Protection of early phase hepatic ischemia-reperfusion injury by cholinergic agonists

BACKGROUND: Cytokine production is critical in ischemia/reperfusion (IR) injury. Acetylcholine binds to macrophages and inhibits cytokine synthesis, through the cholinergic anti-inflammatory pathway. This study examined the role of the cholinergic pathway in cytokine production and hepatic IR- injury. METHODS: Adult male mice underwent 90-min of partial liver ischemia followed by reperfusion. The AChR agonists (1,1-dimethyl-4-phenyl-L-pioperazinium-iodide [DMPP], and nicotine) or saline-vehicle were administered i.p. before ischemia. Plasma cytokine tumor necrosis factor (TNF)-α, macrophage inflammatory protein-2, and Interleukin-6 were measured. Liver injury was assessed by plasma alanine transaminase (ALT) and liver histopathology. RESULTS: A reperfusion time-dependent hepatocellular injury occurred as was indicated by increased plasma-ALT and histopathology. The injury was associated with marked elevation of plasma cytokines/chemokines. Pre-ischemic treatment of mice with DMPP or nicotine significantly decreased plasma-ALT and cytokines after 3 h of reperfusion. After 6 h of reperfusion, the protective effect of DMPP decreased and reached a negligible level by 24 h of reperfusion, despite significantly low levels of plasma cytokines. Histopathology showed markedly diminished hepatocellular injury in DMPP- and nicotine-pretreated mice during the early-phase of hepatic-IR, which reached a level comparable to saline-treated mice at late-phase of IR. CONCLUSION: Pharmacological modulation of the cholinergic pathway provides a means to modulate cytokine production and to delay IR-induced heaptocellular injury

Humans and Insects Decide in Similar Ways

Behavioral ecologists assume that animals use a motivational mechanism for decisions such as action selection and time allocation, allowing the maximization of their fitness. They consider both the proximate and ultimate causes of behavior in order to understand this type of decision-making in animals. Experimental psychologists and neuroeconomists also study how agents make decisions but they consider the proximate causes of the behavior. In the case of patch-leaving, motivation-based decision-making remains simple speculation. In contrast to other animals, human beings can assess and evaluate their own motivation by an introspection process. It is then possible to study the declared motivation of humans during decision-making and discuss the mechanism used as well as its evolutionary significance. In this study, we combine both the proximate and ultimate causes of behavior for a better understanding of the human decision-making process. We show for the first time ever that human subjects use a motivational mechanism similar to small insects such as parasitoids [1] and bumblebees [2] to decide when to leave a patch. This result is relevant for behavioral ecologists as it supports the biological realism of this mechanism. Humans seem to use a motivational mechanism of decision making known to be adaptive to a heterogeneously distributed resource. As hypothesized by Hutchinson et al. [3] and Wilke and Todd [4], our results are consistent with the evolutionary shaping of decision making because hominoids were hunters and gatherers on food patches for more than two million years. We discuss the plausibility of a neural basis for the motivation mechanism highlighted here, bridging the gap between behavioral ecology and neuroeconomy. Thus, both the motivational mechanism observed here and the neuroeconomy findings are most likely adaptations that were selected for during ancestral times

Modelling human choices: MADeM and decision‑making

Research supported by FAPESP 2015/50122-0 and DFG-GRTK 1740/2. RP and AR are also part of the Research, Innovation and Dissemination Center for Neuromathematics FAPESP grant (2013/07699-0). RP is supported by a FAPESP scholarship (2013/25667-8). ACR is partially supported by a CNPq fellowship (grant 306251/2014-0)

Investigation of hospital discharge cases and SARS-CoV-2 introduction into Lothian care homes

