CD4(+) CD25(high) forkhead box protein 3(+) regulatory T lymphocytes suppress interferon-γ and CD107 expression in CD4(+) and CD8(+) T cells from tuberculous pleural effusions.

Tuberculous pleural effusion is characterized by a T helper type 1 (Th1) profile, but an excessive Th1 response may also cause tissue damage that might be controlled by regulatory mechanisms. In the current study we investigated the role of regulatory T cells (Treg ) in the modulation of Th1 responses in patients with tuberculous (TB) pleurisy. Using flow cytometry we evaluated the proportion of Treg (CD4(+) CD25(high) forkhead box protein 3(+) ), interferon (IFN)-γ and interleukin (IL)-10 expression and CD107 degranulation in peripheral blood (PB) and pleural fluid (PF) from patients with TB pleurisy. We demonstrated that the proportion of CD4(+) CD25(+) , CD4(+) CD25(high) FoxP3(+) and CD8(+) CD25(+) cells were increased in PF compared to PB samples. Mycobacterium tuberculosis stimulation increased the proportion of CD4(+) CD25(low/neg) IL-10(+) in PB and CD4(+) CD25(low/neg) IFN-γ(+) in PF; meanwhile, CD25(high) mainly expressed IL-10 in both compartments. A high proportion of CD4(+) CD107(+) and CD8(+) CD107(+) cells was observed in PF. Treg depletion enhanced the in-vitro M. tuberculosis-induced IFN-γ and CD4(+) and CD8(+) degranulation responses and decreased CD4(+) IL-10(+) cells in PF. Our results demonstrated that in TB pleurisy Treg cells effectively inhibit not only IFN-γ expression but also the ability of CD4(+) and CD8(+) cells to degranulate in response to M. tuberculosis.

Difficult clinical management of anti-tuberculosis DRESS syndrome.

We describe 11 cases of anti-tuberculosis DRESS (drug-related rash with eosinophilia and systemic symptoms) syndrome, a potentially serious complication of treatment that led to interruption of treatment for prolonged periods, systemic corticosteroid use and the resumption of treatment with less effective regimens. All patients had rash and toxic hepatitis, one died of multi-organ failure and, contrary to expectations, the evolution of tuberculosis (advanced in most cases) did not progress under corticosteroid treatment. The drug most frequently involved was rifampicin, while retreatment schemes included, in most cases, levofloxacin, ethambutol, streptomycin and cycloserine.

CD3 expression distinguishes two gammadeltaT cell receptor subsets with different phenotype and effector function in tuberculous pleurisy.

Tuberculous pleurisy is a naturally occurring site of Mycobacterium tuberculosis (Mtb) infection. Herein, we describe the expression of activation, natural killer (NK) and cell migration markers, as well as effector functions from gammadeltaT cells in peripheral blood (PB) and pleural effusion (PE) from tuberculosis patients (TB). We observed a decreased percentage of circulating gammadeltaT from TB patients and differential expression of NK as well as of chemokine receptors on PB and PE. Two subsets of gammadeltaT cells were differentiated by the CD3/gammadeltaT cell receptor (gammadeltaTCR) complex. The gammadeltaTCR(low) subset had a higher CD3 to TCR ratio and was enriched in Vdelta2(+) cells, whereas most Vdelta1(+) cells belonged to the gammadeltaTCR(high) subset. In PB from TB, most gammadeltaTCR(high) were CD45RA(+)CCR7(-) and gammadeltaTCR(low) were CD45RA(+/-)CCR7(+)CXCR3(+). In the pleural space the proportion of CD45RA(-)CCR7(+)CXCR3(+) cells was higher. Neither spontaneous nor Mtb-induced interferon (IFN)-gamma production was observed in PB-gammadeltaT cells from TB; however, PE-gammadeltaT cells showed a strong response. Both PB- and PE-gammadelta T cells expressed surface CD107a upon stimulation with Mtb. Notably, PE-gammadeltaTCR(low) cells were the most potent effector cells. Thus, gammadeltaT cells from PB would acquire a further activated phenotype within the site of Mtb infection and exert full effector functions. As gammadeltaT cells produce IFN-gamma within the pleural space, they would be expected to play a beneficial role in tuberculous pleurisy by helping to maintain a T helper type 1 profile.

IL-10 down-regulates costimulatory molecules on Mycobacterium tuberculosis-pulsed macrophages and impairs the lytic activity of CD4 and CD8 CTL in tuberculosis patients.

