RESUMEN
Toxoplasma gondii, an intracellular protozoan parasite, is a major cause of opportunistic infectious disease affecting the brain and has been linked to an increased incidence of schizophrenia. In murine hosts, infection with T. gondii stimulates tryptophan degradation along the kynurenine pathway (KP), which contains several neuroactive metabolites, including 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN) and kynurenic acid (KYNA). As these endogenous compounds may provide a mechanistic connection between T. gondii and the pathophysiology of schizophrenia, we measured KP metabolites in both the brain and periphery of T. gondii-treated C57BL/6 mice 8 and 28 days post-infection. Infected mice showed early decreases in the levels of tryptophan in the brain and serum, but not in the liver. These reductions were associated with elevated levels of kynurenine, KYNA, 3-HK and QUIN in the brain. In quantitative terms, the most significant increases in these KP metabolites were observed in the brain at 28 days post-infection. Notably, the anti-parasitic drugs pyrimethamine and sulfadiazine, a standard treatment of toxoplasmosis, significantly reduced 3-HK and KYNA levels in the brain of infected mice when applied between 28 and 56 days post-infection. In summary, T. gondii infection, probably by activating microglia and astrocytes, enhances the production of KP metabolites in the brain. However, during the first two months after infection, the KP changes in these mice do not reliably duplicate abnormalities seen in the brain of individuals with schizophrenia.
Asunto(s)
Encéfalo/metabolismo , Quinurenina/metabolismo , Transducción de Señal/fisiología , Toxoplasmosis/metabolismo , Toxoplasmosis/patología , Animales , Antiinfecciosos/administración & dosificación , Encéfalo/efectos de los fármacos , Encéfalo/microbiología , Modelos Animales de Enfermedad , Combinación de Medicamentos , Femenino , Ácido Quinurénico/metabolismo , Quinurenina/análogos & derivados , Quinurenina/genética , Ratones , Ratones Endogámicos C57BL , Neuroglía/efectos de los fármacos , Neuroglía/patología , Pirimetamina/administración & dosificación , Ácido Quinolínico/metabolismo , ARN Mensajero/metabolismo , Transducción de Señal/efectos de los fármacos , Sulfadiazina/administración & dosificación , Factores de Tiempo , Toxoplasmosis/tratamiento farmacológico , Triptófano/metabolismoRESUMEN
Helminth infections are generally characterized by dominant T-helper type 2 (Th2) immune response polarization and have been shown in some cases to modulate immune responses to vaccines, i.e., the Bacillus Calmette-Guerin (BCG) vaccine. The filarial nematode secreted product ES-62 has been shown to possess immunomodulatory activities, such as the ability to inhibit pro-inflammatory/Th1 immune responses and to have therapeutic potential against diseases associated with such responses. This study aimed to investigate the ability of ES-62 to modulate the immune response to purified protein derivative (PPD), a component of the BCG vaccine designed to provoke a Th1 response. Overall, the results show that ES-62 was not capable of modulating the Th1 immune response induced by PPD, demonstrating that the helminth product, if employed therapeutically, is unlikely to interfere with the protective effects of the vaccine.
Asunto(s)
Vacuna BCG/inmunología , Proteínas del Helminto/inmunología , Células TH1/inmunología , Tuberculina/inmunología , Animales , Ensayo de Inmunoadsorción Enzimática , Interferón gamma/biosíntesis , Subunidad p40 de la Interleucina-12/biosíntesis , Ratones , Ratones Endogámicos BALB C , Factor de Crecimiento Transformador beta/biosíntesisRESUMEN
Primary infection of IL-10 knockout (KO) mice with the protozoan parasite Toxoplasma gondii leads to a CD4(+)-T-cell dependent shock-like reaction with high systemic levels of IL-12 and IFN-gamma, severe liver pathology and death of mice. In the present study, this immune-mediated pathology was prevented by treatment of IL-10 KO mice with the anti-parasitic drug sulfadiazine, allowing these mice to progress to the chronic phase of infection. To address the role of endogenous IL-10 in the regulation of secondary immune responses to T. gondii, IL-10 KO mice were infected with the avirulent Me49 strain of this parasite, treated with sulfadiazine for 2 weeks starting at day 3 p.i., and were rechallenged 6 weeks p.i. with RH, a highly virulent strain of T. gondii. In these studies, chronically infected IL-10 KO mice survived secondary infection with RH and controlled parasite load. Although serum levels of IL-12 and IFN-gamma were higher in IL-10 KO mice than in wild type (WT) mice 8 days after RH rechallenge, these levels were well controlled in the absence of endogenous IL-10, suggesting that IL-10 is not required to down-regulate cytokine production during the memory response. Antigen-specific ex vivo recall responses further revealed that splenocytes from chronically infected WT and IL-10 KO mice responded to parasite antigen with similar production of IL-12 and IFN-gamma, and there was also no significant difference in ex vivo production of these cytokines by splenocytes in response to parasite antigen 7 days after secondary infection with T. gondii. Furthermore, IL-10 KO mice immunized with the Ts-4 vaccine-strain of T. gondii were protected when rechallenged with the virulent RH strain. Together, these studies demonstrate that the inhibitory effect of IL-10, which is required to prevent immune-mediated pathology during primary infection, is not required to prevent immune hyperactivity during a secondary response to T. gondii, and a highly effective memory response is generated in the absence of endogenous IL-10.
