Synthesis and Structure Elucidation of 5-Aminomethinimino-3-methyl-4-isoxazolecarboxylic Acid Phenylamides and Their Immunological Activity

A series of 5-aminomethinimino-3-methyl-4-isoxazolecarboxylic acid phenylamides 4 has been prepared by condensation of 5-amino-3-methyl-4-isoxazolecarboxylic acid phenylamides 1 with trichloroacetic aldehyde. Alcoholysis of trichloro derivatives 2 gave 5-alkoxymethine derivatives 3 which, on reaction with an appropriate amine, formed the corresponding compounds 4 . The compounds obtained were evaluated for their immunological activity. The properties of three compounds, described in this report, permitted inhibition of the immune response in all possible ways: diminishing both types of immune response ( 4d ), humoral immune response ( 4a ), or cellular immune response ( 4c ). Preparation 4d is comparable in its effectiveness to CsA, so it may be potentially used as an agent for prolongation of the function of transplanted organs. Two other compounds may potentially be used in cases where only one type the immune response is required for combating pathogen invasion.     

Skeletonization of radial and gastroepiploic conduits in coronary artery bypass surgery

The use of a skeletonized internal thoracic artery in coronary artery bypass graft surgery has been shown to confer certain advantages over a traditional pedicled technique, particularly in certain patient groups. Recent reports indicate that radial and gastroepiploic arteries can also be harvested using a skeletonized technique. The aim of this study is to systematically review the available evidence regarding the use of skeletonized radial and gastroepiploic arteries within coronary artery bypass surgery, focusing specifically on it's effect on conduit length and flow, levels of endothelial damage, graft patency and clinical outcome. Four electronic databases were systematically searched for studies reporting the utilisation of the skeletonization technique within coronary revascularisation surgery in humans. Reference lists of all identified studies were checked for any missing publications. There appears to be some evidence that skeletonization may improve angiographic patency, when compared with pedicled vessels in the short to mid-term. We have found no suggestion of increased complication rates or increased operating time. Skeletonization may increase the length of the conduit, and the number of sequential graft sites, but no clear clinical benefits are apparent. Our study suggests that there is not enough high quality or consistent evidence to currently advocate the application of this technique to radial or gastroepiploic conduits ahead of a traditional pedicled technique.     

Self-esteem in a broad-spectrum approach for mental health promotion.

Self-evaluation is crucial to mental and social well-being. It influences aspirations, personal goals and interaction with others. This paper stresses the importance of self-esteem as a protective factor and a non-specific risk factor in physical and mental health. Evidence is presented illustrating that self-esteem can lead to better health and social behavior, and that poor self-esteem is associated with a broad range of mental disorders and social problems, both internalizing problems (e.g. depression, suicidal tendencies, eating disorders and anxiety) and externalizing problems (e.g. violence and substance abuse). We discuss the dynamics of self-esteem in these relations. It is argued that an understanding of the development of self-esteem, its outcomes, and its active protection and promotion are critical to the improvement of both mental and physical health. The consequences for theory development, program development and health education research are addressed. Focusing on self-esteem is considered a core element of mental health promotion and a fruitful basis for a broad-spectrum approach.     

Organization of the state space of a simple recurrent network before and after training on recursive linguistic structures.

Recurrent neural networks are often employed in the cognitive science community to process symbol sequences that represent various natural language structures. The aim is to study possible neural mechanisms of language processing and aid in development of artificial language processing systems. We used data sets containing recursive linguistic structures and trained the Elman simple recurrent network (SRN) for the next-symbol prediction task. Concentrating on neuron activation clusters in the recurrent layer of SRN we investigate the network state space organization before and after training. Given a SRN and a training stream, we construct predictive models, called neural prediction machines, that directly employ the state space dynamics of the network. We demonstrate two important properties of representations of recursive symbol series in the SRN. First, the clusters of recurrent activations emerging before training are meaningful and correspond to Markov prediction contexts. We show that prediction states that naturally arise in the SRN initialized with small random weights approximately correspond to states of Variable Memory Length Markov Models (VLMM) based on individual symbols (i.e. words). Second, we demonstrate that during training, the SRN reorganizes its state space according to word categories and their grammatical subcategories, and the next-symbol prediction is again based on the VLMM strategy. However, after training, the prediction is based on word categories and their grammatical subcategories rather than individual words. Our conclusion holds for small depths of recursions that are comparable to human performances. The methods of SRN training and analysis of its state space introduced in this paper are of a general nature and can be used for investigation of processing of any other symbol time series by means of SRN.     

Risk of basal cell carcinoma in relation to alcohol intake and smoking.

