Increased capsaicin receptor TRPV1 in skin nerve fibres and related vanilloid receptors TRPV3 and TRPV4 in keratinocytes in human breast pain

BACKGROUND: Breast pain and tenderness affects 70% of women at some time. These symptoms have been attributed to stretching of the nerves with increase in breast size, but tissue mechanisms are poorly understood. METHODS: Eighteen patients (n = 12 breast reduction and n = 6 breast reconstruction) were recruited and assessed for breast pain by clinical questionnaire. Breast skin biopsies from each patient were examined using immunohistological methods with specific antibodies to the capsaicin receptor TRPV1, related vanilloid thermoreceptors TRPV3 and TRPV4, and nerve growth factor (NGF). RESULTS: TRPV1-positive intra-epidermal nerve fibres were significantly increased in patients with breast pain and tenderness (TRPV1 fibres / mm epidermis, median [range] – no pain group, n = 8, 0.69 [0–1.27]; pain group, n = 10, 2.15 [0.77–4.38]; p = 0.0009). Nerve Growth Factor, which up-regulates TRPV1 and induces nerve sprouting, was present basal keratinocytes: some breast pain specimens also showed NGF staining in supra-basal keratinocytes. TRPV4-immunoreactive fibres were present in sub-epidermis but not significantly changed in painful breast tissue. Both TRPV3 and TRPV4 were significantly increased in keratinocytes in breast pain tissues; TRPV3, median [range] – no pain group, n = 6, 0.75 [0–2]; pain group, n = 11, 2 [1-3], p = 0.008; TRPV4, median [range] – no pain group, n = 6, [0–1]; pain group, n = 11, 1 [0.5–2], p = 0.014). CONCLUSION: Increased TRPV1 intra-epidermal nerve fibres could represent collateral sprouts, or re-innervation following nerve stretch and damage by polymodal nociceptors. Selective TRPV1-blockers may provide new therapy in breast pain. The role of TRPV3 and TRPV4 changes in keratinocytes deserve further study

"Man up": Medical students’ perceptions of gender and learning in clinical practice: A qualitative study

Context Gender‐related inequality and disparity hinders efforts to develop a medical workforce that facilitates universal access to safe, just and equitable health care. Little is known about how medical students perceive the impact of their gender on their learning in clinical practice. Our aim in this study was to address this gap, establishing students’ perceptions of the impact of their gender on learning in the clinical context as part of the wider medical education community of practice. Methods We undertook a qualitative study that simultaneously gathered data through narrative individual interviews and online case reports from male and female students (n = 31) from different academic cohorts with prior experience of clinical practice in a Russell Group University medical school in the UK. Interviews were transcribed and analysed thematically alongside case report data. Results and discussion The participants revealed that there was a culture in clinical practice where their gender influenced how they were taught and supported by senior medical and surgical colleagues. Gender was also said to determine the clinical learning opportunities afforded to students, especially with regards to the care of patients of a different gender. The mentorship and support for learning provided to students in clinical practice was also said to be influenced by the medical student's gender. Conclusion Our findings suggest that students undergo a gendered clinical apprenticeship within what are in effect gendered communities of practice with some distinct features. These findings underscore the imperative for further work to establish how medical students of all genders can be supported to fulfil their potential in clinical practice

Transnational regulation of temporary agency work compromised partnership between Private Employment Agencies and Global Union Federations

This article critically assesses the potential for the international regulation of temporary agency work (TAW) through building partnership between the Global Union Federations (GUFs) and major Private Employment Agencies (PrEAs). Given the limits of existing national and international regulation of TAW, particularly in developing countries, and the current deadlock in dialogue through the International Labour Organization, the argument of this article is that Transnational Private Labour Regulation (TPLR) offers a unique opportunity to establish a basis for minimum standards for temporary agency workers. This article goes on to propose three potential TPLR frameworks that, although compromised, are transparent, fair and sufficiently elastic to accommodate the distributive and political risks associated with partnership. They also offer important gains, namely increasing the competitive advantage of the PrEAs involved, minimum standards for agency workers and ‘field enlarging’ strategies for the GUFs and their affiliates

