Abstract From a critical review of the evidence on the cholinergic anti-inflammatory pathway and its mode of action, the following conclusions were reached. (1) Both local and systemic inflammation ...may be suppressed by electrical stimulation of the peripheral cut end of either vagus. (2) The spleen mediates most of the systemic inflammatory response (measured by TNF-α production) to systemic endotoxin and is also the site where that response is suppressed by vagal stimulation. (3) The anti-inflammatory effect of vagal stimulation depends on the presence of noradrenaline-containing nerve terminals in the spleen. (4) There is no disynaptic connection from the vagus to the spleen via the splenic sympathetic nerve: vagal stimulation does not drive action potentials in the splenic nerve. (5) Acetylcholine-synthesizing T lymphocytes provide an essential non-neural link in the anti-inflammatory pathway from vagus to spleen. (6) Alpha-7 subunit-containing nicotinic receptors are essential for the vagal anti-inflammatory action: their critical location is uncertain, but is suggested here to be on splenic sympathetic nerve terminals. (7) The vagal anti-inflammatory pathway can be activated electrically or pharmacologically, but it is not the efferent arm of the inflammatory reflex response to endotoxemia.
The handling of missing data is a challenge for inference and regression modelling. A particular challenge is dealing with missing predictor information, particularly when trying to build and make ...predictions from models for use in clinical practice.
We utilise a flexible Bayesian approach for handling missing predictor information in regression models. This provides practitioners with full posterior predictive distributions for both the missing predictor information (conditional on the observed predictors) and the outcome-of-interest. We apply this approach to a previously proposed counterfactual treatment selection model for type 2 diabetes second-line therapies. Our approach combines a regression model and a Dirichlet process mixture model (DPMM), where the former defines the treatment selection model, and the latter provides a flexible way to model the joint distribution of the predictors.
We show that DPMMs can model complex relationships between predictor variables and can provide powerful means of fitting models to incomplete data (under missing-completely-at-random and missing-at-random assumptions). This framework ensures that the posterior distribution for the parameters and the conditional average treatment effect estimates automatically reflect the additional uncertainties associated with missing data due to the hierarchical model structure. We also demonstrate that in the presence of multiple missing predictors, the DPMM model can be used to explore which variable(s), if collected, could provide the most additional information about the likely outcome.
When developing clinical prediction models, DPMMs offer a flexible way to model complex covariate structures and handle missing predictor information. DPMM-based counterfactual prediction models can also provide additional information to support clinical decision-making, including allowing predictions with appropriate uncertainty to be made for individuals with incomplete predictor data.
Advances in scientific computing have allowed the development of complex models that are being routinely applied to problems in disease epidemiology, public health and decision making. The utility of ...these models depends in part on how well they can reproduce empirical data. However, fitting such models to real world data is greatly hindered both by large numbers of input and output parameters, and by long run times, such that many modelling studies lack a formal calibration methodology. We present a novel method that has the potential to improve the calibration of complex infectious disease models (hereafter called simulators). We present this in the form of a tutorial and a case study where we history match a dynamic, event-driven, individual-based stochastic HIV simulator, using extensive demographic, behavioural and epidemiological data available from Uganda. The tutorial describes history matching and emulation. History matching is an iterative procedure that reduces the simulator's input space by identifying and discarding areas that are unlikely to provide a good match to the empirical data. History matching relies on the computational efficiency of a Bayesian representation of the simulator, known as an emulator. Emulators mimic the simulator's behaviour, but are often several orders of magnitude faster to evaluate. In the case study, we use a 22 input simulator, fitting its 18 outputs simultaneously. After 9 iterations of history matching, a non-implausible region of the simulator input space was identified that was 10(11) times smaller than the original input space. Simulator evaluations made within this region were found to have a 65% probability of fitting all 18 outputs. History matching and emulation are useful additions to the toolbox of infectious disease modellers. Further research is required to explicitly address the stochastic nature of the simulator as well as to account for correlations between outputs.
Geoscience methods are increasingly being utilised in criminal, environmental and humanitarian forensic investigations, and the use of such methods is supported by a growing body of experimental and ...theoretical research. Geoscience search techniques can complement traditional methodologies in the search for buried objects, including clandestine graves, weapons, explosives, drugs, illegal weapons, hazardous waste and vehicles. This paper details recent advances in search and detection methods, with case studies and reviews. Relevant examples are given, together with a generalised workflow for search and suggested detection technique(s) table. Forensic geoscience techniques are continuing to rapidly evolve to assist search investigators to detect hitherto difficult to locate forensic targets.
