<Emphasis Type="Italic">TCF7L2</Emphasis>variant genotypes and type 2 diabetes risk in Brazil: significant association,but not a significant tool for risk stratification in the general population

Background  

Genetic polymorphisms of the TCF7L2 gene are strongly associated with large increments in type 2 diabetes risk in different populations worldwide. In this study, we aimed to confirm the effect of the TCF7L2 polymorphism rs7903146 on diabetes risk in a Brazilian population and to assess the use of this genetic marker in improving diabetes risk prediction in the general population.     

Causal pathways of the effects of age and the CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on AIDS development

OBJECTIVE: To investigate the causal pathways by which age and the CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles influence progression to AIDS. DESIGN: Analysis of follow-up data from 2 cohort studies among homosexual men (n=400), having >10 years of follow-up. METHODS: The effects of the 4 cofactors on the CD4 and HIV-1 RNA trajectories after seroconversion were modeled in a random-effects model. A proportional hazards model was used to investigate their effect on the risk of AIDS after correction for CD4 cell count and RNA level. This approach allows investigation as to whether they influence AIDS progression by affecting CD4 count and RNA level or by other pathways. RESULTS: Persons of younger age or having the CCR2-64I or SDF-1 3'A mutation have significantly higher CD4 levels. Persons with the CCR5-Delta32 deletion or CCR2-64I mutation have significantly lower RNA levels. After correction for both CD4 count and RNA level, only the SDF-1 3'A mutation significantly increases the AIDS risk. CONCLUSIONS: Age and the CCR5-Delta32 deletion and CCR2-64I mutation influence AIDS progression by affecting CD4 and HIV-1 RNA. The SDF-1 3'A allele increases the AIDS risk, but this effect is countered by its effect on CD4 and HIV-1 RNA level.     

Molecular typing of Mycobacterium tuberculosis by mycobacterial interspersed repetitive unit-variable-number tandem repeat analysis, a more accurate method for identifying epidemiological links between patients with tuberculosis

IS6110 fingerprinting of Mycobacterium tuberculosis is the standard identification method in studies on transmission of tuberculosis. However, intensive epidemiological investigation may fail to confirm transmission links between patients clustered by IS6110-restriction fragment length polymorphism (RFLP) typing. We applied typing based on variable numbers of tandem repeats (VNTRs) of mycobacterial interspersed repetitive units (MIRUs) to isolates from 125 patients in 42 IS6110 clusters, for which thorough epidemiological data were available, to investigate the potential of this method in distinguishing epidemiologically linked from nonlinked patients. Of seven IS6110 clusters without epidemiological links, five were split by MIRU-VNTR typing, while nearly all IS6110 clusters with proven or likely links displayed conserved MIRU-VNTR types. These results provide molecular evidence that not all clusters determined on the basis of multibanded IS6110 RFLP patterns necessarily reflect transmission of tuberculosis. They support the use of MIRU-VNTR typing as a more reliable and faster method for transmission analysis.     

Hereditary Cerebral Hemorrhage with Amyloidosis-Dutch Type (HCHWA-D): I - A Review of Clinical, Radiologic and Genetic Aspects

Hereditary cerebral hemorrhage with amyloidosis - Dutch type (HCHWA-D) is an autosomal dominant disease caused by deposition of β-amyloid in the leptomeningeal arteries and cortical arterioles, in addition to preamyloid deposits and amyloid plaques in the brain parenchyma.
The disease is due to a point mutation at codon 693 of the amyloid precursor protein (βPP) gene at chromosome 21. Since this point mutation is diagnostic for HCHWA-D, presymptomatic testing is feasible and offered, together with genetic counselling and psychological support, to subjects at risk. HCHWA-D is clinically characterized by recurrent strokes, in addition to dementia, which can occur after the first stroke but also preceding it. Radiological studies revealed focal lesions (hemorrhages, hemorrhagic and non-hemorrhagic infarctions) and diffuse white matter damage. Diffuse white matter hyperintensities on MRI are an early symptom of HCHWA-D since they have been found on MRI scans of subjects who had not suffered a stroke.
The presence of the diagnostic point mutation makes HCHWA-D a useful model to study the effects of cerebral amyloid angiopathy in vivo. The characteristic pathological abnormalities and its implications for Alzheimer's disease will be discussed in Part II of this article     

Variations of the origin of the artery of the sinoatrial node in normal human hearts

Summary The artery of the sino-atrial node was studied in 100 normal human hearts after injection of each coronary artery with coloured gelatine containing a radiopaque substance. The hearts belonged to 69 males and 31 females, being 64 Caucasians and 36 non-Caucasians (Negroes and Mulattoes) whose age ranged from 7 to 80 years. Since the individuals had committed suicide or were victims of accidents, their hearts, after pathologists' evaluation, were considered normal. The sinoatrial node of the normal human heart is supplied by the right coronary artery more frequently (58%±4.9% of the cases) than by the left (42%±4.9). The right anterior medial atrial artery, originating from the right coronary at the level of the medial third of the right anterior quadrant of the atrial dome, is most frequently (50%±5) responsible for the blood supply of the sinoatrial node. Among the branches of the left coronary artery, the left anterior medial atrial artery, originating at the level of the medial third of the left. anterior quadrant of the atrial cupola, was the most frequent blood supplier (25%±4.3) of the sinoatrial node. The origin of the artery of the sinoatrial node from the proximal portion or trunk of the left coronary artery was less frequent (12%±3.2) than the origin from the circumflex artery (30%±4.5). Neither sex nor race influenced the variations of the origin of the sino-atrial node.

