Structural specificity of synthetic peptide adjuvant for induction of experimental allergic encephalomyelitis

The peptide N-acetylmuramyl-l-alanyl-d-isoglutamine (MDP), which has adjuvant activities, and 17 of its derivatives and analogs were synthesized and assayed to elucidate the structure necessary for adjuvant activity in induction of experimental allergic encephalomyelitis (EAE) in guinea pigs. The results revealed the importance of the d configuration and the α-carboxamide group of the isoglutaminyl residue of MDP for adjuvant activity. Replacement of the l-alanyl residue of MDP by d-alanine, but not by l-serine or glycine, resulted in a marked decrease in the activity. The β-methyl glycoside of MDP was found to be more active than the α-methyl derivative. 6-O-Stearoyl-N-acetylmuramyl-l-alanyl-d-isoglutamme showed activity.     

Physical anthropological approaches to aging

The field of gerontology is remarkably diverse; yet there has been relatively little investigation of physical anthropological issues in aging research. This review explores gerontologic topics of actual and/or potential interest to physical anthropologists. The evolution of aging presents a theoretical dilemma in that postreproductively expressed traits may be outside the influence of natural selection. The physiological changes of aging comprise a diversified mosaic of physical deterioration as would be expected from an evolutionary model. Studies of prehistoric aging are limited to estimating lifespan, which may not be indicative of rate of aging. Considerable attention has been devoted to body composition and aging, and notable findings include a loss of lean tissue with age and relatively constant (though redistributing) fat mass. Osteoporosis is a major problem of aging in females, as is tooth loss in both sexes. The study of variation in rates of aging is only beginning, and a number of approaches to measuring biological age in adulthood are presented. Determining the associations of lifestyle, economic, and nutritional status with biological age may reveal sources of variation in rates of aging and may be of practical importance.     

The db mutation improves memory in younger mice in a model of Alzheimer's disease

Alzheimer's disease (AD) is the most common age-related neurodegenerative disease, while obesity is a major global public health problem associated with the metabolic disorder type 2 diabetes mellitus (T2DM). Chronic obesity and T2DM have been identified as invariant risk factors for dementia and late-onset AD, while their impacts on the occurrence and development of AD remain unclear. As shown in our previous study, the diabetic mutation (db, Lepr^db/db) induces mixed or vascular dementia in mature to middle-aged APP^ΔNL/ΔNL x PS1^P264L/P264L knock-in mice (db/AD). In the present study, the impacts of the db mutation on young AD mice at 10 weeks of age were evaluated. The db mutation not only conferred young AD mice with severe obesity, impaired glucose regulation and activated mammalian target of rapamycin (mTOR) signaling pathway in the mouse cortex, but lead to a surprising improvement in memory. At this young age, mice also had decreased cerebral Aβ content, which we have not observed at older ages. This was unlikely to be related to altered Aβ synthesis, as both β- and γ-secretase were unchanged. The db mutation also reduced the cortical IL-1β mRNA level and IBA1 protein level in young AD mice, with no significant effect on the activation of microglia and astrocytes. We conclude that the db mutation could transitorily improve the memory of young AD mice, a finding that may be partially explained by the relatively improved glucose homeostasis in the brains of db/AD mice compared to their counterpart AD mice, suggesting that glucose regulation could be a strategy for prevention and treatment of neurodegenerative diseases like AD.     

Modified frailty index and hypoalbuminemia as predictors of adverse outcomes in older adults presenting to acute general surgical unit

IntroductionHealth professionals are progressively drawing on the concept of frailty as a determinant of adverse surgical outcomes in of older adults. We aimed to determine the prevalence of frailty and the correlation between frailty and mortality among older adults admitted to the acute surgical unit.Materials and methodsThis prospective cohort study was conducted in the acute general surgical unit over a two month period. We recruited 150 consecutive patients aged 65yrs and above. The modified frailty index was employed to measure frailty and the albumin levels on admission were obtained from electronic medical records. The patients were followed up for a period of thirty days.ResultsWe found that more than 40% of the older adults admitted to the acute general surgical unit were frail and frailty was associated with higher rate of mortality at 30 days. Hypoalbuminemia was associated with a longer length of stay, higher rate of complications, and an increased likelihood of discharge to a rehabilitation facility. There was also a significant univariate correlation between frailty and the presence of hypoalbuminemia on admission.ConclusionFrailty and hypoalbuminemia are common in older general surgical patients and predict the likelihood of some of the adverse outcomes relevant to older adults and health economy such as mortality, increased length of stay, rate of complications, and likelihood of discharge to a rehabilitation facility. Further studies should investigate a possible causal association between frailty and low albumin levels in an acute surgical setting.     