Much progress has been made during the past 30 years with respect to elucidating the neural and endocrine pathways by which bodily needs for water and energy are brought to conscious awareness ...through the generation of thirst and hunger. One way that circulating hormones influence thirst and hunger is by acting on neurones within sensory circumventricular organs (CVOs). This is possible because the subfornical organ and organum vasculosum of the lamina terminalis (OVLT), the sensory CVOs in the forebrain, and the area postrema in the hindbrain lack a normal blood‐brain barrier such that neurones within them are exposed to blood‐borne agents. The neural signals generated by hormonal action in these sensory CVOs are relayed to several sites in the cerebral cortex to stimulate or inhibit thirst or hunger. The subfornical organ and OVLT respond to circulating angiotensin II, relaxin and hypertonicity to drive thirst‐related neural pathways, whereas circulating amylin, leptin and possibly glucagon‐like peptide‐1 act at the area postrema to influence neural pathways inhibiting food intake. As a result of investigations using functional brain imaging techniques, the insula and anterior cingulate cortex, as well as several other cortical sites, have been implicated in the conscious perception of thirst and hunger in humans. Viral tracing techniques show that the anterior cingulate cortex and insula receive neural inputs from thirst‐related neurones in the subfornical organ and OVLT, with hunger‐related neurones in the area postrema having polysynaptic efferent connections to these cortical regions. For thirst, initially, the median preoptic nucleus and, subsequently, the thalamic paraventricular nucleus and lateral hypothalamus have been identified as likely sites of synaptic links in pathways from the subfornical organ and OVLT to the cortex. The challenge remains to identify the links in the neural pathways that relay signals originating in sensory CVOs to cortical sites subserving either thirst or hunger.
Background Major depressive disorder (MDD) has a significant impact on global burden of disease. Complications in clinical management can occur when response to pharmacological modalities is ...considered inadequate and symptoms persist (treatment-resistant depression (TRD)). We aim to investigate inflammation, proxied by C-reactive protein (CRP) levels, and body mass index (BMI) as putative causal risk factors for depression and subsequent treatment resistance, leveraging genetic information to avoid confounding via Mendelian randomisation (MR). Methods We used the European UK Biobank subcohort (formula omitted), the mental health questionnaire (MHQ) and clinical records. For treatment resistance, a previously curated phenotype based on general practitioner (GP) records and prescription data was employed. We applied univariable and multivariable MR models to genetically predict the exposures and assess their causal contribution to a range of depression outcomes. We used a range of univariable, multivariable and mediation MR models techniques to address our research question with maximum rigour. In addition, we developed a novel statistical procedure to apply pleiotropy-robust multivariable MR to one sample data and employed a Bayesian bootstrap procedure to accurately quantify estimate uncertainty in mediation analysis which outperforms standard approaches in sparse binary outcomes. Given the flexibility of the one-sample design, we evaluated age and sex as moderators of the effects. Results In univariable MR models, genetically predicted BMI was positively associated with depression outcomes, including MDD (formula omitted (formula omitted CI): 0.133(0.072, 0.205)) and TRD (0.347(0.002, 0.682)), with a larger magnitude in females and with age acting as a moderator of the effect of BMI on severity of depression (0.22(0.050, 0.389)). Multivariable MR analyses suggested an independent causal effect of BMI on TRD not through CRP (0.395(0.004, 0.732)). Our mediation analyses suggested that the effect of CRP on severity of depression was partly mediated by BMI. Individuals with TRD (formula omitted) observationally had higher CRP and BMI compared with individuals with MDD alone and healthy controls. Discussion Our work supports the assertion that BMI exerts a causal effect on a range of clinical and questionnaire-based depression phenotypes, with the effect being stronger in females and in younger individuals. We show that this effect is independent of inflammation proxied by CRP levels as the effects of CRP do not persist when jointly estimated with BMI. This is consistent with previous evidence suggesting that overweight contributed to depression even in the absence of any metabolic consequences. It appears that BMI exerts an effect on TRD that persists when we account for BMI influencing MDD. Keywords: Mendelian randomisation, Body mass index, Depression
Key points
It is believed that the CNS controls inflammation via the autonomic nervous system, but the strength of this action and the neural pathways responsible are unclear.
In anaesthetized rats ...we measured the inflammatory response to lipopolysaccharide (LPS, 60 μg kg−1, i.v.) by plasma tumour necrosis factor α (TNFα) levels 90 min later.
Bilateral section of the splanchnic sympathetic nerves before LPS treatment resulted in a 5‐fold increase in the plasma TNFα response, but bilateral vagotomy had no effect.
LPS treatment strongly increased efferent activity in the splanchnic sympathetic nerve and its splenic branch; vagotomy did not affect this.
These results show that, besides directly stimulating inflammation, LPS engages a powerful anti‐inflammatory reflex that can inhibit the plasma TNFα response by 80%.
