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Interaction of ascorbate and alpha-tocopherol enhances antioxidant reserve of erythrocytes during anemia in visceral leishmaniasis.

Visceral leishmaniasis (V.L.) is associated with enhanced lipid peroxidation along with impaired function of antioxidant defense system in erythrocytes. The effect of chronic treatment with ascorbate and alpha-tocopherol was studied on erythrocytes in hamsters infected with Leishmania donovani. Combination treatment with both antioxidants proved to be a potential suppressor of lipid hydroperoxide formation as well as hypotonic osmotic lysis during the leishmanial infection. Positive correlations between the depleted levels of erythrocyte ascorbate, GSH and alpha-tocopherol exhibit proportionate alterations in the nonenzymatic antioxidant levels at different stages of infection. Indirect measurement of transmembrane electron transfer as ferricyanide reduction suggests an active participation of endogenous contents of ascorbate and alpha-tocopherol in the protection against oxidative damage of membrane lipids. Cooperative behavior of both antioxidants in the ferricyanide reducing capacity was further evinced by resealing the ghosts in presence of exogenous ascorbate and alpha-tocopherol. Furthermore, intravesicular ascorbate serves in the defense of extravesicular ferricyanide induced oxidation of endogenous alpha-tocopherol. The results suggest an interacting role of ascorbate and alpha-tocopherol in maintaining the antioxidant reserve of erythrocytes during anemia in V.L.

Anemia↗

IgG subclass responses in a longitudinal study of canine visceral leishmaniasis.

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.

Animals↗

[Treatment of infantile visceral leishmaniasis].

Visceral leishmaniasis is an endemic disease in the Mediterranean Basin. Children are one of the targets of the infection. Treatment usually requires parenteral injections of pentavalent antimony (Glucantime or Pentostam), but the high frequency of adverse events and the occurrence of primary or secondary resistance cases limit the use of these medications. Diamidines (Pentacarinat) or amphotericin B derivatives are alternatives to antimony. Unfortunately, pharmacokinetics and optimal dosage of diamidines are not well-known, and numerous adverse events are described. Liposomal preparations of amphotericin B enhance its efficiency and tolerance, and the duration of treatment may be reduced to 5 days. Moreover, primary resistance to amphotericin B is not described in immunocompetent children. Allopurinol associated with antimony seems no more efficient than antimony alone. Aminosidine is not evaluated.

Amphotericin B↗

The first probable case of platelet transfusion-transmitted visceral leishmaniasis.

Visceral leishmaniasis (VL; kala-azar), a life-threatening infection of the mononuclear phagocytic system, is transmitted by the bite of infected sand flies. Though peripheral parasitaemia is documented for Leishmania spp. causing VL, reports of transfusion-transmitted infections are rare. A case of probable platelet transfusion-acquired VL is reported from India and issues related to transfusion safety in endemic areas are discussed.

Animals↗

Serum soluble markers in the evaluation of treatment in human visceral leishmaniasis.

Visceral leishmaniasis (VL) has a fatal course if not properly treated. Recovery from VL is linked to cellular immune response. Unresponsiveness to antimonial therapy reinforces the importance of determining parameters for treatment assessment. We analysed the pre- and post-treatment serum levels of soluble CD4 (sCD4), sCD8, sIL-2R, soluble intercellular adhesion molecule-1 (sICAM-1) and neopterin in groups of VL patients either responsive or not to standard antimonial therapy. Pretreatment serum levels of all markers except for sICAM-1 were significantly higher in VL patients than in healthy subjects from the same area (P < 0.05). sICAM-1 levels were similar in healthy controls and in VL patients refractory to antimonial therapy (P = 0.25), but significantly higher in patients responsive to treatment (P = 0.02). The comparison of pre- and post-treatment concentrations showed that all markers, except sCD4 and sICAM-1, presented a significant fall (P < 0.05) in patients responsive to antimonial therapy. However, only neopterin presented with levels compatible with those of healthy subjects at the end of treatment (P = 0.30). In refractory patients sICAM-1 presented with post-treatment levels significantly higher than the pretreatment determinations (P = 0.03), while sCD4 experienced a significant drop (P = 0.01). All markers displayed clearly distinct behaviour according to the patient's response to therapy. This makes all soluble molecules studied suitable for use as indicators of antimonial therapy response. Additionally the comparison of pretreatment levels of the markers between responders and refractory patients to antimonial therapy showed that serum concentrations of sIL-2R and sICAM-1 significantly differed among these two groups (P = 0.02 in each case), suggesting that they may be used in future as predictors of antimonial therapy response.

