The combined effect of chemoprophylaxis with single dose rifampicin and immunoprophylaxis with BCG to prevent leprosy in contacts of newly diagnosed leprosy cases: A cluster randomized controlled trial (MALTALEP study)

Background: Despite almost 30 years of effective chemotherapy with MDT, the global new case detection rate of leprosy has remained quite constant over the past years. New tools and methodologies are necessary to interrupt the transmission of M. leprae. Single-dose rifampicin (SDR) has been shown to prevent 57% of incident cases of leprosy in the first two years, when given to contacts of newly diagnosed cases. Immunization of contacts with BCG has been less well documented, but appears to have a preventive effect lasting up to 9 years. However, one major disadvantage is the occurrence of excess cases within the first year after immunization. The objective of this study is to examine the effect of chemoprophylaxis with SDR and immunoprophylaxis with BCG on the clinical outcome as well as on host immune responses and gene expression profiles in contacts of newly diagnosed leprosy patients. We hypothesize that the effects of both interventions may be complementary, causing the combined preventive outcome to be significant and long-lasting.Methods/design: Through a cluster randomized controlled trial we compare immunization with BCG alone with BCG plus SDR in contacts of new leprosy cases. Contact groups of around 15 persons will be established for each of the 1300 leprosy patients included in the trial, resulting in approximately 20,000 contacts in total. BCG will be administered to the intervention group followed by SDR, 2 months later. The control group will receive BCG only. In total 10,000 contacts will be included in both intervention arms over a 2-year period. Follow-up will take place one year as well as two years after intake. The primary outcome is the occurrence of clinical leprosy within two years. Simultaneously with vaccination and SDR, blood samples for in vitro analyses will be obtained from 300 contacts participating in the trial to determine the effect of these chemo- and immunoprophylactic interventions on immune and genetic host parameters.Discussion: Combined chemoprophylaxis and immunoprophylaxis is potentially a very powerful and innovative tool aimed at contacts of leprosy patients that could reduce the transmission of M. leprae markedly. The trial intends to substantiate this potential preventive effect. Evaluation of immune and genetic biomarker profiles will allow identification of pathogenic versus (BCG-induced) protective host biomarkers and could lead to effective prophylactic interventions for leprosy using optimized tools for identification of individuals who are most at risk of developing disease.Trial registration: Netherlands Trial Register: NTR3087

Recent Food Shortage Is Associated with Leprosy Disease in Bangladesh: A Case-Control Study

Background: Leprosy is remaining prevalent in the poorest areas of the world. Intensive control programmes with multidrug therapy (MDT) reduced the number of registered cases in these areas, but transmission of Mycobacterium leprae continues in most endemic countries. Socio-economic circumstances are considered to be a major determinant, but uncertainty exists regarding the association between leprosy and poverty. We assessed the association between different socio-economic factors and the risk of acquiring clinical signs of leprosy. Methods and Findings: We performed a case-control study in two leprosy endemic districts in northwest Bangladesh. Using interviews with structured questionnaires we compared the socio-economic circumstances of recently diagnosed leprosy patients with a control population from a random cluster sample in the same area. Logistic regression was used to compare cases and controls for their wealth score as calculated with an asset index and other socio-economic factors. The study included 90 patients and 199 controls. A recent period of food shortage and not poverty per se was identified as the only socio-economic factor significantly associated with clinical manifestation of leprosy disease (OR 1.79 (1.06-3.02); p = 0.030). A decreasing trend in leprosy prevalence with an increasing socio-economic status as measured with an asset index is apparent, but not statistically significant (test for a trend: OR 0.85 (0.71-1.02); p = 0.083). Conclusions: Recent food shortage is an important poverty related predictor for the clinical manifestation of leprosy disease. Food shortage is seasonal and poverty related in northwest Bangladesh. Targeted nutritional support for high risk groups should be included in leprosy control programmes in endemic areas to reduce risk of disease

The spatial distribution of leprosy in four villages in Bangladesh: An observational study

BACKGROUND: There is a higher case-detection rate for leprosy among spatially proximate contacts such as household members and neighbors. Spatial information regarding the clustering of leprosy can be used to improve intervention strategies. Identifying high-risk areas within villages around known cases can be helpful in finding new cases. METHODS: Using geographic information systems, we created digital maps of four villages in a highly endemic area in northwest Bangladesh. The villages were surveyed three times over four years. The spatial pattern of the compounds--a small group of houses--was analyzed, and we looked for spatial clusters of leprosy cases. RESULTS: The four villages had a total population of 4,123. There were 14 previously treated patients and we identified 19 new leprosy patients during the observation period. However, we found no spatial clusters with a probability significantly different from the null hypothesis of random occurrence. CONCLUSION: Spatial analysis at the microlevel of villages in highly endemic areas does not appear to be useful for identifying clusters of patients. The search for clustering should be extended to a higher aggregation level, such as the subdistrict or regional level. Additionally, in highly endemic areas, it appears to be more effective to target complete villages for contact tracing, rather than narrowly defined contact groups such as households

