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Background and purpose: Diabetic polyneuropathy (DPN) is a common complication of diabetes. Using the Toronto criteria for diabetic polyneuropathy and the grading system for neuropathic pain, the performance of neuropathy scales and questionnaires were assessed by comparing them to a clinical gold standard diagnosis of DPN and painful DPN in a cohort of patients with recently diagnosed type 2 diabetes. Methods: A questionnaire on neuropathy and pain was sent to a cohort of 5514 Danish type 2 diabetes patients. A sample of 389 patients underwent a detailed clinical examination and completed neuropathy questionnaires and scales. Results: Of the 389 patients with a median diabetes duration of 5.9 years, 126 had definite DPN (including 53 with painful DPN), 88 had probable DPN and 53 had possible DPN. There were 49 patients with other causes of polyneuropathy, neuropathy symptoms or pain, 10 with subclinical DPN and 63 without DPN. The sensitivity of the Michigan Neuropathy Screening Instrument questionnaire to detect DPN was 25.7% and the specificity 84.6%. The sensitivity of the Toronto Clinical Neuropathy Scoring System, including questionnaire and clinical examination, was 62.9% and the specificity was 74.6%. Conclusions: Diabetic polyneuropathy affects approximately one in five Danish patients with recently diagnosed type 2 diabetes but neuropathic pain is not as common as previously reported. Neuropathy scales with clinical examination perform better compared with questionnaires alone, but better scales are needed for future epidemiological studies. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the effectiveness of automated symptom and side effect monitoring on quality of life among individuals with symptomatic diabetic peripheral neuropathy. Methods: We conducted a pragmatic, cluster randomized controlled trial (July 2014 to July 2016) within a large healthcare system. We randomized 1834 primary care physicians and prospectively recruited from their lists 1270 individuals with neuropathy who were newly prescribed medications for their symptoms. Intervention participants received automated telephone‐based symptom and side effect monitoring with physician feedback over 6 months. The control group received usual care plus three non‐interactive diabetes educational calls. Our primary outcomes were quality of life (EQ‐5D) and select symptoms (e.g. pain) measured 4–8 weeks after starting medication and again 8 months after baseline. Process outcomes included receiving a clinically effective dose and communication between individuals with neuropathy and their primary care provider over 12 months. Interviewers collecting outcome data were blinded to intervention assignment. Results: Some 1252 participants completed the baseline measures [mean age (sd): 67 (11.7), 53% female, 57% white, 8% Asian, 13% black, 20% Hispanic]. In total, 1179 participants (93%) completed follow‐up (619 control, 560 intervention). Quality of life scores (intervention: 0.658 ± 0.094; control: 0.653 ± 0.092) and symptom severity were similar at baseline. The intervention had no effect on primary [EQ‐5D: −0.002 (95% CI −0.01, 0.01), P = 0.623; pain: 0.295 (−0.75, 1.34), P = 0.579; sleep disruption: 0.342 (−0.18, 0.86), P = 0.196; lower extremity functioning: −0.079 (−1.27, 1.11), P = 0.896; depression: −0.462 (−1.24, 0.32); P = 0.247] or process outcomes. Conclusions: Automated telephone monitoring and feedback alone were not effective at improving quality of life or symptoms for people with symptomatic diabetic peripheral neuropathy. Trial Registration: ClinicalTrials.gov (NCT02056431). What's new?: Frequent communication between individuals with diabetic peripheral neuropathy and primary care providers about symptoms and medication side effects is critical to optimizing medication dosing to treat painful diabetic peripheral neuropathy. Yet, there are considerable barriers to effective communication.This cluster randomized controlled trial found that a brief intervention to automatically monitor person‐reported data on symptoms and side effects, and provide the information to physicians via an electronic health record was not effective in improving the outcomes valued by individuals with neuropathy.Alerts alone are unlikely to change provider behaviour related to treatment intensification. More intensive interventions focused on individual activation or provider education may be more effective in changing prescribing behaviour and improving outcomes. [ABSTRACT FROM AUTHOR]

Enterochromaffin cells were the first endocrine cells of the gastrointestinal tract to be chemically distinguished, almost 150 years ago. It is now known that the chromaffin reaction of these cells was due to their content of the reactive aromatic amine, 5-hydroxytryptamine (5- HT, also known as serotonin). They have commonly been thought to be a special class of gut endocrine cells (enteroendocrine cells) that are distinct from the enteroendocrine cells that contain peptide hormones. The study by Martin et al. in the current issue of this journal reveals that the patterns of expression of nutrient receptors and transporters differ considerably between chromaffin cells of the mouse duodenum and colon. However, even within regions, chromaffin cells differ; in the duodenum there are chromaffin cells that contain both secretin and 5- HT, cholecystokinin and 5- HT, and all three of secretin, cholecystokinin, and 5- HT. Moreover, the ratios of these different cell types differ substantially between species. And, in terms of function, 5- HT has many roles, including in appetite, motility, fluid secretion, release of digestive enzymes and bone metabolism. The paper thus emphasizes the need to define the many different classes of enterochromaffin cells and relate this to their roles. [ABSTRACT FROM AUTHOR]

