Nicotine inhalant via E-cigarette facilitates sensorimotor function recovery by upregulating neuronal BDNF-TrkB signalling in traumatic brain injury.

BACKGROUND AND PURPOSE: Traumatic brain injury (TBI) causes lifelong physical and psychological dysfunction in affected individuals. The current study investigated the effects of chronic nicotine exposure via E-cigarettes (E-cig) (vaping) on TBI-associated behavioural and biochemical changes. EXPERIMENTAL APPROACH: Adult C57/BL6J male mice were subjected to controlled cortical impact (CCI) followed by daily exposure to E-cig vapour for 6 weeks. Sensorimotor functions, locomotion, and sociability were subsequently evaluated by nesting, open field, and social approach tests, respectively. Immunoblots were conducted to examine the expression of mature brain-derived neurotrophic factor (mBDNF) and associated downstream proteins (p-Erk, p-Akt). Histological analyses were performed to evaluate neuronal survival and neuroinflammation. KEY RESULTS: Post-injury chronic nicotine exposure significantly improved nesting performance in CCI mice. Histological analysis revealed increased survival of cortical neurons in the perilesion cortex with chronic nicotine exposure. Immunoblots revealed that chronic nicotine exposure significantly up-regulated mBDNF, p-Erk and p-Akt expression in the perilesion cortex of CCI mice. Immunofluorescence microscopy indicated that elevated mBDNF and p-Akt expression were mainly localized within cortical neurons. Immunolabelling of Iba1 demonstrated that chronic nicotine exposure attenuated microglia-mediated neuroinflammation. CONCLUSIONS AND IMPLICATIONS: Post-injury chronic nicotine exposure via vaping facilitates recovery of sensorimotor function by upregulating neuroprotective mBDNF/TrkB/Akt/Erk signalling. These findings suggest potential neuroprotective properties of nicotine despite its highly addictive nature. Thus, understanding the multifaceted effects of chronic nicotine exposure on TBI-associated symptoms is crucial for paving the way for informed and properly managed therapeutic interventions.

Nicotine-Mediated Recruitment of GABAergic Neurons to a Dopaminergic Phenotype Attenuates Motor Deficits in an Alpha-Synuclein Parkinson's Model.

Previous work revealed an inverse correlation between tobacco smoking and Parkinson's disease (PD) that is associated with nicotine-induced neuroprotection of dopaminergic (DA) neurons against nigrostriatal damage in PD primates and rodent models. Nicotine, a neuroactive component of tobacco, can directly alter the activity of midbrain DA neurons and induce non-DA neurons in the substantia nigra (SN) to acquire a DA phenotype. Here, we investigated the recruitment mechanism of nigrostriatal GABAergic neurons to express DA phenotypes, such as transcription factor Nurr1 and DA-synthesizing enzyme tyrosine hydroxylase (TH), and the concomitant effects on motor function. Wild-type and α-syn-overexpressing (PD) mice treated with chronic nicotine were assessed by behavioral pattern monitor (BPM) and immunohistochemistry/in situ hybridization to measure behavior and the translational/transcriptional regulation of neurotransmitter phenotype following selective Nurr1 overexpression or DREADD-mediated chemogenetic activation. We found that nicotine treatment led to a transcriptional TH and translational Nurr1 upregulation within a pool of SN GABAergic neurons in wild-type animals. In PD mice, nicotine increased Nurr1 expression, reduced the number of α-syn-expressing neurons, and simultaneously rescued motor deficits. Hyperactivation of GABA neurons alone was sufficient to elicit de novo translational upregulation of Nurr1. Retrograde labeling revealed that a fraction of these GABAergic neurons projects to the dorsal striatum. Finally, concomitant depolarization and Nurr1 overexpression within GABA neurons were sufficient to mimic nicotine-mediated dopamine plasticity. Revealing the mechanism of nicotine-induced DA plasticity protecting SN neurons against nigrostriatal damage could contribute to developing new strategies for neurotransmitter replacement in PD.

A thematic analysis of smokers' and non-smokers' accounts of E-cigarettes.