Sodium Phenylbutyrate Controls Neuroinflammatory and Antioxidant Activities and Protects Dopaminergic Neurons in Mouse Models of Parkinson’s Disease

Neuroinflammation and oxidative stress underlie the pathogenesis of various neurodegenerative disorders. Here we demonstrate that sodium phenylbutyrate (NaPB), an FDA-approved therapy for reducing plasma ammonia and glutamine in urea cycle disorders, can suppress both proinflammatory molecules and reactive oxygen species (ROS) in activated glial cells. Interestingly, NaPB also decreased the level of cholesterol but involved only intermediates, not the end product of cholesterol biosynthesis pathway for these functions. While inhibitors of both geranylgeranyl transferase (GGTI) and farnesyl transferase (FTI) inhibited the activation of NF-κB, inhibitor of GGTI, but not FTI, suppressed the production of ROS. Accordingly, a dominant-negative mutant of p21rac, but not p21ras, attenuated the production of ROS from activated microglia. Inhibition of both p21ras and p21rac activation by NaPB in microglial cells suggests that NaPB exerts anti-inflammatory and antioxidative effects via inhibition of these small G proteins. Consistently, we found activation of both p21ras and p21rac in vivo in the substantia nigra of acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease. Oral administration of NaPB reduced nigral activation of p21ras and p21rac, protected nigral reduced glutathione, attenuated nigral activation of NF-κB, inhibited nigral expression of proinflammatory molecules, and suppressed nigral activation of glial cells. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions in MPTP-intoxicated mice. Consistently, FTI and GGTI also protected nigrostriata in MPTP-intoxicated mice. Furthermore, NaPB also halted the disease progression in a chronic MPTP mouse model. These results identify novel mode of action of NaPB and suggest that NaPB may be of therapeutic benefit for neurodegenerative disorders

Recent Food Shortage Is Associated with Leprosy Disease in Bangladesh: A Case-Control Study

Although intensive control programs reduced the prevalence of leprosy worldwide, new cases of this infectious disease are still detected in several of the poorest areas of the world. Therefore the disease is known as a disease of poverty. To be able to control the disease it is important to know which aspects of poverty play a role in transmission and acquiring clinical signs of disease. In this study socio-economic circumstances of recently diagnosed leprosy patients were compared with those of a control population in the poverty stricken northwest area of Bangladesh where leprosy is common. A recent period of food shortage was the only socio-economic factor that was found related to leprosy disease in this study and not poverty as such. Food shortage is seasonal and poverty related in northwest Bangladesh, while malnutrition is known to lower immunity and make people more vulnerable to infectious diseases. Therefore it was concluded that malnutrition as an aspect of poverty played an important role in the development of the clinical signs of leprosy. We therefore recommend that nutritional support for high risk groups should be included in leprosy control programmes to reduce risk of disease in areas where leprosy is common

The spatial distribution of leprosy cases during 15 years of a leprosy control program in Bangladesh: An observational study

BACKGROUND: An uneven spatial distribution of leprosy can be caused by the influence of geography on the distribution of risk factors over the area, or by population characteristics that are heterogeneously distributed over the area. We studied the distribution of leprosy cases detected by a control program to identify spatial and spatio-temporal patterns of occurrence and to search for environmental risk factors for leprosy. METHODS: The houses of 11,060 leprosy cases registered in the control area during a 15-year period (1989-2003) were traced back, added to a geographic database (GIS), and plotted on digital maps. We looked for clusters of cases in space and time. Furthermore, relationships with the proximity to geographic features, such as town center, roads, rivers, and clinics, were studied. RESULTS: Several spatio-temporal clusters were observed for voluntarily reported cases. The cases within and outside clusters did not differ in age at detection, percentage with multibacillary leprosy, or sex ratio. There was no indication of the spread from one point to other parts of the district, indicating a spatially stable endemic situation during the study period. The overall risk of leprosy in the district was not associated with roads, rivers, and leprosy clinics. The risk was highest within 1 kilometer of town centers and decreased with distance from town centers. CONCLUSION: The association of a risk of leprosy with the proximity to towns indicates that rural towns may play an important role in the epidemiology of leprosy in this district. Further research on the role of towns, particularly in rural areas, is warranted

