Interleukin 2 activation of natural killer cells rapidly induces the expression and phosphorylation of the Leu-23 activation antigen.

IL-2 potentiates both growth and cytotoxic function of T lymphocytes and NK cells. Resting peripheral blood NK cells can respond directly to rIL-2, without requirement for accessory cells or cofactors, and enhanced cytotoxicity can be measured within a few hours after exposure to this lymphokine. In this study, we describe an activation antigen, Leu-23, that is rapidly induced and phosphorylated after IL-2 stimulation of NK cells and a subset of low buoyant density T lymphocytes. Previously, it has been uncertain whether all NK cells or only a subset are responsive to IL-2. Since within 18 h after exposure to IL-2, essentially all NK cells express Leu-23, these findings indicate that all peripheral blood NK cells are responsive to stimulation by IL-2. The Leu-23 antigen is a disulfide-bonded homodimer, composed of 24-kD protein subunits with two N-linked oligosaccharides. Appearance of this glycoprotein on NK cells is IL-2 dependent and closely parallels IL-2-induced cytotoxicity against NK-resistant solid tumor cell targets

The good, the bad and the ugly: pandemic priority decisions and triage.

In this analysis we discuss the change in criteria for triage of patients during three different phases of a pandemic like COVID-19, seen from the critical care point of view. Availability of critical care beds has become a hot topic, and in many countries, we have seen a huge increase in the provision of temporary intensive care bed capacity. However, there is a limit where the hospitals may run out of resources to provide critical care, which is heavily dependent on trained staff, just-in-time supply chains for clinical consumables and drugs and advanced equipment. In the first (good) phase, we can still do clinical prioritisation and decision-making as usual, based on the need for intensive care and prognostication: what are the odds for a good result with regard to survival and quality of life. In the next (bad phase), the resources are mostly available, but the system is stressed by many patients arriving over a short time period and auxiliary beds in different places in the hospital being used. We may have to abandon admittance of patients with doubtful prognosis. In the last (ugly) phase, usual medical triage and priority setting may not be sufficient to decrease inflow and there may not be enough intensive care unit beds available. In this phase different criteria must be applied using a utilitarian approach for triage. We argue that this is an important transition where society, and not physicians, must provide guidance to support triage that is no longer based on medical priorities alone

Adaptive Lévy processes and area-restricted search in human foraging

A considerable amount of research has claimed that animals’ foraging behaviors display movement lengths with power-law distributed tails, characteristic of Lévy flights and Lévy walks. Though these claims have recently come into question, the proposal that many animals forage using Lévy processes nonetheless remains. A Lévy process does not consider when or where resources are encountered, and samples movement lengths independently of past experience. However, Lévy processes too have come into question based on the observation that in patchy resource environments resource-sensitive foraging strategies, like area-restricted search, perform better than Lévy flights yet can still generate heavy-tailed distributions of movement lengths. To investigate these questions further, we tracked humans as they searched for hidden resources in an open-field virtual environment, with either patchy or dispersed resource distributions. Supporting previous research, for both conditions logarithmic binning methods were consistent with Lévy flights and rank-frequency methods–comparing alternative distributions using maximum likelihood methods–showed the strongest support for bounded power-law distributions (truncated Lévy flights). However, goodness-of-fit tests found that even bounded power-law distributions only accurately characterized movement behavior for 4 (out of 32) participants. Moreover, paths in the patchy environment (but not the dispersed environment) showed a transition to intensive search following resource encounters, characteristic of area-restricted search. Transferring paths between environments revealed that paths generated in the patchy environment were adapted to that environment. Our results suggest that though power-law distributions do not accurately reflect human search, Lévy processes may still describe movement in dispersed environments, but not in patchy environments–where search was area-restricted. Furthermore, our results indicate that search strategies cannot be inferred without knowing how organisms respond to resources–as both patched and dispersed conditions led to similar Lévy-like movement distributions

The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice.

