Malaria in humait a county, state of Amazonas, Brazil. XIX - evaluation of clindamycin for the treatment of patients with Plasmodium falciparum infection

A total of 207 patients with malaria caused by Plasmodium falciparum were submitted to 5 different treatment schedules with clindamycin from 1981 to 1984: A - 89 patients were treated intravenously and orally, or intramuscularly and orally with 20 mg/kg/day divided into two daily applications for 5 to 7 days; B-40 patients were treated orally with 20 mg/kg/day divided into two daily doses for 5 to 7 days; C-27 patients were treated with 20 mg/kg/day intravenously or orally divided into two daily applications for 3 days; D-16 patients were treated orally and/or intravenously with a single daily dose of 20 to 40 mg/kg/day for 5 to 7 days; E-35 patients were treated orally with 5 mg/kg/day divided into two doses for 5 days. Patients were examined daily during treatment and reexamined on the 7th, 24th, 21st, 28th and 35th day both clinically and parasitologically (blood test). Eighty three (40.1%) had moderate or severe malaria, and 97 (46.8%) had shown resistance to chloroquine or to the combination ofsulfadoxin and pyrimethamine. The proportion of cured patients was higher than 95% among patients submitted to schedules A and B. Side effects were only occasional and of low intensity. Three deaths occurred (1.4%), two of them involving patients whose signs and symptoms were already very severe when treatment was started. Thus, clindamycin proved to be very useful in the treatment of patients with malaria caused by Plasmodium falciparum and we recommend schedule A for moderate and severe cases and Bfor initial cases.

Leishmanial antigens in the diagnosis of active lesions and ancient scars of American tegumentary leishmaniasis patients

Cutaneous biopsies (n = 94) obtained from 88 patients with American tegumentary leishmaniasis were studied by conventional and immunohistochemical techniques. Specimens were distributed as active lesions of cutaneous leishmaniasis (n = 53) (Group I), cicatricial lesions of cutaneous leishmaniasis (n = 35) (Group II) and suggestive scars of healed mucosal leishmaniasis patients (n = 6) (Group III). In addition, active cutaneous lesions of other etiology (n = 24) (Group C1) and cutaneous scars not related to leishmaniasis (n = 10) (Group C2) were also included in the protocol. Amastigotes in Group I biopsies were detected by routine histopathological exam (30.2%), imprint (28.2%), culture (43.4%), immunofluorescence (41.4%) and immunoperoxidase (58.5%) techniques; and by the five methods together (79.3%). In Group II, 5.7% of cultures were positive. Leishmanial antigen was also seen in the cytoplasm of macrophages and giant cells (cellular pattern), vessel walls (vascular pattern) and dermal nerves (neural pattern). Positive reaction was detected in 49 (92.5%), 20 (57%) and 4 (67%) biopsies of Groups I, II and III, respectively. Antigen persistency in cicatricial tissue may be related to immunoprotection or, on the contrary, to the development of late lesions. We suggest that the cellular, vascular and neural patterns could be applied in the immunodiagnosis of active and cicatricial lesions in which leishmaniasis is suspected.

Leishmanial antigens in the diagnosis of active lesions and ancient scars of American tegumentary leishmaniasis patients

Cutaneous biopsies (n = 94) obtained from 88 patients with American tegumentary leishmaniasis were studied by conventional and immunohistochemical techniques. Specimens were distributed as active lesions of cutaneous leishmaniasis (n = 53) (Group I), cicatricial lesions of cutaneous leishmaniasis (n = 35) (Group II) and suggestive scars of healed mucosal leishmaniasis patients (n = 6) (Group III). In addition, active cutaneous lesions of other etiology (n = 24) (Group C1) and cutaneous scars not related to leishmaniasis (n = 10) (Group C2) were also included in the protocol. Amastigotes in Group I biopsies were detected by routine histopathological exam (30.2%), imprint (28.2%), culture (43.4%), immunofluorescence (41.4%) and immunoperoxidase (58.5%) techniques; and by the five methods together (79.3%). In Group II, 5.7% of cultures were positive. Leishmanial antigen was also seen in the cytoplasm of macrophages and giant cells (cellular pattern), vessel walls (vascular pattern) and dermal nerves (neural pattern). Positive reaction was detected in 49 (92.5%), 20 (57%) and 4 (67%) biopsies of Groups I, II and III, respectively. Antigen persistency in cicatricial tissue may be related to immunoprotection or, on the contrary, to the development of late lesions. We suggest that the cellular, vascular and neural patterns could be applied in the immunodiagnosis of active and cicatricial lesions in which leishmaniasis is suspected.

