Intermittent Exposure Research Articles

A Population-Based Family Case-Control Study of Sun Exposure and Follicular Lymphoma Risk.

Epidemiologic evidence suggests an inverse association between sun exposure and follicular lymphoma risk. We conducted an Australian population-based family case-control study based on 666 cases and 459 controls (288 related, 171 unrelated). Participants completed a lifetime residence and work calendar and recalled outdoor hours on weekdays, weekends, and holidays in the warmer and cooler months at ages 10, 20, 30, and 40 years, and clothing types worn in the warmer months. We used a group-based trajectory modeling approach to identify outdoor hour trajectories over time and examined associations with follicular lymphoma risk using logistic regression. We observed an inverse association between follicular lymphoma risk and several measures of high lifetime sun exposure, particularly intermittent exposure (weekends, holidays). Associations included reduced risk with increasing time outdoors on holidays in the warmer months [highest category OR = 0.56; 95% confidence interval (CI), 0.42-0.76; Ptrend < 0.01], high outdoor hours on weekends in the warmer months (highest category OR = 0.71; 95% CI, 0.52-0.96), and increasing time outdoors in the warmer and cooler months combined (highest category OR = 0.66; 95% CI, 0.50-0.91; Ptrend 0.01). Risk was reduced for high outdoor hour maintainers in the warmer months across the decade years (OR = 0.71; 95% CI, 0.53-0.96). High total and intermittent sun exposure, particularly in the warmer months, may be protective against the development of follicular lymphoma. Although sun exposure is not recommended as a cancer control policy, confirming this association may provide insights regarding the future control of this intractable malignancy.

Home cage voluntary alcohol consumption increases binge drinking without affecting abstinence-related depressive-like behaviors or operant responding in crossed high alcohol-preferring mice (cHAPs)

Chronic alcohol consumption can lead to tolerance and escalation of drinking in humans and animals, but mechanisms underlying these changes are not fully characterized. Preclinical models can delineate which mechanisms are involved. The chronic intermittent ethanol exposure (CIE) procedure uses forced exposure to vaporized alcohol that elicits withdrawal and increased responding for alcohol in operant tasks in C57BL/6J inbred mice. Chronic two-bottle choice (2BC) drinking in the same strain elicits abstinent-related depression-like behavior, suggestive of allostatic changes. Selected lines such as crossed High Alcohol Preferring (cHAP) mice voluntarily drink to blood alcohol concentrations comparable to those attained in CIE and could be used to assess how alcohol affects these same endpoints without the confounds of involuntary vapor inhalation. In three experiments, we assess how 2BC drinking in cHAP mice affects abstinence-related depressive- and anxiety-like behavior, operant responding for alcohol, and binge consumption using drinking-in-the-dark (DID). We hypothesized that cHAPs with home-cage drinking experience would exhibit more depressive behavior after abstinence, increased responding for alcohol in the operant box, and increased DID intake. Of these, a drinking history increased DID intake in female cHAPs only and increased sucrose preference and intake following abstinence, but had no effects on operant responding or NSFT latency and FST immobility following forced abstinence. These results are consistent with recent findings using slice electrophysiology showing tolerance to alcohol's actions on the dorsolateral striatum following 2BC drinking in female, but not male cHAP mice. Overall, these data suggest that cHAPs may require procedures allowing rapid intoxication, such as DID, to demonstrate changes in alcohol's rewarding effects.

Extremely 13C-enriched dolomite records interval of strong methanogenesis following a sulfate decline in the Miocene Ries impact crater lake

