The Relationship Between Immune and Inflammatory Markers and Short-term Clinical Outcomes after Stroke: Side Matters.

BACKGROUND: The two cerebral hemispheres influence the immune response differently. While the left hemisphere enhances cellular immunity, the right hemisphere inhibits it. OBJECTIVES: To determine whether immune and inflammatory markers correlated with stroke severity and hospitalization duration as a function of stroke side. METHODS: The study included 137 patients with unilateral ischemic stroke. The medical records were reviewed for demographic and clinical laboratory data, including C-reactive protein (CRP), white blood cell (WBC) count, its differential stroke side and stroke severity according to the National Institute of Health Stroke Scale (NIHSS), and length of hospital stay (LOS). We examined differences between right side (RS) and left side (LS) stroke on immune and inflammatory markers and compared correlations between these markers and NIHSS and LOS as a function of stroke side. RESULTS: RS stroke patients had higher CRP and monocytes than LS stroke patients. In RS stroke patients, CRP, total WBC, and lymphocyte levels positively correlated with both NIHSS and LOS, whereas levels of neutrophils were positively correlated with NIHSS alone. No correlations were found for LS stroke patients. CONCLUSIONS: Immune-inflammatory markers correlated with stroke severity and LOS only in patients with RS stroke. Neuroimmunological processes influence short-term clinical outcomes after stroke, especially considering the differential effects of the hemispheres on immunity. Prospective studies that evaluate long-term clinical outcomes are needed. Testing the effects of anti-inflammatory treatments on prognosis of RS stroke patients should be considered.

Cognitive assessment in patients treated by immunotherapy: the prospective Cog-Immuno trial.

BACKGROUND: The discovery of the importance of the immune system and its role in oncogenesis led to the development of immunotherapy, a treatment that represents a major advance in oncology management. Due to the recent nature of immunotherapy, little is known about its side effects and their impact on quality of life. To date, there is no published study that accurately assesses the impact of immunotherapy on cognition, mood and/or fatigue in patients treated for cancer, despite potential neurological toxicities. The purpose of this study is to prospectively assess the incidence of cognitive impairment and cognitive complaints among cancer patients naïve for immunotherapy without concomitant anti-cancer treatment. METHODS: The Cog-Immuno trial is a multicentre longitudinal study addressing patients with cancer candidate to receive immunotherapy alone (n = 100). Immunotherapy treatment will include either anti-PD1/PDL1 or anti-CTLA4 monotherapy or combination therapy. Cognitive and quality of life assessment, electrocardiogram (ECG) and biological tests will be performed at baseline, thereafter 3, and 6 months after immunotherapy initiation. The primary endpoint is the proportion of patients treated by immunotherapy who will experience a decline in cognitive performances or in Montreal Cognitive Assessment (MoCA) score within 3 months after inclusion. Secondary endpoints concern: anxiety, depression, fatigue, clinical characteristics, biological data and neurophysiological measures (heart rate variability and hemispheric lateralization). A pre-clinical study will be conducted in cancer bearing mice receiving checkpoint inhibitors (ICI) with the evaluation of cognitive functions and emotional reactivity, collection of blood samples and investigation of neurobiological mechanisms from brain slices. DISCUSSION: Assessing and understanding the incidence and the severity of cognitive impairment and its impact on quality of life in cancer patients treated by immunotherapy is a major issue. The results of this study will provide information on the impact of these treatments on cognitive functions in order to help the physicians in the choice of the treatment. TRIAL REGISTRATION: NCT03599830, registered July 26, 2018. PROTOCOL VERSION: Version 5.1 dated from 2020/10/02.

Suicide in Flanders, Belgium, after terrorist attacks.

Little is known about the association between terrorism and suicide. This study investigates suicide numbers in Flanders, Belgium before and after the Paris-attacks (13/11/2015) and Brussels-attacks (22/03/2016). Population mortality data for suicide were gathered from the Agency for healthcare. Suicides in Flanders, Belgium, were higher after both attacks. The increase was higher after the Paris-attacks, compared to the attacks in Brussels, Belgium. The effect of a close-by, but still foreign attack (the Paris-attacks in France) on suicide numbers is larger than that of an attack inside the country (the Brussels-attacks), possibly due to a difference in threat experience and coping possibilities.

