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SUMMARY Tight control of blood glucose reduces cardiovascular events and total mortality is conflicting. To summarize clinical effects of tight versus conventional glucose control in patients with type 2 diabetes. We systematically searched MEDLINE, EMBASE, Cochrane Library, and ISI Web of Knowledge with no limits of language and time. Further trials were searched from the reference lists of identified studies. We included randomized controlled comparing different levels of blood glucose control intensity in type 2 diabetic patients. Two independent reviewers extracted data of eligible studies using standard case report forms. We investigated total mortality, cardiovascular and microvascular events, and hypoglycemia in patients with type 2 diabetes. We used random-effects models to obtain relative risks (RR) with 95% confidence intervals (CI). We included 6 trials involving 27,654 patients. There was no significant effect of tight blood glucose control on all-cause mortality (RR 1.03; 95% CI 0.90‐1.17) or cardiovascular mortality (RR 1.04; 95% CI 0.83‐1.29). Tight glucose control reduced the risk for nonfatal MI (RR 0.85; 95% CI 0.76‐0.95), although had no effect on the incidence of nonfatal stroke (RR 1.02; 95% CI 0.88‐1.17). For microvascular events, tight glucose control reduced the risk progression of retinopathy (RR 0.80; 95% CI 0.71‐0.91), incidence of peripheral neuropathy (RR 0.94; 95% CI 0.89‐0.99), and progression of nephropathy (RR 0.55; 95% CI 0.37‐0.80), but had not significant effect on the incidence of nephropathy (RR 0.69; 95% CI 0.42‐1.14). The risk of severe hypoglycemia increased with tight glucose control (RR 2.39; 95% CI 1.79‐3.18). Tight blood glucose control reduces the risk for some macrovascular and microvascular events, without effect on all-cause mortality and cardiovascular mortality. Tight glucose control increases the risk of severe hypoglycemia.

It is well known that melatonin participates in the regulation of many important physiological functions such as sleep-wakefulness cycle, motor coordination and neural plasticity, and cognition. However, as there are contradictory results regarding the melatonin production diurnal profile under alcohol consumption, the aim of this paper was to study the phenomenology and mechanisms of the putative modifications on the daily profile of melatonin production in rats submitted to chronic alcohol intake. The present results show that rats receiving 10% ethanol in drinking water for 35 days display an altered daily profile of melatonin production, with a phase delay and a reduction in the nocturnal peak. This can be partially explained by a loss of the daily rhythm and the 25% reduction in tryptophan hydroxylase activity and, mainly, by a phase delay in arylalkylamine N-acetyltransferase gene expression and a 70% reduction in its peak activity. Upstream in the melatonin synthesis pathway, the results showed that noradrenergic signaling is impaired as well, with a decrease in β1 and α1 adrenergic receptors' mRNA contents and in vitro sustained loss of noradrenergic-stimulated melatonin production by glands from alcohol-treated rats. Together, these results confirm the alterations in the daily melatonin profile of alcoholic rats and suggest the possible mechanisms for the observed melatonin synthesis modification.

FA are known to modulate immune function in conditions such as arthritis and lupus erythematosus. The effects of arachidonic (AA) and oleic acids (OA) on function and pleiotropic gene expression of Raji cells were investigated. The following parameters were evaluated: cytotoxicity as assessed by loss of membrane integrity and DNA fragmentation; proliferation as measured by [14C]thymidine incorporation; production of interleukin (IL)-10, interferon (INF)-gamma, and tumor necrosis factor (TNF)-alpha; and expression of pleiotropic genes by a macroarray technique (83 genes in total). AA was more toxic to Raji cells than OA. Both FA promoted an increase in Raji cell proliferation at 75 microM, whereas OA at high concentrations (200 microM) decreased proliferation. AA reduced the production of IL-10, TNF-alpha, and INF-gamma. On the other hand, OA provoked an increase of INF-gamma production but did not affect the production of IL-10 and TNF-alpha. The proportions of genes with altered expression were 27% for AA and 35% for OA. The FA affected the expression of genes clustered as: cytokines, signal transduction pathways, transcription factors, cell cycle, defense and repair, apoptosis, DNA synthesis, cell adhesion, cytoskeleton, and hormone receptors. The most remarkable changes were observed in the genes of signal transduction pathways. These results led us to conclude that the effect of these FA on B-lymphocytes includes regulation of gene expression. Thus, diets enriched with fat containing OA or AA may affect B lymphocyte function in vivo.