Background The first epidemic wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Scotland resulted in high case numbers and mortality in care homes. In Lothian, over one-third of care homes reported an outbreak, while there was limited testing of hospital patients discharged to care homes. Aim To investigate patients discharged from hospitals as a source of SARS-CoV-2 introduction into care homes during the first epidemic wave. Methods A clinical review was performed for all patients discharges from hospitals to care homes from 1st March 2020 to 31st May 2020. Episodes were ruled out based on coronavirus disease 2019 (COVID-19) test history, clinical assessment at discharge, whole-genome sequencing (WGS) data and an infectious period of 14 days. Clinical samples were processed for WGS, and consensus genomes generated were used for analysis using Cluster Investigation and Virus Epidemiological Tool software. Patient timelines were obtained using electronic hospital records. Findings In total, 787 patients discharged from hospitals to care homes were identified. Of these, 776 (99%) were ruled out for subsequent introduction of SARS-CoV-2 into care homes. However, for 10 episodes, the results were inconclusive as there was low genomic diversity in consensus genomes or no sequencing data were available. Only one discharge episode had a genomic, time and location link to positive cases during hospital admission, leading to 10 positive cases in their care home. Conclusion The majority of patients discharged from hospitals were ruled out for introduction of SARS-CoV-2 into care homes, highlighting the importance of screening all new admissions when faced with a novel emerging virus and no available vaccine

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant

Six year follow up of forty five pregnant opiate addicts.

Forty five pregnant addicts had attended the National Drug Treatment Centre between 1984-1986. At that time they received intensive counselling, low dose methandone maintenance and both ante natal and post natal care. Our aim was to follow these women six years later focusing on their drug use and outcome of their children. The women were followed up by chart review, individual interviews and liaison with the social and probation services. Results indicate that a high proportion of the women abused chronically (50%). There is a worryingly high incidence of HIV positive patients (53.4%)and a mortality figure of 15.5% (7). However, only 13 women (28.6%) have had further contact with probation services. Five children (11.3%) are under formal care order and 4 children have become HIV positive in their own right. In conclusion, while these women have benifitted in certain areas e.g. family planning, contact with probation services, in other areas they have remained chaotic e.g. continued drug use or HIV risk taking behaviour. Thus the authors believe the future programmes should concentrate more directly on detoxification and rehabilitation after pregnancy. We also believe that because of the chaotic nature of these women some review of an "at risk" register for the children should be carried out

Hepatitis C infection among injecting drug users attending the National Drug Treatment Centre.

The aim of this research was to quantify the sero-prevalence of antibody to hepatitis C among injecting drug-users and establish whether the harm minimisation programme had had an impact on infection with hepatitis C. A group (n=272) of injecting drug users attending the National Drug Treatment Centre were tested for antibody to hepatitis C virus with a second-generation EIA test. The overall sero-prevalence was found to be 84%. The results suggested that female injecting drug users were involved in greater at-risk behaviour than their male counterparts in relation to hepatitis C, since a significantly higher proportion of females tested positive than males. In relation to the duration of intravenous drug misuse, the researchers found that in patients who had been injecting for two years or more, the sero-prevalence was 95%, while in those with a duration of less than two years it was only 70%. The authors concluded that, in spite of harm reduction programmes, needle sharing continued to occur among drug users during their first two years of injecting

Psychosis and recreational use of MDMA ("ecstasy").

In Dublin there has been an increase in the use of Methylene dioxy methamphetamine (MDMA) or ecstasy among young people. In this case a seventeen-year-old unemployed male attended a drug treatment centre in Dublin with his mother, who had become increasingly worried about his bizarre behaviour. He admitted to taking MDMA over a five-month period, taking approximately 1-2 tablets per week at rave parties. There was evidence of disturbance throughout adolescence, as indicated by behavioural problems and suspensions at school. He had last used MDMA five days previously and almost immediately complained of shivers, cold, sweats, vomiting, and disturbing thoughts. On prior occasions, the patient suffered no adverse affects after using Ecstasy. The patient appeared frightened and had slow, deliberate speech. He exhibited paranoid delusions regarding family members and strangers. He experienced visual hallucinations and third person auditory hallucinations. Routine blood investigation and hepatitis screen were normal, as was the magnetic resonance imaging of the brain