Abstract Respiratory tract infections are the most common acute illnesses, and innate immunity and inflammation are important in defence against these infections. Mannose-binding lectin (MBL) mediates innate immune defences by recognising microbial structures. MBL deficiency caused by polymorphisms in the MBL2 gene has been associated with susceptibility to recurrent infections. Interleukin-6 (IL-6) is a mediator of inflammatory response. Polymorphisms in the IL-6 and IL-6 receptor (IL-6R) genes have been previously associated mainly with metabolic disorders and cardiovascular diseases. Chlamydia pneumoniae is a common pathogen in acute respiratory tract infections, but it also has a tendency to cause persistent infections, which have been associated with cardiovascular diseases and its risk factors, such as obesity. The aims of this study were to investigate if selected polymorphisms of the MBL2, IL-6 and IL-6R genes are associated with respiratory tract infections and markers of C. pneumoniae infection, and to study if persistent C. pneumoniae infection is connected with an elevated body mass index (BMI) in 893 Finnish male military conscripts. Respiratory tract infections were followed during their military service and serum samples were collected at the beginning and end of their service and during each infectious episode. A variation in serum MBL levels between different MBL2 genotypes and a MBL deficiency in homozygous exon 1 variant genotypes (at codons 52, 54 and 57) were observed. Low MBL levels and MBL2 polymorphisms in exon 1 and promoter region were found to be risk factors for susceptibility to respiratory tract infections as well as for positivity and a rise in C. pneumoniae antibodies during military service. Associations between IL-6R gene polymorphisms in the promoter region (-183G/A) and in intron 1 and respiratory tract infections were found. In addition, the IL-6 -174G/C polymorphism was associated with persistently elevated C. pneumoniae antibodies and with slightly elevated serum C-reactive protein (CRP) levels, pointing to chronic C. pneumoniae infection. Furthermore, persistent C. pneumoniae antibodies as a suggestive marker of chronic infection, and elevated serum CRP levels as a marker of systemic inflammation, were associated with an elevated BMI. In conclusion, the findings support the role for MBL in susceptibility to infections and provide new information about the association between MBL and common respiratory tract infections. The results also suggest that the 5’ area of the IL-6R gene may be a possible candidate region for respiratory tract infection susceptibility, and that IL-6 genetics may be associated with C. pneumoniae infection. The study also provides new information about the role of possible chronic C. pneumoniae infection in obesity. / Tiivistelmä Hengitystieinfektiot ovat yleisimpiä äkillisiä sairauksia, ja synnynnäisellä immuunivasteella ja tulehduksella on tärkeä rooli puolustuksessa näitä infektioita vastaan. Synnynnäiseen immuniteettiin kuuluva mannoosia sitova lektiini (MBL) tunnistaa infektioita aiheuttavien mikrobien rakenteita. MBL2-geenin polymorfismien aiheuttaman MBL-proteiinin puutteen on todettu altistavan toistuville infektioille. Interleukiini-6 (IL-6) on tulehduksen välittäjänä toimiva sytokiini. IL-6- ja IL-6-reseptori (IL-6R) -geenien polymorfismit on aikaisemmin yhdistetty lähinnä metabolisiin häiriöihin sekä sydän- ja verisuonitauteihin. Chlamydia pneumoniae eli keuhkoklamydia on yleinen hengitystieinfektioiden aiheuttaja, mutta se voi myös aiheuttaa kroonisia infektioita, jotka on yhdistetty sydän- ja verisuonitauteihin sekä niiden riskitekijöihin kuten lihavuuteen. Työn tarkoituksena oli tutkia tiettyjen MBL2-, IL-6- ja IL-6R-geenien polymorfismien yhteyttä hengitystieinfektiohin ja keuhkoklamydiavasta-ainetasoihin sekä keuhkoklamydiainfektion yhteyttä painoindeksiin 893 suomalaisella varusmiehellä. Hengitystieinfektioita seurattiin palveluksen aikana, ja seeruminäytteet kerättiin palveluksen alussa, lopussa ja jokaisen infektion aikana. Tutkimuksessa havaittiin vaihtelua seerumin MBL-pitoisuudessa eri MBL2-genotyyppien välillä sekä MBL:n puute homotsygooteissa eksoni 1 -alueen varianttigenotyypeissä (kodoneissa 52, 54 ja 57). Alhaiset MBL-tasot sekä MBL2-geenin polymorfismit eksoni 1 -alueella ja säätelyalueella olivat riskitekijöitä hengitystieinfektioalttiudelle sekä keuhkoklamydiavasta-aineiden esiintymiselle ja vasta-aineiden nousulle palveluksen aikana. IL-6R-geenin polymorfismit säätelyalueella (-183G/A) ja introni 1 -alueella liittyivät hengitystieinfektioihin. Lisäksi IL-6-geenin -174G/C polymorfismi oli yhteydessä jatkuvasti kohonneisiin keuhkoklamydiavasta-aineisiin sekä seerumin C-reaktiivisen proteiinin (CRP) tasoihin, jotka mahdollisesti osoittaisivat kroonista keuhkoklamydiainfektiota. Lisäksi krooniseen keuhkoklamydia-infektioon viittaavat vasta-ainetasot sekä tulehdukseen liittyvä kohonnut CRP-pitoisuus olivat yhteydessä ylipainoon. Tutkimuksen tulokset tukevat aikaisemmin havaittua MBL:n vaikutusta infektioalttiuteen ja lisäksi antavat uutta tietoa MBL:n yhteydestä tavallisiin hengitystieinfektioihin. Tulokset viittaavat myös siihen, että IL-6R-geenin 5’-alueella voi olla yhteyttä hengitystieinfektioalttiuteen ja että IL-6-polymorfismi olisi yhteydessä keuhkoklamydiainfektioon. Tutkimus antaa myös uutta tietoa mahdollisen kroonisen keuhkoklamydiainfektion liittymisestä ylipainoon.

