Locus on chromosome 6p linked to elevated HDL cholesterol serum levels and to protection against premature atherosclerosis in a kindred with familial hypercholesterolemia

Heterozygous familial hypercholesterolemia (FH) is a highly atherogenic genetic disorder leading to premature coronary heart disease (CHD), usually before 60 years of age. We studied an extended multigenerational kindred with FH linked to chromosome 1p32 in which atherosclerotic complications were either delayed or prevented in individuals with elevated HDL cholesterol (HDL-C) levels or hyperalphalipoproteinemia (HA). Premature CHD was observed in FH individuals without HA. The study of this family established that the HA trait in the family also followed an autosomal dominant mode of inheritance with a pattern of segregation independent from FH. We identified a locus on chromosome 6 linked to elevated HDL-C levels (HA) in this family. Haplotype analysis refined the localization to a 7.32-cM interval (73 to 80 cM from pter) flanked by markers D6S1280 and D6S1275. Parametric 2-point and multipoint analyses yielded maximum LOD scores of 3.05 and 3.17, respectively. This finding was confirmed with a nonparametric multipoint score of 3.78 (P=0.0009). We propose that this locus, linked to elevated HDL-C levels, confers protection against premature CHD within an FH context.     

Health and economic impact of combining metformin with nateglinide to achieve glycemic control: Comparison of the lifetime costs of complications in the U.K

Background  

To reduce the likelihood of complications in persons with type 2 diabetes, it is critical to control hyperglycaemia. Monotherapy with metformin or insulin secretagogues may fail to sustain control after an initial reduction in glycemic levels. Thus, combining metformin with other agents is frequently necessary. These analyses model the potential long-term economic and health impact of using combination therapy to improve glycemic control.     

Decrease of the platelet 5-HT2A receptor function by long-term imipramine treatment in endogenous depression

BACKGROUND: Animal studies have found that many antidepressants induce decreases in both the density and the functional activity of the serotonin 2A (5-HT2A) receptor subtype. However, the extrapolation of findings to humans has been inconclusive. A physiological platelet response mediated by this receptor, the serotonin-amplified platelet aggregation, was measured to study whether long-term antidepressant treatment induces changes in 5-HT2A receptor functioning in endogenous depressed patients. METHOD: The percentage of serotonin-amplified platelet aggregation to adenosine diphosphate (ADP) was studied in 15 untreated patients with major depressive disorder (DSM-IV) with endogenous features (Newcastle scale). This index was used as an indirect measurement of the functional status of platelet 5-HT2A receptors. Aggregation studies were repeated once remission of the symptoms was achieved during treatment with imipramine (150-300 mg/day). A group of 15 concurrent normal subjects was used as a control. RESULTS: A statistically significant decrease (p = 0.038) in the percentage of serotonin-amplified platelet aggregation to ADP was observed when remission was achieved (after 145 +/- 27 days). CONCLUSIONS: The results showed a decrease in a platelet functional response mediated by 5-HT2A receptors following effective imipramine treatment, suggesting that desensitization or down-regulation of the 5-HT2A receptor function could be linked to the therapeutic effect of some antidepressants. The data also support the use of platelet aggregometry as a surrogate measurement of antidepressant action, particularly in intra-subject designs.     

Intrastriatal methylmalonic acid administration induces convulsions and TBARS production,and alters Na+,K+-ATPase activity in the rat striatum and cerebral cortex

