Dynamics and topography of human temperature regulation in response to thermal and work load

Summary Climatic chamber experiments were carried out with male subjects who were submitted to various rapid temperature changes. All experiments were performed first with the subjects at rest and later at work on a bicycle ergometer. The aims of the study were 1) to obtain quantitative data enabling to determine effects of a) abrupt thermal load, b) abrupt work load, and c) combined load on the topography and the dynamics of temperatures and effectors, and 2) to answer the question whether the effects of combined load may be computed by a linear superposition of pure thermal plus pure work load.Skin temperatures generally respond more directly to abrupt changes of thermal than of work load. This is in contrast to the dynamic behaviour of central temperatures which moreover exhibit the interesting effect of a transient paradoxical respone both to the onset of work and of thermal load.Time constants of the dynamics of metabolic heat production are high in response to changes of thermal load as compared to the time constants at the onset and end of worl. Generally the time constants of skin temperatures are shorter at rest than at work. Temperature topography changes only to a small extent in exercising subjects.The central temperature increase to combined thermal and work load is not significantly different from the added amount of temperature increases due to pure thermal and to pure work load. This suggests a quasi-linear superposition of both thermal effects and confirms, in accordance with further evidence of this and former studies, the hypothesis that work load does not interfere non-linearly with the regulatory processes. However, an input from thermosensitive elements in the muscles should be assumed.Supported by the Deutsche Forschungsgemeinschaft, SFB 114     

DDR2与MMP2在酒精性肝病肝窦毛细血管化中的协同表达

目的:探讨盘状区域受体2(DDR2)与基质金属蛋白酶(MMP2)在酒精性肝纤维化大鼠肝窦毛细血管化病理进程中的表达及可能发挥的作用。方法:橄榄油拌平衡饲料喂养大鼠的基础上给予60%(V/V)白酒胃内灌注制备酒精性肝纤维化模型,分别于4周、8周、12周和16周末观察肝组织网状纤维染色、免疫组化染色(Ⅰ、Ⅳ型胶原及层黏连蛋白),荧光定量-PCR和Western blotting检测肝组织DDR2及MMP2基因和蛋白表达并与肝窦毛细血管化各项评价指标进行相关性分析。结果:大鼠白酒灌胃4周出现肝脏脂肪变性,随灌胃时间延长逐渐加重为肝脏坏死、炎症及纤维化。酒精性肝病模型组大鼠DDR2 mRNA和蛋白表达量显著高于对照组,且随造模时间延长表达增加(P0.01)。MMP2 mRNA和蛋白表达自造模4周开始升高,于12周达峰值,造模16周下降,各模型组MMP2 mRNA和蛋白表达较正常对照组明显升高(P0.05)。相关性分析显示DDR2与MMP2、网状纤维、Ⅰ、Ⅳ型胶原及层黏连蛋白表达均呈显著正相关。结论:在酒精性肝病肝窦毛细血管化病程中DDR2表达呈时间依赖性,其可能通过效应蛋白MMP2在肝窦毛细血管化的发生和进展中发挥重要作用。     

Effect of work rate on the functional 'gain' of Phase II pulmonary O2 uptake response to exercise

It has recently been reported that the 'gain' of Phase II increase in pulmonary oxygen uptake (i.e. the 'fundamental' increase in V(O(2)) per unit increase in work rate; G(p)) does not attain the anticipated value of approximately 10 ml min(-1)W(-1) following the onset of high-intensity exercise. In the present study, we hypothesised that G(p) would fall significantly below 10 ml min(-1)W(-1) only when the work rate exceeded the so-called 'critical power' (CP). Seven healthy males completed several 'square-wave' transitions from 'unloaded' cycling to work rates requiring 60 and 90% of the gas exchange threshold (GET), 40 and 80% of the difference between the GET and V(O(2)) peak (i.e. below and above the CP, respectively), and 100, 110 and 120% of V(O(2)) peak. Pulmonary V(O(2)) was measured breath-by-breath and V(O(2)) kinetics were determined using non-linear regression techniques. The asymptotic G(p) was significantly lower at work rates above (7.2-8.6 ml min(-1)W(-1)) compared to work rates below (9.3-9.7 ml min(-1)W(-1)) the CP (P < 0.05). We conclude that the gain of Phase II increase in V(O(2)) becomes significantly reduced when the work rate exceeds the CP.     

