Cytotoxic effector cells against HLA antigens in strong linkage disequilibrium: identification of a strong,new, CML determinant

Three sets of cytotoxic effector cells were generated against the A1, B8, DR3 haplotype using haptoidentical individuals in three different families. The three sets of effector cells generated against this haplotype showed excellent reproducibility testing, strong cytotoxicity against their specific targets, low autologous kill, and segregation with the sensitizing haplotype within the family. When tested against a panel of cells bearing all combinations the A1, B8. DR3 antigens, a hierarchy of contribution of the individual HLA antigens as CML target determinants was seen. A new strong target cell determinant was identified by cytotoxicity with one of the effector cells not explicable in terms of the A1, B8, DR3 antigens or known HLA cross-reactivity. A family study demonstrated that this determinant clearly segregates with HLA. The success of this approach in defining new CML determinants may result from the generation of effector cells across a single haplotype in strong linkage disequilibrium or from the presentation of CML determinants in the context of self.     

活体亲属供肾肾移植的临床分析

目的　总结分析活体亲属供肾肾移植的手术和治疗经验 ,探讨其临床效果 .方法　回顾性分析 33例活体亲属供肾肾移植的临床资料 ,包括手术方法和创新、免疫抑制药物的用药方案及临床效果 .结果　本组全部切取左肾 ,经腹手术 ,手术顺利 ,移植肾在开放血液循环后 1～ 10分钟内分泌尿液 .供体肾功能在 1周内恢复正常 ,未出现严重并发症 .受者仅 2例出现急性排斥反应 .全部受者至今存活 ,肾功能良好 .结论　活体亲属供肾 ,移植效果明显优于尸体供肾肾移植 .排斥反应发生率低 ,恢复顺利     

A pilot study of the effect of mechanical ventilation and heat exchange on house-dust mites and Der p 1 in New Zealand homes

We have examined the effect of reducing relative humidity (RH), with inbuilt mechanical ventilation and heat-exchange (MVHE) units, on house-dust- mite (HDM) counts and allergen levels, in a pilot study of 10 Wellington dwellings. Recent international prevalence studies in adults and children have confirmed a high prevalence of asthma in New Zealand, Sensitivity to HDM is common among the general population, and HDM is the major allergen associated with asthma. Recent studies of allergen levels have confirmed high concentrations of Der p 1 in the domestic environment. While humidity was significantly reduced in those dwellings fitted with ventilation units, no systematic effect on mites or Der p 1 was observed during the study period. When the reductions in humidity were examined in the context of the time spent below the critical equilibrium humidity (CEH), the intervention led to RH values below the CEH for only 39% of the total of 24-h periods for which measurements were made. Reducing RH by means of MVHE in New Zealand domestic dwellings does not lower humidity sufficiently, or long enough, to have any measurable effect on HDM populations.     

Daytime variation in performance and tiredness/sleepiness ratings in patients with insomnia, narcolepsy, sleep apnea and normal controls

Daytime tiredness or sleepiness and deficits in cognitive performance are common complaints in sleep disordered patients. Till now there are few studies comparing patients from different diagnostic groups of sleep disorders in the same experimental protocol. We studied the time course of cognitive functions and subjective alertness in a parallel group design with four groups of patients [narcolepsy, untreated or treated obstructive sleep apnea (OSA), or psychophysiological insomnia] and a control group of subjects without sleep complaints. Each group consisted of 10 subjects, matched for age and gender. After a night with polysomnography, subjects were studied for 10 h from 08:00 hours to 18:00 hours at 20 min intervals under standardized environmental conditions. Four psychological tests were applied, (1) a critical flicker fusion (CFF) test to measure optical fusion threshold (alertness); (2) a paper-and-pencil visual line tracking test (selective attention); (3) a visual analog scale (VAS) for tiredness/sleepiness; and (4) the Tiredness Symptoms Scale (TSS), a 14 items check list. Each test session lasted for 8 min, followed by a 12 min pause. The level and time course of cognitive performance and self-rating data were analysed with hierarchical linear mixed effects models. Cognitive tests showed decrements in alertness and selective attention in untreated patients with insomnia, narcolepsy, and sleep apnea. Narcoleptic patients and untreated OSA had a lower CFF threshold than controls, and for narcoleptic patients the time course differed from that of all other groups. In the visual tracking test the performance of all groups of patients was worse compared with normal controls. Self-rated tiredness/sleepiness was significantly more pronounced in the three groups of untreated patients than in control subjects.     