Early administration of broad-spectrum antibiotics is the first goal in sepsis treatment. Besides from bacteriostatic/bactericidal effects, some antibiotics may also modify the host´s response to infection. The novel antibiotic tigecycline may exert such properties; however, this property has not been evaluated in large-animal trials. We compared tigecycline with doxycycline and placebo in relation to anti-inflammatory, circulatory and organ dysfunction effects in a sterile pig model of sepsis. Doxycycline, but not tigecycline, reduced the inflammatory response as manifested by tumor necrosis factor alpha levels in plasma. Tigecycline, however, had a stabilizing effect on the circulation not exerted by doxycycline or placebo. To achieve rapid restoration of the circulating blood volume - another major goal in sepsis treatment - fluid bolus administration of is some-times practiced. In addition to crystalloids, albumin-containing solutions are suggested. Yet, some animal-experimental data suggests that rapid bolus administration of albumin reduces albumin’s plasma-expanding effect. We compared a rapid intravenous bolus of radiolabeled albumin with a slow infusion in a sterile pig model of sepsis. Rapid bolus of administration did not reduce plasma levels of albumin following administration and did not increase the amount of albumin that left the circulation. Inadequate oxygen delivery (DO2) by the circulation to the tissues may cause increased plasma lactate, which is the most striking effect of sepsis on the metabolism. However, experimental data and clinical trials refute this link, instead, suggesting other mechanisms, including impaired oxygen extraction, mitochondrial dysfunction and accelerated aerobic glycolysis. We investigated the impact of DO2, oxygen consumption (VO2), hemodynamic parameters and inflammatory response on plasma lactate and organ dysfunction in two experimental sepsis models. In the most severe cases of shock, with DO2, there was an increase in plasma lactate, but without a decrease in VO2, invalidating the assumption that the increase in lactate is due to anaerobic metabolism. To identify critical steps in the sepsis-induced increase in lactate, we inhibited the major energy-producing step in the electron transport chain (ETC). The combination of sepsis and ETC inhibition led to a cellular energy crisis. This finding suggests that early sepsis induces a partial mitochondrial dysfunction.

