Search

The leishmaniases comprise a complex of diseases characterized by clinical outcomes that range from self-limiting to chronic, and disfiguring and stigmatizing to life threatening. Diagnostic methods, treatments, and vector and reservoir control options exist, but deciding the most effective interventions requires a quantitative understanding of the population level infection and disease dynamics. The effectiveness of any set of interventions has to be determined within the context of operational conditions, including economic and political commitment. Mathematical models are the best available tools for studying quantitative systems crossing disciplinary spheres (biology, medicine, economics) within environmental and societal constraints. In 2005, the World Health Assembly and government health ministers of India, Nepal, and Bangladesh signed a Memorandum of Understanding to eliminate the life threatening form of leishmaniasis, visceral leishmaniasis (VL), on the Indian subcontinent by 2015 through a combination of early case detection, improved treatments, and vector control. The elimination target is <1 case/10,000 population at the district or subdistrict level compared to the current 20/10,000 in the regions of highest transmission. Towards this goal, this chapter focuses on mathematical models of VL, and the biology driving those models, to enable realistic predictions of the best combination of interventions. Several key issues will be discussed which have affected previous modelling of VL and the direction future modelling may take. Current understanding of the natural history of disease, immunity (and loss of immunity), and stages of infection and their durations are considered particularly for humans, and also for dogs. Asymptomatic and clinical infection are discussed in the context of their relative roles in Leishmania transmission, as well as key components of the parasite-sandfly-vector interaction and intervention strategies including diagnosis, treatment and vector control. Gaps in current biological knowledge and potential avenues to improve model structures and mathematical predictions are identified. Underpinning the marriage between biology and mathematical modelling, the content of this chapter represents the first step towards developing the next generation of models for VL. [ABSTRACT FROM AUTHOR]

Background. Pentavalent antimony is the agent recommended for treatment of cutaneous leishmaniasis (CL). Its use is problematic, because it is expensive and because of the potential for drug-associated adverse effects during a lengthy and painful treatment course. Methods. We tested the efficacy of thermotherapy for the treatment of CL due to Leishmania tropica in a randomized, controlled trial in Kabul, Afghanistan. We enrolled 401 patients with a single CL lesion and administered thermotherapy using radio-frequency waves (1 treatment of &ges; 1 consecutive application at 50°C for 30 s) or sodium stibogluconate (SSG), administered either intralesionally (a total of 5 injections of 2-5 mL every 5-7 days, depending on lesion size) or intramuscularly (20 mg/kg daily for 21 days). Results. Cure, defined as complete reepithelialization at 100 days after treatment initiation, was observed in 75 (69.4%) of 108 patients who received thermotherapy, 70 (75.3%) of 93 patients who received intralesional SSG, and 26 (44.8%) of 58 patients who received intramuscular SSG. The OR for cure with thermotherapy was 2.80 (95% confidence interval [I], 1.45-5.41), compared with intramuscular SSG treatment (P = .002). No statistically significant difference was observed in the odds of cure in comparison of intralesional SSG and thermotherapy treatments. The OR for cure with intralesional SSG treatment was 3.75 (95% CI, 1.86-7.54), compared with intramuscular SSG treatment (P < .001). The time to cure was significantly shorter in the thermotherapy group (median, 53 days) than in the intralesional SSG or intramuscularly SSG group (median, 75 days and >100 days, respectively; P = .003). Conclusions. Thermotherapy is an effective, comparatively well-tolerated, and rapid treatment for CL, and it should be considered as an alternative to antimony treatment. [ABSTRACT FROM AUTHOR]

The leishmaniases comprise a complex of diseases characterized by clinical outcomes that range from self-limiting to chronic, and disfiguring and stigmatizing to life threatening. Diagnostic methods, treatments, and vector and reservoir control options exist, but deciding the most effective interventions requires a quantitative understanding of the population level infection and disease dynamics. The effectiveness of any set of interventions has to be determined within the context of operational conditions, including economic and political commitment. Mathematical models are the best available tools for studying quantitative systems crossing disciplinary spheres (biology, medicine, economics) within environmental and societal constraints. In 2005, the World Health Assembly and government health ministers of India, Nepal, and Bangladesh signed a Memorandum of Understanding to eliminate the life threatening form of leishmaniasis, visceral leishmaniasis (VL), on the Indian subcontinent by 2015 through a combination of early case detection, improved treatments, and vector control. The elimination target is <1 case/10,000 population at the district or subdistrict level compared to the current 20/10,000 in the regions of highest transmission. Towards this goal, this chapter focuses on mathematical models of VL, and the biology driving those models, to enable realistic predictions of the best combination of interventions. Several key issues will be discussed which have affected previous modelling of VL and the direction future modelling may take. Current understanding of the natural history of disease, immunity (and loss of immunity), and stages of infection and their durations are considered particularly for humans, and also for dogs. Asymptomatic and clinical infection are discussed in the context of their relative roles in Leishmania transmission, as well as key components of the parasite-sandfly-vector interaction and intervention strategies including diagnosis, treatment and vector control. Gaps in current biological knowledge and potential avenues to improve model structures and mathematical predictions are identified. Underpinning the marriage between biology and mathematical modelling, the content of this chapter represents the first step towards developing the next generation of models for VL., (© 2016 Elsevier Ltd.. All rights reserved.)