Association Between Symptoms of Central Sensitization and Cognitive Behavioral Factors in People With Chronic Nonspecific Low Back Pain: A Cross-sectional Study.

OBJECTIVE: The objective of this cross-sectional study was to analyze the relationship between symptoms of central sensitization (CS) and important cognitive behavioral and psychosocial factors in a sample of patients with chronic nonspecific low back pain. METHODS: Participants with chronic nonspecific low back pain for at least 3 months were included in the study. They completed several questionnaires and a functional test. Pearson's correlation was used to analyze associations between symptoms of CS and pain behavior, functioning, pain, pain catastrophizing, kinesiophobia, and illness perceptions. Additionally, a between-group analysis was performed to compare patients with and without clinically relevant symptoms of CS. RESULTS: Data from 38 participants were analyzed. Significant associations were found between symptoms of CS and all other outcomes, especially current pain (r = 0.510, P = .001), mean pain during the past 7 days (r = 0.505, P = .001), and pain catastrophizing (r = 0.518, P = .001). Patients with clinically relevant symptoms of CS scored significantly worse on all outcomes compared with persons without relevant symptoms of CS, except on functioning (P = .128). CONCLUSIONS: Symptoms of CS were significantly associated with psychosocial and cognitive behavioral factors. Patients exhibiting a clinically relevant degree of symptoms of CS scored significantly worse on most outcomes, compared with the subgroup of the sample with fewer symptoms of CS.

The Relationship between Exposure to Missiles and PTSD Symptoms as a Function of Hemispheric Preference in Israelis.

Recent research proposes that left hemispheric lateralization (HL) may protect against the effects of life events on mental distress. This study extends these findings by examining the protective role of left HL in the relationship between war threat (missile exposure) and PTSD symptoms. A sample of 186 Israelis, exposed to missile attacks, completed brief scales of self-reported missile exposure, a subjective and a neuropsychological HL measure, and of PTSD symptoms. The sample was split into right HL and left HL individuals on both HL measures. Self-reported missile exposure was positively associated with PTSD symptoms in right HL, but not in left HL individuals on both HL measures. These results replicate, extend our previous results and suggest that left HL may even protect against the effects of severe life threatening events. Results are discussed in relation to neuropsychological and neurophysiological differences between the hemispheres.

Life events are positively associated with luteinizing hormone in middle age adult men: role of cortisol as a third variable.

Previous studies have tested the relationship between chronic stress and sex hormones, but inconsistent results have been found. One possibility is that this association may depend on other biological factors. This study examined the relationship between stressful life events (LE) and sex hormones in men, and whether cortisol is involved in this relationship. From a total number of 2906 men who completed a screening for the early detection of prostate cancer, 139 healthy men (mean ± SD age, 57.8 ± 5.7 years) were included in this study. Participants were assessed with the Holmes and Rahe questionnaire in relation to their experience of LE during the previous 1-5 years. Salivary and serum cortisol was measured at 08:00-09:00 h, as well as luteinizing hormone (LH), total testosterone, epinephrine (E) and norepinephrine (NE). LE weight sum and LE number positively correlated with LH (r = 0.293, p = 0.004; r = 0.220, p = 0.031, respectively). In a multiple regression analysis, LE-sum explained an additional and significant 10.4% of the variance in LH levels, after statistically controlling for the effects of age, waist circumference (WC) and BMI (F(1,90) = 6.61, p < 0.05). Importantly, cortisol interacted with LE in relation to total testosterone. In men with high cortisol values (≥15.4 µg/dl), there was a statistically significant positive relationship between LE number and total testosterone levels (p = 0.05), while LE were unrelated to total testosterone in men with low cortisol. LE correlated with sex hormones, predicting LH values, and in men with high cortisol levels shows a possible moderator effect of cortisol on the relationship between LE and total testosterone.

Prospective relationship between hemispheric lateralisation and CD4+ T cells in human immunodeficiency virus type 1.

