Double deletion of orexigenic neuropeptide Y and dynorphin results in paradoxical obesity in mice

Objective

Orexigenic neuropeptide Y (NPY) and dynorphin (DYN) regulate energy homeostasis. Single NPY or dynorphin deletion reduces food intake or increases fat loss. Future developments of obesity therapeutics involve targeting multiple pathways. We hypothesised that NPY and dynorphin regulate energy homeostasis independently, thus double NPY and dynorphin ablation would result in greater weight and/or fat loss than the absence of NPY or dynorphin alone.

Design and methods

We generated single and double NPY and dynorphin knockout mice (NPYΔ, DYNΔ, NPYDYNΔ) and compared body weight, adiposity, feeding behaviour, glucose homeostasis and brown adipose tissue uncoupling protein-1 (UCP-1) expression to wildtype counterparts.

Results

Body weight and adiposity were significantly increased in NPYDYNΔ, but not in NPYΔ or DYNΔ. This was not due to increased food intake or altered UCP-1 expression, which were not significantly altered in double knockouts. NPYDYNΔ mice demonstrated increased body weight loss after a 24-h fast, with no effect on serum glucose levels after glucose injection.

Conclusions

Contrary to the predicted phenotype delineated from single knockouts, double NPY and dynorphin deletion resulted in heavier mice, with increased adiposity, despite no significant changes in food intake or UCP-1 activity. This indicates that combining long-term opioid antagonism with blockade of NPY-ergic systems may not produce anti-obesity effects.     

B cells as a critical node in the microbiota–host immune system network

Mutualism with our intestinal microbiota is a prerequisite for healthy existence. This requires physical separation of the majority of the microbiota from the host (by secreted antimicrobials, mucus, and the intestinal epithelium) and active immune control of the low numbers of microbes that overcome these physical and chemical barriers, even in healthy individuals. In this review, we address how B-cell responses to members of the intestinal microbiota form a robust network with mucus, epithelial integrity, follicular helper T cells, innate immunity, and gut-associated lymphoid tissues to maintain host–microbiota mutualism.     

Human Calcitonin Delivery in Rats by Iontophoresis

Abstract— In-vitro iontophoresis (0·33 mA cm⁻²) of calcitonin (50 μg mL⁻¹, pH 4) was performed with the hairless rat skin model. Direct current was as potent as pulse current (2·5 kHz on/off 1/1) iontophoresis in promoting transdermal permeation of calcitonin. Increase in duration of current application from 20 min to 1 h did not increase calcitonin flux. Results suggest that calcitonin can be blocked in the skin pores through which it travels or can accumulate in the skin and be progressively released from the depot. Invivo experiments showed that transdermal iontophoretic administration of calcitonin induced a hypocalcaemic effect in rats.     

The efficacy of postoperative pain management with ketorolac for day case oral surgery

The efficacy of the non-steroidal anti-inflammatory analgesic, ketorolac (Toradol), was investigated in 52 day case patients undergoing removal of impacted third molar teeth under intravenous sedation and local analgesia. The study was double-blind, randomized and placebo-controlled. A single 30 mg dose of ketorolac was administered intravenously just prior to induction of sedation with midazolam. Ketorolac was well tolerated and provided good postoperative analgesia. It is suggested that ketorolac is a useful addition to the analgesic armamentarium and appropriately prescribed, provides good pain relief following day case oral surgery.     

Sentinel lymphadenectomy after neoadjuvant chemotherapy for breast cancer may reliably represent the axilla except for inflammatory breast cancer

Background After neoadjuvant chemotherapy, women with locally advanced breast cancer (LABC) undergo a modified radical mastectomy or lumpectomy with axillary lymph node dissection (ALND) and radiotherapy. Sentinel lymphadenectomy (SL) is accepted for axillary evaluation in early breast cancer. We assessed the feasibility and predictive value of SL after neoadjuvant chemotherapy. Methods Eligible women received neoadjuvant therapy for LABC and were scheduled to undergo a definitive surgical procedure. Vital blue dye SL was attempted followed by level I and II axillary dissection. Results SL was successful in 29 of 34 patients (detection rate, 85%). Thirteen patients (45%) had positive nodes, and eight (28%) had negative nodes on both SL and ALND. In five patients (17%), the sentinel node was the only positive node identified. Overall, there was a 90% concordance between SL and ALND. The false-negative rate and negative predictive value were 14% and 73%, respectively. Among the subgroup without inflammatory cancer, the detection and concordance rates were 89% and 96%, respectively. The false-negative rate was 6%, and the negative predictive value was 88%. Conclusions SL after neoadjuvant chemotherapy may reliably predict axillary staging except in inflammatory breast cancer. Further studies are required to assess the utility of SL as the only mode of axillary evaluation in these women.     