The human genome encodes a gene for an enzymatically active chitinase (CHIT1) located in a single copy on Chromosome 1, which is highly expressed by activated macrophages and in other cells of the innate immune response. Several dysfunctional mutations are known in CHIT1, including a 24-bp duplication in Exon 10 causing catalytic deficiency. This duplication is a common variant conserved in many human populations, except in West and South Africans. Thus it has been proposed that human migration out of Africa and the consequent reduction of exposure to chitin from environmental factors may have enabled the conservation of dysfunctional mutations in human chitinases. Our data obtained from 85 indigenous Amerindians from Peru, representative of populations characterized by high prevalence of chitin-bearing enteroparasites and intense entomophagy, reveal a very high frequency of the 24-bp duplication (47.06%), and of other single nucleotide polymorphisms which are known to partially affect enzymatic activity (G102S: 42.7% and A442G/V: 25.5%). Our finding is in line with a founder effect, but appears to confute our previous hypothesis of a protective role against parasite infection and sustains the discussion on the redundancy of chitinolytic function., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Malignant hyperthermia (MH) is associated, in the majority of cases, with mutations in RYR1, the gene encoding the skeletal muscle ryanodine receptor. Our primary aim was to assess whether different RYR1 variants are associated with quantitative differences in MH phenotype., Methods: The degree of in vitro pharmacological muscle contracture response and the baseline serum creatine kinase (CK) concentration were used to generate a series of quantitative phenotypes for MH. We then undertook the most extensive RYR1 genotype-phenotype correlation in MH to date using 504 individuals from 204 MH families and 23 RYR1 variants. We also determined the association between a clinical phenotype and both the laboratory phenotype and RYR1 genotype., Results: We report a novel correlation between the degree of in vitro pharmacological muscle contracture responses and the onset time of the clinical MH response in index cases (P<0.05). There was also a significant correlation between baseline CK concentration and clinical onset time (P=0.039). The specific RYR1 variant was a significant determinant of the severity of each laboratory phenotype (P<0.0001)., Conclusions: The MH phenotype differs significantly with different RYR1 variants. Variants leading to more severe MH phenotype are distributed throughout the gene and tend to lie at relatively conserved sites in the protein. Differences in phenotype severity between RYR1 variants may explain the variability in clinical penetrance of MH during anaesthesia and why some variants have been associated with exercise-induced rhabdomyolysis and heat stroke. They may also inform a mutation screening strategy in cases of idiopathic hyperCKaemia.

Visceral leishmaniasis (VL), caused by Leishmania infantum, is an important disease of domestic dogs. Here, we present data on the IgG subclass antibody response to crude L. infantum antigen in a cohort of naturally infected Brazilian dogs. Specific IgG1-IgG4 responses could be detected in 98, 58, 70 and 82%, respectively of 57 dogs that were seropositive for specific IgG. Levels of all IgG subclasses were strongly inter-correlated. Levels of all IgG subclasses increased at the time of seroconversion, before reaching a plateau after several months. Levels of all IgG subclasses were higher in sick dogs than healthy dogs, and levels of all except IgG2 were higher in parasite-positive (by PCR) than parasite-negative dogs. However, levels of IgG2 relative to IgG1 were lower in sick or parasite-positive dogs compared to healthy or parasite-negative infected dogs. In contrast to previous studies, the results suggest that canine VL is associated with upregulation of specific antibody of all IgG subclasses, particularly IgG1, IgG3 and IgG4., (Copyright 2002 Elsevier Science B.V.)

To elucidate the local tissue cytokine response of dogs infected with Leishmania chagasi, cytokine mRNA levels were measured in bone marrow aspirates from 27 naturally infected dogs from Brazil and were compared with those from 5 uninfected control animals. Interferon-gamma mRNA accumulation was enhanced in infected dogs and was positively correlated with humoral (IgG1) but not with lymphoproliferative responses to Leishmania antigen in infected dogs. Increased accumulation of mRNA for interleukin (IL)-4, IL-10, and IL-18 was not observed in infected dogs, and mRNA for these cytokines did not correlate with antibody or proliferative responses. However, infected dogs with detectable IL-4 mRNA had significantly more severe symptoms. IL-13 mRNA was not detectable in either control or infected dogs. These data suggest that clinical symptoms are not due to a deficiency in interferon-gamma production. However, in contrast to its role in human visceral leishmaniasis, IL-10 may not play a key immunosuppressive role in dogs.