Antimony↗

Household structure and urban services: neglected targets in the control of visceral leishmaniasis.

Visceral leishmaniasis (VL) caused by Leishmania chagasi is a growing public-health problem in many parts of the New World. Although several studies have focused on the consequences of environmental damage, human migration and land occupation on the incidence of VL, the effects on the disease of the substandard living conditions that often result from the process of urbanization have not been investigated in detail. The present study was based in the Brazilian city of Teresina, where, since 1980, there have been two large outbreaks of VL (one in 1981-1985 and the other in 1993-1996), each involving at least 1000 newly reported cases. The role of household structure and the provision of urban services in the city, as predictors of the occurrence of VL, was studied in a case-control investigation. After controlling for age, crowding, and the background incidence of VL in the area where the subjects lived, the risk of acquiring the disease was found to be significantly higher for those who lived in houses with an inadequate sewage system and those who had no regular rubbish collection. Improving household structure and providing basic urban services might be effective strategies for controlling the spread of VL in urban areas.

Animals↗

Recent understanding in the treatment of visceral leishmaniasis.

Visceral leishmaniasis (VL) is a severe disease associated with infection of the reticuloendothelial system by Leishmania species. The infection is acquired through sandfly bites. Recent large scale epidemics of VL in east Africa and India and the emergence of a HIV epidemic make VL a priority for the World Health Organization. Pentavalent antimonials have been cornerstone of treatment for the last six decades. The appearance of antimonial-resistance and the development of lipid formulations of amphotericin B have changed the pattern of VL treatment. Within the past five years, miltefosine has been demonstrated as the first effective and safe oral treatment against VL. The price of miltefosine is yet to be determined. However, miltefosine will certainly be cheaper than lipid formulations of amphotericin B, which are beyond the financial capacity of the poor countries. Because it can be administered orally, miltefosine is suited for the treatment of large number of patients who get affected during epidemics, particularly in regions where the parasites are resistant to the currently used agents. Here, we recommend different treatment schedules according to the resistance pattern and the region-specific socio-economical and cultural factors.

AIDS-Related Opportunistic Infections↗

Anti-leishmanial IgE antibodies: a marker of active disease in visceral leishmaniasis.

Visceral leishmaniasis (VL) is characterized by a depression of the T helper cell type 1 immune response. Although mRNA expression for interleukin-4 (IL-4) is observed, evidence of the role of this cytokine in the pathogenesis of VL has been lacking. Since IL-4 is involved in IgE synthesis, we measured the total IgE and Leishmania antigen-specific IgE antibody levels in sera from patients with VL. Specific IgE antibodies detected by an ELISA technique after absorbing the sera with purified sheep IgG anti-human IgG were found in all 23 patients with VL and were not detected in subjects with subclinical Leishmania chagasi infection (n = 10), Chagas' disease (n = 10), atopic patients (n = 10), and healthy controls (n = 10). Levels of Leishmania-specific IgE (optical density values) before and after treatment were 0.100 +/- 0.03 (mean +/- SD) and 0.028 +/- 0.002, respectively (P < 0.05). These results indicate that a specific IgE response is useful in the diagnosis of active disease and to evaluate response to treatment.

Acute Disease↗

[Effect of heliogeophysical factors on epizootic activity of a native focus of visceral leishmaniasis].

Visceral leishmaniasis (VL) morbidity in the population of the south-eastern Turkmenistan and the epizootic activity of a natural focus were studied. A definite cyclic recurrence of the processes occurring in the natural focus of VL, which was associated with solar activity changes was found. The regularities found make it possible to predict the increase in the epizootic tension of a natural focus of VL in this region and the incidence of this disease among the population in 2002-2004.

Disease Reservoirs↗

[Childhood Mediterranean visceral leishmaniasis].

Visceral leishmaniasis (VL) is endemic in areas bordering the Mediterranean Sea (Spain, Italy, France, Greece, Morocco, Tunisia) where it is caused by Leishmania infantum and it is transmitted by the bite of hematophagous sandfly belonging to Phlebotomus spp.; dog constitutes the main reservoir of the infection. In comparison with the past, when VL was typically observed more frequently in children, the current ratio of childhood to adult cases is approximately 1:1. The onset of the disease is characterized by a non-specific initial symptomatology; fever, pallor and splenomegaly are always present. Pancytopenia is present very often; the laboratory diagnosis is established by serological tests (indirect fluorescent-antibody assay, immunoassay test, indirect hemagglutination assay) and by demonstration of Leishmania parasites by microscopy, culture or polymerase chain reaction (PCR) in the bone marrow aspirates. The use of PCR performed on peripheral blood has been reported to be highly sensitive for the diagnosis and the follow up of children with VL. Pentavalent antimonial drugs have been used for many decades as standard treatment for VL; in Italy liposomal amphotericin B (AmBisome) is nowadays considered the first-line treatment for VL.

