Pneumocystis carinii: its incidence in rodents and enhancement of the infection by corticosteroids

A survey was made on the incidence of Pneumocystis carinii in 361 rodents including sewer rats, albino rats, albino mice, guinea-pigs and rabbits. P. carinii was found in 4 of the 215 Rattus norvegicus examined (1,8%). These results accord with recent observations but disagree with investigations made by the researchers who first studied this parasite in the past when high indexes of infection were found. However, in 20 albino rats treated with corticosteroids (betamethazone) we found 8 positive (40%) and in 20 albino mice treated by the same way, 9 were positive for P. carinii (45%). These results confirm the opportunistic character of P. carinii in rodents already well demonstrated in man.

Evaluation of an antireflux procedure for colonic interposition in pediatric esophageal replacements.

Background: In 1989, we introduced a 1-stage procedure with orthotopic colonic transplants for esophageal stenosis. A pitfall of this procedure is frequent reflux and/or stasis in the transplants from the cologastric anastomosis. Since 1993, we have used a new antireflux wrap (ARW) using an anterior wrap technique similar to the Dor procedure but fixed to the right crus of the diaphragm.Purpose: The purpose of the study was to evaluate ARWs.Method: From 1993 to 2008, the records of 67 patients with an ARW were compared with 27 without ARW (either operated on before 1993 or ARW was not appropriate) after colonic transplant for caustic esophageal stenosis. Both groups otherwise underwent the same surgical procedure. Postoperative esophagograms done on postoperative day 10 were reviewed for the presence of gastrocolonic reflux and stasis in the transplant.Results: The reflux rate on the initial esophagogram was reduced from 48.1% to 7.5% using ARW. The incidence of reflux on later esophagograms was 40.0% with no ARW and 21.4% with ARW. The 25% long-term rate of stasis in the colonic transplant was not increased with ARW.Conclusions: A loose ARW in patients with colonic esophageal replacements reduces gastrocolic reflux without increasing the rate of stasis. In the long term, children adapt better to stasis than to reflux and are thus protected from occult inflammation.

Mdx myotubes have normal excitability but show reduced contraction-relaxation dynamics.

The pathogenesis of Duchenne muscular dystrophy (DMD), characterised by lack of the cytoskeletal protein dystrophin, is not completely understood. An early event in the degenerative process of DMD muscle could be a rise in cytosolic calcium concentration. In order to investigate whether this leads to alterations of contractile behaviour, we studied the excitability and contractile properties of cultured myotubes from control (C57BL/10) and mdx mice, an animal model for DMD. The myotubes were stimulated electrically and their motion was recorded photometrically. No significant differences were found between control and mdx myotubes with respect to the following parameters: chronaxy and rheobase (0.33 +/- 0.03 ms and 23 +/- 4 V vs. 0.39 +/- 0.07 ms and 22 +/- 2 V for C57 and mdx myotubes, respectively), tetanisation frequency (a similar distribution pattern was found between 5 and 30 Hz), fatigue during tetanus (found in 35% of both types of myotubes) and post-tetanic contracture. In contrast, contraction and relaxation times were longer (P < 0.005) in mdx (36 +/- 2 and 142 +/- 13 ms, respectively) than in control myotubes (26 +/- 1 and 85 +/- 9 ms, respectively). Together with our earlier findings, these results suggest a decreased capacity for calcium removal in mdx cells leading, in particular, to alterations of muscle relaxation.

Ecology of sandflies Diptera: Psychodidae) in a restricted focus of cutaneous leishmaniasis in Northern Venezuela: IV. Sandfly monthly fluctuation and leishmaniasis incidence relationship

An attempt has been made to correlate the monthly incidence of human leishmaniasis with the temporal distribution of sandfly species at San Esteban, Northern Venezuela. Upon statistical analysis, the seasonal fluctuation of L. ovallesi population correlated strongly with the human disease, while the dynamics of L. panamensis, generally believed to be the vector in the Central area of the country, showed only a very weak correlation. These findings support the hypothesis that L. panamensis might not be the main or unique species responsible for the transmission in this area and that L. ovallesi and additionally L. olmeca bicolor might be involved in the epidemiology of the disease.

Which screening strategy using BMD measurements would be most cost effective for hip fracture prevention in elderly women? A decision analysis based on a Markov model.