Activation of T cells requires both TCR-specific ligation and costimulation through accessory molecules during T cell priming. IFNgamma is a key cytokine responsible for macrophage activation during Mycobacterium tuberculosis (Mtb) infection while IL-10 is associated with suppression of cell mediated immunity in intracellular infection. In this paper we evaluated the role of IFNgamma and IL-10 on the function of cytotoxic T cells (CTL) and on the modulation of costimulatory molecules in healthy controls and patients with active tuberculosis (TB). gamma-irradiated-Mtb (i-Mtb) induced IL-10 production from CD14(+) cells from TB patients. Moreover, CD3(+) T cells of patients with advanced disease also produced IL-10 after i-Mtb stimulation. In healthy donors, IL-10 decreased the lytic activity of CD4(+) and CD8(+) T cells whereas it increased gammadelta-mediated cytotoxicity. Furthermore, we found that the presence of IL-10 induced a loss of the alternative processing pathways of antigen presentation along with a down-regulation of the expression of costimulatory molecule expression on monocytes and macrophages from healthy individuals. Conversely, neutralization of endogenous IL-10 or addition of IFNgamma to either effector or target cells from TB patients induced a strong lytic activity mediated by CD8(+) CTL together with an up-regulation of CD54 and CD86 expression on target cells. Moreover, we observed that macrophages from TB patients could use alternative pathways for i-Mtb presentation. Taken together, our results demonstrate that the presence of IL-10 during Mtb infection might contribute to mycobacteria persistence inside host macrophages through a mechanism that involved inhibition of MHC-restricted cytotoxicity against infected macrophages.

Treatment and follow-up of HIV-negative multidrug-resistant tuberculosis patients in an infectious diseases reference hospital, Buenos Aires, Argentina.

SETTING: An Argentinean reference hospital specialising in infectious diseases. OBJECTIVE: To assess the outcomes of all human immunodeficiency virus (HIV) negative multidrug-resistant tuberculosis (MDR-TB) patients referred to or diagnosed at Hospital Muñiz. DESIGN: Clinical study for the period 1996-1999, with follow-up until June 2002. RESULTS: One hundred and forty-one adult patients (52.5% female) with resistance to two to seven drugs were studied. Fifty patients (35.5%) had not been treated previously. The most frequently used second-line drugs were 5-F-quinolones, cycloserine and ethionamide in susceptibility based individually tailored three- to five-drug regimens. Hospital admission was associated with treatment success. Forty-five episodes of severe toxicity occurred. Treatment was successful in 51.8% of cases, but follow-up of 73 patients yielded 11.9% relapse. The mortality rate was 19.1% and default was 19.9%. Logistic regression analysis was statistically significant for treatment success in relation to patient admission, residence and resistance pattern. CONCLUSION: The burden of MDR-TB in this setting--prolonged infection, treatment cost and difficulties, low rates of cure and treatment adherence and high rates of fatality and relapse--can be improved by strengthening TB control programme activities and fighting against poverty and HIV/AIDS.

[Human immunodeficiency virus infection associated with tuberculosis]. / Asociación de la infección por el virus de la inmunodeficiencia humana (HIV) y tuberculosis.

In order to detect an association between HIV infection and tuberculosis (TB), 130 TB inpatients were studied one of whom presented a pulmonary disease due to Mycobacterium avium intracellulare. All had advanced TB, 95.4%, with pulmonary localization. Serum anti-HIV antibodies were detected by ELISA and their presence confirmed by immunoblotting in 4 (3.1%) individuals, three males and one female, with different degrees of pulmonary TB. Of the males, 1 was bisexual, 2 were promiscuous, and the female was the sexual partner of a non symptomatic HIV-infected man. No immunological disturbances or other AIDS related alterations were observed. There was one case of miliary TB, but neither atypical X-ray abnormalities nor extrapulmonary involvement were found. Tuberculin reaction was positive in three of the four HIV infected patients. Clinical, radiological and bacteriological evolution were favorable. Adverse drug reaction occurred in two cases, one of them presenting serious toxidermia caused by isoniazid. Of the 130 individuals, 12 presented risk factors for HIV infection so that the prevalence of anti-HIV antibodies presented here, 4 cases out of 12, is consistent with data from previous reports for high risk populations.

Asociación de la infección por el virus de la inmunodeficiencia humana (HIV) y tuberculosis / Association of human immunodeficiency virus infection and tuberculosis

Se estudiaron 129 enfermos con tuberculosis grave y 1 con micobacteriosis debida a M. avium intracellulare internados en el Pabellón Koch del Hospital Francisco J. Miñiz durante el primer bimestre de 1988. Se hallaron anticuerpos contra HIV en 4 pacientes (3,1%), 3 hombres y una mujer. Todos ellos tenían algun factor de riesgo para infección con HIV: de los hombres, uno era bisexual y los otros dos declararon ser promiscuos; la mujer era pareja sexual de un individuo HIV positivo. En ninguno se detectaron trastornos inmunológicos, ni otras alteraciones atribuibles a la infección con HIV. Los 4 pacientes presentaron formas de tuberculosis pulmonar graves y en un caso diseminación miliar. No se hallaron formas atípiicas ni extrapulmonares. La prueba tuberculínica fue positiva en 3 de los 4 pacientes. La respuesta clínica, radiológica y bacteriológica fue favorable. Se produjeron reacciones adversas medicamentosas en dos pacientes, debiéndose suspender la administración de isoniacida en uno de ellos, debido a una toxidermia grave. La presentación y evolución de la tuberculosis fue similar en todos no habiéndose encontrado ninguna variable que permitera discriminar entre los HIV positivos o negativos. Enfatizamos la necesidad de realizar un estudio epidemiológico similar de mayor envergadura para detectar la tendencia ascendente que problablemente tendrá la asociación entre tuberculosis e infección con HIV

Chest irradiation as an attempt to improve the response after induction chemotherapy in small cell lung carcinoma.

