Cellular mechanisms of prostaglandin E2 and vasopressin interactions in the collecting duct

As the final segment of the nephron, the collecting duct is the ultimate regulator of renal salt and water excretion. Balance between intake and renal excretion of salt and water is fine-tuned by the action of several hormones targeted to the collecting duct. Vasopressin is, perhaps, the prototypical example of such a hormone. As total body water decreases and plasma osmolality rises, vasopressin secretion from the posterior pituitary increases [1]. Picomolar concentrations of circulating vasopressin lead to increased water permeability of the apical membrane of the collecting duct cell, resulting in increased water reabsorption and increased total body water [2,3]. There is abundant evidence demonstrating that vasopressin's effect on water reabsorption in the collecting duct is mediated through the classic second messenger, cAMP [3]. V2 selective receptors are linked via a G protein, to stimulation of plasma membrane adenylyl cyclase, resulting in increased cell cyclic AMP levels [4, 5]. The increased cyclic AMP then leads to augmented water permeability of the apical membrane [6, 7].As one might expect with such an important biologic process, other hormones and autocoids provide a counter-regulatory influence to modulate vasopressin mediated increases in osmotic water permeability. There is good evidence that the arachadonic acid metabolite, prostaglandin E2 (PGE2) plays a critical physiologic and pathophysiologic role in inhibiting vasopressin action in the collecting duct [8, 9]. Not only is the collecting duct the major renal site of synthesis for this cyclo-oxygenase product of arachidonic acid but PGE2 production is stimulated by vasopressin itself [10–12]. PGE2 infusion significantly blunts water reabsorption and cycloxygenase inhibition augments vasopressin antidiuresis [9, 13]. Thus, there is good evidence that the autocoid PGE2 plays an important role in regulating vasopressin-stimulated osmotic water flow

Improving empathy of physicians through guided reflective writing

Objectives: This study was designed to explore how guided reflective writing could evoke empathy and reflection in a group of practicing physicians. Methods: Total participants recruited included 40 staff physicians at Cleveland Clinic, a tertiary care academic medical center. Twenty physicians (intervention group) were assigned to participate in a 6-session faculty development program introducing narrative medicine and engaging in guided reflective writing. Ten physicians (comparison group 1) received the assigned course reading materials but did not participate in the course sessions. Ten physicians (comparison group 2) neither received the reading materials nor participated in the sessions. Qualitative analysis of the physicians\u27 reflective writings was performed to identify major themes. The Jefferson Scale of Empathy was administered three times during the course. Results: Qualitative analysis of physicians\u27 writings showed themes of both compassionate solidarity and detached concern. Exploration of negative emotions occurred more frequently than positive ones. The most common writing style was case presentation. A total of 36 staff physicians completed the Jefferson Scale of Empathy. Results of statistical analysis suggested an improvement in empathy in the intervention group at the end of the course (p \u3c 0 .05). Conclusions: These results suggest a faculty development program using guided narrative writing can promote reflection and may enhance empathy among practicing physicians. These findings should encourage medical educators to design additional strategies for enhancing reflection and empathic behavior in trainees and specifically practicing physicians who can role model these behaviors to achieve the ultimate goal of improving the quality of patient care

Assessing the impact of a national clinical guideline for the management of chronic pain on opioid prescribing rates:a controlled interrupted time series analysis

Background: Opioids can be effective analgesics, but long-term use may be associated with harms. In 2013, the first national, comprehensive, evidence-based pain management guideline was published, from the Scottish Intercollegiate Guideline Network (SIGN 136: Management of Chronic Pain) with key recommendations on analgesic prescribing. This study aimed to examine the potential impact on national opioid prescribing rates in Scotland. Methods: Trends in national and regional community opioid prescribing data for Scotland were analysed from quarter one (Q1) 2005 to Q2 2020. Interrupted time series regression examined the association of SIGN 136 publication with prescribing rates for opioid-containing drugs. Gabapentinoid prescribing was used as a comparison drug. Results: After a positive prescribing trend pre-publication, the timing of SIGN 136 publication was associated with a negative change in the trend of opioid prescribing rates (−2.82 items per 1000 population per quarter [PTPPQ]; P < 0.01). By Q2 2020, the relative reduction in the opioid prescribing rate was −20.67% (95% CI: −23.61, −17.76). This persisted after correcting for gabapentinoid prescribing and was mainly driven by the reduction in weak opioids, whereas strong opioid prescribing rates continued to rise. Gabapentinoid prescribing showed a significant rise in level (8.00 items per 1000 population; P = 0.01) and trend (0.27 items PTPPQ; P = 0.01) following SIGN 136 publication. Conclusions: The publication of SIGN 136 was associated with a reduction in opioid prescribing rates. This suggests that changes in clinical policy through evidence-based national clinical guidelines may affect community opioid prescribing, though this may be partially replaced by gabapentinoids, and other factors may also contribute