RATIONALE Using the drinking-in-the-dark (DID) model, we compared the effects of a novel mu-opioid receptor antagonist, GSK1521498, with naltrexone, a licensed treatment of alcohol dependence, on ethanol consumption in mice. OBJECTIVE We test the ability of GSK1521498 to reduce alcohol consumption and compare its intrinsic efficacy to that of naltrexone by comparing the two drugs at doses matched for equivalent receptor occupancy. METHODS Thirty-six C57BL/6J mice were tested in a DID procedure. In 2-day cycles, animals experienced one baseline, injection-free session, and one test session when they received two injections, one of test drug and one placebo. All animals received GSK1521498 (0, 0.1, 1 and 3 mg/kg, i.p., 30 min pre-treatment) and naltrexone (0, 0.1, 1 and 3 mg/kg, s.c. 10 min pre-treatment) in a cross-over design. Receptor occupancies following the same doses were determined ex vivo in separate groups by autoradiography, using [3H]DAMGO. Binding in the region of interest was measured integrally by computer-assisted microdensitometry and corrected for non-specific binding. RESULTS Both GSK1521498 and naltrexone dose-dependently decreased ethanol consumption. When drug doses were matched for 70-75 % receptor occupancy, GSK1521498 3 mg/kg, i.p., caused a 2.5-fold greater reduction in alcohol consumption than naltrexone 0.1 mg/kg, s.c. Both GSK1521498 and naltrexone significantly reduced sucrose consumption at a dose of 1 mg/kg but not 0.1 mg/kg. In a test of conditioned taste aversion, GSK1521498 (3 mg/kg) reduced sucrose consumption 24 h following exposure to a conditioning injection. CONCLUSIONS Both opioid receptor antagonists reduced alcohol consumption but GK1521498 has higher intrinsic efficacy than naltrexone

Analysis of bolted flanged panel joint for GRP sectional tanks

Peer reviewedPublisher PD

Characterization of N-acetyltransferase 1 and 2 polymorphisms and haplotype analysis for inflammatory bowel disease and sporadic colorectal carcinoma

<p>Abstract</p> <p>Background</p> <p>N-acetyltransferase 1 (NAT1) and 2 (NAT2) are polymorphic isoenzymes responsible for the metabolism of numerous drugs and carcinogens. Acetylation catalyzed by NAT1 and NAT2 are important in metabolic activation of arylamines to electrophilic intermediates that initiate carcinogenesis. Inflammatory bowel diseases (IBD) consist of Crohn's disease (CD) and ulcerative colitis (UC), both are associated with increased colorectal cancer (CRC) risk. We hypothesized that <it>NAT1 </it>and/or <it>NAT2 </it>polymorphisms contribute to the increased cancer evident in IBD.</p> <p>Methods</p> <p>A case control study was performed with 729 Caucasian participants, 123 CRC, 201 CD, 167 UC, 15 IBD dysplasia/cancer and 223 controls. <it>NAT1 </it>and <it>NAT2 </it>genotyping were performed using Taqman based techniques. Eight single nucleotide polymorphisms (SNPs) were characterized for <it>NAT1 </it>and 7 SNPs for <it>NAT2</it>. Haplotype frequencies were estimated using an Expectation-Maximization (EM) method. Disease groups were compared to a control group for the frequencies at each individual SNP separately. The same groups were compared for the frequencies of <it>NAT1 </it>and <it>NAT2 </it>haplotypes and deduced NAT2 phenotypes.</p> <p>Results</p> <p>No statistically significant differences were found for any comparison. Strong linkage disequilibrium was present among both the <it>NAT1 </it>SNPs and the <it>NAT2 </it>SNPs.</p> <p>Conclusion</p> <p>This study did not demonstrate an association between <it>NAT1 </it>and <it>NAT2 </it>polymorphisms and IBD or sporadic CRC, although power calculations indicate this study had sufficient sample size to detect differences in frequency as small as 0.05 to 0.15 depending on SNP or haplotype.</p

Confronting and mitigating the risk of COVID-19 associated pulmonary aspergillosis.

