RESUMO
Earlier experiments in Trypanosoma cruzi-infected rats showed that recombinant rat (Rr) interferon (IFN)-gamma given shortly after infection ameliorated acute disease without modifying the serum titers of endogenously synthesized IFN-gamma and tumor necrosis factor. To gain some insight into the processes underlying this protective effect, 21-day old 'I' rats that were infected with T. cruzi and the following day started with a 20-day cycle of RrIFN-gamma injections (20000 IU/rat/day) were investigated for the in vitro replication of T. cruzi and nitric oxide (NO) production by peritoneal macrophages (day 7 post-infection, pi), antibodies with lytic activity against T. cruzi (days 7, 20, and 28 pi), and serum levels of biologically active interleukin (IL)-6 (days 15 and 30 pi). Therapy with RrIFN-gamma rendered cultured peritoneal macrophages less permissive to infection with T. cruzi. Such an effect was not accompanied by higher amounts of NO in macrophage cultured supernatants, compared with those from T. cruzi-infected rats receiving no RrIFN-gamma, which appeared not to be protected from in vitro infection. Acutely T. cruzi-infected rats had significant amounts of IL-6 in their sera - this not being the case in infected rats given RrIFN-gamma, whose levels appeared decreased as in control rats. The presence of complement-mediated anti-T. cruzi lytic antibodies was not modified by RrIFN-gamma. Likewise, heart histology at day 7 pi revealed that treatment with RrIFN-gamma made no differences as to the amount of acute inflammation, but tended to reduce the myocardial parasite load.
Assuntos
Anticorpos Antiprotozoários/sangue , Doença de Chagas/imunologia , Interleucina-6/sangue , Macrófagos/imunologia , Miocárdio/patologia , Trypanosoma cruzi , Doença Aguda , Animais , Doença de Chagas/patologia , Interferon gama/uso terapêutico , Ativação de Macrófagos , Masculino , Ratos , Proteínas RecombinantesRESUMO
We investigated whether administration of interferon-gamma (IFN-gamma) to pregnant rats, infected or not with Trypanosoma cruzi, was likely to protect their offspring from trypanosomal infection. Upon mating with syngeneic sires, four groups of 70-day-old female 1 rats were subjected to one of the following procedures: treatment with recombinant rat (Rr)IFN-gamma 50,000 IU/rat five times/week for three weeks; infection with 1 x 10(6) trypomastigotes of T. cruzi at 7, 14, and 21 days after mating plus IFN-gamma treatment as given to the former group; the same protocol but IFN-gamma injections being replaced by injection with physiologic saline. Offspring were nursed by their mothers until weaning and then infected with a similar dose of T. cruzi. Pregnant rats showed no exacerbated infection but a self-resolving mild disease, regardless of whether or not they had received IFN-gamma. Maternal infection with T. cruzi and/or IFN-gamma treatment did not affect gestational outcome. Offspring born to both groups of IFN-gamma-treated mothers were almost fully protected from acute infection, and showed higher levels of anti-T. cruzi IgG antibodies when compared with young born to their respective IFN-gamma-untreated mothers. Measurements of IFN-gamma serum activities indicated that ameliorated acute disease in offspring whose mothers were given IFN-gamma during gestation, was not associated with increased levels of endogenously produced IFN-gamma.
Assuntos
Animais Recém-Nascidos/parasitologia , Doença de Chagas/prevenção & controle , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Interferon gama/administração & dosagem , Complicações Parasitárias na Gravidez/prevenção & controle , Animais , Animais Recém-Nascidos/sangue , Animais Recém-Nascidos/imunologia , Anticorpos Antiprotozoários/sangue , Doença de Chagas/transmissão , Modelos Animais de Doenças , Feminino , Interferon gama/sangue , Masculino , Parasitemia/epidemiologia , Gravidez , Ratos , Trypanosoma cruzi/imunologiaRESUMO
To assess the function of the autonomic nervous system in major depression, a series of cardiovascular tests, together with the recording of sympathetic skin response, were performed in 18 depressed patients (melancholic type, DSM-III-R criteria) and in 18 healthy control subjects. Depressed patients showed significantly poorer performance in Valsalva's, deep breathing, and lying to standing manoeuvres than controls, indicating an impairment of parasympathetic function. Depressed patients developed a significantly larger sympathetic skin response than controls during the lying to standing and hand grip manoeuvres, whereas cardiovascular sympathetic performance (as assessed by the responses to hand grip, cold, mental arithmetic, explosive sound, or hyperventilation) was similar in both groups. The results are compatible with the view that a diminished parasympathetic reactivity, and presumably an increased sympathetic reactivity, occur in patients with major depression.
Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Transtorno Depressivo/fisiopatologia , Resposta Galvânica da Pele/fisiologia , Adulto , Sistema Cardiovascular/fisiopatologia , Feminino , Testes de Função Cardíaca , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
In the last decades several authors have observed a frequent association between diabetes mellitus and porphyria, mainly porphyria cutanea tarda. In previous studies, it has been demonstrated that both d delta d-aminolevulic acid dehydratase (ALA-D) and porphobilinogen deaminase (PBG-D), enzymes of the heme pathway, are inhibited by high concentrations of glucose in vitro in crude preparations of erythrocytes. The activity of these same enzymes was diminished in different tissues obtained from streptozotocin induced diabetic mice. Therefore, we decided to investigate the incidence of heme metabolism alterations in diabetes mellitus in a population of 100 non selected adult patients. The activities of erythrocytic ALA-D and PBG-D were measured. Rhodanese, an enzyme of the sulfocompounds pathway closely related to the regulation of heme biosynthesis, was also studied. Urine porphyrin content as well as the chromatographic pattern of esterified porphyrins were determined. ALA-D and PBG-D activities were diminished in diabetic patients (40% and 20% respectively), while rhodanese was only slightly increased (Fig. 1). ALA-D activity was subnormal in a 92% of the complete diabetic population, while PBG-D activity was less than normal in a 79% of the same population. No significative differences between enzymic activities were observed in the groups insulin and non-insulin dependent (Fig. 3). Urine porphyrin content was increased in 5% of the diabetic population. Chromatographic pattern of urinary porphyrins was notably altered in diabetic patients irrespectively of their porphyrin content (Fig. 4), suggesting an alteration in the enzyme uroporphyrinogen decarboxylase resembling the primary enzymic defect observed in porphyria cutanea tarda.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Diabetes Mellitus/metabolismo , Heme/metabolismo , Adulto , Glicemia/análise , Complicações do Diabetes , Diabetes Mellitus/enzimologia , Feminino , Humanos , Hidroximetilbilano Sintase/metabolismo , Masculino , Pessoa de Meia-Idade , Sintase do Porfobilinogênio/metabolismo , Porfiria Cutânea Tardia/etiologia , Porfirinas/urina , Uroporfirinogênio Descarboxilase/metabolismoRESUMO
We examined the effects of recombinant rat interferon-gamma (IFN-gamma) injections on the parasitologic, serologic, immunologic and histopathologic features of acute and chronic experimental Trypanosoma cruzi (T. cruzi) infections in "l" rats. Upon infection at weaning, two rat groups were allocated to receive a 20-day cycle of IFN-gamma injections, 20,000 IU/rat each, which started at 1, and 7 days post-infection (pi). Treatment with IFN-gamma, initiated at either 1 or 7 days pi, resulted in comparatively lower peak parasitemias (P < 0.02) but in similar levels of anti-T. cruzi circulating antibodies and serum IFN-gamma activities. The latter appeared significantly increased during acute infection whereas biologically active tumor necrosis factor was virtually undetectable in serum from infected rats regardless of whether they had been given IFN-gamma or not. The prevalence of chronic focal myocarditis in IFN-gamma-treated infected rats showed no differences with respect to the one recorded in control-infected counterparts. The inverse CD4/CD8 ratio of spleen and lymph node T cells that usually accompanies chronic infection was reversed by IFN-gamma. Mononuclear cells carrying class II I-A and I-E molecules, that were found to have increased at both compartments, appeared also modified upon IFN-gamma treatment with an overincrease of I-A-positive cells, and a normalization of I-E-bearing cells.