Asunto(s)
Memoria Inmunológica/inmunología , Interleucina-10/inmunología , Toxoplasma/inmunología , Toxoplasmosis/inmunología , Animales , Antiprotozoarios/uso terapéutico , Encéfalo/parasitología , Femenino , Histocitoquímica , Interferón gamma/inmunología , Interleucina-10/deficiencia , Interleucina-12/inmunología , Subunidad p40 de la Interleucina-12 , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Noqueados , Cavidad Peritoneal/parasitología , Subunidades de Proteína/inmunología , Estadísticas no Paramétricas , Sulfadiazina/uso terapéutico , Toxoplasmosis/tratamiento farmacológico , Toxoplasmosis/parasitología , Toxoplasmosis/patologíaRESUMEN
Parasite survival and host health may depend on the ability of the parasite to modulate the host immune response by the release of immunomodulatory molecules. Excretory-secretory (ES)-62, one such well-defined molecule, is a major secreted protein of the rodent filarial nematode Acanthocheilonema viteae, and has homologues in human filarial nematodes. Previously we have shown that ES-62 is exclusively associated with a Th2 Ab response in mice. Here we provide a rationale for this polarized immune response by showing that the parasite molecule suppresses the IFN-gamma/LPS-induced production, by macrophages, of bioactive IL-12 (p70), a key cytokine in the development of Th1 responses. This suppression of the induction of a component of the host immune response extends to the production of the proinflammatory cytokines IL-6 and TNF-alpha, but not NO. The molecular mechanism underlying these findings awaits elucidation but, intriguingly, the initial response of macrophages to ES-62 is to demonstrate a low and transient release of these cytokines before becoming refractory to further release induced by IFN-gamma/LPS. The relevance of our observations is underscored by the finding that macrophages recovered from mice exposed to "physiological" levels of ES-62 by the novel approach of continuous release from implanted osmotic pumps in vivo were similarly refractory to release of IL-12, TNF-alpha, IL-6, but not NO, ex vivo. Therefore, our results suggest that exposure to ES-62 renders macrophages subsequently unable to produce Th1/proinflammatory cytokines. This likely contributes to the generation of immune responses with an anti-inflammatory Th2 phenotype, a well-documented feature of filarial nematode infection.
Asunto(s)
Adyuvantes Inmunológicos/fisiología , Citocinas/biosíntesis , Dipetalonema/inmunología , Glicoproteínas/fisiología , Proteínas del Helminto/fisiología , Macrófagos Peritoneales/metabolismo , Adyuvantes Inmunológicos/metabolismo , Animales , Supervivencia Celular/inmunología , Células Cultivadas , Relación Dosis-Respuesta Inmunológica , Combinación de Medicamentos , Glicoproteínas/administración & dosificación , Glicoproteínas/metabolismo , Proteínas del Helminto/administración & dosificación , Proteínas del Helminto/metabolismo , Inmunosupresores/farmacología , Bombas de Infusión Implantables , Interferón gamma/antagonistas & inhibidores , Interferón gamma/farmacología , Interleucina-12/antagonistas & inhibidores , Interleucina-12/biosíntesis , Interleucina-12/genética , Interleucina-6/antagonistas & inhibidores , Interleucina-6/biosíntesis , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Activación de Macrófagos/inmunología , Macrófagos Peritoneales/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Óxido Nítrico/biosíntesis , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
The filarial nematode product ES-62 contains phosphorylcholine (PC) covalently attached to N-linked glycans. ES-62 induced high levels of immunoglobulin G1 (IgG1) antibodies, but no IgG2a, to non-PC epitopes of the molecule following subcutaneous injection into BALB/c mice. Conversely, mice given ES-62 lacking PC demonstrated significant production of both IgG subclasses. Thus, PC appears to block production of IgG2a antibodies to other epitopes on the parasite molecule. A role for interleukin-10 (IL-10) in this effect was shown by the ability of IL-10(-/-) mice to make an IgG2a antibody response to non-PC epitopes of ES-62.
