Insulin and glucagon responses of transplanted intrasplenic pancreatic islets.

Two transplant procedures have been investigated in which one third of the pancreas was autotransplanted into the splenic pulp of dogs. The two procedures consist of simple mechanical dissociation of the pancreas or mechanical dissociation followed by collagenase digestion. The ability of the endocrine segment of the transplant to survive and function was assessed by stimulation with arginine and measurement of insulin and glucagon response. The results demonstrate that both transplant procedures result in functioning beta and alpha cells that rapidly secrete both insulin and glucagon in response to arginine stimulation. However, greater insulin responses were obtained when mechanically dissociated but nonenzyme digested pancreatic tissue was used for transplantation. The spleen appears to be an excellent transplant site for the reception of endocrine pancreatic tissue and allowed both beta and alpha cells to survive following transplantation.     

Hypoxia and its therapeutic possibilities in paediatric cancers

In tumours, hypoxia—a condition in which the demand for oxygen is higher than its availability—is well known to be associated with reduced sensitivity to radiotherapy and chemotherapy, and with immunosuppression. The consequences of hypoxia on tumour biology and patient outcomes have therefore led to the investigation of strategies that can alleviate hypoxia in cancer cells, with the aim of sensitising cells to treatments. An alternative therapeutic approach involves the design of prodrugs that are activated by hypoxic cells. Increasing evidence indicates that hypoxia is not just clinically significant in adult cancers but also in paediatric cancers. We evaluate relevant methods to assess the levels and extent of hypoxia in childhood cancers, including novel imaging strategies such as oxygen-enhanced magnetic resonance imaging (MRI). Preclinical and clinical evidence largely supports the use of hypoxia-targeting drugs in children, and we describe the critical need to identify robust predictive biomarkers for the use of such drugs in future paediatric clinical trials. Ultimately, a more personalised approach to treatment that includes targeting hypoxic tumour cells might improve outcomes in subgroups of paediatric cancer patients.Subject terms: Tumour biomarkers, Paediatric cancer, Cancer microenvironment, Cancer therapy     

Intraoperative contamination and space suits: a potential mechanism

The body exhaust suit (BES) of Charnley creates ‘negative pressure’ inside the gown using intake/outtake tubing. Modern ‘space suit’ (SS) systems incorporate helmet-based intake fans, which use the hood material as a filter and create ‘positive pressure’ inside the gown. While early studies of BES demonstrate a clear reduction in infection rates following arthroplasty, recent clinical data on SS use has paradoxically reported a marked increase. We hypothesized that the positive pressure inside the gown could carry air and particles via the unsealed area around the surgeon’s cuff into the operative field. We performed 12 simulated operations with the surgeons hands covered in fluorescent 0.5 micron powder that approximates the size of shedded skin squames. Photographs under UV light and air particle counts were used to compare potential contamination rates between SS and conventional gowns using a standardised scoring system. The highest powder migration was seen in the SS group with a score of 15.3 out of 28. No powder migration was seen in the standard gown group (p = 0.028). This study provides a plausible explanation for the increase in infection rates seen with SS use. We recommend SS be considered for personal protection only and supplemented with sealant tape around the inner glove.     

Identifying the emergence of the superficial peroneal nerve through deep fascia on ultrasound and by dissection: Implications for regional anesthesia in foot and ankle surgery