The adverse effects of early-life stress are pervasive, with well-established mental and physical health consequences for exposed individuals. The impact of early adverse experiences is also highly persistent, with documented increases in risk for mental illness across the life span that are accompanied by stable alterations in neural function and hormonal responses to stress. Here, we review some of these 'stress phenotypes', with a focus on intermediary factors that may signal risk for long-term mental health outcomes, such as altered development of the fear regulation system. Intriguingly, recent research suggests that such stress phenotypes may persist even beyond the life span of the individuals, with consequences for their offspring and grand-offspring. Phenotypic characteristics may be transmitted to future generations via either the matriline or the patriline, a phenomenon that has been demonstrated in both human and animal studies. In this review, we highlight behavioral and epigenetic factors that may contribute to this multigenerational transmission and discuss the potential of various treatment approaches that may halt the cycle of stress phenotypes. [ABSTRACT FROM AUTHOR]

Background It has been recently demonstrated that the ghrelin receptor agonist, HM01, caused defecation in rats that were treated to provide a model for the constipation of Parkinson's disease. HM01 significantly increased fecal output and increased Fos activity in neurons of the hypothalamus and hindbrain, but not in the spinal defecation center. Other ghrelin agonists act on the defecation center. Methods Receptor pharmacology was examined in ghrelin receptor ( GHSR1a) transfected cells. Anesthetized rats were used to investigate sites and mechanisms of action. Key Results HM01 activated rat GHSR1a at nanomolar concentrations and was antagonized by the GHSR1a antagonist, YIL781. HM01, intravenous, was potent to activate propulsive colorectal contractions. This was prevented by pelvic nerve section and by intravenous YIL781, but not by spinal cord section rostral to the defecation centers. Direct intrathecal application of HM01 to the defecation center at spinal level L6-S1 initiated propulsive contractions of the colorectum. Conclusions & Inferences HM01 stimulates GHSR1a receptors on neurons in the lumbosacral defecation centers to cause propulsive contractions and emptying of the colorectum. It has greater potency when given systemically, compared with other GHSR1a agonists. [ABSTRACT FROM AUTHOR]

Background Discovery of adequate pharmacological treatments for constipation has proven elusive. Increased numbers of bowel movements were reported as a side-effect of ulimorelin treatment of gastroparesis, but there has been no investigation of the site of action. Methods Anesthetized rats were used to investigate sites and mechanisms of action of ulimorelin. Key Results Intravenous ulimorelin (1-5 mg/kg) caused a substantial and prolonged (~1 h) increase in colorectal propulsive activity and expulsion of colonic contents. This was prevented by cutting the nerves emerging from the lumbosacral cord, by the nicotinic receptor antagonist hexamethonium and by antagonists of the ghrelin receptor. The effect of intravenous ulimorelin was mimicked by direct application of ulimorelin (5 μg) to the lumbosacral spinal cord. Conclusions & Inferences Ulimorelin is a potent prokinetic that causes propulsive contractions of the colorectum by activating ghrelin receptors of the lumbosacral defecation centers. Its effects are long-lasting, in contrast with other colokinetics that target ghrelin receptors. [ABSTRACT FROM AUTHOR]

Conotoxins (conopeptides) are small disulfide bonded peptides from the venom of marine cone snails. These peptides target a wide variety of membrane receptors, ion channels and transporters, and have enormous potential for a range of pharmaceutical applications. Structurally related ω-conotoxins bind directly to and selectively inhibit neuronal (N)-type voltage-gated calcium channels (VGCCs) of nociceptive primary afferent neurones. Among these, ω-conotoxin MVIIA (Prialt) is approved by the Food and Drug Administration (FDA) as an alternative intrathecal analgesic for the management of chronic intractable pain, particularly in patients refractory to opioids. A series of newly discovered ω-conotoxins from Conus catus, including CVID-F, are potent and selective antagonists of N-type VGCCs. In spinal cord slices, these peptides reversibly inhibit excitatory synaptic transmission between primary afferents and dorsal horn superficial lamina neurones, and in the rat partial sciatic nerve ligation model of neuropathic pain, significantly reduce allodynic behaviour. Another family of conotoxins, the α-conotoxins, are competitive antagonists of mammalian nicotinic acetylcholine receptors (nAChRs). α-Conotoxins Vc1.1 and RgIA possess two disulfide bonds and are currently in development as a treatment for neuropathic pain. It was initially proposed that the primary target of these peptides is the α9α10 neuronal nAChR. Surprisingly, however, α-conotoxins Vc1.1, RgIA and PeIA more potently inhibit N-type VGCC currents via a GABA(B) GPCR mechanism in rat sensory neurones. This inhibition is largely voltage-independent and involves complex intracellular signalling. Understanding the molecular mechanisms of conotoxin action will lead to new ways to regulate VGCC block and modulation in normal and diseased states of the nervous system. [ABSTRACT FROM AUTHOR]

SUMMARY A case with bilateral Supraspinatus Tendon-itis and associated painful calcification of the Glutei Medius and Minimus has been described. Consideration has been given to whether this forms part of a generalized disease and suggestions have been made as to its etiology. [ABSTRACT FROM AUTHOR]

SUMMARY A case illustrating an unusual cause of radiologically demonstrable duodenal deformation due to secondary megacolon is presented and its differential diagnosis discussed. [ABSTRACT FROM AUTHOR]