Non-glycaemic effects mediated via GLP-1 receptor agonists and the potential for exploiting these for therapeutic benefit: focus on liraglutide

The glucagon-like peptide-1 receptor agonists (GLP-1 RAs) liraglutide and exenatide can improve glycaemic control by stimulating insulin release through pancreatic β-cells in a glucose-dependent manner. GLP-1 receptors are not restricted to the pancreas; therefore, GLP-1 RAs cause additional non-glycaemic effects. Preclinical and clinical trial data suggest a multitude of additional beneficial effects related to GLP-1 RA therapy, including improvements in β-cell function, systolic blood pressure and body weight. These effects are of a particular advantage to patients with type 2 diabetes, as most are affected by β-cell dysfunction, obesity and hypertension. Transient gastrointestinal adverse events, such as nausea and diarrhoea, are also common. To improve gastrointestinal tolerability, an incremental dosing approach is used with liraglutide and exenatide twice daily. A potential protective role for GLP-1 RAs in the cardiovascular and central nervous systems has been suggested from animal studies and short-term clinical trials. These effects and other safety aspects of GLP-1 therapy are currently being investigated in ongoing long-term clinical studies.     

Enhanced Bone Regeneration Using Porcine Small Intestinal Submucosa

Small instestinal submucosa (SIS) is an easily produced material that has been used experimentally for tissue engineering. To evaluate the ability of SIS to facilitate bone growth within a long-bone defect, a segment of the radius was surgically removed in adult, female Sprague-Dawley rats. The defect was either left unfilled or implanted with SIS, demineralized cortical bone (DMCB), or ovalbumin. The defect was evaluated radiographically and histologically after 3, 6, 12, and 24 weeks. Tissue remodeling within the defect was evident by week 3 in SIS- and DMCB-treated rats. Filling was characterized initially by infiltration of mononuclear cells and extracellular material in SIS-implanted rats and multifocal remodeling bone particles and cartilage formation in DMCB implanted rats. Cartilage was observed as early as 3 weeks and bone as early as 6 weeks in SIS-implanted rats. Filling of the defect arose from multiple foci in DMCB-implanted rats, but was contiguous with and parallel to the ulnar shaft in SIS-implanted rats, suggesting that defect repair by SIS may be conductive rather than inductive. Rats in which the defect was left unfilled demonstrated slow but progressive filling of the defect, characterized by mononuclear cell infiltrates and fibrous extracellular material. In summary, SIS facilitated rapid filling of a longbone defect. These results suggest that SIS may be useful as a bone repair material.     

Oberlin transfer and partial radial to axillary nerve neurotization to repair an explosive traumatic injury to the Brachial Plexus in a child: Case report

Purpose

Explosive injuries to the pediatric brachial plexus are exceedingly rare and as such are poorly characterized in the medical literature.

Methods

Herein, we describe an 8-year-old who was struck in the neck by a piece of shrapnel and suffered multiple vascular injuries in addition to a suspected avulsion of the cervical 5 and 6 ventral rami. The patient had a complete upper brachial plexus palsy and failed to demonstrate any clinical improvement at 6-months follow-up. He was taken to the operating from for a partial ulnar to musculocutaneous nerve neurotization as well as a partial radial to axillary nerve neurotization.

Results

The patient’s motor exam improved from a Medical Research Council scale 1 to 4+ for biceps brachii and 0 to 4 deltoid function with greater than 90° of shoulder abduction.

Conclusions

This outcome supports complex neurotization techniques as viable treatment options for persistent motor deficits following an upper brachial plexus injury in older, non-infant age, children.     

Prevention of depressive symptoms in adolescents: a randomized trial of cognitive-behavioral and interpersonal prevention programs

This study evaluated the efficacy of 2 programs for preventing depressive symptoms in adolescents. Participants were 380 high school students randomly assigned to a cognitive-behavioral program (CB), an interpersonal psychotherapy-adolescent skills training program (IPT-AST), or a no-intervention control. The interventions involved eight 90-min weekly sessions run in small groups during wellness classes. At postintervention, students in both the CB and IPT-AST groups reported significantly lower levels of depressive symptoms than did those in the no-intervention group, controlling for baseline depression scores; the 2 intervention groups did not differ significantly from each other. The effect sizes, using Cohen's d, for the CB intervention and the IPT-AST intervention were 0.37 and 0.26, respectively. Differences between control and intervention groups were largest for adolescents with high levels of depressive symptoms at baseline. For a high-risk subgroup, defined as having scored in the top 25th percentile on the baseline depression measure, the effect sizes for the CB and the IPT-AST interventions were 0.89 and 0.84, respectively. For the whole sample, sociotropy and achievement orientation moderated the effect of the interventions. Intervention effects were short term and were not maintained at 6-month follow-up.     