Abstract The aims of this study were to investigate the clinical features, the endoscopic and histological abnormalities of ileocolonic and gastroduodenal mucosa and immunogenetic background of microscopic colitis (MC) and its subtypes collagenous colitis (CC) and lymphocytic colitis (LC). 30 patients with CC and 54 with LC were examined with different control groups used according to the study. The mean age at diagnosis was in the sixties in both CC and LC, with a female preponderance in both Autoimmune conditions such as celiac diseased (CD) were common in MC. Bronchial asthma associated with LC. Lactose intolerance associated with MC but colonic diverticulosis was rare. Ileal histological changes were common in MC. Focal gastritis did not associate with MC. Lymphocytic gastritis was found only in LC. Gastric endoscopic erosions were more prevalent in CC than in LC. The age at diagnosis of MC was higher in H. pylori positive than negative patients. The patients with MC had shorter duodenal villi than controls even when patients with CD were excluded. HLA-DR3-DQ2 haplotype and TNF2 allele carriage were more frequent in patients with MC compared to controls. The genotype GG of IL-6-174 was more prevalent in MC compared to the controls. IL-6 genotype did not associate with the serum IL-6 concentration. The concentration of IL-6 was higher in patients with CC than in LC. In conclusion, in addition to colonic typical inflammation, histological abnormalities were detected also in gastric, duodenal and ileal mucosa. CD was common in MC, but there was no association with specific types of gastritis. HLA association was found in MC. Polymorphism in the proinflammatory IL-6-174 gene displayed a possible association with MC. Although CC and LC share many clinical features, the differences in the occurrence of immune conditions, gastric abnormalities and IL-6 response point to differences in their pathogenesis. / Tiivistelmä Tutkimuksen tavoitteena oli tutkia mikroskooppisen koliitin sekä sen alaryhmien, kollageenikoliitin ja lymfosyyttisen koliitin kliinisiä piirteitä, mahalaukun ja ohutsuolen limakalvon muutoksia sekä immunogeneettistä taustaa. Tutkimukseen osallistui 30 kollageeni- ja 54 lymfosyyttikoliittipotilasta sekä verrokkeja. Sekä kollageenikoliitti että lymfosyyttinen koliitti diagnosoitiin keskimäärin 50–60 v iässä, ja molemmissa tautiryhmissä naisia oli enemmän kuin miehiä. Autoimmuunisairaudet kuten keliakia olivat yleisiä liitännäissairauksia. Astmaa esiintyi lymfosyyttistä koliittia sairastavilla verrokkeja enemmän. Laktoosi-intoleranssi oli yleistä, mutta paksusuolen divertikuloosia oli harvoin mikroskooppista koliittia sairastavilla potilailla. Ileumin muutokset olivat yleisiä. Mikroskooppinen koliitti ei assosioitunut fokaaliseen gastriittiin. Lymfosyyttigastriittia todettiin vain lymfosyyttisessä koliitissa. Mahalaukun eroosioita esiintyi enemmän kollageenikoliitissa kuin lymfosyyttisessa koliitissa. Mikroskooppinen koliitti ilmeni iäkkäämpänä niillä, joilla todettiin helikobakteeri. Pohjukaissuolen suolinukka oli keliakiasta riippumatta matalampaa kuin verrokeilla. HLA-DR3-DQ2 haplotyyppiä, TNF-2 alleelia ja IL-6-174-GG genotyyppiä esiintyi enemmmän mikroskooppista koliittia sairastavilla potilailla kuin verrokeilla. IL-6 genotyyppi ei vaikuttanut seerumin IL-6-pitoisuuteen. IL-6 pitoisuus oli korkeampi kollageenikoliitissa kuin lymfosyyttisessä koliitissa. Havainnot osoittavat, että mikroskooppisessa koliitissa limakalvomuutoksia on paksusuolen lisäksi myös muualla mahasuolikanavassa. Keliakia on tavallinen liitännäistauti. HLA-DR3-DQ2 on yleinen mikroskooppista koliittia sairastavilla myös ilman keliakiaa. IL-6-174-GG genotyypin yleisyys viittaa siihen, että tämä polymorfismi saattaa altistaa mikroskooppiselle koliitille. Vaikka kollageenikoliitti ja lymfosyyttinen koliitti ovat kliinisesti samankaltaisia sairauksia, erot tautiassosiaatioissa, mahan limakalvon muutoksissa ja seerumin IL-6-tasoissa viittaavat erilaisiin syntymekanismeihin.