Assuntos
Doença de Chagas/terapia , Interferon gama/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Doença Aguda , Animais , Anticorpos Antiprotozoários/análise , Relação CD4-CD8 , Doença de Chagas/imunologia , Doença de Chagas/patologia , Doença Crônica , Modelos Animais de Doenças , Antígenos de Histocompatibilidade Classe II/imunologia , Interferon gama/análise , Linfonodos/citologia , Masculino , Miocardite/etiologia , Miocardite/patologia , Parasitemia/imunologia , Parasitemia/patologia , Parasitemia/terapia , Prevalência , Ratos , Proteínas Recombinantes , Baço/citologia , Subpopulações de Linfócitos T/imunologia , Trypanosoma cruzi/imunologia , Fator de Necrose Tumoral alfa/análiseRESUMO
In the last decades several authors have observed a frequent association between diabetes mellitus and porphyria, mainly porphyria cutanea tarda. In previous studies, it has been demonstrated that both d delta d-aminolevulic acid dehydratase (ALA-D) and porphobilinogen deaminase (PBG-D), enzymes of the heme pathway, are inhibited by high concentrations of glucose in vitro in crude preparations of erythrocytes. The activity of these same enzymes was diminished in different tissues obtained from streptozotocin induced diabetic mice. Therefore, we decided to investigate the incidence of heme metabolism alterations in diabetes mellitus in a population of 100 non selected adult patients. The activities of erythrocytic ALA-D and PBG-D were measured. Rhodanese, an enzyme of the sulfocompounds pathway closely related to the regulation of heme biosynthesis, was also studied. Urine porphyrin content as well as the chromatographic pattern of esterified porphyrins were determined. ALA-D and PBG-D activities were diminished in diabetic patients (40
and 20
respectively), while rhodanese was only slightly increased (Fig. 1). ALA-D activity was subnormal in a 92
of the complete diabetic population, while PBG-D activity was less than normal in a 79
of the same population. No significative differences between enzymic activities were observed in the groups insulin and non-insulin dependent (Fig. 3). Urine porphyrin content was increased in 5
of the diabetic population. Chromatographic pattern of urinary porphyrins was notably altered in diabetic patients irrespectively of their porphyrin content (Fig. 4), suggesting an alteration in the enzyme uroporphyrinogen decarboxylase resembling the primary enzymic defect observed in porphyria cutanea tarda.(ABSTRACT TRUNCATED AT 250 WORDS)
RESUMO
T lymphocytes from patients with visceral leishmaniasis treated in vitro with leishmania antigens are unable to proliferate and to produce gamma interferon. These patients have negative specific skin tests. Opposite results are obtained in patients with another clinical form of the disease named mucocutaneous leishmaniasis, in which both tests are positive. Nevertheless, patients with visceral leishmaniasis or mucocutaneous leishmaniasis, refractory to chemotherapy (antimonium complex), were cured when treated with antimonium in combination with gamma interferon, in spite of different immunological profiles. Different interpretative hypotheses of the reversion of chemoresistance induced by gamma interferon are discussed.
Assuntos
Antimônio/uso terapêutico , Interferon gama/uso terapêutico , Leishmaniose Mucocutânea/terapia , Adolescente , Adulto , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Los enfermos afectados de leishmaniasis visceral poseen tests cutáneos específicos negativos. Los linfocitos T de esos enfermos no proliferan ni sintetizan interferon gamma cuando son tratados in vitro por los antígenos de leishmanias. Se observa lo inverso en las leishmaniasis cutáneo-mucosas donde los tests son positivos. Sin embargo, los enfermos refractarios al tratamiento por antimonio, presentando una u otra de estas dos formas de leishmaniiasis, curan cuando son tratados por antimonio combinado al interferon gamma. Numerosas interpretaciones de la inversión de la resistencia a la quimioterapia inducida por interferon gamma pueden ser considaeradas: acción sobre el sistema de tipo MDR (multidrug resistance), modulación de las sub-poblaciones linfocitarias o acción sobre las poblaciones linfocitarias o acción sobre las poblaciones celulares de las lesiones de la leishmaniasis (AU)
Assuntos
Adolescente , Adulto , Pessoa de Meia-Idade , Humanos , Masculino , Feminino , Interferon gama , Leishmaniose Mucocutânea/terapia , Antimônio , Quimioterapia Combinada , SeguimentosRESUMO
T lymphocytes from patients with visceral leishmaniasis treated in vitro with leishmania antigens are unable to proliferate and to produce gamma interferon. These patients have negative specific skin tests. Opposite results are obtained in patients with another clinical form of the disease named mucocutaneous leishmaniasis, in which both tests are positive. Nevertheless, patients with visceral leishmaniasis or mucocutaneous leishmaniasis, refractory to chemotherapy (antimonium complex), were cured when treated with antimonium in combination with gamma interferon, in spite of different immunological profiles. Different interpretative hypotheses of the reversion of chemoresistance induced by gamma interferon are discussed.