Statins in Candidemia: clinical outcomes from a matched cohort study

<p>Abstract</p> <p>Background</p> <p>HMG CoA reductase inhibitors (statins) in patients with bacteremic sepsis have shown significant survival benefits in several studies. There is no data on the effect of statins in candidemic patients, however in-vitro models suggest that statins interfere with ergesterol formation in the wall of yeasts.</p> <p>Methods</p> <p>This retrospective matched- cohort study from 1/2003 to 12/2006 evaluated the effects of statins on patients with candidemia within intensive care units. Statin-users had candidemia as a cause of their systemic inflammatory response and were on statins throughout their antifungal therapy, while non-statin users were matched based on age +/- 5 years and co-morbid factors. Primary analysis was 30-day survival or discharge using bivariable comparisons. Multivariable comparisons were completed using conditional logistic regression. All variables with a p-value less than 0.10 in the bivariable comparisons were considered for inclusion in the conditional logistic model.</p> <p>Results</p> <p>There were 15 statin-users and 30 non-statin users that met inclusion criteria, all with similar demographics and co-morbid conditions except the statin group had more coronary artery disease (P < 0.01) and peripheral vascular disease (P = 0.03) and lower median APCAHE II scores (14.6 vs 17, p = 0.03). There were no differences in duration of candidemia, antifungal therapy or <it>Candida </it>species between the groups. Statins were associated with lower mortality on bivariable (OR 0.09, 95% CI 0.11-0.75, p = 0.03) and multivariable (OR 0.22, 95% CI 0.02-2.4, p = 0.21) analyses compared to controls; although, in the latter the protective effect lacked statistical signficance.</p> <p>Conclusion</p> <p>In our small, single-center matched-cohort study, statins may provide a survival benefit in candidemia, however further studies are warranted to validate and further explore this association.</p

Longitudinal assessment of anti-PGL-I serology in contacts of leprosy patients in Bangladesh

Background: Despite elimination efforts, the number of Mycobacterium leprae (M. leprae) infected individuals who develop leprosy, is still substantial. Solid evidence exists that individuals living in close proximity to patients are at increased risk to develop leprosy. Early diagnosis of leprosy in endemic areas requires field-friendly tests that identify individuals at risk of developing the disease before clinical manifestation. Such assays will simultaneously contribute to reduction of current diagnostic delay as well as transmission. Antibody (Ab) levels directed against the M.leprae-specific phenolic glycolipid I (PGL-I) represents a surrogate marker for bacterial load. However, it is insufficiently defined whether anti-PGL-I antibodies can be utilized as prognostic biomarkers for disease in contacts. Particularly, in Bangladesh, where paucibacillary (PB) patients form the majority of leprosy cases, anti-PGL-I serology is an inadequate method for leprosy screening in contacts as a directive for prophylactic treatment. Methods: Between 2002 and 2009, fingerstick blood from leprosy patients’ contacts without clinical signs of disease from a field-trial in Bangladesh was collected on filter paper at three time points covering six years of follow-up per person. Analysis of anti-PGL-I Ab levels for 25 contacts who developed leprosy during follow-up and 199 contacts who were not diagnosed with leprosy, was performed by ELISA after elution of bloodspots from filter paper. Results: Anti-PGL-I Ab levels at intake did not significantly differ between contacts who developed leprosy during the study and those who remained free of disease. Moreover, anti-PGL-I serology was not prognostic in this population as no significant correlation was identified between anti-PGL-I Ab levels at intake and the onset of leprosy. Conclusion: In this highly endemic population in Bangladesh, no association was observed between anti-PGL-I Ab levels and onset of disease, urging the need for an extended, more specific biomarker signature for early detection of leprosy in this area

The Ras Antagonist, Farnesylthiosalicylic Acid (FTS), Decreases Fibrosis and Improves Muscle Strength in dy2J/dy2J Mouse Model of Muscular Dystrophy

The Ras superfamily of guanosine-triphosphate (GTP)-binding proteins regulates a diverse spectrum of intracellular processes involved in inflammation and fibrosis. Farnesythiosalicylic acid (FTS) is a unique and potent Ras inhibitor which decreased inflammation and fibrosis in experimentally induced liver cirrhosis and ameliorated inflammatory processes in systemic lupus erythematosus, neuritis and nephritis animal models. FTS effect on Ras expression and activity, muscle strength and fibrosis was evaluated in the dy2J/dy2J mouse model of merosin deficient congenital muscular dystrophy. The dy2J/dy2J mice had significantly increased RAS expression and activity compared with the wild type mice. FTS treatment significantly decreased RAS expression and activity. In addition, phosphorylation of ERK, a Ras downstream protein, was significantly decreased following FTS treatment in the dy2J/dy2J mice. Clinically, FTS treated mice showed significant improvement in hind limb muscle strength measured by electronic grip strength meter. Significant reduction of fibrosis was demonstrated in the treated group by quantitative Sirius Red staining and lower muscle collagen content. FTS effect was associated with significantly inhibition of both MMP-2 and MMP-9 activities. We conclude that active RAS inhibition by FTS was associated with attenuated fibrosis and improved muscle strength in the dy2J/dy2J mouse model of congenital muscular dystrophy