Forty-six patients with small cell lung carcinoma received cyclic chemotherapy with cisplatin-VP 16 and vincristine, doxorubicin, and cyclophosphamide. The responding patients were given prophylactic cranial irradiation. Patients without metastases not achieving a complete response (CR) following induction chemotherapy were given chest irradiation. The response rate was 73.9 per cent. Response was improved by radiation therapy in only 9 per cent of the patients with limited disease. Median survival was 39 weeks, with 2 patients surviving for longer than 24 months. The duration of response and survival in complete and partial responders was similar; absence of radiation therapy in the patients with CR might explain this finding.

Cisplatin-containing chemotherapy in the treatment of invasive thymoma: report of five cases.

Invasive thymomas are rare neoplasms arising from the epithelial cells of the thymus. In this paper, we report five cases of invasive thymoma treated with cisplatin either alone or combined with etoposide. Two partial responses (lasting 1 and 27+ months from the start of chemotherapy), two minor responses (lasting 1.5 and 13+ months from the start of chemotherapy), and one mixed response were observed. Further studies with cisplatin-containing regimens are warranted in the treatment of this rare tumor.

Evaluation of patency of synthetic and autogenous venous and arterial micrografts in rats.

Long-term patency rates of synthetic and autogenous venous and arterial microvascular grafts in rats were compared. The grafts were interposed between the carotid arteries. The geometry of the anastomoses was designed in a manner intended to be comparable to the situation commonly encountered in cerebral revascularization procedures in man. Patency rates were 37.5% for synthetic grafts, 90% for venous grafts, and 60% for arterial grafts. Venous grafts are the best currently available microvascular prostheses.

Comparison of methylprednisolone and metoclopramide in the prophylactic treatment of cis-platin-induced nausea and vomiting.

Sixty-one patients undergoing treatment with cis-platin-containing regimens were given prophylactically either metoclopramide or methylprednisolone, in order to reduce the gastrointestinal side effects. Vomiting occurred in 79% of the cycles (128/162), and had a distressing intensity in 39.5% of cycles (64/162). No significant differences were observed between metoclopramide and methylprednisolone with respect to number and duration of vomiting episodes and duration of nausea and anorexia. Two of 6 patients benefited from substitution of metoclopramide for methylprednisolone; only 1/11 benefited from the substitution of methylprednisolone for metoclopramide. Metoclopramide and methylprednisolone, at the dosage and schedule used, were well tolerated and moderately active in preventing nausea and vomiting induced by cis-platin; their use in combination could further improve these results.

Father-son testicular cancer, case report.

A case of familial testicular malignancy in a father and his son is reported. This represents the seventh described case of father-son testicular cancer. The father had seminoma and the son had teratocarcinoma. Both patients' peripheral blood lymphocytes were tested for 52 HLA specificities: the father's antigens were HLA A3, B13, B14, Cw6, Cw8 and the son's were HLA A2, A3, B14, Cw8. (Common haplotype: A3, B14, Cw8). The association between HLA antigens and testicular cancer is discussed.

Combination chemotherapy for metastatic brain tumors.

Forty-four patients with central nervous system metastases were treated with combination chemotherapy (adriamycin, VM 26 and CCNU). The best results were obtained in breast adenocarcinoma and small cell lung carcinoma with multiple, small cerebral metastases and without concomitant visceral involvement at other sites. The potential effectiveness of this regimen to prevent cerebral metastases is discussed.

Interhemispheric steal syndrome.

A case of acute occlusion of the left common carotid artery is reported. The patient presented with symptoms and signs largely on the left side, ipsilateral to an occluded left carotid artery. Angiography revealed occlusion of the left common carotid artery and ulceration within the lumen of the right internal carotid artery bulb. Computerized tomography showed findings compatible with an old infarct within the right temporal lobe. The diagnosis of interhemispheric steal syndrome was made and the patient was treated successfully with staged surgical procedures on the carotid arteries, beginning with the totally occluded vessel, which was obstructed by fresh clot. The pathophysiology of interhemispheric steal syndrome is reviewed. A policy of operating first on the side of the occluded or more severely stenosed carotid artery is recommended, even though this vessel may be ipsilateral to the patient's symptoms.