Bacteria in midguts of field-collected Anopheles albimanus block Plasmodium vivax sporogonic development

Bacterial infections were investigated in midguts of insectary and field-collected Anopheles albimanus Weidemann from southern Mexico. Serratia marcescens, Enterobacter cloacae and Enterobacter amnigenus 2, Enterobacter sp., and Serratia sp. were isolated in field samples obtained in 1998, but only Enterobacter sp. was recovered in field samples of 1997 and no bacteria were isolated from insectary specimens. These bacteria were offered along with Plasmodium vivax infected blood to aseptic insectary An. albimanus, and the number of infected mosquitoes as well as the oocyst densities assessed after 7d. Plasmodium vivax infections in mosquitoes co-infected with En. amnigenus 2, En. cloacae, and S. marcensces were 53, 17, and 210 times, respectively, lower than in control mosquitoes, and the mean oocyst density in mosquitoes co-infected with En. cloacae was 2.5 times lower than in controls. Mortality was 13 times higher in S. marcensces-infected mosquitoes compared with controls. The overall midgut bacterial infection in mosquito field populations may influence P. vivax transmission, and could contribute to explain the annual variations in malaria incidence observed in the area.     

Detecting life-threatening lactic acidosis related to nucleoside-analog treatment of human immunodeficiency virus-infected patients,and treatment with L-carnitine

OBJECTIVE: Our first objective was to determine a blood lactate threshold predictive of survival in human immunodeficiency virus patients experiencing lactic acidosis related to nucleoside analogs, and second, to test l-carnitine for the treatment of patients exceeding that threshold. DESIGN: a) Retrospective study using data from personal and published observations to determine the lactate threshold between survivors and nonsurvivors in human immunodeficiency virus patients being treated with nucleoside analogs. b) Prospective multicenter open trial to test l-carnitine treatment of human immunodeficiency virus patients receiving nucleoside analogs. SETTING: Medical intensive care units of four teaching hospitals and one general hospital. PATIENTS: Retrospective analysis of data from 39 human immunodeficiency virus patients (five personal cases and 34 patients from the literature) receiving nucleoside-analog treatment from which lactate values were available. An additional six patients with high lactate values were included as a pilot study testing the use of l-carnitine therapy. MEASUREMENTS AND MAIN RESULTS: An initial lactate level of 9 mmol/L, which gave good positive and negative predictive values, was determined as a threshold between survivors and nonsurvivors for the patients receiving nucleoside-analog treatment. Six patients with initial lactate levels >10 mmol/L were prospectively treated with l-carnitine; three survived beyond the end of the study. CONCLUSIONS: The blood lactate levels in human immunodeficiency virus patients receiving nucleoside-analog therapy can predict mortality in these patients. The preliminary data from this pilot study suggest that l-carnitine may be helpful for patients who have nucleoside-analog-related lactic acidosis with blood lactate levels >10 mmol/L. Further studies will be necessary to affirm the therapeutic efficacy of l-carnitine in this setting.     

Identification and functional characterization of novel calcium-sensing receptor mutations in familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia

Familial hypocalciuric hypercalcemia (FHH), neonatal severe hyperparathyroidism (NSHPT), and autosomal dominant hypocalcemia (ADH), in which calcium homeostasis is disordered, are associated with mutations in the calcium-sensing receptor (CASR). Six unrelated kindreds with FHH and/or NSHPT and two unrelated kindreds with ADH were studied. Direct sequence analysis of the exons of the CASR gene identified heterozygous mutations in six of the kindreds with FHH and in one of those with ADH. We performed functional analyses on the novel missense and insertion/frameshift mutants by transiently transfecting wild-type and mutant CASRs tagged with a c-Myc epitope in human embryonic kidney (HEK293) cells. All mutant receptors were expressed at a similar level to that of the wild type; however, whereas mutants R220W and A835T (the ADH mutant) were fully glycosylated and were visualized on the cell surface, glycosylation of mutants G549R and C850-851 ins/fs was impaired, resulting in reduced cell surface staining. In fura-2-loaded HEK293 cells expressing the wild-type or mutant receptors, the inactivating R220W mutant produced a significant shift to the right relative to the wild-type CASR in the cytosolic calcium response to increasing extracellular calcium concentrations and the G549R and C850-851 ins/fs mutants were without detectable activity. The activating A835T mutation resulted in a shift to the left in the cytosolic calcium response to extracellular calcium concentrations relative to the wild type. Our studies have identified novel CASR mutations that alter the function of the CASR in several different ways.     