In impact crater lakes, the lacustrine sedimentary records may not solely reflect climatic changes but also potential erosional effects from lithologically distinct impactite formations. The hydrochemical and biogeochemical processes during the deposition of the Nördlinger Ries impact crater lake, which fall in the range of the mid-Miocene Climate Transition, were studied by analysing microcrystalline authigenic carbonates in a drill core succession, using stable oxygen and carbon isotopes in conjunction with biomarkers. These investigations revealed an early sulfidic interval characterized by thiophenes, iso- and anteiso-C15:0 acids derived from sulfate reducing bacteria, and dolomites with low to intermediate δ13Ccarb values. The subsequent distinctive interval is characterized by extremely 13C-enriched dolomite (δ13Ccarb up to +20.93 ± 0.05‰ V-PDB), decline of iso- and anteiso-C15:0 acids and is rich in an Archaea-derived archaeol that is 13C-enriched (−14.7‰), indicating extensive methanogenesis in sulfate-depleted lake porewater during early diagenesis. The sulfate decline results from successive sulfate reduction when replenishment by sulfate-bearing inflow water is limited. The carbonates exhibit enriched 18O due to pronounced evaporation in a long-resided water body and enriched 13C by methanogenesis. A change in provenance of water derived from the sulfur-rich suevite (impact melt-bearing breccia) and crystalline source rocks to the sulfur-poor Bunte Breccia (continuous ejecta blanket) is required. Intermittently high Si/Al and Zr/Al at the high δ13C interval suggests sporadic short-term runoff increase, leading to fluctuating physiochemical lake conditions. A subsequent decline in both δ13Ccarb and archaeol indicates a decreasing lake level with intermittent subaerial exposure events, supported by bioturbation and mud cracks. The concomitant lake oxygenation is well supported by increasing Pr/Ph ratios and lipids derived from aerobic methanotrophs (13C-depleted 3-methyl-hopanoids). In the youngest unit, allochthonous lignites and biomarkers from lacustrine/soil sources appear, high total sulphur contents and thiophenes recur, and stable C and O isotope values decrease again. These observations suggest another major provenance change of the inflowing solutes, with increasing influx from weathered pyrite-bearing Jurassic claystones. These findings demonstrate that the climatic record expected from the stable carbon and oxygen isotopes of the Ries carbonates is strongly overprinted by hydrochemical and biogeochemical processes due to changing ion influx from substrate rocks, along the course of the successive ejecta erosion and catchment changes. Such an intrinsic control of lacustrine biogeochemical processes is also expected for other hydrologically closed impact crater lake basins, where catchment rocks with distinctively different lithologies are present.

Життєздатність та види загибелі лейкоцитів крові щурів з синдромом полікістозних яєчників за умов переривчастого холодового впливу

The aim of our work is to assess the viability and determine the types of death of blood leukocytes in rats with polycystic ovary syndrome (PCOS) under conditions of intermittent cold exposure. The study was performed on 40 immature female rats of the WAG population, aged 27 days, divided into 5 groups of 8 animals each. Group 1 included intact rats. In group 2, rats were subcutaneously injected with 0.2 ml of purified and sterilized olive oil daily for 25 days. In group 3, rats were exposed to periodic cold exposure daily for 25 days. In group 4, dehydroepiandrosterone-induced PCOS was modeled in rats. In group 5, rats were injected with dehydroepiandrosterone against the background of periodic cold exposure. Leukocyte viability and death pathways were determined using a FACS Canto II flow cytometer (Becton Dickinson, USA). Rats with dehydroepiandrosteroneinduced PCOS showed a decrease in the percentage of viable leukocytes and an increase in the percentage of leukocytes in the early stage of apoptosis, while the number of leukocytes in the late stage of apoptosis and necrotic leukocytes did not change. In rats, on the background of the introduction of dehydroepiandrosterone under conditions of intermittent cold exposure, the percentage of viable leukocytes, as well as leukocytes at different stages of apoptosis and necrosis, corresponded to the physiological norm. Thus, the authors revealed a decrease in the viability of neutrophilic leukocytes in the blood of rats with dehydroepiandrosterone-induced PCOS due to the activation of apoptosis processes, as evidenced by an increase in the percentage of leukocytes at the initial stages of apoptosis. Intermittent cold exposure (4 h daily at +4°C for 25 days) against the background of dehydroepiandrosterone administration to rats had an anti-apoptotic effect, normalizing the viability of neutrophilic blood leukocytes.

Adolescent intermittent alcohol exposure produces strain-specific cross-sensitization to nicotine and other behavioral adaptations in adulthood in C57BL/6J and DBA/2J mice

