Pollen NAD(P)H oxidases and their contribution to allergic inflammation

This article provides an overview of NADPH oxidase and its role in allergic inflammation. A background and historical perspectives of NADPH oxidase are first provided, followed by a detailed overview of mammalian NADPH oxidase subunits and their functional organization. Plant NADPH oxidase, the authors' discovery of NADPH oxidase in pollens, and their contribution to allergic inflammation are then discussed, concluding with a discussion of future directions and outstanding questions that require attention.     

Structuring a safer donor-replacement program

BACKGROUND: Replacement donors are more likely than volunteer donors to have positive or abnormal tests for transfusion-transmissible disease. In an effort to increase the donor pool, workers sought to identify a safer replacement-donor subgroup that may be acceptable for routine donations. STUDY DESIGN AND METHODS: In a retrospective review and cohort study, the replacement-donor effect was separated from the new- donor effect. The relative effect the replacement donor has on the risk of transfusion-transmissible diseases, donor retention, and frequency of returning donations was then quantified by comparison against the effect of repeat volunteer donors. RESULTS: The replacement donor had 3.1 times the risk and 0.72 times the donor retention rate and made 0.81 times as many returning donations as the repeat volunteer donor. The figures for the new-donor effect were similar. The two risks were additive, making a new replacement donor particularly hazardous. If replacement donations only from repeat replacement donors were considered, the donor risk and the number of donations per returning donor were made comparable to those for the general (combined) volunteer donor. CONCLUSION: The negative effect of the replacement donor is similar in magnitude to that of the new volunteer donor. A replacement-donation program targeting repeat replacement donors has an acceptable risk profile and may be a valuable adjunct to the collection of blood from general volunteer donors.     

INAUGURAL ARTICLE by a Recently Elected Academy Member:GRINS: Genetic elements that recode assembly-line polyketide synthases and accelerate their diversification

Assembly-line polyketide synthases (PKSs) are large and complex enzymatic machineries with a multimodular architecture, typically encoded in bacterial genomes by biosynthetic gene clusters. Their modularity has led to an astounding diversity of biosynthesized molecules, many with medical relevance. Thus, understanding the mechanisms that drive PKS evolution is fundamental for both functional prediction of natural PKSs as well as for the engineering of novel PKSs. Here, we describe a repetitive genetic element in assembly-line PKS genes which appears to play a role in accelerating the diversification of closely related biosynthetic clusters. We named this element GRINS: genetic repeats of intense nucleotide skews. GRINS appear to recode PKS protein regions with a biased nucleotide composition and to promote gene conversion. GRINS are present in a large number of assembly-line PKS gene clusters and are particularly widespread in the actinobacterial genus Streptomyces. While the molecular mechanisms associated with GRINS appearance, dissemination, and maintenance are unknown, the presence of GRINS in a broad range of bacterial phyla and gene families indicates that these genetic elements could play a fundamental role in protein evolution.

Polyketide synthases (PKSs) are large enzymatic machines that synthesize structurally diverse natural products, many of which are used as antibiotics, immunosuppressants, anticancer agents, and other types of medicines. In bacteria, a substantial fraction of polyketides is synthesized by multimodular PKSs, where each module consists of a set of domains that collectively catalyze one round of elongation and chemical modification of the growing polyketide chain (1) (Fig. 1A). The homologous modules of each PKS operate in a defined assembly-line manner. The emergence of this multimodular architecture and its subsequent diversification has led to an astounding complexity and variety of polyketide natural products. However, the underlying evolutionary processes that drive the evolution of assembly-line PKSs are not well understood (2).Open in a separate windowFig. 1.Gene conversion in assembly-line PKSs. (A) Typical architecture of an assembly-line PKS, exemplified by closely related angolamycin synthase (ANGS) and tylactone synthase (TYLS), which contain the same set of biosynthetic domains and produce the same polyketide, tylactone. Domains: KS, ketosynthase; KS^Q, decarboxylative ketosynthase; AT, acyltransferase; DH, dehydratase; DHt, inactive dehydratase; ER, enoyl-reductase; KR, ketoreductase; KR°, ketoreductase-inactive epimerase; ACP, acyl carrier protein; TE, thioesterase. (B) Phylogenetic tree of protein sequences of angolamycin and tylactone synthase modules. Some orthologous modules clade together, as is expected for closely related PKSs that only recently diverged from a common ancestor through point mutations. However, in many cases paralogous modules clade more closely together, which can be explained by gene conversion between these modules. Sequence alignment performed using ClustalOmega (10); phylogenetic tree constructed using RAxML (30). (C) Gene conversion is a process in which a DNA sequence is nonreciprocally transferred from one homologous region to another and was implicated in the evolution of assembly-line PKSs (6, 7).According to one model, present-day assembly-line PKSs mainly arose through successive duplications of a parent module, whereafter each prototypical multimodular PKS evolved into a family of distinct but functionally related contemporary PKSs. However, this model has several discordances. For instance, it predicts that orthologous modules of closely related PKSs should cluster together in phylogenetic trees, which is often not the case (Fig. 1B). An alternative model proposes that assembly-line PKSs arose through recombination between different modules in a mosaic-like manner (3), whereafter present-day PKSs evolved through a combination of point mutations, recombination, and gene conversion (2).Gene conversion is a process in which a DNA sequence is nonreciprocally transferred from one homologous region to another, thereby homogenizing these homologous sequences (Fig. 1C). It is common in eukaryotic genomes, where it frequently occurs during mitosis, meiosis, and double-strand-break repair and has not only been implicated in the evolution of many gene families but also identified as the mechanism causing certain genetic diseases (4). In bacteria, gene conversion has been described only in a few systems, but its overall evolutionary role in prokaryotic genomes is not well understood (5). Gene conversion has also been implicated in assembly-line PKS evolution (6, 7), although its extent, role, and mechanism remain unclear.We recently proposed that extensive gene conversion between paralogous modules of assembly-line PKSs could explain why paralogous modules are often more similar to each other than orthologous ones (Fig. 1B) (2). In this work we sought to quantify the prevalence of gene conversion in assembly-line PKSs and investigate whether it might confer an evolutionary advantage. We discovered not only that gene conversion is widespread in assembly-line PKSs but also that it is frequently associated with the presence of a genetic element which recodes PKS genes and undergoes gene conversion. This association is particularly strong within Streptomyces bacteria, suggesting a major role in the diversification of assembly-line PKSs and possibly other gene families.     