Ventilatory response to CO2 at rest and during positive and negative work in normoxia and hyperoxia

Summary Ventilation versus alveolar relationships were determined by the steady-state method in 6 normal male subjects at rest and during positive and negative work at one load in both normoxic and hyperoxic condition. In 5 subjects the slopes of the lines during positive and negative work increased in normoxia as compared with rest. This effect was less evident in hyperoxia. It was also found that the slopes of the lines in positive and in negative work were about the same in both normoxic and hyperoxic conditions. Oxygen uptake and CO₂ production during positive work is higher than during negative work.These results suggest that: 1) the disagreement between various authors on the change of the slope of the line may be due to the differences in the method of calculation of the slope or the method of the determination of lines; 2) the stimuli from the muscle spindles in the working muscle during exercise probably do not contribute to the increase in ventilatory response to CO₂; 3) the increased slope of the normoxic line during exercise may be due to the interaction of several factors such as impulses from working muscles, chemosensitivity of central or peripheral chemoreceptors, adrenal-sympathetic pathways or temperature; 4) respiratory oscillations of or do not seem to influence the respiratory response to CO₂.This study was supported in part by a grant from the Netherlands Organization for the Advancement of Pure Research (Z.W.O.)     

Antibody dynamics to SARS-CoV-2 in asymptomatic COVID-19 infections

Background

The missing asymptomatic COVID-19 infections have been overlooked because of the imperfect sensitivity of the nucleic acid testing (NAT). Globally understanding the humoral immunity in asymptomatic carriers will provide scientific knowledge for developing serological tests, improving early identification, and implementing more rational control strategies against the pandemic.

Measure

Utilizing both NAT and commercial kits for serum IgM and IgG antibodies, we extensively screened 11 766 epidemiologically suspected individuals on enrollment and 63 asymptomatic individuals were detected and recruited. Sixty-three healthy individuals and 51 mild patients without any preexisting conditions were set as controls. Serum IgM and IgG profiles were further probed using a SARS-CoV-2 proteome microarray, and neutralizing antibody was detected by a pseudotyped virus neutralization assay system. The dynamics of antibodies were analyzed with exposure time or symptoms onset.

Results

A combination test of NAT and serological testing for IgM antibody discovered 55.5% of the total of 63 asymptomatic infections, which significantly raises the detection sensitivity when compared with the NAT alone (19%). Serum proteome microarray analysis demonstrated that asymptomatics mainly produced IgM and IgG antibodies against S1 and N proteins out of 20 proteins of SARS-CoV-2. Different from strong and persistent N-specific antibodies, S1-specific IgM responses, which evolved in asymptomatic individuals as early as the seventh day after exposure, peaked on days from 17 days to 25 days, and then disappeared in two months, might be used as an early diagnostic biomarker. 11.8% (6/51) mild patients and 38.1% (24/63) asymptomatic individuals did not produce neutralizing antibody. In particular, neutralizing antibody in asymptomatics gradually vanished in two months.

Conclusion

Our findings might have important implications for the definition of asymptomatic COVID-19 infections, diagnosis, serological survey, public health, and immunization strategies.

     

Transient increment of HTLV-2 proviral load in HIV-1-co-infected patients during treatment intensification with raltegravir

BackgroundNumerous studies have analyzed the effects of raltegravir intensification on HIV-1 viral replication in infected individuals receiving suppressive combined antiretroviral treatment (cART). Nevertheless, there are only two studies on the effect of raltegravir in HTLV-1 infection, and none in HTLV-2.ObjectiveTo study the effect of raltegravir on HTLV-2 infection in HIV-1-co-infected individuals.Study designThis retrospective longitudinal study included four HTLV-2-HIV-1-co-infected individuals who received raltegravir-based cART during 48 weeks and 11 HTLV-2-HIV-1-co-infected individuals under cART without raltegravir during 48 weeks. HTLV-2 proviral load, CD4 and CD8 count and frequency were analyzed.ResultsHTLV-2 proviral load significantly increased at week 24 compared to baseline among all the patients who received raltegravir (p = 0.003), while no significant increases were found in the control group. No significant variation in either CD8 or CD4 counts was found during the follow up in both groups.ConclusionsRaltegravir induced a transient increment on total HTLV-2 DNA proviral load in HTLV-2/HIV-1-coinfected individuals on suppressive cART after 24 weeks.     

