[The activity of the neuromediator systems in the cortex and caudate nucleus in rats with different degrees of initial alcohol preference]. / Aktivnost' neiromediatornykh sistem v kore i khvostatom iadre mozga krys s raznoi stepen'iu iskhodnogo predpochteniia alkogolia.

The study was made of functional state of catecholamine, dopaminergic, serotonergic and cholinergic cerebral systems in terms of the activity of some enzymes of neuromediator metabolism, the content of biogenic amines and their correlation in brain and cerebral caudate nucleus. 3 groups of rats with different initial craving for alcohol were examined: rejecting alcohol (RA); consuming it but without preference (WAP); and rats preferring alcohol under the conditions of free choice between water and alcohol (PA). Peculiarities of the functional state of the systems studied depended on the degree of the preference to alcohol. The main changes in PA rats, as compared with RA group, manifested as a decrease of corresponding indices. That confirmed a different degree of the inhibition of their activity as well as alterations in the interaction between neuromediator systems. These changes were more pronounced in the cortex than in caudate nucleus. Such alterations may be related to structural-functional flexibility of CNS and might be the basic mechanism of the genetic predisposition to alcohol consumption.

Postprandial hypertriglyceridemia and insulin resistance in normoglycemic first-degree relatives of patients with type 2 diabetes.

BACKGROUND: Impaired ability to eliminate lipids in the postprandial state is an atherogenic trait associated with insulin resistance. OBJECTIVE: To assess insulin sensitivity and postprandial triglyceride metabolism in prediabetic persons. DESIGN: Cross-sectional study. SETTING: Sahlgrenska University Hospital, Göteborg, Sweden. PARTICIPANTS: 13 healthy, normotriglyceridemic men with two first-degree relatives with type 2 diabetes and 13 carefully matched controls without known diabetes heredity. MEASUREMENTS: Oral glucose tolerance test, insulin sensitivity (euglycemic clamp technique), and fasting and postprandial triglyceride levels after a mixed meal. RESULTS: Relatives of persons with type 2 diabetes were insulin resistant but had normal glucose tolerance. They exhibited postprandial hypertriglyceridemia; the 6-hour triglyceride incremental area under the curve was 50% higher than that of the control group (P = 0.037). CONCLUSIONS: These healthy male first-degree relatives of patients with type 2 diabetes are insulin resistant and exhibit postprandial lipid intolerance despite having normal fasting triglyceride levels. These characteristics, which occur in the absence of glucose intolerance, are associated with an increased risk for macroangiopathy.

Genetic predisposition to skin cancer.

Here we review recent insights in the genetics of skin cancer susceptibility as gleaned from studies of three hereditary syndromes: basal cell nevus syndrome, familial melanoma/dysplastic nevus syndrome, and xeroderma pigmentosum. We provide a brief synopsis of the recent findings related to these syndromes in an attempt to illustrate several emerging themes in the genetics of skin cancer. These themes include 1) the recent identification of multiple cancer susceptibility genes that occur in a myriad of cellular regulatory pathways; 2) the relative specificity of certain regulatory pathways to the development of specific types of cancer; and 3) the important role of DNA damage caused by ultraviolet radiation and defective DNA repair mechanisms in the development of skin cancer. We also review the implications of this knowledge to clinical practice relative to risk assessment, primary prevention, and therapy.

Exceptional stability of the HLA-DQA1*0102/DQB1*0602 alpha beta protein dimer, the class II MHC molecule associated with protection from insulin-dependent diabetes mellitus.

HLA-DQ alleles are closely associated with susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM) but the immunologic mechanisms involved are not understood. Structural studies of the IDDM-susceptible allele, HLA-DQA1*0301/DQB1*0302, have classified it as a relatively unstable dimer, particularly at neutral pH. This is reminiscent of studies in the nonobese diabetic mouse, in which I-A(g7) is relatively unstable, in contrast to other murine I-A alleles, suggesting a correlation between unstable MHC class II molecules and IDDM susceptibility. We have addressed this question by analysis of dimer stability patterns among various HLA-DQ molecules. In EBV-transformed B-lymphoblastoid cell lines and PBL, the protein encoded by the IDDM-protective allele HLA-DQA1*0102/DQB1*0602 was the most SDS stable when compared with other HLA-DQ molecules, including HLA-DQA1*0102/DQB1*0604, a closely related allele that is not associated with protection from IDDM. Expression of six different HLA-DQ allelic proteins and three different HLA-DR allelic proteins in the bare lymphocyte syndrome cell line, BLS-1, revealed that HLA-DQA1*0102/DQB1*0602 is SDS stable even in the absence of HLA-DM, while other HLA class II molecules are not. These results suggest that the molecular property of HLA-DQ measured by resistance to denaturation of the alphabeta dimer in SDS may play a role in IDDM protection.

Establishment of two substrains, diabetes-prone and non-diabetic, from Long-Evans Tokushima Lean (LETL) rats.

Diabetes mellitus in Long-Evans Tokushima Lean (LETL) rats closely resembles type 1 diabetes in human beings, e.g., no gender differences in the incidence of diabetes and no T lymphopenia. Although the LETL rats have been established as an inbred strain, the incidence of diabetes is only approximately 20%. In the present study, we established two substrains, one a diabetes-prone (KDP) and the other a non-diabetic (KND) from the original inbred LETL rats. The features of KDP rats are a high incidence of diabetes (over all approximately 70%) without lymphopenia and 100% development of mild to severe insulitis at 120-220 days of age. In contrast, the KND substrain is characterized by the complete absence of diabetes incidence. Among 165 SSLP marker loci throughout all rat chromosomes, no loci showed variation among KDP and KND substrains and their parental LETL rats. In this regard, the genetic background of these two substrains, KDP and KND, appears to be uniform except for the major gene(s) that is responsible for the diabetes. In this context, these two substrains of LETL rats should serve as useful tools for research on the pathogenesis and for the genetic analysis of type 1 diabetes. In this report, we have not only established, but also characterized these two substrains, and provided their fundamental data.