Summary The molecular characterization of the subgroup A3 remains unclear. Four unrelated A3 blood donors were studied. Family studies were possible in three of them. The A3 subgroup was defined by immunohaematological evaluation with four different commercially available serums. Exons VI and VII of the ABO gene, responsible for 91% of the catalytic active part of the glycosyltransferase, were amplified and subjected to direct sequencing. The results in all samples showed heterozygosity for the G261 deletion. In the A3 allele, the following associations were found: C467T mutation and 1060C deletion in one A3 blood donor and in another G829A and 1060C. In one case, only the 1060C deletion was demonstrated in the A3 allele. One blood donor presented the T646A and the G829A mutations in homozygosity. It was concluded that the A3 blood group is very heterogeneous at the molecular level.

We have studied three Brazilian kindreds presenting spectrin alpha/74 hereditary elliptocytosis (HE) due to a G-->A substitution, responsible for the R28H mutation. The mutant allele was associated with alphaI domain haplotype 1 (XbaI-/MspI-/PvuII+) in all three families and with two different alphaII domain haplotypes (1/RIT, 4/RVR). This result may reflect that this mutation occurs in a "hot spot" and may have arisen more than once or that a crossing over event may have occurred between the two domains studied. We detected one new haplotype in the alphaI domain (haplotype 3 -XbaI(+)/MspI(-)/PvuII(+)). The mutant allele was associated with the lack of the alphaII domain Alu insertion in all three cases. Allele alphaLELY, detected by PCR and restriction enzyme digestion, was present in the heterozygous form in patient 1 (alphaHE/alphaLELY) and in the homozygous form in patients 2 and 3(alphaHE-LEL/alphaLELY). It was found to be associated with domain haplotypes I (RIT) and 4 (RVR) and with the presence and absence of the Alu insertion. This may have arisen through recombination events, since this polymorphism is located in the alphaIV-alphaV domain junction, which is far distant from the alphaII domain.

We have identified three unrelated individuals and three members of a family with the non-deletion form of Agamma-hereditary persistence of fetal hemoglobin (HPFH). Molecular analysis showed that each individual is a heterozygote for a previously described -195 Agamma (C-->G) mutation. The beta-globin gene cluster was studied using the polymerase chain reaction and related techniques. Haplotyping using nine restriction sites identified two closely related chromosomes with the -195Agamma mutation, differing only in a single site 3' to the beta-globin gene. Further analysis of beta-globin framework indicated that the HPFH allele segregates with haplotype V, according to Orkin's classification. The second haplotype probably originated by a point mutation or DNA rearrangement of a pre-existing -195Agamma chromosome. We also determined the sequences from -622 to +55 bp upstream to the Agamma gene and part of the Agamma IVS-2. We found four polymorphisms associated to the -195Agamma promoter region. All -195Agamma chromosomes had a G at positions -588 and +25 relative to the Agamma gene. One individual was also homozygous for polymorphisms at -398 (G-->A), and another at -369 (C-->G). Cloning and sequencing of the polymorphic patterns of the 3' region of Agamma IVS-2 showed that the mutated allele is linked to beta-globin chromosome B. Some correlations between chromosome characteristics and Agamma point mutations were also observed.

The effects of the muscarinic agonist oxotremorine-m (Oxo-m) on 45Ca and 86Rb fluxes, insulin secretion, cytoplasmic Ca2+ concentration ([Ca2+]i) and membrane potential in pancreatic B-cells were studied. Oxo-m (40-200 microM) increased the [Ca2+]i by about 250 nM, irrespective of the glucose concentration present in the medium (2.8-22 mM). This effect was reduced by 50% upon the addition of EGTA. Oxo-m (50 microM) increased the 45Ca efflux from islets perifused in the absence or presence of [Ca2+]o, although under the former condition this efflux was transient. The difference between effluxes measured in the absence and presence of [Ca2+]o represents the sustained second component, which presumably reflects Ca2+ influx. In both the absence and presence of 11.2 mM glucose. Oxo-m (50 microM) transiently increased 86Rb efflux. In the presence of glucose, Oxo-m provoked a transient polarization of the B-cell membrane associated with an increase in the K+ permeability values. K+ permeability returned to basal values (no Oxo-m) after 1-2 min. These results indicate that the initial phase of Oxo-m-induced insulin secretion depends partially on intracellular Ca2+ release, and that the sustained enhancement of release depends on Ca2+ influx. The participation of a calcium release-activated current (ICRAC) is proposed to explain the sustained small changes in membrane potential.