INTRODUÇÃO: A cardiopatia chagásica crônica (CCC) apresenta características específicas, tais como: disfunção autonômica e atividade inflamatória exacerbada. Esta fisiopatologia sugere que alguns parâmetros metabólicos podem estar alterados em pacientes chagásicos. O objetivo deste estudo foi avaliar os parâmetros metabólicos e inflamatórios nas diversas formas evolutivas de doença de Chagas e sua correlação com medidas de avaliação do Sistema Nervoso Autônomo (SNA). MÉTODOS: Foram avaliados 60 indivíduos divididos em 4 grupos (n=15): Grupo controle (GC), Grupo FI - forma indeterminada, Grupo ECG- cardiopatia chagásica com alteração eletrocardiográfica sem disfunção ventricular e Grupo IC - cardiopatia chagásica com disfunção ventricular e insuficiência cardíaca. Todos os grupos foram pareados de acordo com sexo, idade e índice de massa corporal. Os pacientes realizaram dosagens sanguíneas de insulina, leptina, adiponectina, interleucina-6 (IL- 6) e fator de necrose tumoral-alfa (TNF-alfa) pelo método de ELISA. O SNA foi avaliado através da variabilidade da frequência cardíaca no holter 24 horas e no teste de inclinação postural. Os valores de RMSSD, pNN50 e do componente alta frequência (AF) foram utilizados como estimativa da atividade parassimpática. Os valores do componente de baixa frequência (BF) estimaram a atividade simpática. A análise estatística foi feita utilizando-se a ANOVA ou teste de Kruskal-Wallis para a comparação entre os grupos, o coeficiente de Spearman para a análise das correlações e a regressão linear múltipla para a análise multivariada. RESULTADOS: A leptina e insulina não apresentaram diferenças significativas entre os grupos [Leptina: GC=3,42 (7,43); FI=3,03 (6,53); ECG=5,56 (6,2); IC=2,86 (2,67) ng/ml; p=0,626. Insulina: GC=3,41 (1,98); FI=4,31 (2,85); ECG=4,30 (3,06); IC=4,58 (2,88) ng/ml; p=0,901] A adiponectina apresentou níveis maiores nos grupos ECG e IC [GC=4766,5 (5529,5); FI= 4003,5 (2482,5); ECG= 8376,5 (8388,5); IC= 8798 (4188) ng/ml; p < 0,001]. IL-6 e TNF-alfa foram maiores no Grupo IC [IL-6: GC=1,85 (6,41); FI=1,58 (1,91); ECG=1,0 (1,57); IC= 31,44 (72,19) pg/ml; p=0,001. TNF-?: GC=22,57 (88,2); FI=19,31 (33,16); ECG=12,45 (3,07); IC=75,15 (278,57) pg/ml; p=0,04]. A insulina, leptina e TNF-alfa não apresentaram correlações significativas com medidas de avaliação do SNA. A adiponectina apresentou correlação positiva com o componente AF (r= 0,336; p= 0,009) e correlação negativa com o componente BF (r= -0,336; p= 0,009). A interleucina-6 apresentou correlação positiva com o componente AF (r= 0,419; p=0,004) e correlação negativa com o componente BF (r= -0,393; p= 0,007). Porém, na análise multivariada apenas a adiponectina apresentou correlação significativa com medidas de função do SNA. CONCLUSÃO: A adiponectina foi maior nos grupos ECG e IC. A IL-6 e o TNF-alfa foram maiores no grupo IC. O aumento dos níveis de adiponectina esteve associado a diminuição da atividade simpática e predomínio da atividade parassimpática. / BACKGROUND: Chagas disease (CD) has specific characteristics such as autonomic dysfunction and increased inflammatory activity. This pathophysiology suggests that metabolic parameters can be altered in patients with CD. The aim of this study was to evaluate the metabolic and inflammatory parameters in different forms of CD and their correlation with Autonomic Nervous System (ANS) measures. METHODS: We evaluated 60 subjects divided into 4 groups (n=15): control group (CG), group IF (indeterminate form); group ECG (ECG abnormalities and normal left ventricular function in echocardiogram) and HF group (heart failure with left ventricular dysfunction). All groups were matched for age, sex and body mass index. The patients underwent insulin, adiponectin, leptin, interleukin-6 (IL-6) and tumor necrosis factor-alfa (TNF-alfa) measurements by ELISA. The Autonomic Nervous System was assessed by heart rate variability in 24-hour Holter and tilt test. RMSSD, pNN50 and High Frequency (HF) component values were used to estimate parasympathetic activity and low frequency (LF) components were used to estimate sympathetic activity. Statistical analyses were performed using ANOVA or Kruskal- Wallis tests to compare groups. Spearman coefficient was used for correlation analysis and linear regression for multivariate analysis. RESULTS: No significant differences were observed in leptin and insulin levels between groups. [Leptin: CG=3.42 (7.43); IF=3.03 (6.53); ECG=5.56 (6.2); HF=2.86 (2.67) ng/ml; p=0.626. Insulin: CG=3.41 (1.98); IF=4.31 (2.85); ECG=4.30 (3.06); HF=4.58 (2.88) ng/ml; p=0.901]. Adiponectin was higher in ECG and HF groups. [CG=4766.5 .(5529.5); IF= 4003.5 (2482.5); ECG= 8376.5 (8388.5); HF= 8798 (4188) ng/ml; p < 0.001)]. IL-6 and TNF-alfa were higher in HF group. [IL-6: CG=1.85 (6.41); IF=1.58 (1.91); ECG=1.0 (1.57); HF= 31.44 (72.19) pg/ml; p=0.001. TNF-alfa: CG=22.57 (88.2); IF=19.31 (33.16); ECG=12.45 (3.07); HF=75.15 (278.57) pg/ml; p=0.04]. Insulin, leptin and TNF-alfa did not correlate with autonomic dysfunction. Adiponectin correlated positively with HF component (r=0.336; p= 0.009) and inversely with LF component (r= -0.336; p=0.009). IL-6 correlated positively with HF component (r= 0.419; p=0.004) and inversely with LF component (r= -0.393; p= 0.007). However, in multivariate analysis only adiponectin correlated significantly with ANS measures. CONCLUSION: Adiponectin levels were higher in ECG and HF groups. IL-6 and TNF-alfa were higher in HF group. Higher levels of adiponectin were associated with reduced sympathetic activity and predominance of parasympathetic activity