Multiple immunizations with adenovirus and MVA vectors improve CD8+ T cell functionality and mucosal homing

Recombinant adenovirus vectors and MVA vectors were used in prime boost vaccine regimens to address the impact of repeated immunizations on transgene product-specific CD8(+) T cell frequencies, phenotypes, function, and localization. We show that a regimen with three immunizations incorporating MVA, human adenovirus serotype 5 and chimpanzee-derived adenoviruses serotype 68 or 7 yields high transgene product-specific CD8(+) T cell frequencies in spleen, blood, lymph nodes, and peritoneal lavage. Furthermore, upon triple immunization increased frequencies of transgene-specific T cells were measured at mucosal sites such as mesenteric lymph nodes, intestinal epithelium, and Peyer's patches. Multiple dose vaccine regimens that markedly increase functionally active transgene-specific T cells and target them to the appropriate ports of entry may be important in protection against pathogens such as HIV-1.     

Appraisal and coping with daily stressors by pediatric patients with chronic abdominal pain

OBJECTIVE: To test the hypothesis that pain patients differ from well children in their appraisal and coping with daily stressors and to test a model of the relation of stress appraisal and coping to symptoms and disability. METHODS: Pediatric patients with chronic abdominal pain (n = 143) and well children (n = 104) completed a 5-day diary study regarding their appraisal and coping with daily stressors. Somatic symptoms, depressive symptoms, and functional disability were assessed 2 months later. RESULTS: Compared to well children, pain patients were less confident of their ability either to change or to adapt to stress and were less likely to use accommodative coping strategies. Different patterns of stress appraisal were associated with active, passive, and accommodative coping. Both appraisals and coping were significantly related to symptoms and disability. CONCLUSIONS: The relation between stress and symptoms in pediatric pain patients may be explained in part by their appraisal and coping with stressors. The relation between appraisal and coping was consistent with Lazarus, R. S., & Folkman, S. (1984). Stress, Appraisal, and Coping. New York: Springer.     

Lessons learned while conducting research on prevention of pressure ulcers in veterans with spinal cord injury

OBJECTIVE: To describe the challenges of conducting a large randomized controlled trial (RCT) to assess the effectiveness of an intervention to prevent recurrent pressure ulcers among a high-risk population of subjects with spinal cord injury (SCI). DESIGN: Prospective multisite, randomized design comparing outcomes of patients who received individualized education and structured telephone counseling follow-up with those of patients receiving customary care. This study was stopped early because of unanticipated recruitment problems. SETTING: Six Veterans Affairs SCI specialty centers. PARTICIPANTS: Veterans (N=150) treated for stage III or IV pelvic pressure ulcers. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Recurrence (defined as new skin breakdown in the pelvic area) and time to recurrence. The study was stopped early because of slow recruitment, so the focus of this study is lessons learned, not the main planned outcome measures. RESULTS: Subject recruitment did not meet original expectations because almost 50% of those enrolled left the hospital with the study ulcer unhealed (having a healed ulcer was a requirement for participation). No significant differences were observed between groups on rate of or time to recurrence at the time the study was stopped. Among the 6 sites, variability in ulcer management (eg, length of stay, receipt of medical vs surgical treatment, sitting tolerance before discharge) and time to recurrence (median, 4mo) were observed. CONCLUSIONS: RCTs in real-world settings are the most robust method of assessing the effectiveness of prevention strategies. However, in complex, rapidly changing health care organizations, blinding is infeasible, it may be impractical to control for every variable that influences a study's outcome, and any assumptions that usual care is static are probably mistaken. Investigators must be prepared to use innovative approaches to maintain the integrity of the study design, including flexibility in inclusion and exclusion criteria to support accrual, obtaining a better understanding of the important aspects of usual care that may need to be standardized, continuous improvement within the intervention arm, and anticipation and minimization of risks from organizational changes. With attention to these delivery system issues and the usual design features of randomized trials, we believe real-world care settings can serve as important laboratories to test pressure ulcer prevention strategies in this population.