PURPOSE: Methylmalonic acid (MMA) inhibits succinate dehydrogenase (SDH) and beta-hydroxybutyrate dehydrogenase activity in vitro. Acute intrastriatal administration of MMA induces convulsions through glutamatergic mechanisms probably involving primary adenosine triphosphate (ATP) depletion and free radical generation. In this study we investigated whether the intrastriatal administration of MMA causes lipoperoxidation and alteration in Na+, K+-ATPase activity ex vivo and characterized the electrographic changes elicited by the intrastriatal administration of this organic acid. METHODS: MMA-induced lipoperoxidation, alterations in Na+, K+-ATPase activity and electrographic changes were measured by measuring total thiobarbituric acid-reacting substances and inorganic phosphate release by spectrophotometry, and by depth electrode recording, respectively. RESULTS: We demonstrated that intrastriatal MMA (6 mmol) injection causes convulsive behavior and electrographically recorded convulsions that last approximately 2 h. Concomitant with the increase of thiobarbituric acid-reacting substances (TBARS) content, we observed a significant inhibition of Na+,K+-ATPase activity in the striatum, and activation of Na+,K+-ATPase activity in the ipsilateral cerebral cortex. Intrastriatal MMA injection increased the content of TBARS in the striatum measured 30 min (32.4 +/- 12.0%, compared with the noninjected contralateral striatum) and 3 h (39.7 +/- 5.1%, compared with the noninjected contralateral striatum) after MMA injection. TBARS content of the ipsilateral cerebral cortex increased after MMA injection at 30 min (42.1 +/- 6.0%) and 3 h (40.4 +/- 20.2%), and Na+,K+-ATPase activity in the ipsilateral cerebral cortex increased during ictal activity (113.8 +/- 18%) and returned to basal levels as electrographic convulsions vanished in the cortex. Interestingly, intrastriatal MMA administration induced a persistent decrease in Na+,K+-ATPase activity only in the injected striatum (44.9 +/- 8.1% at 30 min and 68.7 +/- 9.4 at 3 h). CONCLUSIONS: These data suggest that MMA induces lipoperoxidation associated with Na+,K+-ATPase inhibition or activation, depending on the cerebral structure analyzed. It is suggested that Na+,K+-ATPase inhibition may play a primary role in generating MMA-induced convulsions.     

Apolipoprotein Eepsilon4 modifies Alzheimer's disease onset in an E280A PS1 kindred

We previously have identified a large kindred from Colombia in which Alzheimer's disease (AD) is caused by the E280A presenilin 1 (PS1) mutation. The objective of this study was to examine whether environmental and genetic factors are responsible for variation in the phenotypic expression of the E280A PS1 mutation. We genotyped coding and promoter polymorphisms of the APOE gene in carriers of the E280A PS1 mutation. Kaplan-Meier product-limit and Cox proportional hazard models were used in the statistical analyses. DNA was available from 114 carriers of the E280A PS1 mutation, including 52 subjects with AD. APOE epsilon 4 allele carriers were more likely to develop AD at an earlier age than subjects without the epsilon 4 allele (hazard ratio, 2.07; 95% confidence interval, 1.07-3.99; p = 0.030). Subjects with low education were more likely to develop AD later than those with higher education (hazard ratio, 0.476; 95% confidence interval, 0.26-0.87). Low educational level was associated with rural residence (p < 0.001). Promoter APOE variants did not influence either the onset or the duration of the disease. This study is the first to our knowledge to demonstrate that genetic and environmental factors influence age of onset in a kindred with a familial AD mutation.     

Alpha 2-adrenoceptors and 5-HT receptors mediate the antinociceptive effect of new pyrazolines, but not of dipyrone

In this study, we investigated whether spinal noradrenergic and serotonergic systems are involved in the antinociception induced by the novel pyrazolines 3-methyl- and 3-phenyl-5-hydroxy-5-trichloromethyl-4,5-dihydro-1H-1-pyrazole-1-carboxyamide (MPCA and PPCA, respectively), and the pyrazolinone dipyrone in the acetic acid writhing (stretching) test in mice. Intrathecal (i.t.) administration of methysergide (3 and 10 microg) and yohimbine (3 microg), but not of prazosin (0.3 and 1 microg) prevented the antinociceptive action of MPCA and PPCA (500 micromol/kg, s.c.). Dipyrone-induced antinociception (500 micromol/kg, s.c.) was not affected by methysergide or adrenoceptor antagonists. These results suggest that spinal 5-HT receptors and alpha2-adrenoceptors are involved in the antinociception induced by MPCA and PPCA, but not in that elicited by dipyrone.     