Adolescent alcohol exposure is associated with lasting behavioral changes in humans and in mice. Prior work from our laboratory and others have demonstrated that C57BL/6J and DBA/2J mice differ in sensitivity to some effects of acute alcohol exposure during adolescence and adulthood. However, it is unknown if these strains differ in cognitive, anxiety-related, and addiction-related long-term consequences of adolescent intermittent alcohol exposure. This study examined the impact of a previously validated adolescent alcohol exposure paradigm (2–3 g/kg, i.p., every other day PND 30–44) in C57BL/6J and DBA/2J male and female mice on adult fear conditioning, anxiety-related behavior (elevated plus maze), and addiction-related phenotypes including nicotine sensitivity (hypothermia and locomotor depression) and alcohol sensitivity (loss of righting reflex; LORR). Both shared and strain-specific long-term consequences of adolescent alcohol exposure were found. Most notably, we found a strain-specific alcohol-induced increase in sensitivity to nicotine's hypothermic effects during adulthood in the DBA/2J strain but not in the C57BL/6J strain. Conversely, both strains demonstrated a robust increased latency to LORR during adulthood after adolescent alcohol exposure. Thus, we observed strain-dependent cross-sensitization to nicotine and strain-independent tolerance to alcohol due to adolescent alcohol exposure. Several strain and sex differences independent of adolescent alcohol treatment were also observed. These include increased sensitivity to nicotine-induced hypothermia in the C57BL/6J strain relative to the DBA/2J strain, in addition to DBA/2J mice showing more anxiety-like behaviors in the elevated plus maze relative to the C57BL/6J strain. Overall, these results suggest that adolescent alcohol exposure results in altered adult sensitivity to nicotine and alcohol with some phenotypes mediated by genetic background.

Brain Cortex Morphology in Rats After Cold Exposures

Morphological changes of the brain cortex sensorimotor area in 6-month-old rats were studied after short-term intermittent and long-term continuous cold exposures (STICE and LTCCE, respectively). Under these conditions, perivascular and pericellular edema, small solitary foci of necrosis with gliosis phenomena, "porous" neuropil (signs under STICE at –12°С and formation during LTCCE), dystrophically changed neurons, neurons with nuclei at different stages of necrobiosis were noted in the brain tissue against the background of native cyto- and myeloarchitectonics, Some of the microvessels had signs of inflammation and thrombi. A moderate constriction (after STICE at –12°С) and a dilatation (after STICE at 10°С) of microvessels were observed. According to the fractal analysis, a decrease in the fractal dimension of the brain cortex sections was found under both STICE at –12°С and LTCCE.

Effects of ruminal lipopolysaccharide exposure on primary bovine ruminal epithelial cells

The objective of this study was to investigate the immunopotential of ruminal lipopolysaccharides (LPS) on cultured primary bovine rumen epithelial cells (REC). Primary bovine REC were isolated from 6 yearling steers and grown in culture for 3 experiments. Experiment 1 aimed to determine the immunopotential of ruminal LPS, experiment 2 aimed to assess tolerance to chronic LPS exposure, and experiment 3 aimed to evaluate antagonistic interactions between ruminal and Escherichia coli LPS. In experiments 1 and 2, REC were exposed to nonpyrogenic water, 20 μg/mL E. coli LPS (EC20), 10 μg/mL ruminal LPS, 20 μg/mL ruminal LPS, and 40 μg/mL ruminal LPS, either continuously or intermittently. For the continuous exposure, REC underwent a 6 h exposure, whereas for the intermittent exposure, the procedure was: (1) a 12 h continuous exposure to treatments followed by LPS removal for 24 h and then another 12 h of exposure (RPT), and (2) a 12 h continuous exposure to treatments followed by LPS removal and a recovery period of 36 h (RCV). In experiment 3, REC were exposed to nonpyrogenic water, 1 μg/mL E. coli LPS, 1 μg/mL ruminal LPS to 1 μg/mL E. coli LPS, 10 μg/mL ruminal LPS to 1 μg/mL E. coli LPS, and 50 μg/mL ruminal LPS to 1 μg/mL E. coli LPS. Each experiment was done as a complete randomized block design with 6 REC donors. The REC-donor was used as blocking factor. Each treatment had 2 technical replicates, and treatment responses for all data were analyzed with the MIXED procedure of SAS. For all experiments, total RNA was extracted from REC and real-time quantitative PCR was performed to determine the relative expression of genes for toll-like receptors (TLR2 and TLR4), proinflammatory cytokines (TNF, IL1B, and IL6), chemokines (CXCL2 and CXCL8), growth factor-like cytokines (CSF2 and TGFB1), and a lipid mediator (PTGS2). In experiment 1, the targeted genes were upregulated by EC20, whereas all ruminal LPS treatments resulted in a lower transcript abundance. Regarding RPT, and RCV condition, in experiment 2, the expression of targeted genes was not affected or was at a lower abundance to EC20 when compared with ruminal LPS treatments. Lastly, in experiment 3, all targeted genes resulted in lower or similar transcript abundance on all ruminal LPS ratios. Overall, our results indicate that ruminal LPS have a limited capacity to activate the TLR4/NF-kB pathway and to induce the expression of inflammatory genes.