Trypanosoma cruzi benznidazole susceptibility in vitro does not predict the therapeutic outcome of human Chagas disease

Therapeutic failure of benznidazole (BZ) is widely documented in Chagas disease and has been primarily associated with variations in the drug susceptibility of Trypanosoma cruzi strains. In humans, therapeutic success has been assessed by the negativation of anti-T. cruzi antibodies, a process that may take up to 10 years. A protocol for early screening of the drug resistance of infective strains would be valuable for orienting physicians towards alternative therapies, with a combination of existing drugs or new anti-T. cruzi agents. We developed a procedure that couples the isolation of parasites by haemoculture with quantification of BZ susceptibility in the resultant epimastigote forms. BZ activity was standardized with reference strains, which showed IC50 to BZ between 7.6-32 µM. The assay was then applied to isolates from seven chronic patients prior to administration of BZ therapy. The IC50 of the strains varied from 15.6 ± 3-51.4 ± 1 µM. Comparison of BZ susceptibility of the pre-treatment isolates of patients considered cured by several criteria and of non-cured patients indicates that the assay does not predict therapeutic outcome. A two-fold increase in BZ resistance in the post-treatment isolates of two patients was verified. Based on the profile of nine microsatellite loci, sub-population selection in non-cured patients was ruled out.

Local immunological factors associated with recurrence of mucosal leishmaniasis

Recurrence of mucosal leishmaniasis (ML) is frequent, but the causative mechanisms are unknown. Our aim was to compare cellular and cytokine patterns of lesions from ML that evolved to recurrence or cure in order to determine the risk factor associated with recurrence. Lesions were evaluated by immunohistochemistry before and after therapy, and patients were followed-up for five years. Higher levels of CD4(+) T and IFN-gamma-producing cells were detected in active lesions and decreased after therapy. Macrophages and IL-10 were markedly increased in cured patients. Conversely, CD8(+) T and NK cells were higher in relapsed than in cured cases. Notably, a decrease in these cells in addition to decreased IL-10 and IFN-gamma was also observed after therapy. These data suggest that exacerbated CD8(+) activity, in addition to a poor regulatory response, could underlie an unfavorable fate with regard to ML. These markers may be useful for predicting the prognosis of ML in lesion studies. (C) 2008 Elsevier Inc. All rights reserved.

Mucosal Leishmaniasis and Abnormalities on Computed Tomographic Scans of Paranasal Sinuses

Studies evaluating radiologic aspects, local complications, and structural alterations of the paranasal sinus in patients with mucosal leishmaniasis (ML) are lacking The aim of this study was to analyze alterations of the paranasal sinuses in patients with ML by using computed tomography (CT) scans This prospective study evaluated 26 patients in Brazil with ML Nom December 2008 through June 2009 All patients underwent CT scans of the paranasal sinuses Paranasal thickening was observed in 25 patients (96%) Nasal perforation was observed in 17 patients (65%) Those patients who received re-treatment showed more abnormalities on CT scan than cured patients (P < 0 05) Complications of ML are not limited to the nasal mucosa but extend to the paranasal sinuses. Mucosa! thickening. pacified air cells. bony remodeling, and bony thickening caused by inflammatory steals of the sinus cavity walls are CT findings suggestive of chronic sinusitis