Differential regulation of Th1/Th2 in relevant tissues for sepsis pathogenesis with a Limulus anti-LPS factor-derived peptide increases survival in Gram-positive sepsis

Severe sepsis and septic shock are important causes of death in intensive care units. Although Gram-negative infections were predominant in the 1960s, Gram-positive infections have increased in the past two decades and now account for about half of the cases of severe sepsis. In this study, we examined the effect of a Limulus anti-LPS factor (LALF)-derived peptide on lung and liver Th1/Th2 cytokine mRNA levels during a Gram-positive sepsis. We also examined the morphopathological changes observed in these organs during the disease. Mice challenged with a high dose of Staphylococcus haemolyticus showed severe damage in lung. In contrast, the liver of challenged mice showed an accumulation of bacterial particles in the sinusoids, associated with a severe inflammatory response due to high levels of tissue mRNA proinflammatory cytokines. Treatment with the peptide LALF(32-51) ameliorated the sepsis-induced effects in the lung and liver and increased the survival of mice in a dose- and time-dependent manner. Pretreatment with the peptide LALF(32-51) differentially regulates TNF-alpha, IFN-gamma, IL-12p40, IL-2 and IL-10 mRNA levels in lung and liver of peptide-treated mice, and limits the systemic inflammatory response. These findings support for the first time the effectiveness of an LALF-derived peptide in the treatment of a Gram-positive sepsis. Modulation of the Th1/Th2 pattern in tissues relevant for sepsis correlates with an improved outcome of the disease as denoted by increased survival.     

Nitric oxide synthesis inhibition increases proliferation of neural precursors isolated from the postnatal mouse subventricular zone

The subventricular zone (SVZ) of rodents retains the capacity to generate new neurons throughout the entire life of the animal. Neural progenitors of the SVZ survive and proliferate in vitro in the presence of epidermal growth factor (EGF). Nitric oxide (NO) has been shown to participate in neural tissue formation during development and to have antiproliferative actions, mediated in part by inhibition of the EGF receptor. Based on these findings, we have investigated the possible effects of endogenously produced and exogenously added NO on SVZ cell proliferation and differentiation. Explants were obtained from postnatal mouse SVZ and cultured in the presence of EGF. Cells migrated out of the explants and proliferated in culture, as assessed by bromodeoxyuridine (BrdU) incorporation. After 72 h in vitro, the colonies formed around the explants were constituted by cells of neuronal or glial lineages, as well as undifferentiated progenitors. Immunoreactivity for the neuronal isoform of NO synthase was observed in neuronal cells with long varicose processes. Cultures treated with the NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) showed an increase in the percentage of BrdU-immunoreactive cells, whereas treatment with the NO donor diethylenetriamine-nitric oxide adduct (DETA-NO) led to a decrease in cell proliferation, without affecting apoptosis. The differentiation pattern was also altered by L-NAME treatment resulting in an enlargement of the neuronal population. The results suggest that endogenous NO may contribute to postnatal neurogenesis by modulating the proliferation and fate of SVZ progenitor cells.     

Activity of chemotherapy with carboplatin plus paclitaxel in a recurrent mesonephric adenocarcinoma of the uterine corpus

BACKGROUND: Malignant lesions derived from mesonephric (Wolffian) remnants are uncommon. The course of these tumors is usually indolent, and the recurrence has only been documented in nine cases. Because of the small number of cases, no current recommendations exist regarding treatment, and little is known about the response to chemotherapeutic agents. CASE: A 33-year-old woman was diagnosed with a mesonephric adenocarcinoma arising in the uterine corpus. Ten months after initial surgery and radiotherapy she presented with local and pulmonary relapse. Salvage chemotherapy with carboplatin plus paclitaxel was administered with a good response. CONCLUSIONS: Mesonephric adenocarcinomas are uncommon neoplasms. Their treatment remains elusive. We report a case of a recurrent uterine mesonephric adenocarcinoma that presented a good response to therapy with carboplatin plus paclitaxel. A review of the previous literature is also presented.