INTRODUÇÃO: Em pacientes com síndromes isquêmicas miocárdicas instáveis (SIMI), tanto a hiperatividade simpática quanto a resposta inflamatória exacerbada se associam a pior prognóstico. No entanto, ainda é desconhecido se existe alguma correlação entre esses dois marcadores de evolução desfavorável. OBJETIVOS: Correlacionar a atividade nervosa simpática muscular com marcadores inflamatórios nas fases precoce e tardia de pacientes portadores de SIMI. MÉTODOS: Pacientes hospitalizados com diagnóstico de SIMI e evolução favorável foram incluídos de forma prospectiva desde que apresentassem idade entre 18 e 65 anos e aterosclerose coronária comprovada por cinecoronariografia. Logo após a inclusão no estudo foram coletadas informações basais, e no quarto dia (± 1 dia) de internação os pacientes foram submetidos à avaliação da ANSM e coleta concomitante de amostra sanguínea para dosagem de proteína CReativa ultrassensível (PCR-us), interleucina-6 (IL6), e fosfolipase A2 associada à lipoproteína (Lp-PLA2). ANSM foi obtida pela técnica de microneurografia do nervo fibular. As medidas e respectivas análises de correlação foram repetidas em 1, 3 e 6 meses após a hospitalização. Correlações entre ANSM e marcadores inflamatórios foram analisadas por meio do teste de Pearson (variáveis de distribuição não-paramétrica foram transformadas logaritmicamente). Modelos de regressão linear múltipla foram criados para avaliar os efeitos independentes. RESULTADOS: Foram estudados 34 pacientes com idade média de 51,7±7,0 anos, sendo 79,4% do sexo masculino. A prevalência de hipertensão arterial foi de 64,7%, diabetes mellitus 8,8%, e doença arterial coronária prévia de 20,6%. A apresentação foi IAM com supradesnível de ST em 18 pacientes (52,9%), IAM sem supra de ST em 14 (41,2%) e angina instável em 02 pacientes (5,9%). Tanto ANSM quanto biomarcadores inflamatórios estavam elevados durante a fase aguda das SIMI e diminuíram ao longo do tempo. Na fase hospitalar, a mediana da PCR-us foi 17,75 (8,57; 40,15) mg/L, e IL-6 6,65 (4,45; 8,20) pg/ml, a Lp- PLA2 média foi 185,8 ± 52,2 nmol/min/ml, e ANSM média 64,2 ± 19,3 impulsos/100bpm. Após 6 meses, houve diminuição significativa de todas essas variáveis quando comparadas com a fase hospitalar. Entretanto, não houve correlação significativa entre a atividade simpática e qualquer dos marcadores inflamatórios analisados, em nenhuma das fases analisadas (p > 0,05), Por outro lado, ANSM se correlacionou independentemente com níveis de CKMB na fase aguda (p=0,027), e com fração de ejeção do VE na fase crônica (p=0,026). CONCLUSÃO: Apesar do aumento inicial dos níveis de marcadores inflamatórios e da atividade simpática em pacientes com SIMI, não houve correlação significativa entre esses parâmetros em nenhuma das fases analisadas, sugerindo que as alterações dessas variáveis estariam relacionadas a diferentes vias fisiopatológicas / INTRODUCTION: Previous publications have shown that both sympathetic hyperactivity and enhanced inflammatory response are associated with worse outcomes during acute coronary syndromes (ACS). However, little is known about the correlation between these two pathologic pathways. OBJECTIVE: To correlate muscle sympathetic nerve activity with inflammatory biomarkers in both acute and chronic phase of ACS. METHODS: Patients hospitalized with uncomplicated ACS were enrolled if they were 18-65 years old and have significant atherosclerosis. Baseline characteristics information were collected and at fourth day (± 1 day) of hospitalization they were submitted to muscle sympathetic nerve activity (MSNA) analysis and blood sample were collected for ultrasensitive C-reactive protein (usCRP), interleukin-6 (IL-6) and Lipoprotein-associated phospholipase A2 activity (Lp-PLA2) measurements. MSNA was recorded directly from the peroneal nerve using the microneurography technique. Measurements were repeated at 1, 3 and 6 months after hospitalization. Correlations between MSNA and inflammatory markers and baseline characteristics were made using Pearson\'s test (nonnormally distributed variables were logarithmically transformed) and multivariate regression models were performed to assess the independent effects. RESULTS: Thirty-four patients were included, 79.4% male, mean age 51.7 (SD 7.0 years). The prevalence of hypertension was 64.7%, diabetes mellitus 8.8%, and previous coronary heart disease 20.6%. The ACS presentation was STEMI in 18 patients (52.9%), NSTEMI in 14 (41.2%) and UA in 02 patients (5.9%). Both MSNA and inflammatory markers were elevated during acute phase of ACS and decreased over