Prognostic value of plasma soluble CD40 ligand in patients with chronic non-valvular atrial fibrillation.

AIMS: We aimed to clarify whether determination of levels of soluble CD40 ligand (sCD40L) could predict subsequent thrombo-embolic events in patients with non-valvular atrial fibrillation (NVAF). METHODS AND RESULTS: Forty-four consecutive outpatients (mean age: 58 +/- 6 years, 20 male) with chronic NVAF who were not receiving aspirin and had no thrombus or spontaneous echo contrast (SEC) on left atrium (LA) or left atrial appendage (LAA) were included in the study. The patients had no history of an embolic event and were followed up 24 +/- 2 months for thrombo-embolic events. sCD40L was determined at the enrollment. All patients were evaluated by means of SEC and thrombus formation by transoesophageal echocardiography at the end of follow-up period. Twelve (27%) patients had SEC and 2 (5%) patients had thrombus on LAA. Ischaemic stroke occurred in 2 (4.5%) patients and transient ischaemic attack developed in 4 (9%) patients during follow-up. sCD40L was significantly higher in patients with LASEC (0.41 +/- 0.05 vs. 0.16 +/- 0.04 ng/mL, P = 0.02) and embolic events (0.74 +/- 0.05 vs. 0.19 +/- 0.03 ng/mL, P = 0.001) than in those without. sCD40L levels were significantly related to the LASEC grade (R = 0.377, P = 0.02). In multivariable analysis, while independent variables for SEC or thrombus formation were LA diameter, sCD40L levels, and the duration of AF, independent variables for cerebrovascular events were the existence of SEC or thrombus formation on LAA, and sCD40L level. CONCLUSION: Plasma sCD40L may prospectively predict stroke in AF. sCD40L may provide useful marker to identify patients at high thrombo-embolic risk with NVAF.     

Elevated blood lactate in COPD exacerbations associates with adverse clinical outcomes and signals excessive treatment with β2-agonists

Background and Objective

Raised blood lactate secondary to high dose β₂-agonist treatment has been reported in asthma exacerbations but has not been investigated during acute exacerbations of COPD (AECOPD). We explored associations of blood lactate measurements with disease outcomes and β₂-agonist treatments during AECOPD.

Methods

Retrospective (n = 199) and prospective studies (n = 142) of patients hospitalized with AECOPD were conducted. The retrospective cohort was identified via medical records and the prospective cohort was recruited during hospitalization for AECOPD. Baseline demographics, comorbidities, β₂-agonist treatment, biochemical measurements and clinical outcomes were compared between patients with normal (≤2.0 mmol/L) versus elevated lactate (>2.0 mmol/L). Regression analyses examined associations of lactate measurements with β₂-agonist dosages.

Results

Demographic data and comorbidities were similar between high versus normal lactate groups in both cohorts. The populations were elderly (mean >70 years), predominantly male (>60%) with reduced FEV₁ (%) 48.2 ± 19 (prospective cohort). Lactate was elevated in approximately 50% of patients during AECOPD and not related to evidence of sepsis. In the prospective cohort, patients with high lactate had more tachypnoea, tachycardia, acidosis and hyperglycaemia (p < 0.05) and received more non-invasive ventilation (37% vs. 9.7%, p < 0.001, prospective cohort). There was a trend to longer hospitalization (6 vs. 5 days, p = 0.06, prospective cohort). Higher cumulative β₂-agonist dosages were linked to elevated lactate levels (OR 1.04, p = 0.01).

Conclusion

Elevated lactate during AECOPD was common, unrelated to sepsis and correlated with high cumulative doses of β₂-agonists. Raised lactate may indicate excessive β₂-agonist treatment and should now be investigated as a possible biomarker.     