Impact of Hypoxia-Hyperoxia Exposures on Cardiometabolic Risk Factors and TMAO Levels in Patients with Metabolic Syndrome.

Along with the known risk factors of cardiovascular diseases (CVDs) constituting metabolic syndrome (MS), the gut microbiome and some of its metabolites, in particular trimethylamine-N-oxide (TMAO), are actively discussed. A prolonged stay under natural hypoxic conditions significantly and multi-directionally changes the ratio of gut microbiome strains and their metabolites in feces and blood, which is the basis for using hypoxia preconditioning for targeted effects on potential risk factors of CVD. A prospective randomized study included 65 patients (32 females) with MS and optimal medical therapy. Thirty-three patients underwent a course of 15 intermittent hypoxic-hyperoxic exposures (IHHE group). The other 32 patients underwent sham procedures (placebo group). Before and after the IHHE course, patients underwent liver elastometry, biochemical blood tests, and blood and fecal sampling for TMAO analysis (tandem mass spectrometry). No significant dynamics of TMAO were detected in both the IHHE and sham groups. In the subgroup of IHHE patients with baseline TMAO values above the reference (TMAO ≥ 5 μmol/l), there was a significant reduction in TMAO plasma levels. But the degree of reduction in total cholesterol (TCh), low-density lipoprotein (LDL), and regression of liver steatosis index was more pronounced in patients with initially normal TMAO values. Despite significant interindividual variations, in the subgroup of IHHE patients with MS and high baseline TMAO values, there were more significant reductions in cardiometabolic and hepatic indicators of MS than in controls. More research is needed to objectify the prognostic role of TMAO and the possibilities of its correction using hypoxia adaptation techniques.

Intermittent Hypoxia in Preterm Neonates and Its Effect on Neonatal Morbidity and Mortality: A Systematic Review.

The goal of the present systematic review was to investigate the occurrence patterns of intermittent hypoxemia in newborns throughout the early postnatal period as well as the link between neonatal intermittent hypoxemia exposure and harmful consequences such as neonatal morbidity and death. We collected data from 2014 to 2023 using several abstracting, referencing, and indexing database libraries in the field of medical sciences. A total of 715 papers were evaluated by both authors, and only seven articles met the specified review criteria after a thorough analysis. In preterm neonates with intermittent hypoxia (IH), severe morbidities such as bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), motor impairment, and cognitive delay were found. Only one study that extended to 18 months noted mortality. The length and occurrence of intermittent hypoxemia and the stage of premature neonates at the time of delivery are all closely associated with these morbidities. Therefore, it becomes important to continuously measure the patterns of occurrence of intermittent hypoxemia during early postnatal life to avoid its long-term morbidity and mortality impact.

Optimal type and dose of hypoxic training for improving maximal aerobic capacity in athletes: a systematic review and Bayesian model-based network meta-analysis.

Objective: This study aimed to compare and rank the effect of hypoxic practices on maximum oxygen consumption (VO2max) in athletes and determine the hypoxic dose-response correlation using network meta-analysis. Methods: The Web of Science, PubMed, EMBASE, and EBSCO databases were systematically search for randomized controlled trials on the effect of hypoxc interventions on the VO2max of athletes published from inception until 21 February 2023. Studies that used live-high train-high (LHTH), live-high train-low (LHTL), live-high, train-high/low (HHL), intermittent hypoxic training (IHT), and intermittent hypoxic exposure (IHE) interventions were primarily included. LHTL was further defined according to the type of hypoxic environment (natural and simulated) and the altitude of the training site (low altitude and sea level). A meta-analysis was conducted to determine the standardized mean difference between the effects of various hypoxic interventions on VO2max and dose-response correlation. Furthermore, the hypoxic dosage of the different interventions were coordinated using the "kilometer hour" model. Results: From 2,072 originally identified titles, 59 studies were finally included in this study. After data pooling, LHTL, LHTH, and IHT outperformed normoxic training in improving the VO2max of athletes. According to the P-scores, LHTL combined with low altitude training was the most effective intervention for improving VO2max (natural: 0.92 and simulated: 0.86) and was better than LHTL combined with sea level training (0.56). A reasonable hypoxic dose range for LHTH (470-1,130kmh) and HL (500-1,415kmh) was reported with an inverted U-shaped curve relationship. Conclusion: Different types of hypoxic training compared with normoxic training serve as significant approaches for improving aerobic capacity in athletes. Regardless of the type of hypoxic training and the residential condition, LHTL with low altitude training was the most effective intervention. The characteristics of the dose-effect correlation of LHTH and LHTL may be associated with the negative effects of chronic hypoxia.