time. In the hospitalization phase the median usCRP was 17.75 (8.57; 40.15) mg/L, median IL-6 6.65 (4.45; 8.20), mean Lp-PLA2 185.8 ± 52.2 nmol/min/mL, and mean MSNA 64.2 ± 19.3 bursts/100heart beats. All of these variables decreased significantly over 6 months when compared to in-hospital phase. However, there were no significant correlations between the sympathetic activity and inflammatory markers in any of the analyzed phases (p>0.05). After adjusted analyzes, MSNA was independently associated with CKMB levels at acute phase (p=0.027) and with left ventricular ejection fraction at 6 months (p=0.026). CONCLUSION: Despite the increased levels of inflammatory markers and sympathetic activity among patients with ACS, there was no correlation between these assessments, suggesting that although they may be present concomitantly during an ACS they might follow different pathological pathways

Nurses are already exposed to plenty of stressors while at work, one of which being the unavoidable nature of rotating shift work scheduling which can have profound physiological effects carrying heightened long-term health risks. Working on the frontlines of the COVID-19 pandemic has introduced new stressors while further exacerbating the effects of pre-existing ones in this already understudied group of essential workers. The purpose of this research was to examine physiological markers of stress and health in nurses during the COVID-19 pandemic. Nine subjects (mean age 32.11 ± 7.25 years) from two hospitals in the Greater Victoria region collected data over an eight-day shift roster consisting of two 12-hour day shifts, two 12-hour night shifts, and four days off in two separate collection periods; remote data collection was used to adhere to COVID-19 safety guidelines. Salimetrics ELISA kits were used to conduct analyses for salivary cortisol, melatonin, and interleukin-6 (IL-6) content. Frequency domain heart rate variability (HRV) was collected with a Polar H10 Chest Strap and Polar Ignite Activity Tracker. A salivary sample and 5-minute HRV recording were obtained upon waking or shortly thereafter on each day; a second saliva sample was obtained after work for the four working days. The Expanded Nursing Stress Scale (ENSS) was completed at the end of the last night shift in each period. There were no significant differences between IL-6 concentrations across the eight days within each period; the same was observed for cortisol. Additionally, no difference was apparent between the morning and evening salivary cortisol concentrations, thus demonstrating a blunting of the diurnal release pattern. Evening salivary cortisol concentrations remained elevated near the level of morning samples and were consistently above reference values for the population age group. Morning salivary melatonin concentrations significantly differed by day (F(5, 25) = 6.626, p < 0.001) but not period; melatonin concentrations were lowest following night shifts, showing a suppression in release due to participants being exposed to light at night with shift work. No statistically significant differences were apparent between any frequency domain HRV parameters in either Period 1 or Period 2. Perceived occupational stress was heightened in comparison to previously published pre-pandemic research using the ENSS. The results of this research reveal alterations to the circadian nature of cortisol and melatonin alongside elevated perceived occupational stress; these physiological and psychological effects can compound the risk for adverse health outcomes. While it is difficult to discern the root cause of these responses, it nevertheless reveals insight into the effects of nurses working during the COVID-19 pandemic and raises concern for potentially related disease risk. / Graduate

Preterm labor with intact membranes (PTL) is responsible for approximately 40% of all preterm deliveries. PTL is frequently complicated by intra-amniotic inflammation (IAI), characterized by the elevation of inflammatory mediators in the amniotic fluid. Based on the presence or absence of microbial invasion of the amniotic cavity (MIAC), two different clinical phenotypes of IAI are distinguished: i) intra-amniotic infection, when microorganisms are present in the amniotic fluid, and ii) sterile IAI, when there are no microorganisms in the amniotic fluid. The clinical severity of both phenotypes of IAI is underlined by their association with adverse neonatal outcomes. In addition to the presence or absence of MIAC, there are also differences between the phenotypes of IAI in terms of their intra-amniotic inflammatory status characteristics. The clinical part of this thesis has addressed these differences in women with PTL. The first specific aim of this clinical study was to determine the concentration of interleukin (IL)-6 in the cervical fluid of women with PTL complicated by intra-amniotic infection and sterile IAI. The second specific aim was to determine the concentration of IgGFc-binding protein (FcgammaBP) in the amniotic and cervical fluids of women with PTL complicated by intra-amniotic...