RESUMO
Los enfermos afectados de leishmaniasis visceral poseen tests cutáneos específicos negativos. Los linfocitos T de esos enfermos no proliferan ni sintetizan interferon gamma cuando son tratados in vitro por los antígenos de leishmanias. Se observa lo inverso en las leishmaniasis cutáneo-mucosas donde los tests son positivos. Sin embargo, los enfermos refractarios al tratamiento por antimonio, presentando una u otra de estas dos formas de leishmaniiasis, curan cuando son tratados por antimonio combinado al interferon gamma. Numerosas interpretaciones de la inversión de la resistencia a la quimioterapia inducida por interferon gamma pueden ser considaeradas: acción sobre el sistema de tipo MDR (multidrug resistance), modulación de las sub-poblaciones linfocitarias o acción sobre las poblaciones linfocitarias o acción sobre las poblaciones celulares de las lesiones de la leishmaniasis
Assuntos
Adolescente , Adulto , Pessoa de Meia-Idade , Humanos , Masculino , Feminino , Antimônio , Interferon gama , Leishmaniose Mucocutânea/terapia , Quimioterapia Combinada , SeguimentosRESUMO
We report on the histologic changes occurring in single cutaneous lesions, from six active lepromatous patients, 1 week following the administration of three daily intradermal injections, 35 micrograms each, of recombinant interferon gamma (rIFN-gamma). Except for a strong induration at the injection site, rIFN-gamma produced no adverse systemic reactions and was able to promote a remarkable influx of T-lymphocytes, mononuclear phagocytes with large nuclei, nonvacuolated cytoplasm, and reduced lysozyme reactivity. Furthermore, despite no clear-cut reduction of mycobacterial dermal burden, bacilli showed a clear increase in the granular appearance. Present findings provide a basis for further elucidation of rIFN-gamma as an additional tool for leprosy treatment.
Assuntos
Interferon gama/uso terapêutico , Hanseníase Virchowiana/terapia , Pele/patologia , Adulto , Idoso , Biópsia , Esquema de Medicação , Feminino , Humanos , Injeções Intralesionais , Interferon gama/administração & dosagem , Hanseníase Virchowiana/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Fatores de TempoRESUMO
The purpose of these audits was to ensure the quality, integrity and validity of investigational data. Audits were performed by control of compliance to standard operational procedures (SOPs) for Good Clinical Practice (GCP). Guidelines were proposed and established by the Food and Drug Administration (FDA) in 1977-1979 and adopted by several countries of the European Community in 1987-1989 and 1990. In Argentina, 12 on site audits of clinical trials performed between 1987 and 1990, were carried out. Basic data of GCP, audited in 58 out of 153 patients included in 12 different centers, were: protection of individual rights, compliance to standard operational procedures, adverse event reports, access to original investigational data and source document archives. The analysis of all audited data showed that patient case reports form recorded findings are credible and reliable and that researchers and monitors had conducted the study with an acceptable level in accordance to SOPs of good clinical practice. Otherwise, several in need of change to obtain better clinical data were identified: ethical committees, written informed consent, protocol adherence, data record, drug accountability, document source archives and the necessity of a thorough theorical and practical training on SOPs for GCP for researchers and monitors of clinical trials.