Intermittent Hypoxic Exposure And Training Have Potential To Maintain Elevated Hemoglobin Mass After Hypoxic Camps

Intermittent Hypoxic Exposure And Training Have Potential To Maintain Elevated Hemoglobin Mass After Hypoxic Camps

Nitrous oxide consistently attenuates thermogenic and thermoperceptual responses to repetitive cold stress in humans.

Divers are at enhanced risk of hypothermia, due to the independent action of the inspired inert gases on thermoregulation. Thus, narcosis induced by acute (≤2 h) exposure to either hyperbaric nitrogen or normobaric nitrous oxide (N2O) impairs shivering thermogenesis and accelerates body core cooling. Animal-based studies, however, have indicated that repeated and sustained N2O administration may prevent N2O-evoked hypometabolism. We, therefore, examined the effects of prolonged intermittent exposure to 30% N2O on human thermoeffector plasticity in response to moderate cold. Fourteen men participated in two ∼12-h sessions, during which they performed sequentially three 120-min cold-water immersions (CWIs) in 20°C water, separated by 120-min rewarming. During CWIs, subjects were breathing either normal air or a normoxic gas mixture containing 30% N2O. Rectal and skin temperatures, metabolic heat production (via indirect calorimetry), finger and forearm cutaneous vascular conductance (CVC; laser-Doppler fluxmetry/mean arterial pressure), and thermal sensation and comfort were monitored. N2O aggravated the drop in rectal temperature (P = 0.01), especially during the first (by ∼0.3°C) and third (by ∼0.4°C) CWIs. N2O invariably blunted the cold-induced elevation of metabolic heat production by ∼22%-25% (P < 0.001). During the initial ∼30 min of the first and second CWIs, N2O attenuated the cold-induced drop in finger (P ≤ 0.001), but not in forearm CVC. N2O alleviated the sensation of coldness and thermal discomfort throughout (P < 0.001). Thus, the present results demonstrate that, regardless of the cumulative duration of gas exposure, a subanesthetic dose of N2O depresses human thermoregulatory functions and precipitates the development of hypothermia.NEW & NOTEWORTHY Human thermoeffector plasticity was evaluated in response to prolonged iterative exposure to 30% N2O and moderate cold stress. Regardless of the duration of gas exposure, N2O-induced narcosis impaired in a persistent manner shivering thermogenesis and thermoperception.

Doxycycline PEP can induce doxycycline resistance in Klebsiella pneumoniae in a Galleria mellonella model of PEP.

Four randomized controlled trials have now established that doxycycline post exposure (sex) prophylaxis (PEP) can reduce the incidence of chlamydia and syphilis in men who have sex with men. These studies have concluded that the risk of selecting for antimicrobial resistance is low. We evaluated this risk in vitro and in vivo using a Galleria mellonella infection model. We evaluated how long it took for doxycycline resistance to emerge during passage on doxycycline containing agar plates in 4 species - Escherichia coli, Klebsiella pneumoniae, Neisseria gonorrhoeae and Neisseria subflava. We then assessed if K. pneumoniae could acquire resistance to doxycycline (and cross resistance to other antimicrobials) during intermittent exposure to doxycycline in a Galleria mellonella model of doxycycline PEP. In our passage experiments, we found that resistance first emerged in K. pneumoniae. By day 7 the K. pneumoniae MIC had increased from 2 mg/L to a median of 96 mg/L (IQR 64-96). Under various simulations of doxycycline PEP in the G. mellonella model, the doxycycline MIC of K. pneumoniae increased from 2 mg/L to 48 mg/L (IQR 48-84). Ceftriaxone and ciprofloxacin MICs increased over ten-fold. Whole genome sequencing revealed acquired mutations in ramR which regulates the expression of the AcrAB-TolC efflux pump. Doxycycline PEP can select for doxycycline, ceftriaxone and ciprofloxacin resistance in K. pneumoniae in a G. mellonella model. The emergent ramR mutations were similar to those seen in circulating strains of K. pneumoniae. These findings suggest that we need to assess the effect of doxycycline PEP on resistance induction on a broader range of bacterial species than has hitherto been the case.