SMOFLipid® is a commonly used fat emulsion for parenteral nutrition. We investigated how enrichment of SMOFLipid® with n-3 polyunsaturated fatty acids (PUFA) in a form of second fat emulsion, Omegaven® , changes fatty acid composition of total plasma phospholipids and erythrocyte phospholipids, cytokine concentrations in serum and in supernatant from in vitro whole blood culture stimulated with lipopolasaccharide (LPS) and we evaluated also changes in oxido- reductive balance. Eight patients on long-term home parenteral nutrition recieved both emulsions, SMOFLipid® (6 weeks) and SMOFLipid® +Omegaven® (4 weeks), one by one. We observed no significant differences in common laboratory and clinical parameters between these two types of diet. Enrichment of SMOFLipid® with Omegaven® led to an increase in eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) in total plasma phospholipids and there was also an increse in proportion of EPA in erythrocyte phospholipids, while proportion of DHA remained unchanged. These changes were in both phospholipids of plasma and erythrocyte compensated for a decrease in proportion of linoleic and arachidonic acid (n-6 PUFA). There were elevated IL-6 and TNF-α serum concentrations in patients after both diets. There was a decrease in IL-6 production by 36% with SMOFLipid®...

The cytokine tumor necrosis factor α (TNFα) stimulates the NF-кB, SAPK/JNK, and p38 mitogen-activated protein (MAP) kinase pathways by recruiting Rip1 and Traf2 proteins to the tumor necrosis factor receptor 1 (TNFR1). Genetic studies have revealed that Rip1 links the TNFR1 to the IкB kinase (IKK) complex, whereas Traf2 couples the TNFR1 to the SAPK/JNK cascade. We found TNFα-induced p38 MAP kinase activation and interleukin-6 (IL-6) production is impaired in rip1-/- murine embryonic fibroblasts (MEF) but unaffected in traj2-/- MEF, demonstrating that Rip1 is also a specific mediator of the p38 MAP kinase response to TNFα. Moreover, we demonstrate that endogenous Rip1 associates with the MAP3K, Mekk3 in response to TNFα and that TNFα-induced p38 MAP kinase activation is impaired in mekk3-/- cells, indicating that Rip1 may mediate the p38 MAP kinase response to TNFα by recruiting Mekk3. We also demonstrate that Rip1 is phosphorylated and ubiquitinated in response to Tnfα and that Rip1 phosphorylation is not required for ubiquitination of Rip1. Furthermore, TNFα-induced ubiquitination of Rip1 is impaired in Traf2-/- cells, suggesting that Traf2 is the E3 ubiquitin ligase responsible for the TNFα-dependent ubiquitination of Rip1. Finally, recruitment of the ubiquitinated Tak1 complex is dependent on the presence of Rip1, suggesting that Rip1 ubiquitination rather than its phosphorylation is critical in TNFR1 signaling.