Quantitation of epinephrine- and glucagon-sensitive adenylate cyclases of rat liver implications of alterations of enzymatic activities during preparation of particulate fractions and membranes

Stimulated and basal adenylate cyclase activities from livers of young and old rats were lower in particulates than in homogenates. Particulates were compared to homogenates by reconstituting the suspensions to the volume of the homogenates from which they were derived; enzyme activities in paired homogenates and particulates therefore reflected the same amounts of membrane-bound enzyme. The magnitude of the losses of hormone-sensitive activities in particulates was dependent on the age and sex of the animals and the concentrations of hormone. Particulates from 3-month-old animals showed glucagon-( (1 · 10^?5 M) and epinephrine-sensitive (1 · 10^?4 M) activities which were 67 and 78% of homogenate activities, respectively; particulates from 24-month-old animals had activities relative to homogenates of 55% for glucagon and as low as 32% for epinephrine. The glucagon dose vs. response curve in particulates and membranes showed maximal activity at 1 · 10^?7 M glucagon while in homogenates activity increased linearly with increasing glucagon concentrations up to 1 · 10^?5 M. Losses of basal and anion-stimulated activities were similar at both ages. Fluoride and azide stimulations relative to basal activities were greater in particulates than in homogenates, while relative epinephrine activity was lower in particulates, suggesting qualitative alteration of adenylate cyclase during preparation of particulates. These studies show that adenylate cyclase activity in rat liver is presently best quantitated in homogenates and suggest caution in comparisons of enzyme activities based on particulates or membranes prepared from animals of differing physiologic states.     

Minimum structural requirements for encephalitogen and for adjuvant in the induction of experimental allergic encephalomyelitis.

Mycobacteria in the adjuvant used for induction of experimental autoimmune encephalomyelitis (EAE) in guinea pigs can be replaced by synthetic N-acetylmuramyl-l-alanyl-d-isoglutamine. A combination of synthetic encephalitogenic peptides and muramyl dipeptides induces EAE effectively at a dose on the microgram level. In this system, the synthetic heptapeptide, H-Trp-Gly-Ala-Glu-Gly-Gln-Arg-OH, with a sequence identical to those of residues 116 to 122 of the basic protein of human myelin, was the shortest peptide causing EAE. These compounds form a simple system which should be useful in studies on the mechanism of the cell-mediated autoimmune reaction.     

Relationship between parathyroid hormone and adenosine 3′,5′-monophosphate metabolism in the kidney of vitamin D-deficient rats

The effect of vitamin D administration on cyclic AMP metabolism in the kidney was examined in rats fed a vitamin D-deficient, low Ca diet. The renal cyclic AMP level in vitamin D-deficient rats was higher than that in normal rats fed a laboratory chow, and in significantly decreased after thyroparathyroidectomy. Parathyroid hormone administered in vitro and in vivo did not cause as great a cyclic AMP response in vitamin D-deficient rats as that seen in the normal rats. The response to calcitonin, however, was not blunted in vitamin D-deficient animals. The blunted cyclic AMP accumulation in the kidney seemed to be related to formation, rather than degradation, of the nucleotide. The rats fed the low Ca diet were still hypocalcemic even after supplementation of the diet with a daily dose of either 0.625 μg of vitamin D-3 for 3 weeks or 2.5 μg of vitamin D-3 for the last 3 days. Vitamin D supplementation did not influence either the basal level or parathyroid hormone-stimulated increase of cyclic AMP in the kidney. On the contrary, when animals maintained on the vitamin D-deficient, low Ca diet were switched to the vitamin D-deficient, high Ca diet containing lactose for several days, they recovered normocalcemia and a normal response. These results suggest that the blunted cyclic AMP response to parathyroid hormone in vitamin D deficiency is due to hypocalcemia or associated secondary hyperparathyroidism and not due to deficiency of vitamin D action.     