The reflex efferent arm is in the splanchnic sympathetic nerves; the vagi play no part.
We investigated a neural reflex that controls the strength of inflammatory responses to immune challenge – the inflammatory reflex. In anaesthetized rats challenged with intravenous lipopolysaccharide (LPS, 60 μg kg−1), we found strong increases in plasma levels of the key inflammatory mediator tumour necrosis factor α (TNFα) 90 min later. Those levels were unaffected by previous bilateral cervical vagotomy, but were enhanced approximately 5‐fold if the greater splanchnic sympathetic nerves had been cut. Sham surgery had no effect, and plasma corticosterone levels were unaffected by nerve sections, so could not explain this result. Electrophysiological recordings demonstrated that efferent neural activity in the splanchnic nerve and its splenic branch was strongly increased by LPS treatment. Splenic nerve activity was dependent on inputs from the splanchnic nerves: vagotomy had no effect on the activity in either nerve. Together, these data demonstrate that immune challenge with this dose of LPS activates a neural reflex that is powerful enough to cause an 80% suppression of the acute systemic inflammatory response. The efferent arm of this reflex is in the splanchnic sympathetic nerves, not the vagi as previously proposed. As with other physiological responses to immune challenge, the afferent pathway is presumptively humoral: the present data show that vagal afferents play no measurable part. Because inflammation sits at the gateway to immune responses, this reflex could play an important role in immune function as well as inflammatory diseases.
Sex as a biological variable has been the focus of increasing interest. Relatively few studies have focused, however, on differences in peripheral taste function between males and females. ...Nonetheless, there are reports of sex-dependent differences in chemosensitivity in the gustatory system. The involvement of endogenous changes in ovarian hormones has been suggested to account for taste discrepancies. Additionally, whether sex differences exist in taste receptor expression, activation, and subsequent signaling pathways that may contribute to different taste responsiveness is not well understood. In this study, we show the presence of both the nuclear and plasma membrane forms of estrogen receptor (ER) mRNA and protein in mouse taste cells. Furthermore, we provide evidence that estrogen increases taste cell activation during the application of fatty acids, the chemical cue for fat taste, in taste receptor cells. We found that genes important for the transduction pathway of fatty acids vary between males and females and that these differences also exist across the various taste papillae. In vivo support for the effect of estrogens in taste cells was provided by comparing the fatty acid responsiveness in male, intact female, and ovariectomized (OVX) female mice with and without hormone replacement. In general, females detected fatty acids at lower concentrations, and the presence of circulating estrogens increased this apparent fat taste sensitivity. Taken together, these data indicate that increased circulating estrogens in the taste system may play a significant role in physiology and chemosensory cellular activation and, in turn, may alter taste-driven behavior.
Using molecular, cellular, and behavioral analyses, this study shows that sex differences occur in fat taste in a mouse model. Female mice are more responsive to fatty acids, leading to an overall decrease in intake and fatty acid preference. These differences are linked to sex hormones, as estradiol enhances taste cell responsiveness to fatty acids during periods of low circulating estrogen following ovariectomy and in males. Estradiol is ineffective in altering fatty acid signaling during a high-estrogen period and in ovariectomized mice on hormone replacement. Thus, taste receptor cells are a direct target for actions of estrogen, and there are multiple receptors with differing patterns of expression in taste cells.
The ‘inflammatory reflex’ acts through efferent neural connections from the central nervous system to lymphoid organs, particularly the spleen, that suppress the production of inflammatory cytokines. ...Stimulation of the efferent vagus has been shown to suppress inflammation in a manner dependent on the spleen and splenic nerves. The vagus does not innervate the spleen, so a synaptic connection from vagal preganglionic neurons to splenic sympathetic postganglionic neurons was suggested. We tested this idea in rats. In a preparatory operation, the anterograde tracer DiI was injected bilaterally into the dorsal motor nucleus of vagus and the retrograde tracer Fast Blue was injected into the spleen. On histological analysis 7–9 weeks later, 883 neurons were retrogradely labelled from the spleen with Fast Blue as follows: 89% in the suprarenal ganglia (65% left, 24% right); 11% in the left coeliac ganglion; but none in the right coeliac or either of the superior mesenteric ganglia. Vagal terminals anterogradely labelled with DiI were common in the coeliac but sparse in the suprarenal ganglia, and confocal analysis revealed no putative synaptic connection with any Fast Blue‐labelled cell in either ganglion. Electrophysiological experiments in anaesthetized rats revealed no effect of vagal efferent stimulation on splenic nerve activity or on that of 15 single splenic‐projecting neurons recorded in the suprarenal ganglion. Together, these findings indicate that vagal efferent neurons in the rat neither synapse with splenic sympathetic neurons nor drive their ongoing activity.
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