OBJECTIVES: Neuromodulation of the immune system has been proposed to be influenced by hemispheric lateralisation (HL). The present study tested whether HL predicted CD4+ levels, statistically controlling for confounders. METHODS: Employing two assessments of HL, 68 human immunodeficiency virus (HIV)-1+ patients were followed prospectively. Numerous exclusion criteria and confounder assessments were employed (e.g. age/medication). RESULTS: Left HL significantly positively predicted CD4+ levels at follow-up, and this was qualified by medication (HAART) status: only in HAART-naïve patients did HL predict CD4 levels. Furthermore, HL significantly predicted whether patients had clinically significantly high/low CD4+ counts. CONCLUSIONS: Using a more rigorous methodology than a previous study, the present work partly corroborated the theory of HL influences on immunity, extended it to HIV immunity and identified a possible moderator: HAART medication. Implications for future research and treatments are provided.

Indirect Exposure to Atrocities and Post-Traumatic Stress Disorder Symptoms among Aid Workers: Hemispheric Lateralization Matters.

Background: Humanitarian aid workers (HAWs) are indirectly exposed to atrocities relating to people of concern (POC). This may result in a risk of secondary traumatization demonstrated by post-traumatic stress symptoms (PTSSs). Previous studies have demonstrated that hemispheric lateralization (HL) moderates the relationship between threat exposure and post-traumatic stress symptoms (PTSSs). Aims: We hypothesized that indirect exposure to atrocities (IETA) would be positively correlated with PTSSs among HAWs with right and not left HL. Method: Fifty-four HAWs from several countries that provided humanitarian support in Greece and Colombia participated in this correlational and cross-sectional observation study. They completed scales relating to IETA, PTSSs were assessed using a brief, valid scale, and HL was measured. Results: IETA was positively and significantly related to PTSSs (r = 0.39, p < 0.005). Considering HL, IETA was unrelated to PTSSs among people with right HL (r = 0.29, p = 0.14), while IETA was related to PTSSs among people with left HL (r = 0.52, p = 0.008). Right HL emerged as a protective factor in the relationship between IETA and PTSS. Conclusions: An assessment of dominant HL can serve as one consideration among others when deploying HAWs in specific locations and roles, vis à vis IETA. Moreover, those found to have a higher risk for PTSSs based on their HL could be monitored more closely to prevent adverse reactions to IETA.

Relationship between cortisol, life events and metabolic syndrome in men.

Psychological factors and stressful life events (LE) are considered to play a role in the onset of the metabolic syndrome (MS). We tested the association between LE and cortisol, a marker of chronic stress, with the risk of developing MS and their interaction. From a total number of 2906 men who completed a screening for the early detection of prostate cancer, 149 healthy men (mean ± SD age, 58.6 ± 7.7 years) were included in this study. Participants were assessed by the Holmes and Rahe questionnaire about their experience of LE during the previous 1-5 years. MS was diagnosed according to National Cholesterol Education Program-Adult Treatment Panel III (ATP-III) and International Diabetes Federation (IDF) criteria. Serum cortisol was measured at 08:00-09:00 h. Participants with MS (IDF criteria) reported significantly more past LE (p = 0.009) and greater summed weight of LE (p = 0.049) than those without MS. Furthermore, LE interacted with cortisol in relation to MS: in men with increased serum cortisol levels ( ≥ 13.7 µg/dl), number of LE significantly predicted MS-status (relative risk (RR) = 1.16, p = 0.03), whereas in men with low cortisol, LE were unrelated to MS (p = 0.52). We conclude that LE were significantly more prevalent in men with the MS than without the MS, according to IDF criteria, independent of the effects of age and body mass index, especially in men with increased serum cortisol levels.

Written emotional disclosure for women with ovarian cancer and their partners: randomised controlled trial.

