Identification of MHC class II restricted T-cell-mediated reactivity against MHC class I binding Mycobacterium tuberculosis peptides

Major histocompatibility complex (MHC) class I restricted cytotoxic T lymphocytes (CTL) are known to play an important role in the control of Mycobacterium tuberculosis infection so identification of CTL epitopes from M. tuberculosis is of importance for the development of effective peptide-based vaccines. In the present work, bioinformatics technology was employed to predict binding motifs of 9mer peptides derived from M. tuberculosis for the 12 HLA-I supertypes. Subsequently, the predicted peptides were synthesized and assayed for binding to HLA-I molecules in a biochemically based system. The antigenicity of a total of 157 peptides with measured affinity for HLA-I molecules of K(D) ≤ 500 nM were evaluated using peripheral blood T cells from strongly purified protein derivative reactive healthy donors. Of the 157 peptides, eight peptides (5%) were found to induce T-cell responses. As judged from blocking with HLA class I and II subtype antibodies in the ELISPOT assay culture, none of the eight antigenic peptides induced HLA class I restricted CD8(+) T-cell responses. Instead all responses were blocked by pan-HLA class II and anti-HLA-DR antibodies. In addition, CD4(+) T-cell depletion before the 10 days of expansion, resulted in total loss of reactivity in the ELISPOT culture for most peptide specificities. FACS analyses with intracellular interferon-γ staining of T cells expanded in the presence of M. tuberculosis peptides confirmed that the responsive cells were indeed CD4(+). In conclusion, T-cell immunity against HLA-I binding 9mer M. tuberculosis-derived peptides might in many cases turn out to be mediated by CD4(+) T cells and restricted by HLA-II molecules. The use of 9mer peptides recognized by both CD8(+) and CD4(+) T cells might be of importance for the development of future M. tuberculosis peptide-based vaccines.     

Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications

Platelets have a central role in the development of arterial thrombosis and subsequent cardiovascular events. An appreciation of this complex process has made antiplatelet therapy the cornerstone of cardiovascular disease management. However, numerous patients will experience a recurrent atherothrombotic vascular event despite adequate antiplatelet therapy. Individual differences in the rate of platelet activation and reactivity markedly influence normal hemostasis and the pathological outcome of thrombosis. Such an individual variability is largely determined by environmental and genetic factors. These are known to either hamper platelets' response to agonists, and thereby mimic the pharmacological modulation of platelet function or mask therapy effect and sensitize platelets. In this article, we reviewed the antiplatelet mechanisms of aspirin and clopidogrel and the possible role of different polymorphisms, which may affect the efficacy of antiplatelet therapy. Heterogeneity in the way patients respond to aspirin and clopidogrel may in part reflect variation in cyclooxygenase (COX)-1, COX-2, glycoprotein (GP) Ib alpha, GP Ia/IIa, GP IIb/IIIa, UGT1A6*2, P2Y₁, P2Y₁₂, CYP2C9, CYP3A4 and CYP3A5 genotypes.     

Characterizing major depression phenotypes by presence and type of psychomotor disturbance in adolescents and young adults

Major depressive disorder (MDD) is phenomenologically heterogeneous, which has prompted investigation of intermediate MDD phenotypes based on specific key symptoms. Presence and type of psychomotor disturbance may be an important psychopathologic feature that differentiates clinically distinct forms of juvenile MDD. This study examined the phenotypic status of three putative MDD phenotypes in a community sample of 941 youths: (1) agitated depression (MDD with psychomotor agitation), (2) retarded depression (MDD with psychomotor retardation), and (3) agitated-retarded depression (MDD with psychomotor agitation and retardation within an episode). Hasler et al.'s [2004: Neuropsychopharmacology 29:1765-1781] criteria of specificity (degree of association with relevant symptoms and conditions related to the disease of interest versus other psychiatric conditions), stability (degree of stability over time), and heritability (degree of familial aggregation with relevant conditions) were used to evaluate the phenotypic significance of these subtypes. Results were suggestive that agitated depression was a relatively specific phenotypic syndrome characterized by irritability, arousal, physical complaints, and vulnerability to anxiety disorders and alcohol dependence; low stability across depressive episodes; and low heritability. Agitated-retarded depression was relatively specific and characterized by increased severity, recurrence, vegetative symptoms, suicidal ideation, social impairment, endogeneity, and vulnerability to anxiety disorders and bulimia; low stability across episodes; and modest heritability. Although retarded depression was associated with some specific distinguishing characteristics, most associations were explained by the increased severity of this phenotype. Retarded depression evidenced little stability or heritability. These findings offer partial support of the phenotypic status of agitated and agitated-retarded depression in youths.     