This study explored smokers' and non-smokers' accounts of E-cigarettes. A total of 51 UK-based participants, 20 men and 31 women, responded to open-ended questions online. Inductive thematic analysis identified that the factors that influence E-cigarette behaviour and opinion in adult smokers and non-smokers are related to social context, informative sources, practical aspects and health implications. Participants presented varying accounts of E-cigarettes, suggesting that individual narratives regarding E-cigarettes are multi-faceted. This is important information for health professionals and policy makers tasked with advising on E-cigarette use.

An investigation of factors encouraging and deterring EC use: a thematic analysis of accounts from UK adults.

OBJECTIVE: This study aimed to explore E-cigarette (EC) accounts from a small sample of UK adults with varied smoking/EC experiences. This was to contribute to existing knowledge of adult perceptions and understand the factors that encourage or deter use to inform health messaging aimed at professionals, policy makers and the general public. DESIGN: Twelve participants, five men and seven women aged 23-55 years (mean age 32.43) with mixed smoking/EC backgrounds took part in face-to-face interviews, analysed using semantic-level inductive thematic analysis. RESULTS: The analysis identified three key themes. Social influence (1) relates to the understanding of the social representations of ECs. Representation and knowledge (2) captures the impact of varied EC related communication on perception. Aspects of addiction (3) conveys aspects of nicotine addiction and how this influences EC use. CONCLUSION: ECs were generally perceived as more socially acceptable than cigarettes by non-smokers, although there were varying levels of acceptability depending on the type of EC device used. There was also unanimity concerning uncertainty surrounding the devices. Behavioural/sensory elements and personal enjoyment of ECs were consistent elements that encouraged or deterred use. Although non-smokers/vapers did not use the devices, they expressed similar apprehensions to those who did.

Exploring Trends and Differences in Health Behaviours of Health Sciences University Students from Germany and England: Findings from the "SuSy" Project.

Objectives: This research aimed to explore the health behaviours of health sciences students over time and across different settings. Methods: A health behaviour surveillance system has been implemented in Hamburg and Manchester among under- and postgraduate health sciences students. Trends among the Hamburg sample were described. In a cross-sectional assessment, health behaviours across both universities were examined using multivariate regression analysis. Results: Between 2014 and 2018, increasing trends in physical activity and cannabis and alcohol consumption were observed in Hamburg (n = 1,366). While fruit and vegetable intake was constantly low, tobacco smoking decreased. No clear trend was observed for stress perception. The comparison (n = 474) revealed that Manchester students had higher odds of smoking, excessive alcohol consumption, and fruit and vegetable consumption; and lower odds of being physically active, and consuming cannabis. No difference in stress perception was observed. Conclusions: Varying trends and potential areas of intervention were identified for health behaviours in Hamburg. The comparison with Manchester students revealed differences in behaviours, which could be further explored to help inform health promotion strategies in both settings.

Chronic presence of blood circulating anti-NMDAR1 autoantibodies impairs cognitive function in mice.

High titers of anti-NMDAR1 autoantibodies in brain cause anti-NMDAR1 encephalitis that displays psychiatric symptoms of schizophrenia and/or other psychiatric disorders in addition to neurological symptoms. Low titers of anti-NMDAR1 autoantibodies are reported in the blood of a subset of the general human population and psychiatric patients. Since ~0.1-0.2% of blood circulating antibodies cross the blood-brain barriers and antibodies can persist for months and years in human blood, it is important to investigate whether chronic presence of these blood circulating anti-NMDAR1 autoantibodies may impair human cognitive functions and contribute to the development of psychiatric symptoms. Here, we generated mice carrying low titers of anti-NMDAR1 autoantibodies in blood against a single antigenic epitope of mouse NMDAR1. Mice carrying the anti-NMDAR1 autoantibodies are healthy and display no differences in locomotion, sensorimotor gating, and contextual memory compared to controls. Chronic presence of the blood circulating anti-NMDAR1 autoantibodies, however, is sufficient to impair T-maze spontaneous alternation in the integrity of blood-brain barriers across all 3 independent mouse cohorts, indicating a robust cognitive deficit in spatial working memory and/or novelty detection. Our studies implicate that chronic presence of low titers of blood circulating anti-NMDAR1 autoantibodies may impair cognitive functions in both the general healthy human population and psychiatric patients.