OBJECTIVE: Written emotional disclosure for 15-20 min a day over 3 to 4 days improves physical and psychological health and may benefit cancer patients. However, no studies have tested the effectiveness of guided writing in cancer patients and their partners. A randomised controlled trial tested whether writing about the patient's diagnosis and treatment of ovarian cancer using the Guided Disclosure Protocol (GDP) is effective in reducing perceived stress and improving quality of life (QoL) in ovarian cancer couples. The study also tested two theories that may account for beneficial effects of written emotional disclosure, the cognitive processing hypothesis and the social interaction hypothesis. METHODS: Patients and their partners (N = 102 couples) were randomised to write at home for 15 min a day over 3 days about the patient's diagnosis and treatment using the GDP or what the patient did the previous day (control). Couples were assessed at baseline, 3- and 6-month follow-ups on the primary outcomes of perceived stress and QoL and secondary outcomes of intrusive thoughts (testing the cognitive processing hypothesis) and illness-related couple communication (testing the social interaction hypothesis). RESULTS: There were no main effects for any outcomes. However, in patients, the GDP improved QoL if illness-related couple communication improved and buffered the effect of intrusive thoughts on perceived stress. CONCLUSIONS: The GDP might benefit patients in certain circumstances, through changes in communication (in line with the social interaction hypothesis). Further research is needed to determine whether patients benefit from interventions to improve illness-related couple communication and under which conditions.

The Vagal Nerve, Inflammation, and Diabetes-A Holy Triangle.

Type 2 diabetic mellitus (T2DM) is a common chronic disease and a substantial risk factor of other fatal illnesses. At its core is insulin resistance, where chronic low-level inflammation is among its main causes. Thus, it is crucial to modulate this inflammation. This review paper provides scientific neuroimmunological evidence on the protective roles of the vagal nerve in T2DM. First, the vagus inhibits inflammation in a reflexive manner via neuroendocrine and neuroimmunological routes. This may also occur at the level of brain networks. Second, studies have shown that vagal activity, as indexed by heart-rate variability (HRV), is inversely related to diabetes and that low HRV is a predictor of T2DM. Finally, some emerging evidence shows that vagal nerve activation may reduce biomarkers and processes related to diabetes. Future randomized controlled trials are needed to test the effects of vagal nerve activation on T2DM and its underlying anti-inflammatory mechanisms.

Effects of an automatized psychological inoculation (PI) intervention on anxiety, resilience and adherence to COVID-19 recommendations.

OBJECTIVES: The covid-19 pandemic calls for adherence to multiple health behaviours. While authorities mostly use health information to deal with these issues, such an approach may be insufficient. This study examined the effects of a cognitive method, namely psychological inoculation (PI) + health information (experimental) versus health information alone (control) on anxiety, resilience and adherence. DESIGN: A randomized controlled trial was used. Participants were assigned to the experimental or control conditions, all provided on an automatized computerized system. MAIN OUTCOME MEASURES: These included anxiety, adherence to the Covid-19 Israeli health ministry's recommendations, and mental resilience. Participants were assessed before, immediately after and a week after the interventions. RESULTS: Controls increased only in adherence at 1 week compared to baseline. In contrast, those in the PI increased in resilience and adherence and reported lower anxiety immediately after treatment compared to baseline levels. In the PI condition, degree of refuting challenging sentences correlated with less anxiety. CONCLUSIONS: Results showed better immediate improvements in anxiety, resilience and intention to adhere in the experimental condition compare to the controls. Authorities may wish to add PI to help the public deal with the effects of such a pandemic and to increase adherence to health recommendations.

Vagal Nerve Activity and Short-Term Clinical Outcomes after Stroke: What Is Left May Not Be Right.

Stroke is a leading cause of death worldwide. Multiple factors influence the severity of stroke. Normal functional and biological differences seen between the hemispheres may also be related to stroke severity. In the present study, we examined the differences in the severity of stroke as a function of stroke side, and whether patients' vagal nerve activity moderated such differences. We included 87 patients with an ischemic stroke, whose medical records were retrospectively examined for background information (age, gender), stroke side and severity by NIHSS, length of stay in hospital, inflammation such as C-reactive protein, and vagal nerve activity. The vagal activity was indexed by patients' heart-rate variability (HRV), fluctuations in the intervals between normal heartbeats, derived from patients' ECG. Results revealed that patients with left-side stroke had significantly worse NIHSS scores (10.6) than those with right-sided stroke (7.6, p < 0.05). However, when dividing the sample into those with low versus high HRV (at the median), only when HRV was low, did patients with left-side stroke have a worse NIHSS score (10.9) compared to those with right-sided stroke (6.5, p < 0.05). In contrast, no differences in stroke severity were seen between left stroke (10.2) and right stoke (8.7, p > 0.05), when HRV was high. These results tended to remain the same when statistically controlling for age effects, which was related to NIHSS, but not to the stroke side. These findings suggest that patients with left-sided stroke may have more severe strokes than those with right-sided ones, but that adequate vagal nerve activity may protect against such differences. Possible mechanisms and suggestions for future directions are provided.

