Orthostatic intolerance and autonomic dysfunction following bariatric surgery: A retrospective study and review of the literature

The prevalence and costs of the obesity epidemic and obesity-related conditions, including diabetes mellitus, is consistently increasing worldwide. Bariatric medicine is attempting to address this with weight loss and exercise programmes, and with increasing frequency, various forms of bariatric surgery. There has been considerable success reported after bariatric surgery but not without. We describe 14 patients with orthostatic intolerance (OI) post bariatric surgery. We report on OI (postural dizziness, palpitations and fainting), the results of cardiovascular autonomic testing and the associated and/or causative findings as well as reviewing the literature to consider the possible mechanisms. Comprehensive autonomic testing revealed that 35.7% (Buchwald et al., 2004) of these patients fulfilled the criteria for the Postural Tachycardia Syndrome (PoTS), 57.1% (Cremieux et al., 2008) had low levels of basal BP and 42.9% (Cammisotto & Bendayan, 2007) patients were presyncopal and 14.3% (Billakanty et al., 2008) experienced syncope. We propose that the incidence of OI post-bariatric surgery is higher than considered, that certain cohorts may be more susceptible to complications, and that further research is needed to identify the prevalence and, ideally anticipate occurrence. With the increasing prevalence of obesity and required clinical interventions, further understanding of the pathophysiological processes causing autonomic dysfunction after bariatric interventions will aid management, which may differ in those with an underlying disposition to autonomic involvement, such as diabetics, in whom such procedures are increasingly used

Radial Evolution of Sunward Strahl Electrons in the Inner Heliosphere

The heliospheric magnetic field (HMF) exhibits local inversions, in which the field apparently “bends back” upon itself. Candidate mechanisms to produce these inversions include various configurations of upstream interchange reconnection; either in the heliosphere, or in the corona where the solar wind is formed. Explaining the source of these inversions, and how they evolve in time and space, is thus an important step towards explaining the origins of the solar wind. Inverted heliospheric magnetic field lines can be identified by the anomalous sunward (i.e. inward) streaming of the typically anti-sunward propagating, field-aligned (or anti-aligned), beam of electrons known as the “strahl”. We test if the pitch angle distribution (PAD) properties of sunward-propagating strahl are different from those of outward strahl. We perform a statistical study of strahl observed by the Helios spacecraft, over heliocentric distances spanning ≈0.3 – 1 AU. We find that sunward strahl PADs are broader and less intense than their outward directed counterparts; particularly at distances 0.3 – 0.75 AU. This is consistent with sunward strahl being subject to additional, path-length dependent, scattering in comparison to outward strahl. We conclude that the longer and more variable path from the Sun to the spacecraft, along inverted magnetic field, leads to this additional scattering. The results also suggest that the relative importance of scattering along this additional path length drops off with heliocentric distance. These results can be explained by a relatively simple, constant-rate, scattering process

Investigating the relationship between cardiac interoception and autonomic cardiac control using a predictive coding framework

Predictive coding models, such as the ‘free-energy principle’ (FEP), have recently been discussed in relation to how interoceptive (afferent visceral feedback) signals update predictions about the state of the body, thereby driving autonomic mediation of homeostasis. . This study appealed to ‘interoceptive inference’, under the FEP, to seek new insights into autonomic (dys)function and brain-body integration by examining the relationship between cardiac interoception and autonomic cardiac control in healthy controls and patients with forms of orthostatic intolerance (OI); to (i) seek empirical support for interoceptive inference and (ii) delineate if this relationship was sensitive to increased interoceptive prediction error in OI patients during head-up tilt (HUT)/symptom provocation. Measures of interoception and heart rate variability (HRV) were recorded whilst supine and during HUT in healthy controls (N=20), postural tachycardia syndrome (PoTS, N=20) and vasovagal syncope (VVS, N=20) patients. Compared to controls, interoceptive accuracy was reduced in both OI groups. Healthy controls’ interoceptive sensibility positively correlated with HRV whilst supine. Conversely, both OI groups’ interoceptive awareness negatively correlated with HRV during HUT. Our pilot study offers initial support for interoceptive inference and suggests OI cohorts share a central pathophysiology underlying interoceptive deficits expressed across distinct cardiovascular autonomic pathophysiology. From a predictive coding perspective, OI patients’ data indicates a failure to attenuate/modulate ascending interoceptive prediction errors, reinforced by the concomitant failure to engage autonomic reflexes during HUT. Our findings offer a potential framework for conceptualising how the human nervous system maintains homeostasis and how both central and autonomic processes are ultimately implicated in dysautonomia