Assessment of oltipraz in schistosomiasis mansoni clinical trial

Seventy three children (6-15 years) and 75 adults (18-47 years) with active schistosomiasis mansoni were treated with oltipraz. All cases had at least 100 eggs per gram of feces as determined by the Kato-Katz technique. Children and adults were divided in two groups receiving respectively 25 or 30 mg/kg, as a single oral dose. Clinical examination, laboratories tests (haemogram, urinalysis, hepatic and kidney functions tests, glycemia, cholesterol, triglicerides, lipoprotein — HLD and LDL) and ECG were performed before, 3 or 7 days and 1 month after treatment. Parasitological control with 3 daily coprological examinations, was done on the 1st, 3rd j 6th month after drug administration. Giddiness, somnolence, headache, nausea, vomiting and abdominal distress were the most frequent side effects. Pain in the finger tips that need further investigations also occurred. No significant alteration in complementary tests were observed, whereas eosinophilia 1 month after treatment was detected, probably indicating worm death. The cure rate in children was 81.8% and 74.2% with 25 and 30 mg/kg respectively, and in adults 75.0% and 81.2% of the patients. No statistical significant difference was observed between cure rate and side effects at different dosages employed, neither between adults nor children. In all groups the percentage of egg reduction in feces in the non cured patients was higher than 96.0%. Further investigation with this new compound is necessary to accomplish the real value of oltipraz in the schistosomiasis chemotherapy.

Efficacy of oxamniquine, praziquantel and a combination of both drugs in schistosomiasis mansoni in Brazil

A randomized clinical trial was carried out to compare the efficacy of a low-dosage combination of oxamniquine (7.5 mg/kg) plus praziquantel (20 mg/kg) against either agent, oxamniquine (15 mg/kg) or praziquantel (40 mg/kg) alone, in the treatment of schistosomiasis mansoni in the Brazilian north-east. The drugs were randomly administered per os to 91 patients. Six and twelve months after treatment 89% of those admitted to the trial were reexamined by Kato-Katz method (ten slides) and MIF technique (one gram of stool) The achieved cure rates, as defined by absence of S. mansoni eggs in the faeces of individual patients at all points during the parasitological follow-up, were 81.8%, 81.2% and 67.6% for praziquantel, oxamniquine and the combination respectively. The reduction of eggs excretion in non cured patients six months after therapy ranged from 93.8-96.8% with praziquantel, 32.5-97% with oxamniquine and 76.9-99.5% with the combination. It is concluded that, at the used dosages, the three therapeutical regimens give similar and satisfactory results in the treatment of uncomplicated S. mansoni infection in Brazil.

Does a spontaneous cure for chagas' disease exist?

Six Costa Rican Chagas' disease patients, with wellknown acute phase history and no specific treatment were examined in several occasions during 39, 24, 32, 16 and 14 years, respectively, from the onset. Nome of the patients presented heart abnormalities as revealed by the conventional EKG and ergometry, exceptfor one of them with an incomplete block of the right bundle branch. Also, no alterations of the oesophagus motility was detected manometrically except for another patient who presented a slight hypersensivity reaction to a pharmacological test (Mecholyl). Three out of six patients became serologically negative in 1981, remaining as such until 1986. Besides the conventional serology, the search of protective ("lytic") antibodies was also performed in 1985 and 1986, being completely negative in one of the "cured" patients and dubious in the other two. The hypothesis that these three patients had as spontaneous cure, based on the clinical, serological and parasitologica l findings is discussed.

Estimation of statistical cure from cancer using population-based data

Dissertação de mestrado em Estatística

Schistosomiasis mansoni: immunodiagnosis aspects and search for an immunological marker related to therapeutic efficacy

The recent findings on immunodiagnosis of schistosomiasis mansoni have shown that purified Schistosoma mansoni antigens do not provide maximum positivity. Therefore, the authors suggest the use of semi-purified antigens for diagnostic purposes. So far, no serological marker for cured patients as shown by negative stool examination was found. However, a tendency of IgG antibody titre decrease was observed, when egg antigen was used.

Strategies to promote translational research within the European Organisation for Research and Treatment of Cancer (EORTC) Head and Neck Cancer Group: a report from the Translational Research Subcommittee.