Elderly patients have increased perioperative morbidity and mortality from oesophagectomy for oesophageal cancer: A systematic review and meta-analysis.

BACKGROUND: Although oesophagectomy remains technically challenging and associated with high morbidity and mortality, it is now increasingly performed in an ever-ageing population with improvement in perioperative care. However, the risks in the elderly population are poorly quantified. The study aims to review the current evidence to quantify further the postoperative risk of oesophagectomy for cancer in the elderly population compared to younger patients. METHOD: A systematic literature search of PubMed, EMBASE and the Cochrane Library databases was conducted including studies reporting oesophagectomy for cancer in the elderly population. A meta-analysis was reported in accordance with the recommendations of the Cochrane Library and PRISMA guidelines. Primary outcome was overall complications and secondary outcomes were pulmonary and cardiac complications, anastomotic leaks, overall and disease-free survival. RESULTS: This review identified 37 studies incorporating 30,836 patients. Increasing age was significantly associated with increased rates of overall complications (OR 1.67, CI95%: 1.42-1.96), pulmonary complications (OR 1.87, CI95%: 1.48-2.35), and cardiac complications (OR: 2.22, CI95%: 1.95-2.53). However, there was no increased risk of anastomotic leak (OR: 0.98, CI95%: 0.85-1.18). Elderly patients were significantly more likely to have lower rates of 5-year overall survival (OR: 1.36, CI95%: 1.11-1.66) and 5-year disease-free survival (OR: 1.72, CI95%: 1.51-1.96). CONCLUSION: Elderly patients undergoing oesophagectomy for cancer are at increased risk of overall, pulmonary and cardiac complications, irrespective of age subgroups, albeit no difference in anastomotic leaks. Therefore, they represent high-risk patients warranting implementation of preoperative pathways such as prehabilitation to improve cardiopulmonary fitness prior to surgery, although benefit of prehabilitation is yet to be proven. This information will also aid future pre-operative counselling and informed consent.

Perioperative outcomes after laparoscopic cholecystectomy in elderly patients: a systematic review and meta-analysis.

BACKGROUND: Laparoscopic cholecystectomy is increasingly performed in an ever ageing population; however, the risks are poorly quantified. The study aims to review the current evidence to quantify further the postoperative risk of cholecystectomy in the elderly population compared to younger patients. METHOD: A systematic literature search of PubMed, EMBASE and the Cochrane Library databases were conducted including studies reporting laparoscopic cholecystectomy in the elderly population. A meta-analysis was reported in accordance with the recommendations of the Cochrane Library and PRISMA guidelines. Primary outcome was overall complications and secondary outcomes were conversion to open surgery, bile leaks, postoperative mortality and length of stay. RESULTS: This review identified 99 studies incorporating 326,517 patients. Increasing age was significantly associated with increased rates of overall complications (OR 2.37, CI95% 2.00-2.78), major complication (OR 1.79, CI95% 1.45-2.20), risk of conversion to open cholecystectomy (OR 2.17, CI95% 1.84-2.55), risk of bile leaks (OR 1.50, CI95% 1.07-2.10), risk of postoperative mortality (OR 7.20, CI95% 4.41-11.73) and was significantly associated with increased length of stay (MD 2.21 days, CI95% 1.24-3.18). CONCLUSION: Postoperative outcomes such as overall and major complications appear to be significantly higher in all age cut-offs in this meta-analysis. This study demonstrated there is a sevenfold increase in perioperative mortality which increases by tenfold in patients > 80 years old. This study appears to confirm preconceived suspicions of higher risks in elderly patients undergoing cholecystectomy and may aid treatment planning and informed consent.

Structural Analysis of Hippocampal Kinase Signal Transduction.