美国教学医院教师专业发展的全国性调查

在当前医学教育持续变革的背景中,医学教师的专业发展成为广泛关注的焦点.为了解目前美国以提高教师的教学技能为目标的教师专业发展(faculty development,FD)活动的参与率、课程设计、教学方法和评估策略等情况,美国约翰·霍普金斯大学预防、流行病学和临床研究中心采取邮件调查的方式,对美国277家教学医院进行了调查.     

Epidemiology of preinvasive lesions.

OBJECTIVE: Review of epidemiological data on pre-invasive cervical lesions. MATERIAL AND METHODS: Literature review and analysis of data from our Department. RESULTS: Prevalence of data on preinvasive cervical lesions varies widely and depends on factors such as differences among countries or regions and among ethnic groups, and especially, differences in the type of population studied. Most important risk factors are: number of sexual partners, smoking, contraceptive use, HPV, age at first intercourse, and screening. CONCLUSIONS: In order to reduce risk, pap smears should be performed regularly, safe sex practices should be recommended, and the use of tobacco products should be avoided.     

Importance of chronic musculoskeletal problems in the population of Catalonia (Spain): prevalence and effect on self-perceived health, activity restriction and use of health services

Objective

To determine the importance of chronic musculoskeletal problems in the adult population of Catalonia (Spain) and their effect on self-perceived health, activity restriction and use of health services.

Methods

A population-based survey of 15,926 adults was performed. Multistage stratified sampling was performed. The variables gathered were sociodemographic characteristics, self-reported chronic health problems, self-perceived health, activity restriction and use of health services. Musculoskeletal problems were grouped into four categories: osteoarthritis-arthritis or rheumatism (OA), chronic dorsal or lumbar pain (LBP), chronic cervical pain (UBP), and osteoporosis.

Results

Chronic health problems were reported by 77.4% of the adult population. The most frequent health problem was LBP, followed by UBP and OA. After adjustment by age was performed, female sex increased the risk of reporting OA, LBP, UBP and osteoporosis (OR = 2.6, 1.5, 2.3, and 5.3, respectively). The prevalence increased with greater age and with lower socioeconomic status. After adjustment was performed by age, sex, social class and obesity, self-perceived health was worse in people with these problems (42.7% vs 11%). The four categories were the main causes of activity restriction in the last year (OR 2.70) and the last 15 days (OR = 2.32) and were associated with a higher use of health services.

Conclusiones

Los problemas reumáticos son los principales problemas de salud crónicos declarados por la población adulta. La prevalencia es mayor es las mujeres, aumenta con la edad y en las clases desfavorecidas. Hay una asociación significativa entre declarar problemas musculoesqueléticos y salud autopercibida mala o regular, y mayor restricción de actividades y uso de servicios sanitarios.     

Urinary aspartate transaminase (AST) activity and detection of its inhibitors in normal urine

Urinary aspartate-transaminase activity in the whole urine was found to be mean +/- S.D. = 8.46 +/- 0.69 l.U/l when measured immediately after urine collection. About 50% loss in enzyme activity was observed after 18 hours dialysis. An overall 176% increase in enzyme activity followed by Sephadex G-25 (fine) whole urine fractionation and a highly significant (P less than .001) partial inhibition by earlier Sephadex fractions and maximum inhibition by earlier Sephadex fractions and maximum inhibition of enzyme by fraction 7 have suggested the presence of both high and low molecular weight urinary inhibitors of aspartate-transaminase. Urea and ammonia presence and inhibitor activity in fraction 6 to 8 bear a close parallelism; both the substances produced 31% inhibition of partially purified goat liver GOT at concentrations approximating normal human urine. Therefore, low enzyme activity and its substantial loss in the whole urine and during dialysis may be due to the concomitant inhibitory effects of urea, ammonia and unidentified nature of high molecular weight substance(s). The present method may be effective in separating inhibitors and overcoming the disadvantages of dialysis in determining true urinary aspartate-transaminase activity.