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Variations d'origine de l'artère du noeud sinu-atrial du coeur humain normal

Résumé L'a. du noeud sinu-atrial a été étudiée sur 100 coeurs humains normaux après injection de chaque a. coronaire à la gélatine colorée additionnée d'une substance radio-opaque. Les coeurs provenaient de 69 hommes et 31 femmes, 64 caucasiens et 36 non caucasiens (nègres et mulâtres) âgés de 7 à 80 ans. Ces sujets étant décédés par suicide ou des suites d'accidents, leurs coeurs ont été considérés comme normaux après examen anatomo-pathologique. Le noeud sinu-atrial du coeur humain est vascularisé par l'a. coronaire droite plus fréquemment (58 %±4,9) que par l'a. coronaire gauche (42 %±4). L'a. atriale antéro-médiale droite, issue de l'a. coronaire droite au niveau du tiers médial du quadrant antérieur droit du dôme atrial est l'artère la plus fréquemment en cause (50 %±5) dans la vascularisation du noeud sinuatrial. Parmi les branches de l'a. coronaire gauche, l'a. atriale antéro-médiale gauche, née au niveau du tiers médial du quadrant antérieur gauche du dôme atrial, était la branche la plus fréquemment en cause (25 %±4,3) dans la vascularisation du noeud sinu-atrial. La naissance de l'a. du noeud sinu-atrial à partir de la partie proximale ou du tronc de l'a. coronaire gauche était moins fréquente (12 %±3,2) que son origine à partir du rameau circonflexe (30 %±4,5). Les variations d'origine de l'a. du noeud sinu-atrial n'apparaissaient pas influencées par le sexe ou la race.

     

Cellular basis for the age-associated increase in autoimmune reactions

The mechanisms that lead to the increased expression of autoantibodies with age are poorly understood. We have studied the number, size, and density of spleen and peritoneal cells from young and old BALB/c and C57BL/6 mice as well as the frequency of clonal precursors for antibodies to mouse erythrocytes, thyroglobulin, and IgG in these lymphoid preparations. Old mice have a 6-fold increase in the number of resident peritoneal cells and a 2-fold increase in the absolute number of Ly1-bearing B cells in this population. Furthermore, old mice have twice as many large, low density splenic B cells as young mice. The frequencies of B cell clonal precursors for anti-BrMRBC and anti-thyroglobulin antibody-forming cells in old mice were 3-10 times greater than in young mice. In the same cultures, however, no increase in the frequencies of B cell clonal precursors for anti-IgG or anti-DNA antibody forming cells was detected in old compared to young mice. These findings and other data suggest that there are at least two families of B cell autoantibody precursors, one including anti-BrMRBC and anti-thyroglobulin autoantibodies, the other including anti-IgG and anti-DNA antibodies. Studies of the differential regulation of these two families of autoantibody precursors might contribute to a greater understanding of autoimmune phenomena in age and disease.     

Stimulation of murine B lymphocytes to IgG synthesis and secretion by the mitogens lipopolysaccharide and lipoprotein and its inhibition by anti-immunoglobulin antibodies.

The two mitogens, lipopolysaccharide (LPS) and lipoprotein (LP), both stimulate to an equal extent murine B lymphocytes to develop IgG-synthesizing and IgG-secreting cells. IgG synthesis and secretion was detected either by biosynthetic labeling of stimulated B cells, followed by immunoprecipitation and polyacrylamide gel electrophoresis of labeled Ig, or by the protein A plaque assay detecting all IgG-secreting cells with IgG-specific developing antisera. B cells from spleen, lymph node, thoracic duct and fetal liver of normal and T cell-deficient nu/nu mice are all stimulated by the two mitogens to develop IgG-secreting cells. Mitogen-induced IgG secretion, therefore, can occur independently of T cells and of external antigen. Anti-Ig antibodies inhibit the mitogen-induced development of Ig-secreting cells. Antibodies with specificities for μ chains when added before or soon after mitogenic stimulation of small, resting B cells, will inhibit these cells from developing into IgG-secreting cells. Later in culture, antibodies with specificities for γ chains also become inhibitory for the mitogen-induced development of IgG-secreting cells. These results indicate that the precursors of the IgG-secreting cells carry IgM in the outer surface membrane. They also suggest that during mitogen-stimulated growth of B cell clones, IgG becomes expressed in the surface membrane in a functional way which allows the inhibition of mitogen-induced IgG secretion by anti-γ antibodies.