Personal exposure to radiofrequency electromagnetic fields in various occupations in Spain and France

BackgroundA preliminary job-exposure matrix (JEM) for radiofrequency electromagnetic fields (RF-EMF) was created based on self-reported occupational information from a multi-country population-based study of approximately 10,000 participants combined with available measurement data compiled in a source-exposure matrix (spot measurements). In order to address the limited personal occupational RF-EMF measurement data available in the literature, we performed a measurement campaign among workers in various occupations in Spain and France. MethodsPersonal full-shift measurements were conducted using RadMan 2XT™ (Narda) devices. A worker diary was used to capture information on occupational and background sources of RF exposure during the shift. Inclusion of occupations to be measured was initially based on exposure prevalence and level information in the preliminary JEM and expert judgment. ResultsPersonal full-shift measurements were conducted among 333 workers representing 46 ISCO88 occupations. Exposure to electric (E) and magnetic (H) fields was infrequent with >99% of measurements below the detection limit of the device (≥1% of the 1998 ICNIRP standards). A total of 50.2% and 77.2% of workers were ever exposed to E and H fields respectively (having at least one recorded 1-second measurement above the detection limit). Workers in elementary occupations, technicians and associate professionals, plant and machine operators and assemblers had somewhat greater numbers of measurements above the detection limit, higher maximum values and longer exposure durations. A small proportion of measurements were ≥100% of the standards, though these exceedances were brief (generally a few seconds in duration). Female workers and workers reporting use of any RF-EMF emitting source were more likely to have a measured exposure to E and H fields. ConclusionWe conducted personal RF-EMF measurements among workers in various occupations in Spain and France. Overall, RF-EMF exposure ≥1 % ICNIRP was infrequent, despite some intermittent exposures ≥100% observed among workers in some occupations.

Hydrogen Sulfide Improves Outcomes in a Murine Model of Necrotizing Enterocolitis via the Cys440 Residue on Endothelial Nitric Oxide Synthase

BackgroundHydrogen sulfide (H2S) has been shown to improve outcomes in a murine model of necrotizing enterocolitis (NEC). There is evidence in humans that H2S relies on endothelial nitric oxide synthase (eNOS) to exert its protective effects, potentially through the persulfidation of eNOS at the Cysteine 443 residue. We obtained a novel mouse strain with a mutation at this residue (eNOSC440G) and hypothesized that this locus would be critical for GYY4137 (an H2S donor) to exert its protective effects. MethodsNecrotizing enterocolitis was induced in 5-day old wild type (WT) and eNOSC440G mice using intermittent exposure to hypoxia and hypothermia in addition to gavage formula feeds. On postnatal day 9, mice were humanely euthanized. Data collected included daily weights, clinical sickness scores, histologic lung injury, intestinal injury (macroscopically and histologically), and intestinal perfusion. During the NEC model, pups received daily intraperitoneal injections of either GYY4137 (50 mg/kg) or PBS (vehicle). Data were tested for normality and compared using t-test or Mann–Whitney, and a p-value <0.05 was considered significant. ResultsIn WT mice, the administration of GYY4137 significantly improved clinical sickness scores, attenuated intestinal and lung injury, and improved mesenteric perfusion compared to vehicle (p < 0.05). In eNOSC440G mice, the treatment and vehicle groups had similar clinical sickness scores, intestinal and lung injury scores, and intestinal perfusion. ConclusionsGYY4137 administration improves clinical outcomes, attenuates intestinal and lung injury, and improves perfusion in a murine model of necrotizing enterocolitis. The beneficial effects of GYY4137 are dependent on the Cys440 residue of eNOS.

A randomized controlled crossover trial of acute intermittent and continuous hypoxia exposure in mild-moderate obstructive sleep apnea: A feasibility study.