We prospectively investigated whether alcohol intake and smoking affect the risk of basal cell carcinoma (BCC) in subjects from the United States Radiological Technologists (USRT) cohort study. We evaluated 68,371 radiological technologists certified during 1926-1982 who were free of cancer at the time they answered a first questionnaire (1983-1989) and who completed a second questionnaire (1994-1998). The first questionnaire provided baseline information on numerous risk factors, including smoking and alcohol intake, and the second provided self-reported cancer diagnoses. During 698,190 person-years of follow-up, we identified 1,360 cases of BCC: 1,036 in women and 324 in men. Cox proportional hazards regression indicated that the trend in BCC was significantly associated with increased alcohol intake (P for trend = 0.001). Compared with those who reported no alcohol consumption, those who drank <1-2, 3-6, 7-14, and >14 drinks/week had multivariate risks of 1.1 [95% confidence interval (CI), 0.9-1.3], 1.3 (95% CI, 1.1-1.5), 1.4 (95% CI, 1.2-1.7), and 1.0 (95% CI, 0.7-1.6), respectively. We found no clear association between smoking and BCC. This is the second large prospective study to report a significant but nonmonotonic trend in increased risk associated with alcohol consumption.     

Serial in vivo MR tracking of magnetically labeled neural spheres transplanted in chronic EAE mice.

Neural stem cell (NSC) transplantation has been shown to attenuate the severity of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Central to the future success of NSC transplantation in MS is the ability of transplanted cells to migrate from the site of transplantation to relevant foci of disease. Using magnetically labeled mouse neurospheres and human embryonic stem cell (hESC)-derived neurospheres, we applied serial magnetic resonance imaging (MRI) to assess the biodynamics of transplanted cell migration in a chronic mouse EAE model. Magnetic labeling did not affect the in vitro and in vivo characteristics of cells as multipotential precursors. Cell migration occurred along white matter (WM) tracts (especially the corpus callosum (CC), fimbria, and internal capsule), predominantly early in the acute phase of disease, and in an asymmetric manner. The distance of cell migration correlated well with clinical severity of disease and the number of microglia in the WM tracts, supporting the notion that inflammatory signals promote transplanted cell migration. This study shows for the first time that hESC-derived neural precursors also respond to tissue signals in an MS model, similarly to rodent cells. The results are directly relevant for designing and optimizing cell therapies for MS, and achieving a better understanding of in vivo cell dynamics and cell-tissue interactions.     

Female sexual receptivity is defective in juvenile hormone-deficient mutants of theapterous gene ofDrosophila melanogaster

During reproductive maturation of female insects, the acquisition of sexual receptivity is coordinated with ovarian development. Juvenile homone regulates vitellogenesis in the ovaries, but the action of this hormone in the development of sexual behavior is less well-understood. A strain ofDrosophila melanogaster carrying a mutation in theapterous gene(ap ⁴) was known to exhibit arrested vitellogenesis (rescuable by applying exogenous juvenile hormone), sterility of both sexes, and a deficiency of juvenile hormone. In this study, we examined the effects of mutations ofap on female receptivity and its relationship to juvenile hormone. We observed abnormally low female receptivity in homozygousap strains, and heteroallelic combinations ofap mutations exhibited low receptivity. For female receptivity,ap showed no dominance (i.e.,ap/ap ⁺ was intermediate betweenap/ap andap ⁺/ap ⁺). Low receptivity mapped genetically to theap locus. The reduction in female receptivity in these mutants is positively correlated with levels of juvenile hormone synthesized by their corpora allata.This work was supported in part by The Scheinfeld Center for Humans Genetics in the Social Sciences (J.R.), The National Science Foundation (BNS-882 1339 to J.R.), BARD (No. IS-1664-89R to D.S.), The Israel Cancer Research Fund (grant to D.S.), The Rekanati Foundation of Tel Aviv University (grant to D.S.), and The Israeli Fruit Council (award to M.A.)     

Genetic testing for hearing loss: different motivations for the same outcome

Autism is a complex genetic disorder. Chromosome 15 is of particular interest in this disorder, because of previous reports of individuals with autism with chromosomal abnormalities in the 15q11-q13 region. Transmission disequilibrium between polymorphisms in this region and autism has been also been reported in some, but not all studies. Recently, a novel maternally expressed gene, ATP10C, was characterized and mapped to the chromosome 15q11-q13 region, 200 kb distal to UBE3A. It encodes a putative aminophospholipid translocase likely to be involved in the asymmetric distribution of proteins in the cell membrane. Preferential maternal expression has been demonstrated in fibroblasts and brain. Because of its physical location and imprinting pattern, ATP10C was considered to be a candidate gene for chromosome 15-associated autism. In an effort to find the genes responsible for autism in this chromosomal region, 1.5 kb of the 5' flanking region, as well as the coding and splicing regions of ATP10C, were screened for sequence variants. Several polymorphic markers including five nonsynonymous SNPs were identified. To investigate transmission disequilibrium between ATP10C and autism, a family-based association study was conducted for 14 markers in 115 autism trios. No significant transmission disequilibrium was found, suggesting ATP10C is unlikely to contribute strongly to susceptibility to autism in these families. However, due to limited power to detect genes of modest effect, the possible functional role of the nonsynonymous SNPs and the functional implications of the SNPs identified from 5' flanking region and intron 2 splicing region may be evaluated in further studies.