Comparison of the efficacy and tolerability of policosanol with atorvastatin in elderly patients with type II hypercholesterolaemia

BACKGROUND: Hypercholesterolaemia is a risk factor for coronary heart disease (CHD). Clinical studies have shown that lowering elevated serum total cholesterol (TC) levels, and particularly low density lipoprotein-cholesterol (LDL-C) levels, reduces the frequency of coronary morbidity and deaths, whereas high serum levels of high density lipoprotein-cholesterol (HDL-C) protect against CHD. Policosanol is a cholesterol-lowering drug purified from sugar cane wax with a therapeutic dosage range from 5-20 mg/day. Atorvastatin is an HMG-CoA reductase inhibitor which across its dosage range (10-80 mg/day) has shown significantly greater lipid-lowering effects than all previously marketed statins. OBJECTIVE: This study was undertaken to compare the efficacy and tolerability of policosanol with atorvastatin in older patients with type II hypercholesterolaemia. PATIENTS AND METHODS: This randomised, single-blind, parallel-group study was conducted in older patients (60-80 years) with type II hypercholesterolaemia. After 4 weeks on a cholesterol-lowering diet, 75 patients were randomised to policosanol or atorvastatin 10mg tablets taken once daily with the evening meal for 8 weeks. An interim and final check-up were performed at 4 and 8 weeks, respectively, after treatment was initiated. RESULTS: At 4 (p < 0.0001) and 8 (p < 0.00001) weeks, policosanol 10 mg/day significantly lowered serum LDL-C levels by 17.5 and 23.1%, respectively compared with baseline; corresponding values for atorvastatin were 28.4 and 29.8%. At study completion, policosanol significantly (p < 0.0001) reduced serum TC (16.4%), LDL-C/HDL-C ratio (25.5%) and TC/HDL-C ratio (19.3%), as well as (p < 0.001) triglyceride levels (15.4%). Atorvastatin significantly (p < 0.0001) decreased serum TC (22.6%), LDL-C/HDL-C (26.2%) and TC/HDL-C (19.8%) ratios, as well as (p < 0.001) triglyceride levels (15.5%). Atorvastatin was significantly more effective than policosanol in reducing LDL-C and TC, but similar in reducing both atherogenic ratios and triglyceride levels. Policosanol, but not atorvastatin, significantly (p < 0.05) increased serum HDL-C levels by 5.3%. Both treatments were well tolerated. At study completion, atorvastatin mildly, but significantly (p < 0.05) increased creatine phosphokinase (CPK) and creatinine, whereas policosanol significantly reduced AST and glucose (p < 0.01) and CPK (p < 0.05) levels. All individual values, however, remained within normal limits. Three atorvastatin but no policosanol patients withdrew from the study because of adverse events: muscle cramps (1 patient), gastritis (1 patient) and uncontrolled hypertension, abdominal pain and myalgia (1 patient). Overall, no policosanol and seven atorvastatin patients (18.9%) reported a total of nine mild or moderate adverse events during the study (p < 0.01). CONCLUSIONS: This study shows that policosanol (10 mg/day) administered for 8 weeks was less effective than atorvastatin (10 mg/day) in reducing serum LDL-C and TC levels in older patients with type II hypercholesterolaemia. Policosanol, but not atorvastatin, however, significantly increased serum HDL-C levels, whereas both drugs similarly reduced atherogenic ratios and serum triglycerides. Policosanol was better tolerated than atorvastatin as revealed by patient withdrawal analysis and overall frequency of adverse events. Nevertheless, further studies must be conducted in larger sample sizes and using dose-titration methods to achieve target lipid levels in order to reach wider conclusions.     