In a prospective, randomized, controlled crossover study, we explored the effects of acute intermittent hypoxia and acute continuous hypoxia on patients with mild-moderate obstructive sleep apnea. Over three single-night sessions, subjects were alternately exposed to normoxia, acute continuous hypoxia and acute intermittent hypoxia before sleep. The apnea-hypopnea index and oxygen desaturation index were used to diagnose obstructive sleep apnea and evaluate efficacy. A responder was defined as a participant with a ≥ 50% reduction in apnea-hypopnea index between normoxia and hypoxia exposure. Sixteen participants with mild-moderate obstructive sleep apnea completed the study. Compared with normoxia, the mean apnea-hypopnea index decreased by 8.9 events per hr (95% confidence interval, 4.2-13.6, p = 0.001) with acute intermittent hypoxia and by 4.1 events per hr (95% confidence interval, 0.5-8.8, p = 0.082) with acute continuous hypoxia, equating to a mean decrease in apnea-hypopnea index of 4.8 events per hr (95% confidence interval, 0.1-9.5, p = 0.046) with acute intermittent hypoxia compared with acute continuous hypoxia. Compared with normoxia, the mean oxygen desaturation index decreased by 9.8 events per hr (95% confidence interval, 4.4-15.1, p = 0.001) with acute intermittent hypoxia but did not significantly decrease with acute continuous hypoxia; the mean oxygen desaturation index decreased by 7.2 events per hr (95% confidence interval, 1.8-12.6, p = 0.010) with acute intermittent hypoxia compared with acute continuous hypoxia. Of the 16 participants, 11 responded to acute intermittent hypoxia and four responded to acute continuous hypoxia (p = 0.032), of whom eight of 11 cases and all four cases had oxygen desaturation indexes <5 events per hr, respectively (p = 0.273). All participants tolerated acute intermittent hypoxia and there were no obvious adverse events during acute intermittent hypoxia exposure. In conclusion, acute intermittent hypoxia exposure improved apnea-hypopnea index and oxygen desaturation index in patients with mild-moderate obstructive sleep apnea, suggesting that further prospective validation of intermittent hypoxia exposure in patients with obstructive sleep apnea is needed to establish its clinical feasibility as a therapeutic modality.

Iron increases the profibrotic properties of the senescent peritoneal mesothelial cells.

Treatment of anemia in peritoneal dialysis patients often requires intravenous iron supplementation. Iron diffuses into the peritoneal cavity and is injurious to the peritoneum. We studied how intermittent exposure to iron changes the properties of the senescent peritoneal mesothelial cells (MC). Replicative senescence was induced in MC in control medium (Con) or in control medium with intermittent exposure to iron isomaltoside 15 µg/dL (Con-IIS). After 10 passages properties of MC from both groups were compared to MC not exposed to replicative senescence. In senescent MC population doubling time was elongated, intracellular generation of free radicals and staining for β-galactosidase was stronger than in MC not exposed to replicative senescence. All these effects were stronger in MC intermittently exposed to IIS. In these cells intracellular iron content was also higher. Also expression of genes p21 and p53 was stronger in MC intermittently treated with IIS. In senescent cells higher release and expression of IL6 and TGFβ1 was observed and that effect was stronger in MC treated with iron. Senescent MC had reduced fibrinolytic activity, what may predispose to the peritoneal fibrosis. Synthesis of collagen was higher in senescent cells, more in MC treated with iron. MC aging results in change of their genotype and phenotype which lead to their profibrotic effect. Exposure to iron enhances these changes.

Intermittent Exposure to a Single Bottle of Ethanol Modulates Stress Sensitivity: Impact of Age at Exposure Initiation.

Alcohol use during adolescence is a serious public health problem, with binge drinking and high-intensity drinking being particularly harmful to the developing adolescent brain. To investigate the adverse consequences of binge drinking and high-intensity adolescent drinking, adolescent rodents were intermittently exposed to ethanol through intragastric gavage, intraperitoneal injection, or vapor inhalation. These models revealed the long-lasting behavioral and neural consequences of adolescent intermittent ethanol (AIE) exposure. The present study was designed to characterize a different AIE model, namely, intermittent exposure to a single bottle of 10% ethanol as the only source of fluids on a 2 days on/2 days off (water days) schedule, and to determine whether this AIE exposure model would produce changes in hormonal and neuroimmune responsiveness to challenges of differing modalities. Assessments of ethanol intake as well as blood and brain ethanol concentrations (BECs and BrECs, respectively) in adult male and female rats (Experiment 1) revealed that BECs and BrECs peaked following access to ethanol for a 2 h period when assessed 1 h into the dark cycle. Experiment 2 revealed age differences in ethanol intake, BECs, and BrECs following a 2 h access to ethanol (1 h into the dark cycle), with adolescents ingesting more ethanol and reaching higher BECs as well as BrECs than adults. In Experiment 3, intermittent exposure to a single bottle of 10% ethanol for 10 cycles of 2 days on/2 days off was initiated either in early or late adolescence, followed by an acute systemic immune challenge with lipopolysaccharide (LPS) in adulthood. LPS increased corticosterone and progesterone levels regardless of sex and prior ethanol history, whereas an LPS-induced increase in cytokine gene expression in the hippocampus was evident only in ethanol-exposed males and females, with females who underwent early exposure to ethanol being more affected than their later-exposed counterparts. In Experiment 4, intermittent ethanol exposure in females was initiated either in adolescence or adulthood and lasted for 12 ethanol exposure cycles. Then, behavioral (freezing behavior), hormonal (corticosterone and progesterone levels), and neuroimmune (cytokine gene expression in the PVN, amygdala, and hippocampus) responses to novel environments (mild stressors) and shock (intense stressors) were assessed. More pronounced behavioral and hormonal changes, as well as changes in cytokine gene expression, were evident in the shock condition than following placement in the novel environment, with prior history of ethanol exposure not playing a substantial role. Interleukin (IL)-1β gene expression was enhanced by shock in the PVN, whereas shock-induced increases in IL-6 gene expression were evident in the hippocampus. Together, these findings demonstrate that our intermittent adolescent exposure model enhances responsiveness to immune but not stress challenges, with females being more vulnerable to this AIE effect than males.