The role of fitness on VO2 and VCO2 kinetics in response to proportional step increases in work rate

Summary The purpose of this study was to determine the effect of fitness and work level on the O₂ uptake and CO₂ output kinetics when the increase in work rate step is adjusted to the subject's maximum work capacity. Nine normal male subjects performed progressive incremental cycle ergometer exercise tests in 3-min steps to their maximum tolerance. The work rate step size was selected so that the symptom-limited maximum work rate would be reached in four steps at 12 min in all subjects. Oxygen consumption (VCO₂) and carbon dioxide production VCO₂ were calculated breath by breath. For the group, the time (mean, SEM) to reach 75% of the 3-min response (T _0.75) for VO₂ increased significantly (P<0.01) at progressively higher work rate steps, being 53.3 (5.5) s, 63.5 (4.6) s, 79.5 (5.0) s, and 94.5 (5.8) s, respectively. In contrast, T _0.75 for VCO₂ did not change significantly [74.9 (7.4) s,. 75.6 (5.0) s, 85.1 (5.3) s, and 89.4 (6.3) s, respectively]. VCO₂ kinetics were slower than VO₂ kinetics at the low fractions of the subjects' work capacities but were the same of faster at the high fractions because of the slowing of VO₂ kinetics. The first step showed the fastest rise in VO₂. While VO₂ kinetics slowed at each step, they were faster at each fraction of the work capacity in the fitter subjects. The step pattern in VO₂ disappeared at high work rates for the less fit subjects. The heart rate response paralleled that of VO₂. We conclude that VO₂ and VCO₂ kinetics are slower in the less fit subjects but only VO₂ kinetics are significantly attenuated in response to proportional step increases in work rate.     

Estimating the parameters of aerobic function during exercise using an exponentially increasing work rate protocol

A new exercise protocol has been proposed, with respect to cardiopulmonary exercise testing, which starts at a low work rate (WR) and increases exponentially by a standard percentage of the previous work rate every minute: the test is termed STEEP (standardised exponential exercise protocol). The potential advantage of this protocol is that it can accommodate a wide range of subjects, since it allows a maximum to be attained with a relatively narrow variation of tolerance time, regardless of subjects exercise capacity. To date, only the VO _2max has been compared with that from the current standard ramp protocol. The ramp, however, also allows other important parameters of aerobic function to be estimated: the anaerobic threshold (AT); the response time constant; and ΔVO₂/ΔWR. The aim of this study was, therefore, to clarify whether these aerobic parameters can be readily discerned from the responses to the STEEP protocol both from a theoretical and practical viewpoint. As a result of theoretical considerations, we demonstrated that the VO₂ time constant and ΔVO₂/ΔWR may not both be estimated uniquely. As a practical expedient, a procedure was proposed for estimating the parameter analogues. The preliminary results for six subjects between the STEEP and ramp protocols showed consistent positive correlation for VO _2max (r=0.997) and AT-VO₂ (r=0.980), whereas the correlation for the VO₂ time constant and ΔVO₂/ΔWR were not significant. Further study is needed to clarify the reason(s) for the discrepancies both from a theoretical and practical viewpoint.     