Cases of COVID-19 associated pulmonary aspergillosis (CAPA) are being increasingly reported and physicians treating patients with COVID-19-related lung disease need to actively consider these fungal co-infections. The SARS-CoV-2 (COVID-19) virus causes a wide spectrum of disease in healthy individuals as well as those with common comorbidities [1]. Severe COVID-19 is characterised acute respiratory distress syndrome (ARDS) secondary to viral pneumonitis, treatment of which may require mechanical ventilation or extracorporeal membrane oxygenation (ECMO) [2]. Clinicians are alert to the possibility of bacterial co-infection as a complication of lower respiratory tract viral infection; for example a recent review found that 72% of patients with COVID-19 received antimicrobial therapy [3]. However, the risk of fungal co-infection, in particular COVID-19 associated pulmonary aspergillosis (CAPA), remains underappreciated. Fungal disease consistent with invasive aspergillosis (IA) has been observed with other severe Coronaviruses such as Severe Acute Respiratory Syndrome (SARS-CoV-2003) [4, 5] and Middle East Respiratory Syndrome (MERS-CoV) [6]. From the outset of the COVID-19 pandemic, there were warning signs of secondary invasive fungal infection; Aspergillus flavus was isolated from the respiratory tract from one of 99 patients in the first COVID-19 cohort from Wuhan to be reported in any detail [2] and Aspergillus spp. were isolated from 2/52 (3.8%) of a subsequent cohort of critically unwell patients from this region [7]. More recently, retrospective case series from Belgium [8], France [9], The Netherlands [10] and Germany [11] have reported evidence of CAPA in an alarming 20–35% of mechanically ventilated patients

Combined effects of time spent in physical activity, sedentary behaviors and sleep on obesity and cardio-metabolic health markers: a novel compositional data analysis approach

<div><p>The associations between time spent in sleep, sedentary behaviors (SB) and physical activity with health are usually studied without taking into account that time is finite during the day, so time spent in each of these behaviors are codependent. Therefore, little is known about the combined effect of time spent in sleep, SB and physical activity, that together constitute a composite whole, on obesity and cardio-metabolic health markers. Cross-sectional analysis of NHANES 2005–6 cycle on N = 1937 adults, was undertaken using a compositional analysis paradigm, which accounts for this intrinsic codependence. Time spent in SB, light intensity (LIPA) and moderate to vigorous activity (MVPA) was determined from accelerometry and combined with self-reported sleep time to obtain the 24 hour time budget composition. The distribution of time spent in sleep, SB, LIPA and MVPA is significantly associated with BMI, waist circumference, triglycerides, plasma glucose, plasma insulin (all p<0.001), and systolic (p<0.001) and diastolic blood pressure (p<0.003), but not HDL or LDL. Within the composition, the strongest positive effect is found for the proportion of time spent in MVPA. Strikingly, the effects of MVPA replacing another behavior and of MVPA being displaced by another behavior are asymmetric. For example, re-allocating 10 minutes of SB to MVPA was associated with a lower waist circumference by 0.001% but if 10 minutes of MVPA is displaced by SB this was associated with a 0.84% higher waist circumference. The proportion of time spent in LIPA and SB were detrimentally associated with obesity and cardiovascular disease markers, but the association with SB was stronger. For diabetes risk markers, replacing SB with LIPA was associated with more favorable outcomes. Time spent in MVPA is an important target for intervention and preventing transfer of time from LIPA to SB might lessen the negative effects of physical inactivity.</p></div

Socio-demographic, behavioural and cognitive correlates of work-related sitting time in German men and women

Background: Sitting time is ubiquitous for most adults in developed countries and is most prevalent in three domains: in the workplace, during transport and during leisure time. The correlates of prolonged sitting time in workplace settings are not well understood. Therefore, the aim of this study was to examine the gender-specific associations between the socio-demographic, behavioural and cognitive correlates of work-related sitting time. Methods: A cross-sectional sample of working German adults (n = 1515; 747 men; 43.5 ± 11.0 years) completed questionnaires regarding domain-specific sitting times and physical activity (PA) and answered statements concerning beliefs about sitting. To identify gender-specific correlates of work-related sitting time, we used a series of linear regressions. Results The overall median was 2 hours of work-related sitting time/day. Regression analyses showed for men (β = -.43) and for women (β = -.32) that work-related PA was negatively associated with work-related sitting time, but leisure-related PA was not a significant correlate. For women only, transport-related PA (β = -.07) was a negative correlate of work-related sitting time, suggesting increased sitting times during work with decreased PA in transport. Education and income levels were positively associated, and in women only, age (β = -.14) had a negative correlation with work-related sitting time. For both genders, TV-related sitting time was negatively associated with work-related sitting time. The only association with cognitive correlates was found in men for the belief ‘Sitting for long periods does not matter to me’ (β = .10) expressing a more positive attitude towards sitting with increasing sitting durations. Conclusions: The present findings show that in particular, higher educated men and women as well as young women are high-risk groups to target for reducing prolonged work-related sitting time. In addition, our findings propose considering increasing transport-related PA, especially in women, as well as promoting recreation-related PA in conjunction with efforts to reduce long work-related sitting times