Kikuchi disease: an unusual clinico-pathologic presentation

Histiocytic necrotizing lymphadenitis, also known as KIKUCHI disease is rare self-limited condition of young adults. Manifestations include enlargements of the cervical lymph nodes, sometimes with fever, and can be associated with other non-specific signs. The aetiologie of this affection is still unclear. This is a case report of a 27 year-old man who presented cervical and sus-clavicular lymphadenopathy diagnosed first as lymph nodes tuberculosis before the diagnostic of KIKUCHI disease was made.     

Olfactory dysfunction in hereditary ataxia and basal ganglia disorders

In the present study the olfactory system of hereditary ataxia patients was tested using the smell identification test. Two previous findings suggested a possible olfactory impairment in these patients. First, an olfactory dysfunction has been found in different neurodegenerative diseases, and second, human functional imaging has shown cerebellar activation during olfaction. As an initial approach to determine if cerebellar ataxia impairs the olfactory process, cerebellar ataxia patients, along with basal ganglia patients, were tested. The results show an olfactory deficit in both basal ganglia and hereditary ataxia patients. Further exploration of the olfactory capacities in hereditary ataxia is necessary to elucidate the specific nature of the deficits.     

Interactions of carboplatin with fibrin(ogen), implications for local slow release chemotherapy.

The effect of carboplatin (CPt) on fibrin(ogen) clot formation and the possible use of this combination for local slow release chemotherapy were examined. CPt significantly reduced thrombin-induced fibrin clotting time (CT) and increased clot turbidity in a concentration-dependent manner. When CPt was mixed with physiological levels of fibrinogen (>1 mg/ml), electron-dense nanoparticles (3 nm) were formed, as demonstrated by both optical particle counter and transmission electron microscopy (TEM). Upon thrombin-induced coagulation, the CPt nanoparticles were trapped within the fibrin mesh. At higher fibrinogen levels (>5 mg/ml), the 3-nm CPt nanoparticles aggregated, so that approximately 2% and approximately 0.5% of the CPt on the fibrinogen appeared as larger particles of 10 and 50 nm, respectively. Dialysis experiments showed that 60-70% of the CPt was released from the fibrin clot within one hour as a non-particulate soluble form, while approximately 30% of particulate CPt were retained. Up to 5 mg/ml this portion of firmly attached CPt was dependent of the initial drug level. CPt released from the fibrin by either diffusion or by fibrinolysis exhibited cytotoxic activity towards retinoblastoma (RB) cell lines (Y-79 and Weri RB1) equivalent to free drug. Our study indicates that CPt enhances fibrin clot formation and suggests the use of fibrin with high dose CPt for slow release chemotherapy against localized tumors such as retinoblastoma.     

A randomized, double-blind, placebo-controlled study of the efficacy and tolerability of policosanol in adolescents with type II hypercholesterolemia