Aging, evolvability, and the individual benefit requirement; medical implications of aging theory controversies

There is a class of theories of aging (variously termed adaptive aging, aging by design, aging selected for its own sake, or programmed death theories) that hold that an organism design that limits life span conveys benefits and was selected specifically because it limits life span. These theories have enjoyed a resurgence of popularity because of the discovery of genes that promote aging in various organisms.However, traditional evolution theory has a core tenet that excludes the possibility of evolving and retaining an individually adverse organism design, i.e. a design characteristic that reduces the ability of individual organisms to survive or reproduce without any compensating individual benefit. Various theories of aging dating from the 1950s and based on traditional evolution theory enjoy substantial popularity. Therefore, any theorist proposing an adaptive theory of aging must necessarily also propose some adjustment to traditional evolution theory that specifically addresses the individual benefit issue. This paper describes an adaptive theory of aging and describes how one of the proposed adjustments (evolvability theory) supports adaptive aging.This issue is important because adaptive theories are generally more optimistic regarding prospects for medical intervention in the aging process and also suggest different approaches in achieving such intervention.     

PBL结合LBL教学法在老年医学教学中的应用

目的:通过研究PBL结合LBL教学法在老年医学教学中的应用,观察与传统的LBL教学方法比较,PBL结合LBL教学法对学生考核成绩提高的作用,并探讨PBL结合LBL教学法加强对学生自主学习、综合实践、团队协作等各方面能力的提升。方法:选择2014年9月-2015年5月第三军医大学临床医学系2013级学生145名,随机分为实验组(PBL结合LBL教学法,75名)和对照组(传统的LBL教学法,70名)作为研究对象,通过考核与问卷调查评估结果。结果:以冠心病相关知识作为考核内容,与对照组比较,实验组考核成绩高于对照组(91.50±4.36 vs.83.24±4.12,P0.01);对实验组学生75名发放调查问卷,87%以上学生认为该教学法对提高自身学习能力、激发学习兴趣、增强表达能力等方面有较大帮助。结论:PBL结合LBL的教学法有助于提高老年医学教学效果。     

The evolutionary origin of proinsulin: Amino acid sequence homology with the trypsin-related serine proteases detected and evaluated by new statistical methods

Proinsulins and pancreatic serine proteases were analyzed for possible amino acid sequence similarity, using an adapted version of the nucleotide sequence alignment technique of Sankoff (1972). The technique allowed us to determine simultaneously the statistical significance of both the sequence alignment and the number of gaps necessary to achieve that alignment. In the course of this work, it was realized that a rigorous analysis required non-parametric statistics.For the B-chain (amino-terminal) of insulin a highly significant gap-free sequence alignment with the serine proteases was found. For the A-chain (carboxy-terminal) of insulin a sequence alignment of modest statistical significance with two gaps could be obtained, while the search for a corresponding alignment for the C-peptide remained unsuccessful. Presumably the rapid evolution of the C-peptide has obscured its origin. Reconstruction of ancestral sequences was of no help. In contrast to the amino acid sequences, three-dimensional structures of the two protein families are quite different.Considering current histophysiological understanding of ontogeny and phylogeny of exocrine and endocrine pancreas, the observed sequence similarity of proinsulins and serine proteases was interpreted to mean that the two protein families have diverged from a common genetic ancestor. Moreoever, from the organismic distribution of these proteins it was concluded that at least one serine protease existed first, and that proinsulin was generated after duplication of a serine protease gene and subsequent drastic modification, such as a large deletion. Thus proinsulin, basically an anabolic hormone, is derived from a serine protease, an enzyme involved in digestion. This constitutes a refinement of a similar proposal by Steiner et al. (1973).The emergence of proinsulin seems to have occurred after coelenterates diverged, and possibly before most other major animal phyla diverged from the line leading to vertebrates, i.e. 520 to 700 million years ago. The evolution of proinsulin seems to have paralleled the evolution of endocrine cells. Homology of the secreted products of endocrine and exocrine cells was most readily reconciled with a common embryological and phylogenetic origin of the two cell types, as considered by Pictet & Rutter (1972).