Kinases are a major clinical target for human diseases. Identifying the proteins that interact with kinases in vivo will provide information on unreported substrates and will potentially lead to more specific methods for therapeutic kinase regulation. Here, endogenous immunoprecipitations of evolutionally distinct kinases (i.e., Akt, ERK2, and CAMK2) from rodent hippocampi were analyzed by mass spectrometry to generate three highly confident kinase protein-protein interaction networks. Proteins of similar function were identified in the networks, suggesting a universal model for kinase signaling complexes. Protein interactions were observed between kinases with reported symbiotic relationships. The kinase networks were significantly enriched in genes associated with specific neurodevelopmental disorders providing novel structural connections between these disease-associated genes. To demonstrate a functional relationship between the kinases and the network, pharmacological manipulation of Akt in hippocampal slices was shown to regulate the activity of potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel(HCN1), which was identified in the Akt network. Overall, the kinase protein-protein interaction networks provide molecular insight of the spatial complexity of in vivo kinase signal transduction which is required to achieve the therapeutic potential of kinase manipulation in the brain.

A Quality Improvement Initiative to Increase Colorectal Cancer (CRC) Screening: Collaboration between a Primary Care Clinic and Research Team.

BACKGROUND: Multiple randomized controlled trials have demonstrated that mailed fecal testing programs are effective in increasing colorectal cancer screening participation. However, few healthcare organization in the US have Implemented such programs. METHODS: Stakeholders from one clinic in an integrated healthcare system in Washington State initiated collaboration with researchers with expertise in CRC screening, aiming to increase screening rates at their clinic. Age-eligible individuals who were overdue for CRC screening and had previously completed a fecal test were randomized to receive mailed fecal immunochemical test kits (FIT) at the start of the project (Early) or 6 months later (Late). Outcomes included comparing FIT completion at 6 months by randomization group, and overall CRC screening rates at 12 months. We also assessed implementation facilitators and challenges. RESULTS: Overall 2,421 FIT tests were mailed at a cost of $10,739. At 6 months, FIT completion was significantly higher among the Early compared to the Late group (62% vs.47%, p <0.001). By 12 months, after both groups had received mailings, 71% in each group had completed a FIT. The clinic's overall CRC screening rate was 75.1% at baseline and 78.0% 12 months later. Key constructs associated with successful program implementation included strong stakeholder involvement, use of evidence-based strategies, simplicity, and low cost. Challenges included lack of a plan for maintaining the program. DISCUSSION: Collaboration between clinic stakeholders and researchers led to a successful project that rapidly increased CRC screening rates. However, institutional normalization of the program would be required to maintain it.

Healthy Universities: a guiding framework for universities to examine the distinctive health needs of its own student population.

AIMS: The underlying principle of settings for health is that investments in health are made within social systems in which health is not necessarily the main remit. In order to understand the health needs of its own community, a growing movement of Healthy Universities is interested in applying the approach within the higher education sector. This study examined the student health behaviours of one university so that future initiatives can be tailored to its own student population. METHOD: Quantitative data were gathered from 3,683 students studying at a UK urban university. A 60-question online student questionnaire focusing on seven key topic areas was used to gather data and simple descriptive statistics are used to present key findings. RESULTS: The study has identified a need for considering alternative ways of engaging students with appropriate health services throughout the academic year. A focus for university initiatives around healthy eating options, how to cook healthy food and the importance of keeping hydrated is highlighted as a common need. Risky behaviour involving alcohol, drug and substance use and sexual activity suggests a strong argument for not separating university sexual health and alcohol interventions. CONCLUSION: Underpinned by the Healthy Universities settings concept, this study examined the health and wellbeing behaviours of one university's own student population. It highlights behaviours within the university that are similar to national averages, and some that are not. This understanding can inform the planning of future health promoting university initiatives to meet the distinctive needs of its own students.

Emergency surgery in the elderly: challenges and solutions.