Regional anesthesia relies on a sound understanding of anatomy and the utility of ultrasound in identifying relevant structures. We assessed the ability to identify the point at which the superficial peroneal nerve (SPN) emerges through the deep fascia by ultrasound on 26 volunteers (mean age 27.85 years ± 13.186; equal male: female). This point was identified, characterized in relation to surrounding bony landmarks (lateral malleolus and head of the fibula), and compared to data from 16 formalin‐fixed human cadavers (mean age 82.88 years ± 6.964; equal male: female). The SPN was identified bilaterally in all subjects. On ultrasound it was found to pierce the deep fascia of the leg at a point 0.31 (±0.066) of the way along a straight line from the lateral malleolus to the head of the fibula (LM‐HF line). This occurred on or anterior to the line in all cases. Dissection of cadavers found this point to be 0.30 (±0.062) along the LM‐HF line, with no statistically significant difference between the two groups (U = 764.000; exact two‐tailed P = 0.534). It was always on or anterior to the LM‐HF line, anterior by 0.74 cm (±0.624) on ultrasound and by 1.51 cm (±0.509) during dissection. This point was significantly further anterior to the LM‐HF line in cadavers (U = 257.700, exact two‐tailed P < 0.001). Dissection revealed the nerve to divide prior to emergence in 46.88% (n = 15) limbs, which was not identified on ultrasound (although not specifically assessed). Such information can guide clinicians when patient factors (e.g., obesity and peripheral edema) make ultrasound‐guided nerve localization more technically challenging. Clin. Anat. 32:390–395, 2019. © 2019 Wiley Periodicals, Inc.     

Irs2 Inactivation Suppresses Tumor Progression in Pten+/− Mice

Mutations in the phosphatase and tensin homologue (PTEN)/phosphatidylinositol-3 kinase-α (PI3K) signaling pathway are frequently found in human cancer. In addition, Pten^+/− mice develop tumors in multiple organs because of the activation of the PI3K signaling cascade. Because activation of PI3K signaling leads to feedback inhibition of insulin receptor substrate-2 (IRS2) expression, an upstream activator of PI3K, we therefore anticipated that IRS2 expression would be low in tumors that lack PTEN. Surprisingly, however, an elevation of IRS2 was often detected in tumor samples in which PTEN levels were compromised. To determine the potential contribution of Irs2 to tumor progression, Pten^+/− mice were crossed with Irs2^+/− mice. Deletion of Irs2 did not affect the initiation of neoplasia found in Pten^+/− mice but suppressed cancer cell growth, proliferation, and invasion through the basement membrane. Deletion of Irs2 also attenuated the expression of Myc in prostatic intraepithelial neoplasia in Pten^+/− mice. In addition, the expression levels of IRS2 and MYC were highly correlated in human prostate cancer, and IRS2 could stimulate MYC expression in cultured cells. Our findings provide evidence that the PI3K-activating adaptor Irs2 contributes to tumor progression in Pten^+/− mice by stimulating both Myc and DNA synthesis.     

Low subcutaneous degradation and slow absorption of insulin in insulin-dependent diabetic patients during continuous subcutaneous insulin infusion at basal rate

Summary As information on the absorption kinetics and local degradation of infused insulin is relevant to programming strategies for continuous subcutaneous insulin infusion, we examined the time relationship of systemic insulin appearance and quantitated subcutaneous degradation during a near-basal rate of continuous subcutaneous insulin infusion in five insulin-dependent diabetic patients. Plasma free insulin was monitored for 8 h during and 3 h after a subcutaneous (abdominal wall) infusion of neutral insulin at 2.4 U/h. An identical intravenous infusion (2–4 h) was given on a separate occasion. Plateau levels of free insulin were not significantly different during the subcutaneous (37±8 mU/l) and intravenous (40±7 mU/l) infusions. Fitting of the free insulin data to our two-pool model of the subcutaneous space gave a mean estimate of 9.2 units insulin (= 3.8 h infusion) for the subcutaneous depot after 8 h. Model estimates of systemic insulin appearance, as a percentage of subcutaneous infusion rate, were 59% and 93% after 4 and 8 h respectively, and 76% 2 h after cessation of infusion. In insulin-dependent diabetic patients subcutaneous degradation of infused insulin is negligible but local accumulation in the subcutaneous space is considerable. The delay in absorption has important clinical implications for interruption and resumption of continuous subcutaneous insulin infusion and also for programming of variable basal rates.     