Gm allotypes in blacks with systemic lupus erythematosus

Serum samples were collected from 328 healthy American Blacks and from 61 American Blacks with systemic lupus erythematosus (SLE). Sera were typed for the Gm1,2,3,5,6,13,17, and 21 allotypes as well as for the Km(1) allotype. The frequency of Gm phenotype 1,17;5,6,13 was significantly increased in the SLE patients (p = 0.0001, RR = 3.19, EF = 0.29). Our data suggest the existence of at least two immunoglobulin allotype associated genes that somehow interact to increase susceptibility to SLE in Blacks. To our knowledge, this is the first report of an association of Gm and SLE in Blacks.     

Kinetics of methotrexate binding to dihydrofolate reductase from Neisseria gonorrhoeae

The kinetics of methotrexate inhibition of dihydrofolate reductase from Neisseria gonorrhoeae have been investigated. Methotrexate was shown to be a tight-binding inhibitor (Kt = 13 pM) competitive with dihydrofolate. However, "stoichiometric" or "pseudoirreversible" inhibition could not be demonstrated. Progress curves of inhibited assays quickly attained steady state regardless of the order of substrate addition, indicating that methotrexate association and dissociation processes were rapid. Kinetic techniques were used to measure the rate of methotrexate dissociation from the enzyme-NADPH-methotrexate ternary complex. At 30 degrees, the first-order off-rate constant (koff) was calculated to be 0.56 min-1. This value is approximately 40-fold greater than the dissociation rate constant of methotrexate for Escherichia coli dihydrofolate reductase. At lower temperatures, progress curves of methotrexate-inhibited gonococcal enzyme assays displayed marked increases in both curvature and the time to reach steady state. At 9 degrees, the methotrexate dissociation rate was slow enough (koff = 0.04 min-1) so that initial velocities of the reaction could be measured, and under these conditions methotrexate inhibition was shown to be "stoichiometric".     

饮酒与慢性阻塞性肺疾病风险关系的meta分析

目的 探讨饮酒与慢性阻塞性肺疾病风险(chronic obstructive pulmonary disease, COPD)的关系。 方法 计算机检索PubMed、Web of Science、Embase、中国知网、万方数据库和维普数据库,搜集各数据库建库至2021年11月公开发表的有关饮酒与COPD风险的观察性研究。由2位研究者根据文献纳入及排除标准独立筛选文献并提取数据。采用Stata 12.0软件进行统计学分析。 结果 共纳入8篇文献(2篇队列研究文献和6篇横断面研究文献),共纳入209 489例研究对象。meta分析结果显示,与最低饮酒量组相比,最高饮酒量组发生COPD的风险无显著变化(RR=0.97, 95%CI:0.87~1.08);与不饮酒组相比,少量或中度饮酒组发生COPD的风险降低(RR=0.87, 95%CI:0.81~0.94);与少量或中度饮酒组相比,过量饮酒组发生COPD的风险无显著变化(RR=1.26, 95%CI:0.98~1.63)。 结论 meta分析结果提示少量或中度饮酒可降低COPD的风险。过量饮酒是否会增加COPD的风险尚需进一步研究。     

Reported Challenges in Health Technology Assessment of Complex Health Technologies

