The roles of prostaglandin E2 and D2 in lipopolysaccharide-mediated changes in sleep

When living organisms become sick as a result of a bacterial infection, a suite of brain-mediated responses occur, including fever, anorexia and sleepiness. Systemic administration of lipopolysaccharide (LPS), a common constituent of bacterial cell walls, increases body temperature and non-rapid eye movement (NREM) sleep in animals and induces the production of pro-inflammatory prostaglandins (PGs). PGE₂ is the principal mediator of fever, and both PGE₂ and PGD₂ regulate sleep–wake behavior. The extent to which PGE₂ and PGD₂ are involved in the effect of LPS on NREM sleep remains to be clarified. Therefore, we examined LPS-induced changes in body temperature and NREM sleep in mice with nervous system-specific knockouts (KO) for the PGE₂ receptors type EP₃ or EP₄, in mice with total body KO of microsomal PGE synthase-1 or the PGD₂ receptor type DP, and in mice treated with the cyclooxygenase (COX) inhibitor meloxicam. We observed that LPS-induced NREM sleep was slightly attenuated in mice lacking EP₄ receptors in the nervous system, but was not affected in any of the other KO mice or in mice pretreated with the COX inhibitor. These results suggest that the effect of LPS on NREM sleep is partially dependent on PGs and is likely mediated mainly by other pro-inflammatory substances. In addition, our data show that the main effect of LPS on body temperature is hypothermia in the absence of nervous system EP₃ receptors or in the presence of a COX inhibitor.     

A systematic integrative review of the literature on midwives and student midwives engaged in problematic substance use

ObjectiveThe objective of this systematic integrative review was to review the literature in relation to problematic substance use (PSU) in midwifery populations. Associated aims were to aggregate existing knowledge about midwives and student midwives’ personal engagement in PSU, to generate a holistic conceptualisation and synthesis of the existing literature regarding midwives and student midwives personally engaged in PSU and to present new understandings and perspectives to inform the development of future research questions. This review is the first of its kind.DesignSystematic searches were conducted in CINAHL, Academic Search Complete, MEDLINE, PSYCInfo, Scopus and the Cochrane Library. Findings were grouped into themes and subthemes relating to both midwives and student midwives and then analysed critically in relation to the wider literature. A quality assessment was conducted using the Mixed Methods Appraisal Tool (MMAT). The PRISMA statement was used to guide reporting.SettingIncluded studies were conducted in Scotland, Ireland, Australia and New Zealand.ParticipantsStudies included a total of 6,182 participants.FindingsA total of 3 studies were included. All included study types comprised quantitative survey designs, yet one also included a mixed methods design with the use of semi structured interviews. Two overarching themes emerged relating to both midwives and student midwives engaged in problematic substance use. For midwives, three subthemes are described: harmful daily alcohol consumption, working hours and harmful daily alcohol consumption and features associated with harmful daily alcohol consumption. For student midwives, two subthemes are presented: escape avoidance and alcohol, tobacco and cannabis use.Key conclusionsThere is limited evidence available in relation to problematic substance use in midwifery populations in comparison to that available for other healthcare populations. Further research is required, and could usefully focus upon midwives and student midwives as distinct professions to be separated out from the wider healthcare workforce.Implications for practiceProblematic substance use among the healthcare workforce is associated with an increase in medical errors and inadequate care. Those affected can be reluctant to seek help, experience psychological distress and even contemplate suicide. Whilst evidence remains lacking for midwifery populations, they form a part of the general healthcare workforce and are exposed to similar workplace stressors. As such, it is likely that they too would be affected in similar ways.     

Pain Trajectories and Predictors: A 7-Year Longitudinal Study of Women With Vulvodynia

IntroductionA significant proportion of women report a reduction of symptoms over time—even without treatment—yet the natural progression of vulvodynia and which factors may explain decrease vs persistence of pain remain unclear.AimTo identify subgroups of pain trajectories in women with vulvodynia and to predict these different trajectories by treatments undertaken, pain characteristics, and psychosocial factors.MethodsData on pain intensity, treatments undertaken, pain characteristics, and psychosocial factors were collected 3 times over a 7-year period from 173 women who screened positive for vulvodynia. Latent class growth analysis was conducted to identify homogeneous subgroups with distinct pain trajectories. A multivariate binomial logistic regression was used to examine whether treatments, pain characteristics, and psychosocial factors predicted these trajectories.Main Outcome MeasureThe main outcome was pain intensity (0–10), measured at 3 time points with the numerical rating scale.Results2 pain trajectories were identified: 1 where pain persisted (28.9%), and 1 where pain decreased over time (71.1%). Whether a treatment had been undertaken was not predictive of the course of pain over time. Women who were older at first pain onset, had pain at another location than the entrance of the vagina, and reported more anxiety were more likely to have a persistent pain trajectory relative to the decreased pain trajectory.Clinical ImplicationsFindings suggest that the evolution of pain differs among women with vulvodynia depending on pain characteristics and anxiety.Strengths & LimitationsStrengths of the study include the 7-year longitudinal design to examine the natural history of provoked vestibulodynia and the inclusion of biopsychosocial factors as predictors of pain trajectories. However, women with major medical and psychiatric illnesses or deep dyspareunia were not included, and, thus, these factors could not be examined as predictors.ConclusionAssessing baseline characteristics associated with different pain trajectories during medical visits could have positive implications for the management of vulvodynia.Pâquet M, Vaillancourt-Morel M-P, Jodouin J-F, et al. Pain Trajectories and Predictors: A 7-Year Longitudinal Study of Women With Vulvodynia. J Sex Med 2019;16:1606–1614.     