'Asexual isn't who I am': the politics of asexuality

Some literature on asexuality has claimed that it is inherently radical and contains the potential for resistance. Unfortunately, this literature has tended to be unempirical, has imagined asexuality as a disembodied entity, and has marginalised the multiple identities held by asexual people. This article, inspired by Plummer’s critical humanist approach, seeks to explore how individuals understand their asexuality to encourage forms of political action in the areas of identity, activism, online spaces, and LGBT politics. What we found was a plurality of experiences and attitudes with most adopting a pragmatic position in response to their social situation which saw large-scale political action as irrelevant. We conclude by reflecting on what these results mean for those who see asexuality as potentially radical

A One Health Framework for the Evaluation of Rabies Control Programmes: A Case Study from Colombo City, Sri Lanka

<div><p>Background</p><p>One Health addresses complex challenges to promote the health of all species and the environment by integrating relevant sciences at systems level. Its application to zoonotic diseases is recommended, but few coherent frameworks exist that combine approaches from multiple disciplines. Rabies requires an interdisciplinary approach for effective and efficient management.</p><p>Methodology/Principal Findings</p><p>A framework is proposed to assess the value of rabies interventions holistically. The economic assessment compares additional monetary and non-monetary costs and benefits of an intervention taking into account epidemiological, animal welfare, societal impact and cost data. It is complemented by an ethical assessment. The framework is applied to Colombo City, Sri Lanka, where modified dog rabies intervention measures were implemented in 2007. The two options included for analysis were the control measures in place until 2006 (“baseline scenario”) and the new comprehensive intervention measures (“intervention”) for a four-year duration. Differences in control cost; monetary human health costs after exposure; Disability-Adjusted Life Years (DALYs) lost due to human rabies deaths and the psychological burden following a bite; negative impact on animal welfare; epidemiological indicators; social acceptance of dogs; and ethical considerations were estimated using a mixed method approach including primary and secondary data. Over the four years analysed, the intervention cost US $1.03 million more than the baseline scenario in 2011 prices (adjusted for inflation) and caused a reduction in dog rabies cases; 738 DALYs averted; an increase in acceptability among non-dog owners; a perception of positive changes in society including a decrease in the number of roaming dogs; and a net reduction in the impact on animal welfare from intermediate-high to low-intermediate.</p><p>Conclusions</p><p>The findings illustrate the multiple outcomes relevant to stakeholders and allow greater understanding of the value of the implemented rabies control measures, thereby providing a solid foundation for informed decision-making and sustainable control.</p></div

Multi-spacecraft study of the solar wind at solar minimum: Dependence on latitude and transient outflows

Context: The recent launches of Parker Solar Probe, Solar Orbiter (SO), and BepiColombo, along with several older spacecraft, have provided the opportunity to study the solar wind at multiple latitudes and distances from the Sun simultaneously. Aims: We take advantage of this unique spacecraft constellation, along with low solar activity across two solar rotations between May and July 2020, to investigate how the solar wind structure, including the heliospheric current sheet (HCS), varies with latitude. Methods: We visualise the sector structure of the inner heliosphere by ballistically mapping the polarity and solar wind speed from several spacecraft onto the Sun’s source surface. We then assess the HCS morphology and orientation with the in situ data and compare this with a predicted HCS shape. Results: We resolve ripples in the HCS on scales of a few degrees in longitude and latitude, finding that the local orientations of sector boundaries were broadly consistent with the shape of the HCS but were steepened with respect to a modelled HCS at the Sun. We investigate how several CIRs varied with latitude, finding evidence for the compression region affecting slow solar wind outside the latitude extent of the faster stream. We also identified several transient structures associated with HCS crossings and speculate that one such transient may have disrupted the local HCS orientation up to five days after its passage. Conclusions: We have shown that the solar wind structure varies significantly with latitude, with this constellation providing context for solar wind measurements that would not be possible with a single spacecraft. These measurements provide an accurate representation of the solar wind within ±10° latitude, which could be used as a more rigorous constraint on solar wind models and space weather predictions. In the future, this range of latitudes will increase as SO’s orbit becomes more inclined

Human α2β1HI CD133+VE epithelial prostate stem cells express low levels of active androgen receptor