ObjectivesWith complex health technologies entering the market, methods for health technology assessment (HTA) may require changes. This study aimed to identify challenges in HTA of complex health technologies.MethodsA survey was sent to European HTA organizations participating in European Network for HTA (EUnetHTA). The survey contained open questions and used predefined potentially complex health technologies and 7 case studies to identify types of complex health technologies and challenges faced during HTA. The survey was validated, tested for reliability by an expert panel, and pilot tested before dissemination.ResultsA total of 22 HTA organizations completed the survey (67%). Advanced therapeutic medicinal products (ATMPs) and histology-independent therapies were considered most challenging based on the predefined complex health technologies and case studies. For the case studies, more than half of the reported challenges were “methodological,” equal in relative effectiveness assessments as in cost-effectiveness assessments. Through the open questions, we found that most of these challenges actually rooted in data unavailability. Data were reported as “absent,” “insufficient,” “immature,” or “low quality” by 18 of 20 organizations (90%), in particular data on quality of life. Policy and organizational challenges and challenges because of societal or political pressure were reported by 8 (40%) and 4 organizations (20%), respectively. Modeling issues were reported least often (n = 2, 4%).ConclusionsMost challenges in HTA of complex health technologies root in data insufficiencies rather than in the complexity of health technologies itself. As the number of complex technologies grows, the urgency for new methods and policies to guide HTA decision making increases.     

Pediatric Multi-Organ Dysfunction Syndrome: Analysis by an Untargeted “Shotgun” Lipidomic Approach Reveals Low-Abundance Plasma Phospholipids and Dynamic Recovery over 8-Day Period,a Single-Center Observational Study

Lipids are molecules involved in metabolism and inflammation. This study investigates the plasma lipidome for markers of severity and nutritional status in critically ill children. Children with multi-organ dysfunction syndrome (MODS) (n = 24) are analyzed at three time-points and cross-referenced to sedation controls (n = 4) for a total of N = 28. Eight of the patients with MODS, needed veno-arterial extracorporeal membrane oxygenation (VA ECMO) support to survive. Blood plasma lipid profiles are quantified by nano-electrospray (nESI), direct infusion high resolution/accurate mass spectrometry (MS), and tandem mass spectrometry (MS/MS), and compared to nutritional profiles and pediatric logistic organ dysfunction (PELOD) scores. Our results show that PELOD scores were not significantly different between MODS and ECMO cases across time-points (p = 0.66). Lipid profiling provides stratification between sedation controls and all MODS patients for total lysophosphatidylserine (lysoPS) (p-value = 0.004), total phosphatidylserine (PS) (p-value = 0.015), and total ether-linked phosphatidylethanolamine (ether-PE) (p-value = 0.03) after adjusting for sex and age. Nutrition intake over time did not correlate with changes in lipid profiles, as measured by caloric and protein intake. Lipid measurement in the intensive care environment shows dynamic changes over an 8-day pediatric intensive care unit (PICU) course, suggesting novel metabolic indicators for defining critically ill children.     

Relative Validity of MijnEetmeter: A Food Diary App for Self-Monitoring of Dietary Intake

This study aimed to evaluate the relative validity of intake of energy, nutrients and food groups assessed with MijnEetmeter food diary as compared to 24-h dietary recalls, and if this differed between experienced and new users. One hundred men and women aged 18–70 y participated, of whom 47 had prior experience with the tool. Participants kept MijnEetmeter on three days. Trained dietitians called them three times for a 24-h dietary recall interview, once recalling food consumption on the same day as the food recording in MijnEetmeter. Systematic differences and correlations were assessed, and Bland–Altman plots were created; both for 3-day mean intakes and for intakes on the same day. Relative to 24-h dietary recalls, MijnEetmeter underestimated consumption of drinks, added fat, cereal products, and potatoes. Relative underestimation was observed for energy intake (6%) and about half of the nutrients. Experienced MijnEetmeter users underestimated intake the least. For intake of energy and six key nutrients, correlations between 3-day mean intakes were above 0.7 except for sodium intake. In conclusion, MijnEetmeter moderately underestimates intakes of energy and some nutrients and food groups. To improve the self-monitoring of dietary intake, it is recommended that the users record food consumption for several days and that the apps probes for easily forgotten foods and drinks.