INTRODUCTION: Hip fractures are responsible for excessive mortality, decreasing the 5-year survival rate by about 20%. From an economic perspective, they represent a major source of expense, with direct costs in hospitalization, rehabilitation, and institutionalization. The incidence rate sharply increases after the age of 70, but it can be reduced in women aged 70-80 years by therapeutic interventions. Recent analyses suggest that the most efficient strategy is to implement such interventions in women at the age of 70 years. As several guidelines recommend bone mineral density (BMD) screening of postmenopausal women with clinical risk factors, our objective was to assess the cost-effectiveness of two screening strategies applied to elderly women aged 70 years and older. METHODS: A cost-effectiveness analysis was performed using decision-tree analysis and a Markov model. Two alternative strategies, one measuring BMD of all women, and one measuring BMD only of those having at least one risk factor, were compared with the reference strategy "no screening". Cost-effectiveness ratios were measured as cost per year gained without hip fracture. Most probabilities were based on data observed in EPIDOS, SEMOF and OFELY cohorts. RESULTS: In this model, which is mostly based on observed data, the strategy "screen all" was more cost effective than "screen women at risk." For one woman screened at the age of 70 and followed for 10 years, the incremental (additional) cost-effectiveness ratio of these two strategies compared with the reference was 4,235 euros and 8,290 euros, respectively. CONCLUSION: The results of this model, under the assumptions described in the paper, suggest that in women aged 70-80 years, screening all women with dual-energy X-ray absorptiometry (DXA) would be more effective than no screening or screening only women with at least one risk factor. Cost-effectiveness studies based on decision-analysis trees maybe useful tools for helping decision makers, and further models based on different assumptions should be performed to improve the level of evidence on cost-effectiveness ratios of the usual screening strategies for osteoporosis.

Reduced capacity of peritoneal exudate cells for oxidative killing of Schistosoma mansoni schistosomula

Peritoneal exudate cells from mice infected with Schistosoma mansoni (S-PEC) can kill schistosomula in vitro in the presence of immune serum. S-PEC produce a low level of respiratory burst, and schistosomula mortality in their presence is not reduced when exogenous antioxidants are added, suggesting that with S-PEC, oxidative killing is not important. Hydrogen peroxide (H2O2) and superoxide production by S-PEC, and cells from BCG and thioglycollate (THGL) injected non-infected mice, non-specifically stimulated with opsonized zymosan, were measured. Levels of H2O2 produced by S-PEC were significantly lower than BCG or THGL PEC, and were below the H2O2 threshold for schistosomula killing. This resulted in lower levels of cell-mediated killing of schistosomula in vitro by S-PEC than by BCG or THGL PEC. Superoxide levels, however, were similar between the three cell populations. The efficiency of PEC to kill schistosomules in vitro correlated with H2O2 rather than superoxide levels. The lower tolerance of schistosomula, compared to adult S. mansoni to GSH depleting agents increases their sensitivity to oxidative attack and resulted in higher levels of cell-mediated killing in vitro.

A contribution to the study of simulium and Culicoides of Rio de Janeiro: monthly incidence and biting activity

During March 1984 to February 1985, we captured simuliids and biting midges in the National Park of Tijuca, Rio de Janeiro. A study on monthly incidence and biting activity and their correlation to air temperature, relative humidity, and rainfall was made.

Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy

BACKGROUND: Vitamin D is an important immune modulator and preliminary data indicated an association between vitamin D deficiency and sustained virologic response (SVR) rates in patients with chronic hepatitis C. We therefore performed a comprehensive analysis on the impact of vitamin D serum levels and of genetic polymorphisms within the vitamin D cascade on chronic hepatitis C and its treatment. METHODS: Vitamin D serum levels, genetic polymorphisms within the vitamin D receptor and the 1α- hydroxylase were determined in a cohort of 468 HCV genotype 1, 2 and 3 infected patients who were treated with interferon-alfa based regimens. RESULTS: Chronic hepatitis C was associated with a high incidence of severe vitamin D deficiency compared to controls (25(OH)D3<10 ng/mL in 25% versus 12%, p<0.00001), which was in part reversible after HCV eradication. 25(OH)D3 deficiency correlated with SVR in HCV genotype 2 and 3 patients (63% and 83% SVR for patients with and without severe vitamin D deficiency, respectively, p<0.001). In addition, the CYPB27-1260 promoter polymorphism rs10877012 had substantial impact on 1-25- dihydroxyvitamin D serum levels and SVR rates in HCV genotype 1, 2 and 3 infected patients. CONCLUSIONS: Chronic hepatitis C virus infection is associated with vitamin D deficiency. Reduced 25- hydroxyvitamin D levels and CYPB27-1260 promoter polymorphism are associated with failure to achieve SVR in HCV genotype 1, 2, 3 infected patients.