Epidemiology of neuropathic pain:an analysis of prevalence and associated factors in UK Biobank

Abstract. Introduction:. Previous epidemiological studies of neuropathic pain have reported a range of prevalences and factors associated with the disorder. Objectives:. This study aimed to verify these characteristics in a large UK cohort. Methods:. A cross-sectional analysis was conducted of 148,828 UK Biobank participants who completed a detailed questionnaire on chronic pain. The Douleur Neuropathique en Quatre Questions (DN4) was used to distinguish between neuropathic pain (NeuP) and non-neuropathic pain (non-NeuP) in participants with pain of at least 3 months' duration. Participants were also identified with less than 3 months' pain or without pain (NoCP). Multivariable regression was used to identify factors associated with NeuP compared with non-NeuP and NoCP, respectively. Results:. Chronic pain was present in 76,095 participants (51.1%). The overall prevalence of NeuP was 9.2%. Neuropathic pain was significantly associated with worse health-related quality of life, having a manual or personal service type occupation, and younger age compared with NoCP. As expected, NeuP was associated with diabetes and neuropathy, but also other pains (pelvic, postsurgical, and migraine) and musculoskeletal disorders (rheumatoid arthritis, osteoarthritis, and fibromyalgia). In addition, NeuP was associated with pain in the limbs and greater pain intensity and higher body mass index compared with non-NeuP. Female sex was associated with NeuP when compared with NoCP, whereas male sex was associated with NeuP when compared with non-NeuP. Conclusion:. This is the largest epidemiological study of neuropathic pain to date. The results confirm that the disorder is common in a population of middle- to older-aged people with mixed aetiologies and is associated with a higher health impact than non-neuropathic pain

Development and external validation of multivariable risk models to predict incident and resolved neuropathic pain:a DOLORisk Dundee study

Neuropathic pain is difficult to treat, and an understanding of the risk factors for its onset and resolution is warranted. This study aimed to develop and externally validate two clinical risk models to predict onset and resolution of chronic neuropathic pain. Participants of Generation Scotland: Scottish Family Health Study (GS; general Scottish population; n = 20,221) and Genetic of Diabetes Audit and Research in Tayside Scotland (GoDARTS; n = 5236) were sent a questionnaire on neuropathic pain and followed- -up 18 months later. Chronic neuropathic pain was defined using DN4 scores (≥ 3/7) and pain for 3 months or more. The models were developed in GS using logistic regression with backward elimination based on the Akaike information criterion. External validation was conducted in GoDARTS and assessed model discrimination (ROC and Precision-Recall curves), calibration and clinical utility (decision curve analysis [DCA]). Analysis revealed incidences of neuropathic pain onset (6.0% in GS [236/3903] and 10.7% in GoDARTS [61/571]) and resolution (42.6% in GS [230/540] and 23.7% in GoDARTS [56/236]). Psychosocial and lifestyle factors were included in both onset and resolved prediction models. In GoDARTS, these models showed adequate discrimination (ROC = 0.636 and 0.699), but there was evidence of miscalibration (Intercept = − 0.511 and − 0.424; slope = 0.623 and 0.999). The DCA indicated that the models would provide clinical benefit over a range of possible risk thresholds. To our knowledge, these are the first externally validated risk models for neuropathic pain. The findings are of interest to patients and clinicians in the community, who may take preventative or remedial measures. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00415-022-11478-0

MicroRNA-277 Modulates the Neurodegeneration Caused by Fragile X Premutation rCGG Repeats

Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder, has been recognized in older male fragile X premutation carriers and is uncoupled from fragile X syndrome. Using a Drosophila model of FXTAS, we previously showed that transcribed premutation repeats alone are sufficient to cause neurodegeneration. MiRNAs are sequence-specific regulators of post-transcriptional gene expression. To determine the role of miRNAs in rCGG repeat-mediated neurodegeneration, we profiled miRNA expression and identified selective miRNAs, including miR-277, that are altered specifically in Drosophila brains expressing rCGG repeats. We tested their genetic interactions with rCGG repeats and found that miR-277 can modulate rCGG repeat-mediated neurodegeneration. Furthermore, we identified Drep-2 and Vimar as functional targets of miR-277 that could modulate rCGG repeat-mediated neurodegeneration. Finally, we found that hnRNP A2/B1, an rCGG repeat-binding protein, can directly regulate the expression of miR-277. These results suggest that sequestration of specific rCGG repeat-binding proteins could lead to aberrant expression of selective miRNAs, which may modulate the pathogenesis of FXTAS by post-transcriptionally regulating the expression of specific mRNAs involved in FXTAS