Evolution of drug-resistance genes in Plasmodium falciparum in an area of seasonal malaria transmission in Eastern Sudan

We investigated the evolution of drug-resistant Plasmodium falciparum in a village in eastern Sudan. The frequencies of alleles of 4 genes thought to be determinants of drug resistance were monitored from 1990 through 2001. Changes in frequencies of drug-resistance genes between wet and dry seasons were monitored from 1998 through 2000. Parasites were also typed for 3 putatively neutral microsatellite loci. No significant variation in frequencies was observed for the microsatellite loci over the whole study period or between seasons. However, genes involved in resistance to chloroquine showed consistent, significant increases in frequencies over time (rate of annual increase, 0.027/year for pfcrt and 0.018/year for pfmdr1). Genes involved in resistance to the second-line drug used in the area (Fansidar) remained at low frequencies between 1990 and 1993 but increased dramatically between 1998 and 2000, which is consistent with the advent of Fansidar usage during this period. For mutant alleles of the primary drug-resistance targets for chloroquine and pyrimethamine, higher frequencies were seen during the dry season than during the wet season. This cyclical fluctuation in drug-resistance genes most likely reflects seasonal variation in drug pressure and differences in the fitness of resistant and sensitive parasites.     

Subacute sclerosing panencephalitis with generalized seizure as a first symptom: a case report

Subacute sclerosing panencephalitis (SSPE) can show variations in its clinical course. Typical initial symptoms consist of intellectual decline, deterioration in school performance, and myoclonic jerks. Atypical forms of presentation such as generalized seizures and acute or subacute coma can be observed rarely. This report describes a 5-year-old boy with an atypical feature of SSPE, generalized seizures. For 1 month his only symptom was seizures, followed by personality and behavioral changes and myoclonic jerks. A diagnosis of SSPE was made based on the boy's history of measles, characteristic electroencephalogram changes and compatible magnetic resonance, and elevated anti-measles antibody titers in the cerebrospinal fluid and serum. The case presented in this article is a good example of SSPE in which, at early stages, some of the signs and symptoms can lead to an erroneous diagnosis.     

The presence of Plasmodium falciparum gametocytes in human blood increases the gravidity of Anopheles gambiae mosquitoes

We conducted a field study in an area of endemic malaria transmission in western Kenya to determine whether mosquitoes that feed on gametocyte-infected blood but do not become infected have reduced or enhanced fecundity in comparison to mosquitoes fed on uninfected blood. Fifteen paired membrane-feeding experiments were conducted in which two strains of Anopheles gambiae mosquitoes were simultaneously fed on either Plasmodium falciparum-infected blood from children or uninfected control blood from adults. The presence of noninfecting gametocytes in blood increased the probability that An. gambiae would produce eggs after one blood meal by sixfold (odds ratio for control relative to infected blood group 0.16; 95% CI 0.10-0.23). This result could not be explained by variation in blood meal size or hemoglobin content between hosts. When children cleared their infections, the difference in gravidity between mosquitoes fed on their blood and uninfected adults disappeared, suggesting this phenomenon is due to the presence of Plasmodium gametocytes in blood and not to host-specific factors such as age. This result was observed in two mosquito strains that differ in their innate fecundity, suggesting it may apply generally. To our knowledge, this is the first time that Plasmodium has been implicated as enhancing vector gravidity.     

Prevalence of occult HBV infection in haemodialysis patients with chronic HCV

AIM: To study the prevalence and clinical effects of occult HBV infection in haemodialysis patients with chronic HCV. METHODS: Fifty chronic hemodialysis patients with negative HbsAg, and positive anti-HCV were included in the study. These patients were divided into two groups: HCV-RNA positive and HCV-RNA negative, based on the results of HCV-RNA PCR. HBV-DNA was studied using the PCR method in both groups. RESULTS: None of the 22 HCV-RNA positive patients and 28 HCV-RNA negative patients revealed HBV-DNA in serum by PCR method. The average age was 47.2±17.0 in the HCV-RNA positive group and 39.6±15.6 in the HCV-RNA negative group. CONCLUSION: The prevalence of occult HBV infection is not high in haemodialysis patients with chronic HCV in our region. This result of our study has to be evaluated in consideration of the interaction between HBsAg positivity (8%-10%) and frequency of HBV mutants in our region.     