Polysomy 8 defines a clinico-cytogenetic entity representing a subset of myeloid hematologic malignancies associated with a poor prognosis: report on a cohort of 12 patients and review of 105 published cases.

Tetrasomy, pentasomy, and hexasomy 8 (polysomy 8) are relatively rare compared to trisomy 8. Here we report on a series of 12 patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or myeloproliferative disorder (MPD) associated with polysomy 8 as detected by conventional cytogenetics and fluorescence in situ hybridization (FISH). In an attempt to better characterize the clinical and hematological profile of this cytogenetic entity, our data were combined with those of 105 published patients. Tetrasomy 8 was the most common presentation of polysomy 8. In 60.7% of patients, polysomy 8 occurred as part of complex changes (16.2% with 11q23 rearrangements). No cryptic MLL rearrangements were found in cases in which polysomy 8 was the only karyotypic change. Our study demonstrates the existence of a polysomy 8 syndrome, which represents a subtype of AML, MDS, and MPD characterized by a high incidence of secondary diseases, myelomonocytic or monocytic involvement in AML and poor overall survival (6 months). Age significantly reduced median survival, but associated cytogenetic abnormalities did not modify it. Cytogenetic results further demonstrate an in vitro preferential growth of the cells with a high level of aneuploidy suggesting a selective advantage for polysomy 8 cells.

A behavioral study of alpha-1b adrenergic receptor knockout mice: increased reaction to novelty and selectively reduced learning capacities.

Knockout mice lacking the alpha-1b adrenergic receptor were tested in behavioral experiments. Reaction to novelty was first assessed in a simple test in which the time taken by the knockout mice and their littermate controls to enter a second compartment was compared. Then the mice were tested in an open field to which unknown objects were subsequently added. Special novelty was introduced by moving one of the familiar objects to another location in the open field. Spatial behavior and memory were further studied in a homing board test, and in the water maze. The alpha-1b knockout mice showed an enhanced reactivity to new situations. They were faster to enter the new environment, covered longer paths in the open field, and spent more time exploring the new objects. They reacted like controls to modification inducing spatial novelty. In the homing board test, both the knockout mice and the control mice seemed to use a combination of distant visual and proximal olfactory cues, showing place preference only if the two types of cues were redundant. In the water maze the alpha-1b knockout mice were unable to learn the task, which was confirmed in a probe trial without platform. They were perfectly able, however, to escape in a visible platform procedure. These results confirm previous findings showing that the noradrenergic pathway is important for the modulation of behaviors such as reaction to novelty and exploration, and suggest that this is mediated, at least partly, through the alpha-1b adrenergic receptors. The lack of alpha-1b adrenergic receptors in spatial orientation does not seem important in cue-rich tasks but may interfere with orientation in situations providing distant cues only.

Mutations of the Serine Protease CAP1/Prss8 Lead to Reduced Embryonic Viability, Skin Defects, and Decreased ENaC Activity.

CAP1/Prss8 is a membrane-bound serine protease involved in the regulation of several different effectors, such as the epithelial sodium channel ENaC, the protease-activated receptor PAR2, the tight junction proteins, and the profilaggrin polypeptide. Recently, the V170D and the G54-P57 deletion mutations within the CAP1/Prss8 gene, identified in mouse frizzy (fr) and rat hairless (fr(CR)) animals, respectively, have been proposed to be responsible for their skin phenotypes. In the present study, we analyzed those mutations, revealing a change in the protein structure, a modification of the glycosylation state, and an overall reduction in the activation of ENaC of the two mutant proteins. In vivo analyses demonstrated that both fr and fr(CR) mutant animals present analogous reduction of embryonic viability, similar histologic aberrations at the level of the skin, and a significant decrease in the activity of ENaC in the distal colon compared with their control littermates. Hairless rats additionally had dehydration defects in skin and intestine and significant reduction in the body weight. In conclusion, we provided molecular and functional evidence that CAP1/Prss8 mutations are accountable for the defects in fr and fr(CR) animals, and we furthermore demonstrate a decreased function of the CAP1/Prss8 mutant proteins. Therefore, fr and fr(CR) animals are suitable models to investigate the consequences of CAP1/Prss8 action on its target proteins in the whole organism.

Ecologic correlations of selected food groups with disease incidence and mortality in Switzerland.