The response of horizontal semicircular canal afferents to sinusoidal rotation in the cat

Summary Dynamic characteristics of primary vestibular afferents innervating the horizontal semicircular canal were studied in decerebrate, unanesthetized cats. Activities of individual afferent fibers were recorded intracranially by glass micropipettes. Frequency of sinusoidal rotation was varied from 0.014 Hz to 0.42 Hz, and phase and gain properties were examined.All of the fibers recorded fired spontaneously, and their firing rate ranged from 7 to 128 spikes/sec. Regularity of firing, phase lags, and gains were calculated in individual fibers. There was a tendency that the units with high spontaneous firing rates showed regular firing, larger phase lags, and lower gains than the units with low spontaneous firing rates.The transfer function of the system (firing rate of the primary afferent per angular acceleration of the head) was . A high frequency phase lead component was needed to account for the data obtained, indicating a slight deviation from the relationship predicted by the torsion pendulum model.The present phase properties were compared with those of vestibular nucleus neurons reported previously. It was suggested that a group of vestibular nucleus neurons transmits fairly faithfully the phase properties of primary afferents, and that another group of vestibular nucleus neurons receive additional influences from central structures, exhibiting larger phase lags than primary afferents.     

Monitoring the response to antiretroviral therapy in HIV-1 group O infected patients using two new RT-PCR assays.

Failure to recognise infection caused by human immunodeficiency virus type 1 (HIV-1) group O variants has been described using both serological and genetic procedures. Moreover, monitoring the response to antiretroviral therapy is a difficult task in patients infected with HIV-1 group O since commercial tests are not available so far for the quantitation of this virus. In this study, the virological response to antiretroviral therapy were assessed in five HIV-1 group O-infected patients living in Spain by using two new and different RT-PCR methods (MUPROVAMA and LCx). Twenty-four plasma samples belonging to these five patients were selected. As reference, p24 antigenaemia levels and CD4+ cell counts were used. All samples yielded positive viral load values using MUPROVAMA (range: 138 to 595,500 HIV-RNA copies/ml) and 23 of 24 using LCx (range: < 178 to 98,356 HIV-RNA copies/ml). Overall, the results obtained using both assays showed a good correlation among themselves, and in respect to p24 antigenaemia and CD4+ cell counts. However, the values provided by LCx were significantly lower (0.33 logs on average) than those provided by MUPROVAMA. In conclusion, both the highly sensitive MUPROVAMA and LCx Quantitative assays might represent an useful tool for guiding the decision on when start treatment and for monitoring the response to antiretroviral therapy in HIV-1 group O-infected patients.     

The influence of cognitive load on maternal postural sway and heart rate in response to infant vocalizations

Infants communicate their emotions to their caregivers through cries and laughter. Recent work suggests that adaptive parenting requires cognitive regulation of intuitive behaviors toward infants’ signals. In this study, we examined the effects of cognitive regulation on mothers’ unconscious behavioral and cardiac responses to infant cries and laughs. In all, 55 mothers took part in this study. To manipulate cognitive load, mothers were asked to memorize alphabet characters (two letters in the low cognitive load condition and eight in the high cognitive load condition). Then, they heard infant vocalizations (cries or laughs) for 6 s. During this time, we measured mothers’ behavioral (center of pressure, an index of approach–avoidance behavior) and physiological (heart rate) responses. Regardless of vocalization type (infant cries or laughs), high cognitive load increased mothers’ forward movement toward the infant sounds as well as mothers’ heart rate. These findings advance our understanding of the link between executive function and maternal response to infant signals by utilizing postural and physiological measures of maternal response during memory tasks that require cognitive resources.     

Inhibition by indomethacin of the renal response to an acute saline load in the dog

The kidneys of sodium-loaded dogs, treated by indomethacin before their transplantation to the neck vessels of sodium-depleted animals, lose their ability to increase the fractional excretion of sodium following an intravenous infusion of saline; they behave similarly to the kidneys of sodium-depleted dogs. Moreover, they become unable to potentiate the response of the kidneys of the sodium-depleted perfusors. The experimental conditions exclude a direct effect of the drug eo ipso. The results indicate that renal prostaglandins are involved in the adjustment of the renal response to saline loading, depending on the previous dietary sodium balance, and that they are related with the potentiating factors released into the blood by the kidneys of sodium-loaded animals.     