Effects of CRL 41034 on the adrenergic neuroeffector interaction in the canine saphenous vein

Experiments were designed to determine the effect of CRL 41034, a buflomedil analogue, on the adrenergic responsiveness of canine veins. Rings of saphenous vein (without endothelium) were suspended for isometric tension recording in modified Krebs-Ringer bicarbonate solution at 37 degrees C. CRL 41034 produced a concentration-dependent inhibition of the contractions evoked by the alpha adrenergic agonists norepinephrine, phenylephrine and UK 14304 which was insensitive to the blockade of neuronal uptake by cocaine. CRL 41034 was more potent in inhibiting the concentration-dependent contractions evoked by UK 14304 than those by phenylephrine and the antagonism it caused against the response to UK 14304 fulfilled the criteria for competitivity. CRL 41034, at 10(-5) M significantly depressed, and at 10(-4) M abolished the contractions induced by electrical stimulation of the adrenergic nerves and those evoked by the indirect sympathomimetic amine tyramine. Strips of canine saphenous vein were superfused after incubation with [3H] norepinephrine. During sympathetic nerve activation, CRL 41304 increased the stimulation-evoked overflow of [3H] norepinephrine and 3-methoxy-4-dihydroxyphenylglycol; in the presence of rauwolscine the compound only increased the stimulation-evoked overflow of 3,4-dihydroxyphenylglycol. These experiments suggest that the major vascular effects of CRL 41034 in canine veins are blockade of alpha 2-adrenoceptors on vascular smooth muscle, and inhibition of prejunctional alpha 2-adrenoceptors on adrenergic nerve endings.     

Development and natural history of mood disorders.

To expand and accelerate research on mood disorders, the National Institute of Mental Health (NIMH) developed a project to formulate a strategic research plan for mood disorder research. One of the areas selected for review concerns the development and natural history of these disorders.The NIMH convened a multidisciplinary Workgroup of scientists to review the field and the NIMH portfolio and to generate specific recommendations. To encourage a balanced and creative set of proposals, experts were included within and outside this area of research, as well as public stakeholders.The Workgroup identified the need for expanded knowledge of mood disorders in children and adolescents, noting important gaps in understanding the onset, course, and recurrence of early-onset unipolar and bipolar disorder. Recommendations included the need for a multidisciplinary research initiative on the pathogenesis of unipolar depression encompassing genetic and environmental risk and protective factors. Specifically, we encourage the NIMH to convene a panel of experts and advocates to review the findings concerning children at high risk for unipolar depression. Joint analyses of existing data sets should examine specific risk factors to refine models of pathogenesis in preparation for the next era of multidisciplinary research. Other priority areas include the need to assess the long-term impact of successful treatment of juvenile depression and known precursors of depression, in particular, childhood anxiety disorders. Expanded knowledge of pediatric-onset bipolar disorder was identified as a particularly pressing issue because of the severity of the disorder, the controversies surrounding its diagnosis and treatment, and the possibility that widespread use of psychotropic medications in vulnerable children may precipitate the condition. The Workgroup recommends that the NIMH establish a collaborative multisite multidisciplinary Network of Research Programs on Pediatric-Onset Bipolar Disorder to achieve a better understanding of its causes, course, treatment, and prevention. The NIMH should develop a capacity-building plan to ensure the availability of trained investigators in the child and adolescent field.Mood disorders are among the most prevalent, recurrent, and disabling of all illnesses. They are often disorders of early onset. Although the NIMH has made important strides in mood disorders research, more data, beginning with at-risk infants, children, and adolescents, are needed concerning the etiology and developmental course of these disorders. A diverse program of multidisciplinary research is recommended to reduce the burden on children and families affected with these conditions.     

Antioxidant action of Vaccinium myrtillus extract on human low density lipoproteins in vitro: initial observations

Summary— Oxidative modifications of low density lipoproteins (LDL) are now recognised as one of the major processes in atherogenesis. Various drugs, as well as a number of natural products, have been proposed to inhibit such processes. Among the naturally-occurring constituents of plants which appear to possess antioxidant activity are polyphenolic compounds such as flavonoids. The aqueous extract of Vaccinium myrtillus is rich in such molecules. In this report, we describe the in vitro antioxidative potential of this extract on human LDL. The copper-induced oxidative modification of these lipoproteins was assessed using 1) measurement of oxidative resistance as determined by the lag-phase preceding conjugated diene formation; 2) quantification of the amount of lipoperoxides and thiobarbituric acid-reactive substances generated, and measurement of the modification in the net negative electrical charge of the lipoproteins, over a 7-hour time course experiment. Trace amounts of V myrtillus extract (15 to 20 μg/mL) induce statistically significant changes in the oxidation behaviour of LDL, which include 1) prolongation of the lag-phase of conjugated diene production ( P < 0.01); 2) reduction in the formation of lipoperoxides and of thiobarbituric acid-reactive substances up to 7 hours and especially between 1 and 5 hours ( P < 0.01); and 3) inhibition of modification in the net negative charge of LDL. These results demonstrate that V myrtillus extract exerts potent protective action on LDL particles during in vitro copper-mediated oxidation. Calculation of IC₅₀ values indicates that, on a molar basis, this extract may indeed be more potent than either ascorbic acid or butylated hydroxytoluene in the protection of LDL particles from oxidative stress.     

Design and evaluation protocol of "FATaintPHAT", a computer-tailored intervention to prevent excessive weight gain in adolescents

Background  

Computer tailoring may be a promising technique for prevention of overweight in adolescents. However, very few well-developed, evidence-based computer-tailored interventions are available for this target group. We developed and evaluated a computer-tailored intervention for adolescents targeting energy balance-related behaviours: i.e. consumption of snacks, sugar-sweetened beverages, fruit, vegetables, and fibre, physical activity, and sedentary behaviours. This paper describes the planned development of a school-based computer-tailored intervention aimed at improving energy balance-related behaviours in order to prevent excessive weight gain in adolescents, and the protocol for evaluating this intervention.