Synthesis,Structure and Thermal Behavior of Oxalato-Bridged Rb+ and H3O+ Extended Frameworks with Different Dimensionalities

Correlative studies of three oxalato-bridged polymers, obtained under hydrothermal conditions for the two isostructural compounds {Rb(HC₂O₄)(H₂C₂O₄)(H₂O)₂}_∞¹, 1, {H₃O(HC₂O₄)(H₂C₂O₄).2H₂O}_∞¹, 2, and by conventional synthetic method for {Rb(HC₂O₄)}_∞³, 3, allowed the identification of H-bond patterns and structural dimensionality. Ferroïc domain structures are confirmed by electric measurements performed on 3. Although 2 resembles one oxalic acid sesquihydrate, its structure determination doesn’t display any kind of disorder and leads to recognition of a supramolecular network identical to hybrid s-block series, where moreover, unusual H₃O⁺ and NH₄⁺ similarity is brought out. Thermal behaviors show that 1D frameworks with extended H-bonds, whether with or without a metal center, have the same stability. Inversely, despite the dimensionalities, the same metallic intermediate and final compounds are obtained for the two Rb⁺ ferroïc materials.     

Essential role for Atox1 in the copper-mediated intracellular trafficking of the Menkes ATPase

The metallochaperone Atox1 directly interacts with the copper-transporting ATPases and plays a critical role in perinatal copper homeostasis. To determine the cell biological mechanisms of Atox1 function, intracellular copper metabolism, and Menkes ATPase abundance, localization and trafficking were examined in immortalized fibroblast cell lines derived from Atox1(+/+) and Atox1(-/-) embryos. Consistent with the proposed role for Atox1 in copper delivery to the secretory pathway, a marked increase in intracellular copper content secondary to impaired copper efflux was observed in Atox1-deficient cells. Although the localization of the Menkes ATPase was identical in Atox1(+/+) and Atox1(-/-) cells under conditions of equivalent intracellular copper content, a significant impairment in copper-mediated Menkes ATPase trafficking was observed in the absence of Atox1. When quantitative confocal immunofluorescence was used, significant differences in the time and dose-dependent trafficking of the Menkes ATPase from the Golgi compartment in response to copper were observed between Atox1(+/+) and Atox1(-/-) cells. These data reveal an essential role for Atox1 in establishing the threshold for copper-dependent movement of the copper-transporting ATPases within the secretory compartment and that, in the absence of Atox1, this movement alone is not sufficient to restore normal copper efflux. Taken together, these findings provide a cell biological model for the role of this metallochaperone under the physiological conditions of copper limitation in mammalian cells.     

Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome

Membrane cofactor protein (MCP; CD46) is a widely expressed transmembrane complement regulator. Like factor H it inhibits complement activation by regulating C3b deposition on targets. Factor H mutations occur in 10-20% of patients with hemolytic uremic syndrome (HUS). We hypothesized that MCP mutations could predispose to HUS, and we sequenced MCP coding exons in affected individuals from 30 families. MCP mutations were detected in affected individuals of three families: a deletion of two amino acids (D237/S238) in family 1 (heterozygous) and a substitution, S206P, in families 2 (heterozygous) and 3 (homozygous). We evaluated protein expression and function in peripheral blood mononuclear cells from these individuals. An individual with the D237/S238 deletion had reduced MCP levels and approximately 50% C3b binding compared with normal controls. Individuals with the S206P change expressed normal quantities of protein, but demonstrated approximately 50% reduction in C3b binding in heterozygotes and complete lack of C3b binding in homozygotes. MCP expression and function was evaluated in transfectants reproducing these mutations. The deletion mutant was retained intracellularly. S206P protein was expressed on the cell surface but had a reduced ability to prevent complement activation, consistent with its reduced C3b binding and cofactor activity. This study presents further evidence that complement dysregulation predisposes to development of thrombotic microangiopathy and that screening patients for such defects could provide informed treatment strategies.