Chronic intermittent ethanol exposure during adolescence produces sex- and age-dependent changes in anxiety and cognition without changes in microglia reactivity late in life.

Binge-like ethanol exposure during adolescence has been shown to produce long lasting effects in animal models including anxiety-like behavior that can last into young adulthood and impairments in cognition that can last throughout most of the lifespan. However, little research has investigated if binge-like ethanol exposure during adolescence produces persistent anxiety-like behavior and concomitantly impairs cognition late in life. Furthermore, few studies have investigated such behavioral effects in both female and male rats over the lifespan. Finally, it is yet to be determined if binge-like ethanol exposure during adolescence alters microglia activation in relevant brain regions late in life. In the present study female and male adolescent rats were exposed to either 3.0 or 5.0 g/kg ethanol, or water control, in a chronic intermittent pattern before being tested in the elevated plus maze and open field task over the next ∼18 months. Animals were then trained in a spatial reference task via the Morris water maze before having their behavioral flexibility tested. Finally, brains were removed, sectioned and presumptive microglia activation determined using autoradiography for [3H]PK11195 binding. Males, but not females, displayed an anxiety-like phenotype initially following the chronic intermittent ethanol exposure paradigm which resolved in adulthood. Further, males but not females had altered spatial reference learning and impaired behavioral flexibility late in life. Conversely, [3H]PK11195 binding was significantly elevated in females compared to males late in life and the level of microglia activation interacted as a function of sex and brain regions, but there was no long-term outcome related to adolescent alcohol exposure. These data further confirm that binge-like ethanol exposure during adolescence produces alterations in behavior that can last throughout the lifespan. In addition, the data suggest that microglia activation late in life is not exacerbated by prior binge-like ethanol exposure during adolescence but the expression is sex- and brain region-dependent across the lifespan.

Outbreak Investigation of Cutaneous Lesihmaniasis

Objective: to assess the magnitude, evaluate risk factors and recommend control measures for Cutaneous Lesihmaniasis. Study Design: Cross-sectional study. Place and Duration of Study: Combined Military Hospital, Landikotal Pakistan, from Jan to Feb 2017 Methodology: Active case finding was conducted amongst entire group of 414 individuals. A case was defined as skin lesion in a person residing in nomadic group of Khar Kamar from October 2015 to January 2017. Age and gender-matched controls were identified at 1:2. Data was collected using a pretested structured questionnaire. Results: A total of 31 cases were identified with mean age of 26.4±6.5 years (range 18-48). Epi curve showed intermittent exposure. The index case had onset of symptoms in January 2016 with a peak in November 2016, 10(32%) while last case appeared in January 2017. Overall attack rate (AR) was 7.5% while most severely affected age group was 18-27 years 21(9.1%). A total of 17(55%) cases had 2-4 multiple lesions with size of 0.5-3.5 cm. Of the 31 cases, 25 reported sleeping on the ground (OR 3.2, 95% CI 1.2-9.0, p&lt;0.02), however wearing full clothing and use of repellents showed a protective effect. Conclusion: Most probable cause of outbreak was sleeping on the floor. Awareness lectures were imparted and repellent was issued to entire group.