Stem cells are thought to be the cell of origin in malignant transformation in many tissues, but their role in human prostate carcinogenesis continues to be debated. One of the conflicts with this model is that cancer stem cells have been described to lack androgen receptor (AR) expression, which is of established importance in prostate cancer initiation and progression. We re-examined the expression patterns of AR within adult prostate epithelial differentiation using an optimised sensitive and specific approach examining transcript, protein and AR regulated gene expression. Highly enriched populations were isolated consisting of stem (α(2)β(1)(HI) CD133(+VE)), transiently amplifying (α(2)β(1)(HI) CD133(-VE)) and terminally differentiated (α(2)β(1)(LOW) CD133(-VE)) cells. AR transcript and protein expression was confirmed in α(2)β(1)(HI) CD133(+VE) and CD133(-VE) progenitor cells. Flow cytometry confirmed that median (±SD) fraction of cells expressing AR were 77% (±6%) in α(2)β(1)(HI) CD133(+VE) stem cells and 68% (±12%) in α(2)β(1)(HI) CD133(-VE) transiently amplifying cells. However, 3-fold lower levels of total AR protein expression (peak and median immunofluorescence) were present in α(2)β(1)(HI) CD133(+VE) stem cells compared with differentiated cells. This finding was confirmed with dual immunostaining of prostate sections for AR and CD133, which again demonstrated low levels of AR within basal CD133(+VE) cells. Activity of the AR was confirmed in prostate progenitor cells by the expression of low levels of the AR regulated genes PSA, KLK2 and TMPRSS2. The confirmation of AR expression in prostate progenitor cells allows integration of the cancer stem cell theory with the established models of prostate cancer initiation based on a functional AR. Further study of specific AR functions in prostate stem and differentiated cells may highlight novel mechanisms of prostate homeostasis and insights into tumourigenesis

Health-economic evaluation of fluocinolone acetonide 190 µg implant in people with diabetic macular edema

Objectives: To assess healthcare resource use and costs of treating people with clinically significant diabetic macular edema (DME) with fluocinolone acetonide (FAc) 190 µg intravitreal implant in routine clinical practice. Methods: The retrospective Iluvien Clinical Evidence (ICE-UK) study collected data on people prescribed the FAc implant in any one of 13 ophthalmology centers between April 1, 2013 and April 15, 2015. Data were collected for 12 months before and after implantation. Standard UK costs were attributed to healthcare resource use. Results: In total, 208 people contributing 233 FAc-treated eyes were selected. Mean age was 68.1 years and 62% were male. The mean (standard deviation, SD) number of anti-vascular endothelial growth factor (anti-VEGF) injections per FAc treated eye in the 12 months prior to implant was 2.8 (2.5), decreasing to 0.6 (1.4) for the same period after implant (p < .001). The corresponding figures for other steroid injections (dexamethasone and triamcinolone) were 0.14 (0.4) before and 0.08 (0.4) after implant (p = .016). There was no statistically significant difference in the number of laser therapies required in the 12 months before and after FAc implant (mean = 0.12 vs 0.11, respectively; p = .626). Overall, mean (SD) healthcare costs were £2,691 (£1,850) before and £1,239 (£1,203) after FAc implant (p < .001). The unit drug and administration cost per FAc implant was £5,680. Conclusions: Excluding the cost of the FAc implant, healthcare costs were significantly reduced in the 12 months post-implant. FAc implant has a duration of 3 years. This needs to be considered when interpreting the cost associated with the FAc implant

Rhesus TRIM5α disrupts the HIV-1 capsid at the inter-hexamer interfaces

TRIM proteins play important roles in the innate immune defense against retroviral infection, including human immunodeficiency virus type-1 (HIV-1). Rhesus macaque TRIM5α (TRIM5αrh) targets the HIV-1 capsid and blocks infection at an early post-entry stage, prior to reverse transcription. Studies have shown that binding of TRIM5α to the assembled capsid is essential for restriction and requires the coiled-coil and B30.2/SPRY domains, but the molecular mechanism of restriction is not fully understood. In this study, we investigated, by cryoEM combined with mutagenesis and chemical cross-linking, the direct interactions between HIV-1 capsid protein (CA) assemblies and purified TRIM5αrh containing coiled-coil and SPRY domains (CC-SPRYrh). Concentration-dependent binding of CC-SPRYrh to CA assemblies was observed, while under equivalent conditions the human protein did not bind. Importantly, CC-SPRYrh, but not its human counterpart, disrupted CA tubes in a non-random fashion, releasing fragments of protofilaments consisting of CA hexamers without dissociation into monomers. Furthermore, such structural destruction was prevented by inter-hexamer crosslinking using P207C/T216C mutant CA with disulfide bonds at the CTD-CTD trimer interface of capsid assemblies, but not by intra-hexamer crosslinking via A14C/E45C at the NTD-NTD interface. The same disruption effect by TRIM5αrh on the inter-hexamer interfaces also occurred with purified intact HIV-1 cores. These results provide insights concerning how TRIM5α disrupts the virion core and demonstrate that structural damage of the viral capsid by TRIM5α is likely one of the important components of the mechanism of TRIM5α-mediated HIV-1 restriction. © 2011 Zhao et al