Asunto(s)
Anticuerpos Antihelmínticos/sangre , Filarioidea/inmunología , Inmunoglobulina G/clasificación , Interleucina-10/fisiología , Fosforilcolina/inmunología , Animales , Inmunoglobulina G/sangre , Interleucina-4/fisiología , Ratones , Ratones Endogámicos BALB CRESUMEN
This study draws on decision analysis to estimate the utility of seminal variables in predicting pregnancy. The infertile couples selected (n = 709) excluded those who had donor insemination or known female factors (history of pelvic infection, ovulatory disorders, endometriosis, and tubal disease). Diagnostic test properties were calculated with respect to pregnancy for two variables derived from the semen analysis report: sperm density, and the total number of motile sperm in the ejaculate (TMS). Receiver-operating characteristic (ROC) curves based on sensitivity and specificity revealed that none of the proposed thresholds for sperm density or TMS is clearly a best choice. The highest positive predictive values for sperm density (75%) and TMS (75%) were associated with cutoff points at five million sperm per milliliter and five million motile sperm per ejaculate, respectively. The false positive rates when these cutoff points were used were 4.3% (sperm density) and 5.6% (TMS). ROC analysis provides visual and numeric evidence of the quality of a diagnostic test and constitutes a set of procedures for incorporating information from new tests of male gamete function into the diagnostic assessment of infertility.
Asunto(s)
Gametogénesis , Infertilidad Masculina/diagnóstico , Semen/análisis , Recuento de Espermatozoides , Motilidad Espermática , Técnicas de Laboratorio Clínico , Reacciones Falso Positivas , Femenino , Humanos , Masculino , Valores de ReferenciaRESUMEN
Among the male partners of 1074 infertile couples the mean results of semen analysis were sperm count 78 X 10(6)/ml, seminal volume 4.0 ml, proportion of progressively motile sperm 54%, proportion of sperm with normal morphologic features 81.4% and total motile sperm count 152.3 X 10(6) per ejaculate. After excluding 65 couples who chose donor insemination and 300 with known female causes of infertility, the cumulative pregnancy rates in the remaining 709 couples were higher with increasing sperm density and motility and seminal volume, but the higher rates were significant only when these variables were combined into total motile sperm count per ejaculate. The cumulative pregnancy rates were 20% with a total motile sperm count of 9 X 10(6) or less, 37% with a count of 10 to 19 X 10(6) and 52% with a count of 20 X 10(6) or more (p = 0.001). Counts higher than 20 X 10(6) were not associated with a further improvement in pregnancy rates, but variability in the results was high, which suggests that the test should be repeated as necessary to determine the true range. Although standards for these and other seminal variables are ill defined, the total motile sperm count incorporates the most useful prognostic information from semen analysis, and the associated pregnancy rates can help guide clinical decisions.
Asunto(s)
Infertilidad Femenina/diagnóstico , Infertilidad Masculina/diagnóstico , Semen/análisis , Femenino , Estudios de Seguimiento , Humanos , Masculino , Embarazo , Pronóstico , Recuento de Espermatozoides , Motilidad Espermática , Espermatozoides/anatomía & histologíaRESUMEN
To determine the reason for the higher pregnancy rate in couples with secondary infertility, the authors compared 237 infertile couples who had a previous pregnancy in the current partnership (secondary infertility) with 135 infertile couples in whom the woman had been pregnant only in a previous partnership and 925 couples with primary infertility. Couples with secondary infertility had the highest proportion of ovulation disorders (36%); these couples with secondary infertility and an ovulation disorder had the shortest duration of infertility (26 months). Cumulative pregnancy rates at 36 months were 56% in secondary fertility, 44% in primary infertility, and 42% in pregnancy in a previous partnership (P = 0.001). In this study, the better prognosis in secondary infertility may be related to the higher proportion of couples with ovulation disorders, who had a shorter duration of infertility. Abortion rates in the earlier pregnancies with current or previous partners were 37% and 30%, respectively; after the period of infertility, the abortion rates were 14% and 12%, respectively.
Asunto(s)
Anovulación , Infertilidad Femenina , Infertilidad , Aborto Espontáneo/epidemiología , Adulto , Factores de Edad , Anovulación/complicaciones , Femenino , Humanos , Infertilidad/etiología , Infertilidad Femenina/etiología , Masculino , Paridad , Embarazo , Pronóstico , Factores de TiempoRESUMEN
Major vascular, nonthromboembolic complications of total hip arthroplasty are rare: only 23 have been reported over the last 20 years. This is a report of two additional cases. In an 84-year-old woman, the external iliac artery was lacerated following removal of the acetabular component. Two such injuries have been reported previously, but this is the first case that resulted from a posterolateral approach to the hip. In a 69-year-old woman, a heretofore unrecorded complication consisted of external iliac vein compression occurring 20 months after total hip arthroplasty and culminating in iliac artery thrombosis and an ischemic foot. A below-knee amputation was performed after removal of the total hip components.