Assuntos
Ensaios Clínicos como Assunto/normas , Auditoria Médica , Argentina , HumanosRESUMO
The purpose of these audits was to ensure the quality, integrity and validity of investigational data. Audits were performed by control of compliance to standard operational procedures (SOPs) for Good Clinical Practice (GCP). Guidelines were proposed and established by the Food and Drug Administration (FDA) in 1977-1979 and adopted by several countries of the European Community in 1987-1989 and 1990. In Argentina, 12 on site audits of clinical trials performed between 1987 and 1990, were carried out. Basic data of GCP, audited in 58 out of 153 patients included in 12 different centers, were: protection of individual rights, compliance to standard operational procedures, adverse event reports, access to original investigational data and source document archives. The analysis of all audited data showed that patient case reports form recorded findings are credible and reliable and that researchers and monitors had conducted the study with an acceptable level in accordance to SOPs of good clinical practice. Otherwise, several in need of change to obtain better clinical data were identified: ethical committees, written informed consent, protocol adherence, data record, drug accountability, document source archives and the necessity of a thorough theorical and practical training on SOPs for GCP for researchers and monitors of clinical trials.
RESUMO
The purpose of these audits was to ensure the quality, integrity and validity of investigational data. Audits were performed by control of compliance to standard operational procedures (SOPs) for Good Clinical Practice (GCP). Guidelines were proposed and established by the Food and Drug Administration (FDA) in 1977-1979 and adopted by several countries of the European Community in 1987-1989 and 1990. In Argentina, 12 on site audits of clinical trials performed between 1987 and 1990, were carried out. Basic data of GCP, audited in 58 out of 153 patients included in 12 different centers, were: protection of individual rights, compliance to standard operational procedures, adverse event reports, access to original investigational data and source document archives. The analysis of all audited data showed that patient case reports form recorded findings are credible and reliable and that researchers and monitors had conducted the study with an acceptable level in accordance to SOPs of good clinical practice. Otherwise, several in need of change to obtain better clinical data were identified: ethical committees, written informed consent, protocol adherence, data record, drug accountability, document source archives and the necessity of a thorough theorical and practical training on SOPs for GCP for researchers and monitors of clinical trials.
RESUMO
The purpose of these audits was to ensure the quality, integrity and validity of investigational data. Audits were performed by control of compliance to standard operational procedures (SOPs) for Good Clinical Practice (GCP). Guidelines were proposed and established by the Food and Drug Administration (FDA) in 1977-1979 and adopted by several countries of the European Community in 1987-1989 and 1990. In Argentina, 12 on site audits of clinical trials performed between 1987 and 1990, were carried out. Basic data of GCP, audited in 58 out of 153 patients included in 12 different centers, were: protection of individual rights, compliance to standard operational procedures, adverse event reports, access to original investigational data and source document archives. The analysis of all audited data showed that patient case reports form recorded findings are credible and reliable and that researchers and monitors had conducted the study with an acceptable level in accordance to SOPs of good clinical practice. Otherwise, several in need of change to obtain better clinical data were identified: ethical committees, written informed consent, protocol adherence, data record, drug accountability, document source archives and the necessity of a thorough theorical and practical training on SOPs for GCP for researchers and monitors of clinical trials.
Assuntos
Humanos , Ensaios Clínicos como Assunto/normas , Auditoria Médica , ArgentinaRESUMO
From December 1984 to June 1986, a prospective clinical trial was carried out in 48 patients with acute community-acquired pneumonia, comparing 2 possible therapeutic schemes: one, using only one antibiotic (roxithromycin: RXT) presumptively active on most of the germs usually involved. In a second group, the identification of the germs involved was attempted on the basis of clinical, epidemiological and radiological data, followed by treatment with the antibiotic/s (ATB) known to be more active against the suspected organisms. The dosage of RXT was 300 mg/day, orally during an average of 9 days. The mean duration of treatment in ATB group was 12 days. In both groups, the following microorganisms were identified: RXT group: St. pneumoniae (13 cases), H. influenzae (1), B. catarrhalis (1); mixed infections: St. pneumoniae + H. influenzae (2); Mycoplasma pneumoniae (3) and 4 patients with unidentified germ; in ATB group: St. aureus (3), St. pneumoniae (5), H. influenzae (2), B. catarrhalis (1); mixed infections: St. aureus + Enterobacter + E. coli (1); Mycoplasma pneumoniae (2) and 10 patients with unidentified germ. The therapeutic results were satisfactory (curation rate: 92%) and similar for both groups of treatment, concluding that both schemes are comparable. Therefore, the choice for one or the other scheme should be based on other reasons, such as easy administration and cost of the treatment.