Head and neck squamous cell cancer (HNSCC) is the sixth leading cause of cancer-related deaths worldwide. These tumors are commonly diagnosed at advanced stages and mortality rates remain high. Even cured patients suffer the consequences of aggressive treatment that includes surgery, chemotherapy, and radiotherapy. In the past, in clinical trials, HNSCC was considered as a single disease entity. Advances in molecular biology with the development of genomic and proteomic approaches have demonstrated distinct prognostic HNSCC patient subsets beyond those defined by traditional clinical-pathological factors such as tumor subsite and stage [Cho W (ed). An Omics Perspective on Cancer Research. New York/Berlin: Springer 2010]. Validation of these biomarkers in large prospective clinical trials is required before their clinical implementation. To promote this research, the European Organisation for Research and Treatment of Cancer (EORTC) Head and Neck Cancer Program will develop the following strategies-(i) biobanking: prospective tissue collection from uniformly treated patients in the setting of clinical trials; (ii) a group of physicians, physician-scientists, and EORTC Headquarters staff devoted to patient-oriented head and neck cancer research; (iii) a collaboration between the basic scientists of the Translational Research Division interested in head and neck cancer research and the physicians of the Head and Neck Cancer Group; and (iv) funding through the EORTC Grant Program and the Network Core Institutions Consortium. In the present report, we summarize our strategic plans to promote head and neck cancer research within the EORTC framework.

Epidemiological and immunological aspects of human visceral leishmaniasis on Margarita Island, Venezuela

Sixty-five patients were diagnosed with visceral leishmaniasis (VL) on Margarita Island in the decade from 1990 to1999; 86.2% were <= 3 years old. All were leishmanin-negative at diagnosis. Evaluation of 23 cured patients in 1999 revealed that 22/23 had converted to leishmanin-positive; five had persisting antibodies to rK39 antigen, with no clinical evidence of disease. Leishmanin tests were positive in 20.2% of 1,643 healthy individuals from 417 households in endemic areas. Of the positive reactors, 39.8% were identified in 35 (8.4%) of the households, 15 of which had an antecedent case of VL, a serologically positive dog or both. Weak serological activity to rK39 antigen was detected in 3 of 488 human sera from the endemic areas. The presence of micro-foci of intense peri-urban transmission and the apparent absence of other Trypanosomatidae causing human disease offer a unique opportunity for the study of reservoirs, alternative vectors and evaluation of control measures on the Island.

Trypanosoma cruzi benznidazole susceptibility in vitro does not predict the therapeutic outcome of human Chagas disease

Therapeutic failure of benznidazole (BZ) is widely documented in Chagas disease and has been primarily associated with variations in the drug susceptibility of Trypanosoma cruzi strains. In humans, therapeutic success has been assessed by the negativation of anti-T. cruzi antibodies, a process that may take up to 10 years. A protocol for early screening of the drug resistance of infective strains would be valuable for orienting physicians towards alternative therapies, with a combination of existing drugs or new anti-T. cruzi agents. We developed a procedure that couples the isolation of parasites by haemoculture with quantification of BZ susceptibility in the resultant epimastigote forms. BZ activity was standardized with reference strains, which showed IC50 to BZ between 7.6-32 µM. The assay was then applied to isolates from seven chronic patients prior to administration of BZ therapy. The IC50 of the strains varied from 15.6 ± 3-51.4 ± 1 µM. Comparison of BZ susceptibility of the pre-treatment isolates of patients considered cured by several criteria and of non-cured patients indicates that the assay does not predict therapeutic outcome. A two-fold increase in BZ resistance in the post-treatment isolates of two patients was verified. Based on the profile of nine microsatellite loci, sub-population selection in non-cured patients was ruled out.

IFN-g in human Chagas' disease: protection or pathology?

An apparently paradoxical role for IFN-g in human Chagas' disease was observed when studying the pattern of cytokine production by peripheral blood mononuclear cells (PBMC) obtained from two groups of chagasic patients after specific stimulation with Trypanosoma cruzi-derived antigens. The groups studied were 1) patients treated with benznidazole during the acute phase of Trypanosoma cruzi infection and 2) chronically infected untreated patients. In the treated group, higher levels of IFN-g were produced by PBMC from individuals cured after treatment when compared to non-cured patients. In contrast, in the chronically infected group (not treated) higher levels of IFN-g were produced by PBMC from cardiac patients in comparison with asymptomatic (indeterminate) patients. This apparently paradoxical role for IFN-g in human Chagas' disease is discussed in terms of the possibility of a temporal difference in IFN-g production during the initial stages of the infection (acute phase) in the presence or absence of chemotherapy. The maintenance of an immune response with high levels of IFN-g production during the chronic phase of the infection may favor cure or influence the development of the cardiac form of the disease