Background: Atherosclerosis begins in childhood and is influenced by risk factors for coronary heart disease (CHD), of which hypercholesterolemia is crucial. The rationale for treating hypercholesterolemia in childhood is to limit atherosclerosis development, for which adherence to a cholesterol-lowering diet is the first-choice therapy. Nevertheless, pharmacological intervention with bile acid-binding resins may be prescribed for patients older than 10 years, mainly those with family history of CHD, multiple risk factors, and/or severe hypercholesterolemia. Resins are effective and tolerable in this population, but their clinical use has been limited because of poor compliance due to unpalatability; other effective cholesterol-lowering drugs have not been recommended in this population because of the potential impact of drug-related adverse effects such as increases in transaminases, myopathies, and gastrointestinal disturbances. Thus, the need for safer, easy-to-take, and effective cholesterol-lowering agents for this population continues. Policosanol is a mixture of higher primary aliphatic alcohols purified from sugar cane wax with cholesterol-lowering effects proven in patients with type II hypercholesterolemia and dyslipidemia due to type 2 diabetes mellitus. Policosanol shows good safety and tolerability profiles, with no evidence of drug-related adverse events (AEs) to date. This background supports the idea that policosanol could be a good candidate for treating hypercholesterolemia in children and adolescents, but it requires clinical demonstration.Objective: This 12-week study was undertaken to investigate the cholesterol-lowering effects and tolerability of policosanol in hypercholesterolemic patients aged 11 to 19 years.Methods: In this randomized, double-blind, placebo-controlled study, after 4 weeks of dietary stabilization, adolescents with type II hypercholesterolemia were randomly assigned (1:1 ratio) to receive placebo or policosanol 5-mg tablets once daily for 12 weeks. Physical examinations were performed, and lipid profiles and blood samples were obtained at baseline and after 6 and 12 weeks of therapy. The treatment was considered effective if mean reductions of low-density lipoprotein cholesterol (LDL-C) were >15%. In addition, the percentages of patients reaching final values of LDL-C <3.4 mmol/L and optimal values of <2.8 mmol/L were also evaluated. The doses were doubled if LDL-C values were ≥3.4 mmol/L after 6 weeks of therapy. The incidence of AEs and compliance with study medications were also evaluated after 6 and 12 weeks of treatment.Results: Fifty-five patients were enrolled in the study (28 policosanol, 27 placebo). Twenty-three patients (17 placebo, 6 policosanol) required dose titration at 6 weeks. After 12 weeks of therapy, policosanol significantly decreased LDL-C with respect to baseline and placebo (both P < 0.001), showing a mean reduction of 32.6%. Total cholesterol (TC) and TC/high-density lipoprotein cholesterol (HDL-C) and LDL-C/HDL-C ratios were reduced by 21.9%, 27.8%, and 37.2%, respectively, in the policosanol group (P < 0.001, compared with baseline and placebo). HDL-C rose 10.1% (P < 0.001), compared with baseline and placebo. Triglycerides were unaffected by policosanol. LDL-C, TC, and both atherogenic ratios were reduced significantly in the policosanol group (P < 0.001), and significant increases in HDL-C values were observed at the 6-week interim checkup (P < 0.001 vs baseline, P < 0.01 vs placebo). Twenty-five (89.3%) of 28 patients in the policosanol group showed LDL-C reductions >15% compared with 2 (7.4%) of 27 patients in the placebo group (P < 0.001). In addition, 26 (92.8%) of 28 policosanol patients reached LDL-C values < 3.4 mmol/L compared with 4 (14.8%) of 27 patients in the placebo group (P < 0.001). Likewise, the response rate for achievement of optimal values (LDL-C < 2.8 mmol/L) was also larger in the policosanol group (20/28; 71.4%) than in the placebo group (0/27; 0.0%) (P < 0.001). Policosanol was well tolerated, with no drug-related effects found on physical examination. Blood biochemistry determinations revealed significantly lower alanine aminotransferase levels in the policosanol group after 6 weeks of therapy compared with placebo (P < 0.05), as well as significant reductions in aspartate aminotransferase levels at 6 weeks (P < 0.01) and 12 weeks (P < 0.05) compared with baseline. No patients withdrew from the study, and only 3 patients (2 placebo, 1 policosanol) experienced mild AEs during the study; the placebo patients reported abdominal pain and constipation (1 each), and the policosanol patient reported polyphagia.Conclusions: Policosanol 5 mg/d appears to be well tolerated and effective as short-term treatment of hypercholesterolemia in adolescents.