Nursing home staff perspectives on adoption of an innovation in goals of care communication

Nursing homes (NH) are important settings for end-of-life care, but limited implementation may impede goals of care discussions. The purpose of this study was to understand NH staff perceptions of adoption and sustainability of the Goals of Care video decision aid for families of residents with advanced dementia. Study design was a cross-sectional survey of staff at 11 NHs in North Carolina who participated in the Goals of Care (GOC) cluster randomized clinical trial. Staff perceived the GOC decision aid intervention as a positive innovation; it was perceived as more compatible with current practices by male staff, nurses, and more experienced NH staff. Perceptions were correlated with experience, implying that experience with an innovative approach may help to promote improved GOC communication in nursing homes. Nurses and social work staff could be effective champions for implementing a communication technique, like the GOC intervention.     

l-Glutamine and Whole Protein Restore First-Phase Insulin Response and Increase Glucagon-Like Peptide-1 in Type 2 Diabetes Patients

l-glutamine triggers glucagon-like peptide-1 (GLP-1) release from L cells in vitro and when ingested pre-meal, decreases postprandial glycaemia and increases circulating insulin and GLP-1 in type 2 diabetes (T2D) patients. We aimed to evaluate the effect of oral l-glutamine, compared with whole protein low in glutamine, on insulin response in well-controlled T2D patients. In a randomized study with a crossover design, T2D patients (n = 10, 6 men) aged 65.1 ± 5.8, with glycosylated hemoglobin (HbA1c) 6.6% ± 0.7% (48 ± 8 mmol/mol), received oral l-glutamine (25 g), protein (25 g) or water, followed by an intravenous glucose bolus (0.3 g/kg) and hyperglycemic glucose clamp for 2 h. Blood was frequently collected for analyses of glucose, serum insulin and plasma total and active GLP-1 and area under the curve of glucose, insulin, total and active GLP-1 excursions calculated. Treatments were tested 1–2 weeks apart. Both l-glutamine and protein increased first-phase insulin response (p ≤ 0.02). Protein (p = 0.05), but not l-glutamine (p = 0.2), increased second-phase insulin response. Total GLP-1 was increased by both l-glutamine and protein (p ≤ 0.02). We conclude that oral l-glutamine and whole protein are similarly effective in restoring first-phase insulin response in T2D patients. Larger studies are required to further investigate the utility of similar approaches in improving insulin response in diabetes.     

Effect of short-term consumption of a high-fat, low-carbohydrate diet on metabolic control in insulin-deficient diabetic rats

This study examined the effect of changing the proportion of dietary fat on metabolic control in rats rendered mildly diabetic with streptozotocin (STZ). The high-fat (HF) diet contained 66% energy as fat and 12% as carbohydrate while the low-fat (LF) diet contained 12% energy as fat and 66% as carbohydrate. Both diets had a P/S ratio of 1:3. Young male rats weighing 100 g were treated with STZ (60 mg/kg IV) and randomly allocated to either the LF of HF diet. After 2 weeks, the fasting plasma glucose concentrations were significantly higher in the HF-STZ rats than in the LF-STZ rats (13.2 +/- 1.2 mmol/L v 7.1 +/- 0.8 mmol/L, respectively, P less than 0.001). The increase in plasma glucose above the basal level following the intravenous glucose load (0.5 g/kg body wt) was similar in both groups of STZ-treated rats and glucose clearance was similarly impaired. The fall in glucose concentrations in the 30 minutes following the IV insulin (0.5 U Actrapid insulin/kg body wt) was greater in the LF-STZ rats (delta AUC = -1.60 +/- 0.20 mmol/L 0.5h) than in the HF-STZ group (delta AUC = -0.97 +/- 0.20 mmol/L 0.5 h, P less than 0.05) and either of the control groups (delta AUC = -0.94 +/- 0.37, -0.83 +/- 0.09 mmol/L 0.5 h for LF and HF rats, respectively, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)