Associations Between Implicit and Explicit Condom Use Measures With Condom Use Barriers: Relationships Make A Difference.

OBJECTIVE: The association between explicit and implicit psychological measures might be affected by the similarity of the assessment method and by the overlap of the components of the constructs being assessed. This study examined the association between condom use barriers and explicit and implicit measurements of condom use and the moderating role of sexual intercourse in these associations. DESIGN: This was a cross sectional correlational study. An analysis of baseline data from a randomized controlled trial including 149 university students was included. MAIN MEASURES: These included a questionnaire assessing condom use barriers, an implicit condom use test (a structured semi-projective test), and an explicit condom use question. Hierarchical regressions and correlations were examined in the full sample and by groups of participants with and without sexual intercourse. RESULTS: In those without sexual intercourse, all barriers sub-scales were significantly and negatively correlated with implicit condom use and unrelated to explicit condom use. In contrast, among those engaged in sexual intercourse, barriers were significantly and negatively correlated with the explicit condom use measure, and only barriers concerning partner and motivation correlated with implicit condom use tendencies. CONCLUSION: Having a sexual partner plays a major role in the relations between barriers and implicit and explicit condom use measures. The pattern of the results is discussed in relation to cognitive and social factors.

Linear and non­linear indices of vagal nerve in relation to sex and inflammation in patients with Covid­19.

Hyperinflammation is one of the most important pathophysiological risk factors for poor prognosis in patients with coronavirus disease-2019 (Covid-19). Low vagal neuro-immune modulation can lead into this kind of immune dysregulation. The association between vagal activity, sex and inflammatory markers were investigated in patients with Covid-19. A total of 19 patients with Covid-19 were included in the present study. Vagus nerve activity was indexed by heart rate variability (HRV) derived from electrocardiogram at hospital admission. Linear HRV parameters included the root mean square of successive RR interval differences (RMSSD) and high-frequency HRV (HF-HRV), while non-linear parameters included 2 UV%. Immune/inflammatory parameters included C-reactive protein (CRP), interleukin-6 (IL-6), neutrophil/lymphocyte ratio (NLR), systemic inflammatory index (SII), and procalcitonin (PCT). It has been revealed that both linear HRV indices HF-HRV and RMSSD, are significantly negatively correlated with CRP and IL-6, independent of age. The non-linear index of 2 UV% is significantly negatively correlated with NLR and SII, which reflect subtle changes in the response of immunocompetent cells. Patients that received high-flow nasal oxygen therapy had significantly higher IL-6 and CRP levels and lower levels of HF-HRV and RMSSD. These patients also had a significantly longer length of stay in hospital (LOS) than patients receiving low-flow oxygen therapy. Men had higher plasma PCT levels and longer LOS in hospital than women, and PCT statistically explained (mediated) the association between sex and LOS. The present study showed different correlations of linear and non-linear vagal indexes of HRV and inflammatory markers in patients with Covid-19. Significant sex differences in certain inflammatory markers were also observed, which may very well verify previous findings of poor prognosis in men with Covid-19. HRV reflects a continuous interaction between the sympathetic and parasympathetic autonomic nervous systems, which are affected by mental or physical stress, and certain disease states. The increased sympathetic and decreased parasympathetic vagal tone contribute to a higher risk of diseases associated with inflammation, cardiovascular disease, cancer, pulmonary diseases and other pathologies, including infectious diseases such as Covid-19. The present study showed that higher RMSSD (a marker of vagal activity) in Covid-19 patients is associated with lower levels of inflammatory biomarkers, a lower need for treatment and is negatively correlated with intensive care unit admission, leading to a shorter hospital stay. These findings support the idea that activation of vagus nerve may help certain Covid-19 patients by reducing the cytokine storm and excessive inflammation.

Prognostic implications of ultra-short heart rate variability indices in hospitalized patients with infective endocarditis.

