 1 hypotrophy and predominance. A repeat muscle biopsy at age 6 years revealed numerous peripherally located cap-like structures containing nemaline rods and exhibited a spectrum of Z-disk and myofibrillar abnormalities. Molecular genetic testing was performed for NEB, TPM2, TPM3, ACTA1, TNNT1, SEPN1, SMN1, DMPK, FSHMD1A, and mtDNA. A known pathogenic mutation, c.1152+1G>A, and a previously unreported variant, c.1782+4_1782+5delAG, were detected in NEB. CONCLUSION: Our patient has a more severe phenotype than most reported patients and is the first patient with cap myopathy to have a mutation in NEB. Our case supports the identification of cap myopathy as a congenital myopathy with significant overlapping features with nemaline myopathies and further elucidates the phenotype of this disease.

The role of physician assistants in pediatric emergency medicine: the physician's view.

OBJECTIVE: To define the range of clinical conditions Canadian emergency pediatricians consider appropriate for management by physician assistants (PAs) and the degree of autonomy PAs should have in the pediatric emergency department (PED). METHODS: We conducted a cross-sectional, pan-Canadian survey using electronic questionnaire technology: the Active Campaign Survey tool. We targeted PED physicians using the Pediatric Emergency Research Canada (PERC) network database (N  =  297). Three outcome measures were assessed: demographic information, familiarity with PAs, and PA clinical roles in the PED. The level of PA involvement was assessed for 57 common nonemergent clinical conditions. RESULTS: Of 297 physicians, 152 completed the survey, for a response rate of 51.2%. None of the 57 clinical categories achieved at least 85% agreement regarding PA management without direct physician involvement. Twenty-four clinical conditions had ≥ 15% agreement that any PA involvement would be inappropriate. For the remaining 33 clinical conditions, more than 85% of respondents felt that PA could appropriately manage but were divided between requiring direct and only indirect physician supervision. Respondents' selection of the number of conditions felt to be appropriate for PA involvement varied between the size of the emergency department (ED) in which they work (larger EDs 87.7-89.1% v. smaller EDs 74.2%) and familiarity with the clinical work of PAs in the ED (90.5-91.5% v. 82.2-84.7%). CONCLUSION: This national survey of Canadian PED physicians suggests that they feel PAs could help care for a large number of nonemergent clinical cases coming to the PED, but these clinical encounters would have to be directly supervised by a physician.

Clinical and radiographic characteristics associated with abusive and nonabusive head trauma: a systematic review.

BACKGROUND AND OBJECTIVE: To systematically review the literature to determine which clinical and radiographic characteristics are associated with abusive head trauma (AHT) and nonabusive head trauma (nAHT) in children. METHODS: We searched MEDLINE, EMBASE, PubMed, conference proceedings, and reference lists to identify relevant studies. Two reviewers independently selected studies that compared clinical and/or radiographic characteristics including historical features, physical exam and imaging findings, and presenting signs or symptoms in hospitalized children ≤ 6 years old with AHT and nAHT. RESULTS: Twenty-four studies were included. Meta-analysis was complicated by inconsistencies in the reporting of characteristics and high statistical heterogeneity. Notwithstanding these limitations, there were 19 clinical and radiographic variables that could be meta-analyzed and odds ratios were determined for each variable. In examining only studies deemed to be high quality, we found that subdural hemorrhage(s), cerebral ischemia, retinal hemorrhage(s), skull fracture(s) plus intracranial injury, metaphyseal fracture(s), long bone fracture(s), rib fracture(s), seizure(s), apnea, and no adequate history given were significantly associated with AHT. Epidural hemorrhage(s), scalp swelling, and isolated skull fracture(s) were significantly associated with nAHT. Subarachnoid hemorrhage(s), diffuse axonal injury, cerebral edema, head and neck bruising, any bruising, and vomiting were not significantly associated with either type of trauma. CONCLUSIONS: Clinical and radiographic characteristics associated with AHT and nAHT were identified, despite limitations in the literature. This systematic review also highlights the need for consistent criteria in identifying and reporting clinical and radiographic characteristics associated with AHT and nAHT.

Reversal of islet GIP receptor down-regulation and resistance to GIP by reducing hyperglycemia in the Zucker rat.

In type 2 diabetes (T2DM) beta-cell responsiveness to glucose-dependent insulinotropic polypeptide (GIP) is reduced. In a model of T2DM, the VDF Zucker rat, GIP receptor mRNA and protein levels were shown to be down-regulated. Possible restoration of responsiveness to GIP in Zucker rats by reducing hyperglycemia has been examined. ZDF rats with extreme hyperglycemia demonstrated greater islet GIP receptor mRNA down-regulation (94.3+/-3.8%) than ZF rats (48.8+/-22.8%). GIP receptor mRNA levels in ZDF rats returned to 83.0+/-17.9% of lean following normalization of hyperglycemia by phlorizin treatment and pancreas perfusions demonstrated markedly improved GIP responsiveness. Treatment of VDF rats with a DP IV inhibitor (P32/98) resulted in improved glucose tolerance and restored sensitivity to GIP in isolated pancreata. These findings support the proposal that GIP receptor down-regulation in rodent T2DM is secondary to chronic hyperglycemia and that normalization of glycemia can restore GIP sensitivity.