Effects of estrogens and bladder inflammation on mitogen-activated protein kinases in lumbosacral dorsal root ganglia from adult female rats

BACKGROUND: Interstitial cystitis is a chronic condition associated with bladder inflammation and, like a number of other chronic pain states, symptoms associated with interstitial cystitis are more common in females and fluctuate during the menstrual cycle. The aim of this study was to determine if estrogens could directly modulate signalling pathways within bladder sensory neurons, such as extracellular signal-related kinase (ERK) and p38 mitogen-activated protein (MAP) kinases. These signalling pathways have been implicated in neuronal plasticity underlying development of inflammatory somatic pain but have not been as extensively investigated in visceral nociceptors. We have focused on lumbosacral dorsal root ganglion (DRG) neurons projecting to pelvic viscera (L1, L2, L6, S1) of adult female Sprague-Dawley rats and performed both in vitro and in vivo manipulations to compare the effects of short- and long-term changes in estrogen levels on MAPK expression and activation. We have also investigated if prolonged estrogen deprivation influences the effects of lower urinary tract inflammation on MAPK signalling. RESULTS: In studies of isolated DRG neurons in short-term (overnight) culture, we found that estradiol and estrogen receptor (ER) agonists rapidly stimulated ER-dependent p38 phosphorylation relative to total p38. Examination of DRGs following chronic estrogen deprivation in vivo (ovariectomy) showed a parallel increase in total and phosphorylated p38 (relative to beta-tubulin). We also observed an increase in ERK1 phosphorylation (relative to total ERK1), but no change in ERK1 expression (relative to beta-tubulin). We observed no change in ERK2 expression or phosphorylation. Although ovariectomy increased the level of phosphorylated ERK1 (vs. total ERK1), cyclophosphamide-induced lower urinary tract inflammation did not cause a net increase of either ERK1 or ERK2, or their phosphorylation. Inflammation did, however, cause an increase in p38 protein levels, relative to beta-tubulin. Prior ovariectomy did not alter the response to inflammation. CONCLUSIONS: These results provide new insights into the complex effects of estrogens on bladder nociceptor signalling. The diversity of estrogen actions in these ganglia raises the possibility of developing new ways to modulate their function in pelvic hyperactivity or pain states

Combined Point-of-Care Nucleic Acid and Antibody Testing for SARS-CoV-2 following Emergence of D614G Spike Variant

Rapid COVID-19 diagnosis in the hospital is essential, although this is complicated by 30%–50% of nose/throat swabs being negative by SARS-CoV-2 nucleic acid amplification testing (NAAT). Furthermore, the D614G spike mutant dominates the pandemic and it is unclear how serological tests designed to detect anti-spike antibodies perform against this variant. We assess the diagnostic accuracy of combined rapid antibody point of care (POC) and nucleic acid assays for suspected COVID-19 disease due to either wild-type or the D614G spike mutant SARS-CoV-2. The overall detection rate for COVID-19 is 79.2% (95% CI 57.8–92.9) by rapid NAAT alone. The combined point of care antibody test and rapid NAAT is not affected by D614G and results in very high sensitivity for COVID-19 diagnosis with very high specificity

Differences in Efficacy and Safety of Pharmaceutical Treatments between Men and Women: An Umbrella Review