Elderly patients frequently present with surgical emergencies to health care providers, and outcomes in this group of patients remain poor. Contributing factors include frailty, preexisting comorbidity, polypharmacy, delayed diagnosis, and lack of timely and consultant-led treatment. In this review, we address common emergency surgical presentations in the elderly and highlight the specific challenges in caring for these patients. We summarize 20 years of reports by various medical bodies that have aimed to improve the care of these patients. To improve morbidity and mortality, several aspects of care need to be addressed. These include accurate and timely preoperative assessment to identify treatable pathology and, where possible, to consider and correct age-specific disease processes. Identification of patients in whom treatment would be futile or associated with high risk is needed to avoid unnecessary interventions and to give patients and carers realistic expectations. The use of multidisciplinary teams to identify common postoperative complications and age-specific syndromes is paramount. Prevention of complications is preferable to rescue treatment due to the high proportion of patients who fail to recover from adverse events. Even with successful surgical treatment, long-term functional decline and increased dependency are common. More research into emergency surgery in the elderly is needed to improve care for this growing group of vulnerable patients.

A systematic review of transarterial embolization versus emergency surgery in treatment of major nonvariceal upper gastrointestinal bleeding.

BACKGROUND: Emergency surgery or transarterial embolization (TAE) are options for the treatment of recurrent or refractory nonvariceal upper gastrointestinal bleeding. Surgery has the disadvantage of high rates of postoperative morbidity and mortality. Embolization has become more available and has the advantage of avoiding laparotomy in this often unfit and elderly population. OBJECTIVE: To carry out a systematic review and meta-analysis of all studies that have directly compared TAE with emergency surgery in the treatment of major upper gastrointestinal bleeding that has failed therapeutic upper gastrointestinal endoscopy. METHODS: A literature search of Ovid MEDLINE, Embase, and Google Scholar was performed. The primary outcomes were all-cause mortality and rates of rebleeding. The secondary outcomes were length of stay and postoperative complications. RESULTS: A total of nine studies with 711 patients (347 who had embolization and 364 who had surgery) were analyzed. Patients in the TAE group were more likely to have ischemic heart disease (odds ratio [OR] =1.99; 95% confidence interval [CI]: 1.33, 2.98; P=0.0008; I (2)=67% [random effects model]) and be coagulopathic (pooled OR =2.23; 95% CI: 1.29, 3.87; P=0.004; I (2)=33% [fixed effects model]). Compared with TAE, surgery was associated with a lower risk of rebleeding (OR =0.41; 95% CI: 0.22, 0.77; P<0.0001; I (2)=55% [random effects]). There was no difference in mortality (OR =0.70; 95% CI: 0.48, 1.02; P=0.06; I (2)=44% [fixed effects]) between TAE and surgery. CONCLUSION: When compared with surgery, TAE had a significant increased risk of rebleeding rates after TAE; however, there were no differences in mortality rates. These findings are subject to multiple sources of bias due to poor quality studies. These findings support the need for a well-designed clinical trial to ascertain which technique is superior.

The public health view on closing the gap between public health and primary care.

This paper outlines the public health issues relating to the north-west region of England. The role of Primary Care Trusts in addressing the health and well-being issues is described and the development of Teaching Public Health Networks to support capacity and capability building in the public health workforce is outlined. Healthy weight management is used as a case study of how public health and primary care can be brought closer together by describing the role of the Food and Health Action Plan in addressing healthy weight management and its relationship with primary care.

Expression of estrogen receptors alpha and beta in the corpus luteum and uterus from non-pregnant and pregnant llamas.

Because estrogen may be involved in maternal recognition of pregnancy and embryonic migration in llamas, expression of estrogen receptor subtypes alpha (ERalpha) and beta (ERbeta) was evaluated in corpus luteum (CL), endometrium, and uterus using relative RT-PCR. Tissues were recovered from sterile-mated (SM) and pregnant (PG) females during Days 7-11 and 7-13 (Day 0 = day of mating), respectively, and follicular phase and juvenile females. Luteal expression of ERalpha and beta was similar (P > 0.10) in SM and PG females and within Days 7-11, however, expression of ERalpha in ovarian tissue from follicular phase females was greater (P < 0.05) than Days 7 and 9 CL. Uterus expressed less ERalpha and beta compared to endometrium (P = 0.07 and P < 0.01, respectively). Expression of ERalpha was greater (P < 0.05) in Day 7 and follicular phase uteri than Days 9 and 11, Day 13 PG and juvenile uteri. Uterine ERbeta expression was greater (P = 0.09) in PG versus SM females and in mated compared to follicular phase females (P < 0.05). Endometrial expression of ERalpha and beta did not differ (P > 0.10) between SM and PG females or by day. The presence of luteal ER during this period may mean a role for estradiol in maternal recognition of pregnancy. Observed increases in uterine ER expression with no changes in endometrium suggest expression increased in myometrium and/or perimetrium. Upregulation of myometrial ERbeta in PG females may be involved in supporting uterine migration of the embryo.