Humans↗

Haematological profile of childhood visceral leishmaniasis.

Visceral leishmaniasis is the most severe form of the disease affecting children. Definite diagnosis relies on the demonstration of the parasite in various tissues. Bone marrow examination is a well accepted method, but has sensitivity between 60-85%. In the present study we analyzed other associated bone marrow features in 28 cases of pediatric leishmaniasis, which would help raise the suspicion level and thus bring about more positive results. Pancytopenia was observed in 54% cases and bicytopenias in another 20.5% cases. Peripheral absolute lymphocyte count did not increase in any case. Increase in plasma cells (mean 6.7%) and increase of phagocytic cells (28.5%) with haemophagocytosis (21.43%) was observed frequently in the bone marrow.

Animals↗

Childhood visceral leishmaniasis.

Visceral leishmaniasis (VL) is caused by the protozoan parasite Leishmania donovani and transmitted by the bite of infected sandfly Phlebotomus argentipes. Nearly half of the VL cases occur in children (childhood or paediatric VL). The clinical manifestations of childhood VL are more or less same as in the adults. Prolonged fever with anorexia and loss of appetite are the major presenting features. Marked enlargement of the spleen and liver (spleen larger than liver) with moderate to severe anaemia and changes in hair take place. Bacterial infection is a common coinfection and intestinal parasitic infestations are very common in children with VL. Liver function tests, blood, urine and stool may show abnormalities. Confirmation of diagnosis is made by demonstration of parasite by microscopic examination and culture of materials obtained by bone marrow aspiration or splenic puncture. Sodium antimony gluconate (stibogluconate) has been the drug of choice for over past 50 yr. Pentamidine isothionate, though effective is relatively toxic. Amphotericin B is the most effective drug for the treatment of VL. Miltefosine is the first-ever oral drug, is highly effective. Post kala-azar dermal leishmaniasis (PKDL) in children poses a therapeutic challenge. In the absence of an ideal vaccine for VL, control measures would essentially include prevention of transmission through vector control and community awareness.

Administration, Oral↗

[Quality control of the micro-ELISA technic applied to the diagnosis of human and canine visceral leishmaniasis].

Visceral leishmaniasis (VL) or kala-azar is, in Portugal, a zoonosis with the dog as reservoir. A quality control of the technique of micro-ELISA was carried out, using as reference the technique of IFI, the most commonly used for the diagnosis of this protozoosis, both for human and canine sera. Three different methods were used to estimate the cut-off point: X + 2sd (average for negative sera plus two standard deviation), P/N and J index. As quality parameteres were used sensitivity, specificity, efficacy and positive predictive value. The cut-off point for human sera was established at 0.100 A, with 100% sensitivity, 90.5% specificity, 95.3% efficacy and 91.4% positive predictive value, and for canine sera in 0.200 A, with 80.0% sensitivity, 94.3% specificity, 87.7% efficacy and 96.6% positive predictive value. Reproducibility was not fully satisfactory and two different ways of improving it are proposed: P/N and a correction factor. A statistically significant correlation was observed between micro-ELISA's absorbances and IFI titres regarding human sera, though it was not possible to do the same for dog sera.

Animals↗

[Liver involvement during visceral leishmaniasis].

Visceral leishmaniasis is a life-threatening infection due to Leishmania parasites that has been reported in 62 countries. The Mediterranean area is endemic for Leishmania infantum and cases have been reported in Spain, France, Italy and Portugal. During the infection, parasites disseminate in the phagocyte cells of bone marrow, the spleen, liver and lymph nodes. In this paper, we review the clinical and biological signs observed in visceral cases of leishmaniasis with hepatic involvement. We also focus on experimental and pathophysiological data to clarify our understanding of liver involvement during this infection.

Antiprotozoal Agents↗

Splenic granulomatous lesions in immunocompetent pediatric patients with visceral leishmaniasis.

Visceral focal lesions are rarely encountered in patients with leishmaniasis despite the fact that splenomegaly, and to a lesser extent hepatomegaly, predominate among the clinical features of the disease. We present, using high resolution ultrasonography, the first 3 reported cases of focal splenic involvement in immunocompetent children with visceral leishmaniasis. All patients showed a prompt response to the conventional anti-leishmanial treatment administered. This favorable outcome indicates that localized splenic lesions should not be considered as a poor prognostic factor and that alteration of the standard anti-leishmanial regimens is not justified.