Intranasal immunization with protective antigen of Bacillus anthracis induces a long-term immunological memory response

Although intranasal vaccination has been shown to be effective for the protection against inhalational anthrax, establishment of long-term immunity has yet to be achieved. Here, we investigated whether intranasal immunization with recombinant protective antigen (rPA) of Bacillus anthracis induces immunological memory responses in the mucosal and systemic compartments. Intranasal immunization with rPA plus cholera toxin (CT) sustained PA-specific antibody responses for 6 months in lung, nasal washes, and vaginal washes as well as serum. A significant induction of PA-specific memory B cells was observed in spleen, cervical lymph nodes (CLNs) and lung after booster immunization. Furthermore, intranasal immunization with rPA plus CT remarkably generated effector memory CD4⁺ T cells in the lung. PA-specific CD4⁺ T cells preferentially increased the expression of Th1- and Th17-type cytokines in lung, but not in spleen or CLNs. Collectively, the intranasal immunization with rPA plus CT promoted immunologic memory responses in the mucosal and systemic compartments, providing long-term immunity.     

The U.S.-FORTA (Fit fOR The Aged) List: Consensus Validation of a Clinical Tool to Improve Drug Therapy in Older Adults

Background/ObjectivesPolypharmacy and multimorbidity is a threat to older people; hence, listing approaches should support physicians to optimize medication. The FORTA (Fit fOR The Aged) classification of drug appropriateness for older people provides positive or negative labels: A (A-bsolutely), B (B-eneficial), C (C-areful), and D (D-on't). Based on these categories, FORTA-labeled drug lists were developed in 7 European countries or regions; the same approach was used to develop a U.S.-FORTA List reflecting the country-specific availability and usage of drugs.Design/SettingA 2-step Delphi-type approach was employed to add, remove, or relabel drugs from the listing proposal and to add or remove new indications. The proposal utilized the European (EURO)-FORTA list as template.ParticipantsEight US-based geriatricians/pharmacists served as raters. Measurements: Raters gave recommendations and comments on the list items.ResultsThe first U.S.-FORTA List contains 273 items aligned to 27 main indication groups; 30 drugs and drug groups were added, and 23 removed as being unavailable in the United States. The highest percentage of changes in FORTA labels as compared to the EURO-FORTA List occurred for sleep disorders associated with dementia (40%). In 8 indications, the labels for 11 items were different from the proposal. Thus, for the majority of the items (n = 232, 95.5%), the proposals were accepted by the US raters. Only 16 (6.6%) of the proposed items (n = 243) had to be re-evaluated in the second round as a result of inconsistent rating in the first round.Conclusions and ImplicationsThe U.S.-FORTA List addresses the appropriateness of drugs for older people in the United States reflecting country-specific availability, usage, and expert rating. As shown for the FORTA list in Europe, this listing approach is among the few that are clinically validated and improve well-being and geriatric outcomes. The U.S.-FORTA List now largely enhances the global availability of this approach.     

Internalization and cytotoxicity effects of carbon-encapsulated iron nanoparticles in murine endothelial cells: Studies on internal dosages due to loaded mass agglomerates

Carbon-encapsulated iron nanoparticles (CEINs) qualified as metal-inorganic hybrid nanomaterials offer a potential scope for an increasing number of biomedical applications. In this study, we have focused on the investigation of cellular fate and resulting cytotoxic effects of CEINs synthesized using a carbon arc route and studied in murine endothelial (HECa-10) cells. The CEIN samples were characterized as pristine (the mean diameter between 47 and 56 nm) and hydrodynamic (the mean diameter between 270 and 460 nm) forms and tested using a battery of methods to determine the cell internalization extent and cytotoxicity effects upon to the exposures (0.0001–100 μg/ml) in HECa-10 cells. Our studies evidenced that the incubation with CEINs for 24 h is accompanied with substantial changes of Zeta potential in cells which can be considered as a key factor for affecting the membrane transport, cellular distribution and cytotoxicity of these nanoparticles. The results demonstrate that CEINs have entered the endothelial cell through the endocytic pathway rather than by passive diffusion and they were mainly loaded as agglomerates on the cell membrane and throughout the cytoplasm, mitochondria and nucleus. The studies show that CEINs induce the mitochondrial and cell membrane cytotoxicities in a dose-dependent manner resulting from the internal dosages due to CEIN agglomerates. Our results highlight the importance of the physicochemical characterization of CEINs in studying the magnetic nanoparticle–endothelial cell interactions because the CEIN mass agglomerates can sediment more or less rapidly in culture models.