Asunto(s)
Prótesis de Cadera , Arteria Ilíaca/lesiones , Vena Ilíaca , Complicaciones Posoperatorias/etiología , Anciano , Constricción Patológica , Femenino , Humanos , Complicaciones Posoperatorias/cirugía , Reoperación , Rotura , Enfermedades Vasculares/etiologíaRESUMEN
Late follicular phase postcoital tests in 355 infertile couples (selected to exclude severe defects in ovulation, seminal or tubal function) were scored for mucus characteristics and sperm motility. Cervical mucus characteristics were associated with postcoital sperm motility (P less than 0.001) but not with pregnancy. Postcoital sperm motility in cervical mucus was strongly associated with total motile sperm count per ejaculate (F = 5.38, P less than 0.001). Postcoital sperm motility was a weak predictor of pregnancy when more than five motile sperm were observed per high power microscopic field. When the log rank tests for postcoital sperm motility were repeated in groups with low (less than 10 million) and high (10 million or more) total motile sperm count per ejaculate, the association between postcoital sperm motility and pregnancy was not statistically significant. Regression analysis controlling for other potential predictors revealed no independent association between postcoital sperm motility and the later occurrence of pregnancy in this group of infertile couples.
Asunto(s)
Moco del Cuello Uterino/análisis , Coito , Infertilidad/diagnóstico , Motilidad Espermática , Adulto , Femenino , Humanos , Masculino , Embarazo , Pronóstico , Factores de TiempoRESUMEN
Evaluated were methods of ordering the many possible predictors of infertility outcome. The clinical characteristics of infertile couples were studied with respect to the occurrence of pregnancy during follow-up, by means of the methods of survival analysis. Among 1,297 couples who were infertile for 12 months or more, the cumulative pregnancy rate at 36 months with 95% confidence limits was 49% +/- 4%. The proportional hazards analysis identified three independent predictors of the occurrence of pregnancy from the couple's history (with P values in brackets): a history of pregnancy in the partnership (0.0001); shorter duration of infertility (0.0001); and shorter length of marriage (0.005). The predictors arising from the diagnostic process (with P values in brackets) were: fewer infertility diagnoses (0.0001); a favorable primary clinical diagnosis (0.001); and the presence of any tubal disease, regardless of the primary clinical diagnosis (0.001). The analysis selected an economical set of significant predictor variables and demonstrated that a longer period of contraception was associated with a lower pregnancy rate among infertile couples. Also, three simple questions from the history were nearly equivalent to the entire diagnostic process as predictors of the outcome.
Asunto(s)
Infertilidad/diagnóstico , Embarazo , Adulto , Femenino , Humanos , Infertilidad/etiología , Masculino , PronósticoRESUMEN
In a follow-up study of 1297 couples registered at a Nova Scotia infertility clinic with a complaint of infertility of at least 12 months' duration, the cumulative pregnancy rate at 36 months, with 95% confidence limits, was found to be 49 +/- 4%. The predictors of pregnancy by univariate analysis were a favourable primary clinical diagnosis (p less than 0.001), a duration of infertility of less than 3 years (p less than 0.001), a single diagnosis for the infertility (p less than 0.001), a previous pregnancy in the partnership (p = 0.001) and a length of marriage of less than 4 years (p = 0.002). Proportional hazards analysis confirmed these variables as predictors of pregnancy. The highest cumulative pregnancy rates after 12 and 36 months of follow-up were observed in cases of ovulation deficiency, and the lowest were seen in cases of tubal defects. However, before the process of diagnosing infertility begins, useful prognostic information can be determined from the length of marriage, the duration of infertility and the partnership's history of previous pregnancy.
Asunto(s)
Infertilidad Femenina/terapia , Infertilidad Masculina/terapia , Embarazo , Adulto , Femenino , Estudios de Seguimiento , Humanos , Infertilidad Femenina/etiología , Infertilidad Masculina/etiología , Masculino , Pronóstico , Estadística como AsuntoRESUMEN
We analyzed a two- to seven-year follow-up of 1145 infertile couples to determine the frequency of pregnancy occurring independently of treatment. Pregnancy occurred in 246 of 597 treated couples (41 per cent) and in 191 of 548 untreated couples (35 per cent). Thirty-one per cent of the pregnancies in treated couples occurred more than 3 months after the last medical treatment or more than 12 months after adnexal surgery. These pregnancies plus the 191 pregnancies in untreated couples constituted the category of "treatment-independent pregnancies" and accounted for 61 per cent of all pregnancies; for 44 per cent of those among couples with ovulation deficiency; for 61 per cent of those in couples with endometriosis, tubal defects, or seminal deficiencies; and for 96 per cent of those in couples with cervical factors or idiopathic infertility. We conclude that the potential for a spontaneous cure of infertility is high, that treatment for many classes of infertility should be evaluated by randomized clinical trials, and that in such trials random assignment of subjects to untreated control groups would be ethically acceptable.