Antiprotozoal Agents↗

Animal models for vaccine studies for visceral leishmaniasis.

Visceral leishmaniases (VL) or kala-azar is the most dreaded and devastating amongst the various forms of leishmaniases. The disease, though localized in certain areas only, has gained immense importance because of high mortality rate, mainly in children. The parasite is responsible for a spectrum of clinical syndromes, which can, in most extreme cases, go from an asymptomatic infection to a fatal form of VL. Chemotherapeutic measures, alone are not sufficient to control and contain the disease. As an alternate strategy, vaccination is also under experimental and clinical trails. The situation unquestionably demands the use of proper screening system, rationale chemical synthesis, vaccine development and targeted vaccine delivery. Thus, development of an acceptable vaccine is not an easy task. While the factors, which determine clinical outcomes, are in part, a feature of the parasite, it is the nature of the host and its genetic make up and immune status that play crucial role. The prerequisite of reliable animal model is that it should have a considerably good correlation with the clinical situation and is expected to mimic the pathological features and immunological responses observed in humans when exposed to a variety of Leishmania spp. with different pathogenic characteristics. Many experimental animal models like rodents, dogs and monkeys have been developed, each with specific features, but none accurately reproduces what happens in humans. In addition to the nature of the host, the major difference between natural and experimental infections is the parasite inoculum; in natural conditions, the infected sand fly vector deposits a few hundred metacyclic promastigotes into the dermis of the host, whereas experimental infections are induced by the injection (subcutaneous or intravenous) of millions of promastigotes grown in axenic cultures in vitro or amastigotes recovered from infected spleens. In public health terms, VL is the disease of humans and dogs (which may be considered secondary or 'accidental' hosts in the leishmanial life cycle) who often exhibit severe clinical signs and symptoms when infected, whereas reservoir hosts generally show a few, minor or no signs. This situation makes the definition of a suitable laboratory model a difficult one since the various experimental hosts may behave either like a reservoir or an accidental host. This review discusses the concept of animal models for VL and provides a critical evaluation of the most common experimental models and their respective advantages and disadvantages. Particular emphasis is given to the value of using mouse, hamster, dog and primate models, especially in the context of testing potential antileishmanial vaccines.

Animals↗

[Lutzomyia longipalpis and Leishmaniasis visceral in Argentina].

Lutzomyia longipalpis is reported for the second time after 50 years in Misiones Province, Argentina. This insect is the vector of Leishmania (L.) chagasi, visceral leishmaniasis' parasite. The literature concerning the 16 visceral leishmaniasis cases in the country is reviewed. The cases were reported from Salta, Jujuy, Santiago del Estero and Chaco Provinces. Based on the clinical and entomo-epidemiological data two alternative hypotheses were evaluated: a) visceral leishmaniasis in Argentina is due to the visceralization of L. (V.) braziliensis or their variants, b) L (L.) chagasi remains in enzootic foci where the human contact is very unusual. Recommendations concerning the management of new cases have been made in order to confirm either one or both hypotheses. In consequence, the appropriate diagnosis and therapy could be arrived at according to the parasite actual identity, and the risk of outbreaks and mitigation measures could be estimated.

Adult↗

Efficacies of KY62 against Leishmania amazonensis and Leishmania donovani in experimental murine cutaneous leishmaniasis and visceral leishmaniasis.

Current therapy for leishmaniasis is unsatisfactory because parenteral antimonial salts and pentamidine are associated with significant toxicity and failure rates. We examined the efficacy of KY62, a new, water-soluble, polyene antifungal, against cutaneous infection with Leishmania amazonensis and against visceral infection with Leishmania donovani in susceptible BALB/c mice. Mice were infected with L. amazonensis promastigotes in the ear pinna and in the tail and were treated with KY62 or amphotericin B. The cutaneous lesions showed a remarkable response to therapy with KY62 at a dose of 30 mg per kg of body weight per day. At this dose, the efficacy of KY62 was equivalent to or better than that of amphotericin B at 1 to 5 mg/kg/day. Mice infected intravenously with 10(7) L. donovani promastigotes and treated with KY62 showed a 4-log reduction in the parasite burden in the liver and spleen compared to untreated mice. These studies indicate potent activity of KY62 against experimental cutaneous leishmaniasis caused by L. amazoniensis and against experimental visceral leishmaniasis caused by L. donovani.

Amphotericin B↗