血管生成素-1通过调节PI3K/AKT信号途径抑制H2O2诱导小鼠心肌细胞凋亡

目的 观察血管生成素-1(Ang-1)对H2O2诱导小鼠心肌细胞凋亡的影响及其与磷脂酰肌醇3激酶(PI3K) / 丝氨酸苏氨酸蛋白激酶(Akt)信号通路活化的关系。方法 培养新生小鼠心肌细胞,分为对照组、H2O2诱导组、Ang-1干预组、共同干预组,用Hoechst-33342染色法观察细胞凋亡形态学特征,流式细胞仪检测细胞凋亡率;Westernblot检测蛋白p-AKT、AKT、active Caspase-3的表达。结果 H2O2可以诱导心肌细胞发生凋亡,凋亡的心肌细胞呈现细胞核聚集、皱缩、碎裂等典型的凋亡形态学特征;与H2O2诱导组相比对照组、Ang-1干预组的细胞凋亡率均降低（2.13%±0.61% vs 48.16%±1.37% p<0.01;31.20%±2.01% vs 48.16%±1.37% p<0.01）;共同干预组的细胞凋亡率高于Ang-1干预组（47.42±2.02% vs 31.20±2.01% p<0.01）,与H2O2诱导组没有统计学差异（47.42%±2.02% vs 48.16%±1.37%）;与H2O2诱导组相比Ang-1干预组磷酸化AKT（p-AKT）水平升高、active Caspase-3的表达水平降低,这种差别在共同干预组中不明显。结论 Ang-1通过调节PI3K/AKT信号途径对H2O2诱导的小鼠心肌细胞凋亡起到保护作用。     

The core-specific precursor T cell response is directed to the N-terminal and central parts of the protein and positively correlates to the viral load in chronically HCV-infected patients

The cellular immune response to hepatitis C virus (HCV) plays a critical role in determining the clearance or persistence of HCV. Moreover, in chronic HCV infection, these responses that are insufficient to eradicate virus completely may cause liver injury. In this study, the memory T cells responses specific to the core protein were measured by interferon-gamma Elispot assay after in vitro stimulation of peripheral blood mononuclear lymphocytes from chronically infected subjects. Ten out of the 22 patients studied (45%) present a core-specific response with a preferential recognition of the N-terminal and central parts. There was no relationship between T cell responses and the parameters of disease evolution as determined by ALT (serum alanine transaminase levels), and histologic hepatic damage (Metavir score A and F), but there was a positive relationship between the presence of a core-specific T cell responses and the viraemia.     

Relevance of immune response and vaccination strategies of SARS-CoV-2 in the phase of viral red queen dynamics

BackgroundFollowing a relatively mild first wave of coronavirus disease 2019 (COVID-19) in India, a deadly second wave of the pandemic overwhelmed the healthcare system due to the emergence of fast-transmitting SARS-CoV-2 genetic variants. The emergence and spread of the B.1.617.2/Delta variant considered to be driving the devastating second wave of COVID-19 in India. Currently, the Delta variant has rapidly overtaken the previously circulating variants to become the dominant strain. Critical mutations in the spike/RBD region of these variants have raised serious concerns about the virus's increased transmissibility and decreased vaccine effectiveness. As a result, significant scientific and public concern has been expressed about the impact of virus variants on COVID-19 vaccines.ObjectivesThe purpose of this article is to provide an additional explanation in the context of the evolutionary trajectory of SARS-CoV-2 variants in India, the vaccine-induced immune response to the variants of concern (VOC), and various vaccine deployment strategies to rapidly increase population immunity.ContentPhylogenetic analysis of SARS-CoV-2 isolates circulating in India suggests the emergence and spread of B.1.617 variant. The immunogenicity of currently approved vaccines indicates that the majority of vaccines elicit an antibody response and some level of protection. According to current data, vaccines in the pre-fusion configuration (2p substitution) have an advantage in terms of nAb titer, but the duration of vaccine-induced immunity, as well as the role of T cells and memory B cells in protection, remain unknown. Since vaccine efficacy on virus variants is one of the major factors to be considered for achieving herd immunity, existing vaccines need to be improved or effective next-generation vaccines should be developed to cover the new variants of the virus.