Background: There is little information regarding the impact of diet on disease incidence and mortality in Switzerland. We assessed ecologic correlations between food availability and disease.Methods: In this ecologic study for the period 1970-2009, food availability was measured using the food balance sheets of the Food and Agriculture Organization of the United Nations. Standardized mortality rates (SMRs) were obtained from the Swiss Federal Office of Statistics. Cancer incidence data were obtained from the World Health Organization Health For All database and the Vaud Cancer Registry. Associations between food availability and mortality/incidence were assessed at lags 0, 5, 10, and 15 years by multivariate regression adjusted for total caloric intake.Results: Alcoholic beverages and fruit availability were positively associated, and fish availability was inversely associated, with SMRs for cardiovascular diseases. Animal products, meat, and animal fats were positively associated with the SMR for ischemic heart disease only. For cancer, the results of analysis using SMRs and incidence rates were contradictory. Alcoholic beverages and fruits were positively associated with SMRs for all cancer but inversely associated with all-cancer incidence rates. Similar findings were obtained for all other foods except vegetables, which were weakly inversely associated with SMRs and incidence rates. Use of a 15-year lag reversed the associations with animal and vegetal products, weakened the association with alcohol and fruits, and strengthened the association with fish.Conclusions: Ecologic associations between food availability and disease vary considerably on the basis of whether mortality or incidence rates are used in the analysis. Great care is thus necessary when interpreting our results.

Treatment of essential hypertension with calcium channel blockers: what is the place of lercanidipine?

In all actual clinical guidelines, dihydropyridine calcium channel blockers (CCBs) belong to the recommended first line antihypertensive drugs to treat essential hypertension. Several recent large clinical trials have confirmed their efficacy not only in lowering blood pressure but also in reducing cardiovascular morbidity and mortality in hypertensive patients with a normal or high cardiovascular risk profile. In clinical trials such as ALLHAT, VALUE or ASCOT, an amlodipine-based therapy was at least as effective, when not slightly superior, in lowering blood pressure and sometimes more effective in preventing target organ damages than blood pressure lowering strategies based on the use of diuretics, beta-blockers and blockers of the renin-angiotensin system. One of the main clinical side effects of the first and second generation CCBs including amlodipine is the development of peripheral edema. The incidence of leg edema can be markedly reduced by combining the CCB with a blocker of the renin-angiotensin system. This strategy has now led to the development of several fixed-dose combinations of amlodipine and angiotensin II receptor antagonists. Another alternative to lower the incidence of edema is to use CCBs of the third generation such as lercanidipine. Indeed, although no major clinical trials have been conducted with this compound, clinical studies have shown that lercanidipine and amlodipine have a comparable antihypertensive efficacy but with significantly less peripheral edema in patients receiving lercanidipine. In some countries, lercanidipine is now available in a single-pill association with an ACE inhibitor thereby further improving its efficacy and tolerability profile.

Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis.

BACKGROUND: A single infusion of intravenous zoledronic acid decreases bone turnover and improves bone density at 12 months in postmenopausal women with osteoporosis. We assessed the effects of annual infusions of zoledronic acid on fracture risk during a 3-year period. METHODS: In this double-blind, placebo-controlled trial, 3889 patients (mean age, 73 years) were randomly assigned to receive a single 15-minute infusion of zoledronic acid (5 mg) and 3876 were assigned to receive placebo at baseline, at 12 months, and at 24 months; the patients were followed until 36 months. Primary end points were new vertebral fracture (in patients not taking concomitant osteoporosis medications) and hip fracture (in all patients). Secondary end points included bone mineral density, bone turnover markers, and safety outcomes. RESULTS: Treatment with zoledronic acid reduced the risk of morphometric vertebral fracture by 70% during a 3-year period, as compared with placebo (3.3% in the zoledronic-acid group vs. 10.9% in the placebo group; relative risk, 0.30; 95% confidence interval [CI], 0.24 to 0.38) and reduced the risk of hip fracture by 41% (1.4% in the zoledronic-acid group vs. 2.5% in the placebo group; hazard ratio, 0.59; 95% CI, 0.42 to 0.83). Nonvertebral fractures, clinical fractures, and clinical vertebral fractures were reduced by 25%, 33%, and 77%, respectively (P<0.001 for all comparisons). Zoledronic acid was also associated with a significant improvement in bone mineral density and bone metabolism markers. Adverse events, including change in renal function, were similar in the two study groups. However, serious atrial fibrillation occurred more frequently in the zoledronic acid group (in 50 vs. 20 patients, P<0.001). CONCLUSIONS: A once-yearly infusion of zoledronic acid during a 3-year period significantly reduced the risk of vertebral, hip, and other fractures. (ClinicalTrials.gov number, NCT00049829.)