Cardiotrophin-1 ist ein Zytokin der Familie Interleukin-6-Familie, zu der auch IL-11, CNTF, OSM und LIF gehören. Diese Substanzen wirken über die gemeinsame Rezeptoruntereinheit gp130. CT-1 induziert die Hypertrophie von Kardiomyozyten und inhibiert die Apoptose kardialer und Zellen. In verschiedenen Tiermodellen der Herzinsuffizienz konnte eine gesteigerte myokardiale CT-1 Expression beobachtet werden. Kardiomyopathien sind wiederum kardiale Erkrankungen, die mit einer Hypertrophie und Apoptose einhergehen und zu einer Herzinsuffizienz führen können. Man geht davon aus, dass 25-50 Prozent der familiär sind. Hierbei handelt es sich um eine monogenetische Erkrankung, die überwiegend autosomal-dominant vererbt werden. Daneben konnten aber auch modifizierende Polymorphismen in neurohumoralen Faktoren identifiziert werden. Basierend auf diesen Ergebnissen war das Ziel dieser Arbeit die Analyse der möglichen Beteiligung genetischer Varianten der kodierenden sowie der regulatorischen Region an der Pathogenese der Hypertrophen bzw. Dilatativen Kardiomyopathie. Zusätzlich sollte die mRNA-Expression von CT-1 in Myokardbiopsien von Patienten mit Herzinsuffizienz quantifiziert werden. Hierfür musste zunächst die Sequenzen der 5´-flankierenden Region identifiziert und bezüglich ihrer regulatorischen Eigenschaften analysiert werden. Es konnten 1,1 kb der 5´-flankierenden Region sequenziert werden. Die anschließende Luciferase-Reportergen-Analyse wies regulatorische Aktivitäten für den gesamten Bereich nach. Diese Region enthält zahlreiche cis-aktive DANN-Sequenzen aber keine TATA-Box. Für die Mutationssuche wurden 64 Patienten mit DCM, 53 Patienten mit HCM sowie 100 Kontrollpersonen mittels PCR-SSCP-Analyse untersucht. Es konnte eine kodierende Variante A92T bei jeweils einem DCM- bzw. HCM-Patienten identifiziert werden. Diese Substitution liegt in einem Bereich, der zwischen verschiedenen Spezies (Ratte, Maus, Mensch) konserviert ist. Diese Mutation könnte eine Veränderung der Sekundärstruktur bewirken und liegt in einem möglichen funktionellen Bereich. Die Promotorregion wies eine Basenpaarsubstitution bei -130 (G/T) sowie eine Deletion der Basen CTTT zwischen -992 und -995 auf. Der Polymorphismus an Position -130 fand sich tendenziell häufiger bei Patienten mit Dilatativer Kardiomyopathie. Die CTTT-Deletion konnte nur bei einer Patientin mit HCM nachgewiesen werden. Für die Quantifizierung der CT-1 mRNA wurden rechtsventrikuläre Endomyokardbiopsien von 6 Patienten mit eingeschränkter LVEF (CHI), 5 Patienten nach Herztransplantation (TX) sowie 3 Kontrollpatienten (KO) eingesetzt. Es konnte ein relativer Anstieg der CT-1 Expression um 82% bei den Patienten mit eingeschränkter LVEF festgestellt werden. Interessanterweise besteht eine enge Korrelation zur Schwere der eingeschränkten Herzfunktion sowie zur Zunahme der Hypertrophie. / Cardiotrophin-1 is a cytokine, which belongs to the interleukin-6 family, which includes IL-11, CNTF, OSM and LIF. These factors act via the receptor subunit gp130. CT-1 induces the hypertrophy of cardiomyocytes and inhibits the apoptosis of cardiac cells. Studies in animal models of congestive heart failure showed an enhanced expression of CT-1 in the myocardium. Cardiomyopathies are cardiac diesorders, which are charakterized by hypertrophy and apoptosis and which can terminate with congestive heart failure. About 25-50 percent of all cases are familial. It is a monogenetic mendelian disorder with an autosomal-dominant inheritance in most cases. Beside this, modifying polymorphisms in neurohunoral factors could be identified. Based on these facts, the aim of this study was to identify genetic variants within the coding and regulatory region of the CT-1 gene, which could influence the pathogenesis of hypertrophic or dilated cardiomyopathy. Additionally, the mRNA-expression of CT-1 in myocardial biopsies of heart failure patients should be quantified. First, it was necessary to sequence the 5´-untranslated region and to analyse its regulatory function. We could sequence 1.1 kb of the 5´-UTR. The luciferase reportergene assay showed a significant promoter activity for the whole region. The region contains various cis-active DNA sequences but no TATA-box.The TRANSFAC-analysis identified different binding sites for transcription factors but no TATA-box. The genetic material of 64 DCM and 53 HCM patients and 100 controls was screened for mutaions by using a PCR-based SSCP-analysis. A coding variant A92T could be identified for a patient with DCM and for an HCM patient. This mutation lies within a region which is conserved between different species (rat, mouse, human). This variant could disturb the secondary structure and lies in a probable functional region. Within the promoter we could identify a basepair substitution at position -130 (G/T) and a 4-basepair deletion between -992 and -995 (CTTTdel). The polymorphism at -130 showed a tendency for a higher occurrence in DCM patients. One HCM patient was heterozygous for the CTTT-deletion. To quantify the CT-1 mRNA we used endomyocardial biopsies of 6 patients with reduced LVEF (CHI), 5 patients after heart transplantation (TX) and 3 controls (KO). We performed a semiquantitative analysis by using HPLC and an external standard (PDH mRNA). We found an increased expression of CT-1 by 82% for patients with heart failure. Interestingly, we saw a tight correlation with to the reduction in LV function and to the degree of hypertrophy.