Estradiol production by preimplantation blastocysts and increased serum progesterone following estradiol treatment in llamas.

Estradiol is a potential candidate for the blastocyst signal responsible for maternal recognition of pregnancy in the llama (Lama glama). Two experiments were conducted to determine if the llama blastocyst produces estradiol during the presumed period of maternal recognition of pregnancy and if exogenous estradiol can extend the luteal phase. In Experiment 1, llamas were superovulated with eCG and mated 7 days later (Day 0=day of mating). Blastocysts were collected nonsurgically on Days 7, 9, or 11 or at necropsy on Days 13 and 15 post-mating and cultured for 48h. Conditioned medium was recovered, replaced with fresh medium at 24-h intervals, and assayed for estradiol-17beta. Estradiol production (pg/blastocyst) over the 48-h culture increased (P<0.05) by day of gestation where more estradiol (P<0.05) was produced by Day 11 compared to Day 7 blastocysts, Day 13 compared to Days 7-11 blastocysts, and Day 15 compared to Days 7-13 blastocysts. A dramatic increase was observed between Days 11 and 13 when estradiol production by Day 13 blastocysts increased (P<0.05) more than 50-fold. In Experiment 2, 30 females were induced to ovulate with hCG (Day 0=day of hCG injection). Starting on Day 7 and continuing through Day 15, animals received daily injections i.m. of 0 (n=11), 5 (n=7), or 10mg (n=12) estradiol benzoate (EB) dissolved in isopropylmyristate. Sera were collected immediately prior to each injection and on Days 16, 17, 18, 20, and 22 and analyzed for progesterone. Progesterone concentrations were greater (P<0.05) on Days 14, 15, 16, and 17 in llamas treated with 10mg EB compared to llamas treated with 0mg EB. These results demonstrate that llama blastocysts produce estradiol and exogenous estradiol can enhance and transiently extend luteal progesterone production. Estradiol produced by the preimplantation llama blastocyst may play a role in maternal recognition of pregnancy and early luteal support.

Iloperidone reduces sensorimotor gating deficits in pharmacological models, but not a developmental model, of disrupted prepulse inhibition in rats.

Iloperidone is a novel atypical antipsychotic which acts as a broad spectrum dopamine/serotonin/norepinephrine receptor antagonist. To compare iloperidone behaviorally to other known antipsychotics, we evaluated the drug in three pharmacological models and one developmental model of disrupted prepulse inhibition (PPI) in rats. Firstly, 0.5 mg/kg apomorphine induced PPI deficits that were prevented by pretreatment with iloperidone (1 and 3 mg/kg). Secondly, treatment with the N-methyl-D-aspartate (NMDA)-receptor antagonist phencyclidine (PCP) produced robust deficits in PPI. Both doses of iloperidone (1 and 3 mg/kg) prevented the PPI-disruptive effects of treatment with 1 mg/kg PCP. Thirdly, treatment with the alpha1-adrenoceptor agonist cirazoline (0.6 mg/kg) disrupted PPI, and produced a concurrent large increase in startle magnitude. A relatively low dose of iloperidone (0.3 mg/kg) prevented cirazoline-induced PPI deficits, independent of its effects on startle magnitude. Finally, iloperidone (1 mg/kg) did not reverse PPI deficits in the isolation-rearing model of schizophrenia. These results indicate that iloperidone exerts behavioral effects in pharmacological models of disrupted sensorimotor gating consistent with "atypical" antipsychotics, mediated by antagonism of dopaminergic and noradrenergic receptors. The absence of effect in isolation-reared rats may be due to the relatively small effect size of isolation rearing on PPI or dose of iloperidone.