BACKGROUND: Infective endocarditis (IE) is a disease that poses a serious health risk. It is important to identify high-risk patients early in the course of their treatment. In the current study, we evaluated the prognostic value of ultra-short heart-rate variability (HRV), an index of vagal nerve activity, in IE. METHODS: Retrospective analysis was performed on adult patients admitted to a tertiary hospital due to IE. A logistic regression (LR) was used to determine whether clinical, laboratory, and HRV parameters were predictive of specific clinical features (valve type, staphylococcal infection) or severe short-term complications (cardiac, metastatic infection, and death). The accuracy of the model was evaluated through the measurement of the area under the curve (AUC) of the receiver operating characteristic curve (ROC). An analysis of survival was conducted using Cox regression. A number of HRV indices were calculated, including the standard deviation of normal heart-beat intervals (SDNN) and the root mean square of successive differences (RMSSD). RESULTS: 75 patients, aged 60.3(±18.6) years old, were examined. When compared with published age- and gender-adjusted HRV norms, SDNN and RMSSD were found to be relatively low in our cohort (75%-76% lower than the median; 33%-41% lower than the 2nd percentile). 26(34.6%) patients developed a metastatic infection, with RMSSD<7.03ms (adjusted odds ratio (aOR) 9.340, p = 0.002), incorporated in a multivariate LR model (AUC 0.833). Furthermore, 27(36.0%) patients were diagnosed with Staphylococcus IE, with SDNN<4.92ms (aOR 5.235, p = 0.004), a major component of the multivariate LR model (AUC 0.741). Multivariate Cox regression survival model, included RMSSD (HR 1.008, p = 0.012). CONCLUSION: SDNN, and particularly RMSSD, derived from ultra-short ECG recordings, may provide prognostic information about patients presenting with IE.

Vagal Nerve Activity Predicts Prognosis in Diffused Large B-Cell Lymphoma and Multiple Myeloma.

This study examined the prognostic role of vagal nerve activity in patients with relapsed/refractory diffused large B-cell lymphoma (R/R-DLBCL) treated with chimeric antigen receptor cell therapy (CAR-T) and in patients with multiple myeloma (MM) undergoing an autologous hematopoietic cell transplantation (AutoHCT). Participants included 29 patients with R/R-DLBCL and 37 patients with MM. Inclusion criteria were: (1) age over 18; (2) diagnosed with DLBCL or MM; (3) being treated with CAR-T or AutoHCT; and (4) having an ECG prior to cell transfusion. The predictor was vagal nerve activity indexed by heart rate variability (HRV) and obtained retroactively from 10 s ECGs. The main endpoint for R/R-DLBCL was overall survival (OS), and for MM the endpoint was progression-free survival (PFS). Data of 122 patients were obtained, 66 of whom were included in the study. In DLBCL, HRV significantly predicted OS independently of confounders (e.g., performance status, disease status at cell therapy), hazard ratio (HR), and 95% confidence interval (HR = 0.20; 95%CI: 0.06-0.69). The prognostic role of disease severity was moderated by HRV: among severely disease patients, 100% died with low HRV, while only 37.5% died with high HRV. In MM, HRV significantly predicted PFS (HR = 0.19; 95%CI: 0.04-0.90) independently of confounders. Vagal nerve activity independently predicts prognosis in patients with R/R-DLBCL and with MM undergoing cell therapy. High vagal activity overrides the prognostic role of disease severity. Testing the effects of vagal nerve activation on prognosis in blood cancers is recommended.

Role of Heart Rate Variability in the Association between Myocardial Infarction Severity and Post-Myocardial Infarction Distress.