A pilot study of the SNOT 22 score in adults with no sinonasal disease

Objective: To determine the SNOT 22 score in a normal population. Study design: Analysis of SNOT 22 scores participants with no sinonasal disease. Setting: Bath, UK. Participants: 116 participants from a local hospital and tennis club. Results: Results were obtained from 54 men and 62 women with a mean age of 40 (range 19–75). SNOT score ranged from 0–50 with a mean score of 9.3 (95% confidence interval range of 7.5–11.1). The modal score was 0 and the median score 7 (95% confidence interval range of 5–8). Conclusion: Due to the scewed nature of the data, the median score (7) is taken as the normal SNOT 22 score. We recommend that in an clincial situation a SNOT 22 score of 7 be used a a guide for “normal”, and that care should be taken when suggesting treatment on patients with a score below this level.     

Urinary C-peptide creatinine ratio to detect absolute insulin deficiency in type 2 diabetes

BackgroundNational Institute for Health and Clinical Excellence guidelines (CG87) recommend neutral protamine hagedorn (NPH) insulin for the provision of basal insulin in type 2 diabetes, but use of analogue insulin is as much as 40%. Where residual endogenous insulin secretory capacity is present there is no evidence that analogue insulins provide any additional benefit over human insulins, and they come at an expensive premium. Anecdotally, however, there is a reluctance to switch people back to NPH insulin, partly because of a perceived risk of pancreatic failure and potential ketosis. Urinary C-peptide creatinine ratio (UCPCR) has been validated as a method for evaluating residual endogenous insulin secretion in type 1 and type 2 diabetes, with a UCPCR of no more than 0·2 nmol/mmol suggestive of absolute insulin deficiency. We aimed to evaluate the prevalence of true insulin deficiency among patients with type 2 diabetes with UCPCR, and confirm findings with the gold standard mixed meal tolerance test (MMTT).Methods191 insulin-treated patients with a clinical diagnosis of type 2 diabetes (diagnosed at or after age 45 years and who did not start insulin within the first year of diagnosis) collected a 2-h post-prandial urine sample for UCPCR measurement. Nine patients from two subgroups (UCPCR ≤0·2 nmol/mmol and UCPCR >0·2) completed a standard MMTT.Findings11 (5·8%) of 191 patients had two consistent UCPCRs of less than or equal to 0·2 nmol/mmol. Nine were able to do the MMTT, of whom five were confirmed to have absolute insulin deficiency (stimulated serum c-peptide <0·2 nmol/L). Three of these five patients were glutamic acid decarboxylase antibody-negative. Nine of nine patients with UCPCR of more than 0·2 nmol/L had confirmed endogenous insulin secretion in their MMTT. Those with insulin deficiency had a shorter time to starting insulin (median 2·5 years [IQR 1·5–3·0] vs 6·0 [3·0–10·75], p=0·005) and lower body-mass index (25 kg/m² vs 29, p=0·04) but no other significant differences in clinical characteristics.InterpretationWe have demonstrated a very low prevalence of true pancreatic failure in this population of insulin-treated patients with type 2 diabetes. This requires further exploration by comparison of a population being treated with NPH insulin with one on analogue insulin, and then determining whether UCPCR could act as a clinical decision support tool to safely switch from analogue insulin to NPH insulin.FundingNational Institute for Health Research.     

Randomized controlled trial of dexamethasone treatment in very-low-birth-weight infants with ventilator-dependent chronic lung disease

This randomized controlled trial was designed to answer the question: does administration of dexamethasone to neonates with bronchopulmonary dysplasia decrease the need for assisted ventilation? Twenty-five infants with a birth weight < 1501 g, requiring mechanical ventilation and FiO₂ of ± 0.30 at 21-35 days of age, were randomized to treatment with iv dexamethasone or to sham injections for 12 days. The primary outcome criterion was extubation within seven days after study entry. Treatment (n= 12) and control (n= 13) groups were well matched at entry. Dexamethasone facilitated weaning from assisted ventilation (p= 0.0154). There was no increased incidence of infection. Dexamethasone treatment resulted in a significant increase in glucosuria (p= 0.0002) and in systolic blood pressure (p= 0.0034). There was a significant decrease in heart rate (p= 0.0001) and a significant weight loss (p= 0.0002) following dexamethasone treatment. Dexamethasone treatment facilitated weaning from assisted ventilation but several systemic effects were noted that deserve further evaluation before dexamethasone becomes routine treatment.     

Correlation in ages at death from familial ovarian cancer among sisters.

The analysis of pedigrees taken from 97 of 1466 women attending a screening clinic for early familial ovarian cancer showed that there was a strong correlation in the ages at death from the disease among sisters (r = 0.68, confidence limits 0.51-0.82, P < 0.001), but not between mothers and daughters. This information can be used to help counsel women who are considering the appropriate time for more intensive screening or prophylactic oophorectomy.     

Education in stroke: strategies to improve stroke patient care

'Stroke units save lives', but organized care requires expert staff and regular training to be effective. However, the quality of inpatient care for stroke remains poor, and stroke education is often fragmented between the health-care professions. This review describes some national and local strategies aimed at ensuring that all patients are cared for by expert staff.