Being male or female is an important determinant of risks for certain diseases, patterns of illness and life expectancy. Although differences in risks for and prognoses of several diseases have been well documented, sex-based differences in responses to pharmaceutical treatments and accompanying risks of adverse events are less clear. The objective of this umbrella review was to determine whether clinically relevant differences in efficacy and safety of commonly prescribed medications exist between men and women. We retrieved all available systematic reviews of the Oregon Drug Effectiveness Review Project published before January 2010. Two persons independently reviewed each report to identify relevant studies. We dually abstracted data from the original publications into standardized forms. We synthesized the available evidence for each drug class and rated its quality applying the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Findings, based on 59 studies and data of more than 250,000 patients suggested that for the majority of drugs no substantial differences in efficacy and safety exist between men and women. Some clinically important exceptions, however, were apparent: women experienced substantially lower response rates with newer antiemetics than men (45% vs. 58%; relative risk 1.49, 95% confidence interval 1.35–1.64); men had higher rates of sexual dysfunction than women while on paroxetine for major depressive disorder; women discontinued lovastatin more frequently than men because of adverse events. Overall, for the majority of drugs sex does not appear to be a factor that has to be taken into consideration when choosing a drug treatment. The available body of evidence, however, was limited in quality and quantity, confining the range and certainty of our conclusions

The importance of water transport on short-side chain perfluorosulfonic acid membrane fuel cells operating under low relative humidity

Polarization curves of fuel cells incorporating PFSA short-side chain (SSC) ionomer membranes having ion exchange capacity (IEC) 1.30, 1.37, 1.43 and 1.50\ua0meq\ua0g-1 and NRE-211 are compared. Under low humidity conditions, fuel cells incorporating SSC membranes show higher performance than NRE-211. SSC PFSA membranes possessing an IEC of 1.37\ua0meq\ua0g-1 exhibit the highest performance. Differences in fuel cell polarization curves are due to differences in the high frequency resistance, which in turn is found related to ex-situ measurements of both the effective proton mobility and the rate of water flux through the membrane, which also exhibit a maximum for membranes of IEC 1.37\ua0meq\ua0g-1. Water permeation and proton mobility are shown to be inherently linked, but it is found that simply increasing the membrane's IEC does not necessarily translate to increased water transport and effective proton mobility, despite the increased water content. \ua9 2013 Crown Copyright and Elsevier Inc.Peer reviewed: YesNRC publication: Ye

Controlling Crystallinity in Graft Ionomers, and Its Effect on Morphology, Water Sorption, and Proton Conductivity of Graft Ionomer Membranes

To gain insight into the role of crystallinity and morphology on proton transport through solid polymer electrolytes, we synthesized graft copolymers, poly­(vinylidene difluoride-<i>co</i>-chlorotrifluoroethylene)-<i>g</i>-polystyrene [P­(VDF-<i>co</i>-CTFE)-<i>g</i>-PS], consisting of a hydrophobic, fluorous backbone and styrenic graft chain of varied length (DP_styrene = 39, 62, and 79), by graft atom transfer radical polymerization (ATRP). The polystyrene graft chains were subsequently sulfonated to different degrees to provide three series of polymers with controlled ion exchange capacity (IEC). The crystallinity and morphology of solution-cast membranes were examined by XRD and TEM, respectively. The grafting of the parent side chain is found to hinder crystallization of the fluorous backbone and the impact of the degree of sulfonation of the side chain on the crystallinity of the polymer is dependent on the graft length: No impact is found for medium and long graft lengths, but for short graft length copolymers (PS₃₉), the degree of crystallinity in the sulfonated membranes is twice that of the unsulfonated membrane. A phase-separated morphology consisting of 2–5 (±1) nm ion-rich domains is observed for all of the graft copolymers. These graft copolymers allow access to very high IEC membranes (>3 mmol/g), which are insoluble in water. The shorter graft length series, P­(VDF-<i>co</i>-CTFE)-<i>g</i>-SPS₃₉, swells less in the intermediate IEC range (<3.0 mmol/g) because of its higher degree of crystallinity and lower PS to VDF ratio, and provides membranes with exceptionally high proton conductivity. Two graft series possessing similar weight fraction of PS but different graft density were also examined in order to evaluate the effect of graft density. It was found that lower graft density copolymers possess higher crystallinity and more contiguous PVDF domains, which allow high IEC membranes to be prepared that swell to lower extents