OBJECTIVE: Myocardial infarction (MI) results in mental health consequences, including depression and post-traumatic stress disorder (PTSD). The risk and protective factors of such mental consequences are not fully understood. This study examined the relation between MI severity and future mental health consequences and the moderating role of vagal nerve activity. METHODS: In a reanalysis of data from the Myocardial Infarction-Stress Prevention Intervention (MI-SPRINT) study, 154 post-MI patients participated. MI severity was measured by the Killip Scale and by troponin levels. Depression and PTSD symptoms were assessed with valid questionnaires, both at 3 and 12 months. Vagal nerve activity was indexed by the heart rate variability (HRV) parameter of the root-mean square of successive R-R differences (RMSSD). Following multivariate analyses, the association between MI severity and distress was examined in patients with low and high HRV (RMSSD = 30 ms). RESULTS: In the full sample, the Killip index predicted post-MI distress only at 3 months, while troponin predicted distress at 3- and 12-months post-MI. However, HRV moderated the effects of the Killip classification; Killip significantly predicted symptoms of depression and PTSD at 3- and 12-months post-MI, but only in patients with low HRV. Such moderation was absent for troponin. CONCLUSION: MI severity (Killip classification) predicted post-MI depression and PTSD symptoms, but only in patients with low HRV, suggesting that the vagal nerve is a partial protective (moderating) factor in the relation between Killip score and post-MI distress.

You may need the vagus nerve to understand pathophysiology and to treat diseases.

Can different pathophysiological mechanisms and risk factors leading to various diseases be linked with altered transmission of signals by one common pathway? The present article provides evidence for the hypothesis that adequate vagal nerve activity reduces the risk of major diseases, via common basic mechanisms and interim risk factors. These diseases include cardiovascular disease, cancer, Alzheimer's disease and the metabolic syndrome. Three basic mechanisms contribute to such illnesses: local oxidative stress and DNA damage, inflammatory reactions and excessive sympathetic responses, all of which are inhibited by vagal nerve activity. Efferent vagal activity that can be non-invasively measured by HRV (heart rate variability), derived from an ECG, is inversely related to all three basic mechanisms, to various risk factors (e.g. diabetes and dyslipidaemia) and, more broadly, to the diseases as well. Finally, vagal activity is proposed to moderate the effects of risk factors on developing such illnesses. By proposing an integrative neurobiological model of major diseases, identifying people at risk for, and treating patients with, such diseases may be done more efficiently. People with low HRV may be identified and subsequently treated by vagus nerve activation to possibly prevent or treat such illnesses. This proposed disease paradigm may have important preventative and therapeutic implications, whose clinical effects need to be investigated.

Placental DEPTOR as a stress sensor during pregnancy.

DEPTOR [DEP-domain-containing and mTOR (mammalian target of rapamycin)-interacting protein] is a modulator of mTOR signalling that binds to mTORC (mTOR complex) 1 and mTORC2. However, to date, the precise functions of DEPTOR are not fully elucidated, particularly in reproductive tissues where mTOR acts as a placental nutrient sensor. Pregnancy is associated with major physiological and psychosocial changes and adaptation to these changes is crucial for normal fetal development. In the present study, we tested the hypothesis that maternal stress can affect mTOR signalling at term, and, as a result, influence placental growth. We first investigated the expression of DEPTOR, mTOR, rictor (rapamycin-insensitive companion of mTOR) and raptor (regulatory associated protein of mTOR) from human placentas (n=23) using Q-PCR (quantitative PCR), and correlated these data to days of pregnancy and maternal stress, as well as placental and fetal weight. Maternal and fetal cortisol levels were also measured. JEG-3 and BeWo cells, used as placental in vitro models, were treated with cortisol and DEPTOR expression was assessed using Q-PCR. DEPTOR appears to be the predominant transcript in the human placenta compared with mTOR, rictor and raptor in both term (n=13) and preterm (n=10) placentas as assessed by Q-PCR. There was a significantly lower level only of log-DEPTOR gene expression in the high stress group (-1.34) than in the low stress group (0.07; t20=2.41, P=0.026). Interestingly, mothers with high stress had significantly elevated levels of cortisol (8555 pg/ml) compared with those with low stress (4900 pg/ml). We then tested the hypothesis that cortisol can directly affect DEPTOR expression. When BeWo cells were treated with cortisol 10, 100 and 1000 nM, the expression of DEPTOR was significantly down-regulated by 50, 41 and 39% (all P<0.05) respectively when compared with basal levels. Treatment of JEG-3 cells with cortisol, led to a significant decrease of DEPTOR expression at 100 nM (39%, P<0.05) and at 1000 nM (73%, P<0.01). These novel findings are indicative of a higher order of complexity of DEPTOR signalling in the human placenta that is affected by maternal stress, which could affect pregnancy outcome.