Persistent hepatitis C virus (HCV) infection impairs HCV-specific cytotoxic T cell reactivity through Mcl-1/Bim imbalance due to CD127 down-regulation.

In persistent hepatitis C virus (HCV) infection, HCV-specific cytotoxic T lymphocyte (CTL) reactivity is impaired and this affects HCV control. Interleukin-7 receptor (CD127) expression on these cells could regulate CTL reactivity through Mcl-1/Bim balance modulation. Bim is a pro-apoptotic molecule blocked by the action of Mcl-1. Mcl-1/Bim expression and T cell reactivity on HCV-specific CTLs were compared according to CD127 phenotype. Peripheral blood lymphocytes (PBL) from HLA-A2(+) HCV(+) patients were obtained. HCV-specific CTLs were visualized by staining PBL with anti-CD8 and HLA-A2/peptide pentameric complexes (pentamer). Mcl-1/Bim/CD127 phenotype of HCV-specific CTLs was tested by staining detectable CD8(+)/pentamer(+) cells with anti-Mcl-1/Bim/CD127 antibodies. HCV-specific CTL proliferation ability after specific in vitro challenge was tested in the presence and absence of pancaspase inhibitor z-VAD-fmk. All stained cells were analysed by flow cytometry. CD127(low)-expressing HCV-specific CTLs associated with high HCV viraemia, while CD127(high) correlated with undetectable viral loads (P < 0.001). Directly ex vivo, pentamer(+) cell frequency was similar according to CD127 expression level. Nevertheless, CD127(low) pentamer(+) cell proliferation after specific in vitro challenge was impaired (P < 0.05), although this was corrected by z-VAD-fmk treatment (P < 0.05). Mcl-1 expression was low directly ex vivo (P < 0.01), and Bim was up-regulated after antigen encounter (P < 0.05) of CD127(low) pentamer(+) cells. The ex vivo difference between Mcl-1 and Bim expression on pentamer(+) cells correlated positively with CD127 expression level (P < 0.001) and with pentamer(+) cell reactivity (P < 0.05). In summary, a low ex vivo Mcl-1 expression and Bim up-regulation after antigen encounter are involved in CD127(low) HCV-specific CTL hyporeactivity during chronic infection, but it can be overcome by apoptosis blockade.

Cytokines - their pathogenic and therapeutic role in chronic viral hepatitis.

Cytokines make up a network of molecules involved in the regulation of immune response and organ functional homeostasis. Cytokines coordinate both physiological and pathological processes occurring in the liver during viral infection, including infection control, inflammation, regeneration, and fibrosis. Hepatitis B and hepatitis C viruses interfere with the complex cytokine network brought about by the immune system and liver cells in order to prevent an effective immune response, capable of viral control. This situation leads to intrahepatic sequestration of nonspecific inflammatory infiltrates that release proinflammatory cytokines, which in turn favor chronic inflammation and fibrosis. The therapeutical administration of cytokines such as interferon alpha may result in viral clearance during persistent infection, and revert this process.

Cytokines – their pathogenic and therapeutic role in chronic viral hepatitis

Cytokines make up a network of molecules involved in the regulationof immune response and organ functional homeostasis. Cytokinescoordinate both physiological and pathological processesoccurring in the liver during viral infection, including infection control,inflammation, regeneration, and fibrosis. Hepatitis B and hepatitisC viruses interfere with the complex cytokine networkbrought about by the immune system and liver cells in order to preventan effective immune response, capable of viral control. This situationleads to intrahepatic sequestration of nonspecific inflammatoryinfiltrates that release proinflammatory cytokines, which in turnfavor chronic inflammation and fibrosis. The therapeutical administrationof cytokines such as interferon alpha may result in viral clearanceduring persistent infection, and revert this process(AU)

Fascitis necrotizante secundaria a inserción de sonda de gastrostomía endoscópica percutánea / Necrotizing fascitis secondary to percutaneous endoscopic gastrostomy

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[Acute promyelocytic leukemias: clinico-biological aspects, prognostic factors, therapeutic response, and possibilities of cure in 34 cases (1970-1988)]. / Leucemias agudas promielocíticas: aspectos clínico-biológicos, factores pronósticos, respuesta terapéutica y posibilidades de curación de 34 casos (1970-1988).

Thirty-four new cases of acute promyelocytic leukaemia (M3) were diagnosed at the authors' Centre between 1970 and 1988 (19 males and 15 females) with ages between 5 and 73 years (median age, 32 years). Three cases were of the hypogranular variant or M3-v (8.8%). The clinical picture included: haemorrhagic diathesis (85%), pallor/malaise (82%), fever/infection (41%), hepatomegaly (26%), splenomegaly (12%). Leucopenia of less than 5 x 10(9)/L was present in 23/34 cases, laboratory signs of DIC in 26/31, increased LDH, over 400 U/mL, in 6/31, and abnormal karyotype in 7/15. One of the patients rejected any treatment; two others died of brain haemorrhage before therapy was started, and seven died in the first two weeks of treatment. Of the 31 patients treated, complete remission (CR) was achieved in 21 cases (67.7%). Allogeneic BMT was carried out in two of them, with further relapse and death. Post-remission treatment was given to the remaining 19 patients, and there were 13 relapses. Six patients have been in CR, 5 of them after cessation of therapy, for the last 1.5-11.5 years. Age under 50 years and leucocyte count below 5 x 10(9)/L at diagnosis were favourable prognostic factors according to the univariate statistical analysis performed. The survival plateau of the actuarial curve was reached beyond 2.75 years by 15% of all the patients treated (33 cases), 23% of the patients who achieved CR (21 cases), 31% of the patients under 50 years of age and 5 x 10(9)/L leucocyte count at diagnosis (15 cases) and 36% of these last achieving CR (13 cases).

[Endocarditis caused by Staphylococcus aureus in drug addicts and non-addicts: the same microbe in 2 diseases]. / Endocarditis por Staphylococcus aureus en adictos y no adictos: un mismo microbio para dos enfermedades distintas.

46 Staphylococcus aureus endocarditis episodes diagnosed with strict criteria in non drug addict patients, and 25 episodes in drug addict patients have been comparatively analyzed. Infection was found in the left side of the heart in 87% of the non addict patients and in 16% of the addicts. On the contrary, 84% of the addicts had endocarditis of the tricuspid and pulmonary valves while only 13% of the non addicts had right heart involvement. The right side endocarditis in the non addicts was always due to intracardiac catheters. 54% of the endocarditis episodes in the non addicts were fatal. Only two addicts, both when had left side endocarditis, died. Mortality was conditioned by infection of the left side of the heart as well as by the existence of heart failure. No significant differences were found between the evolution of patients treated with only one agent or of those treated with a beta-lactam antibiotic plus gentamicin. The emergency valve replacement significantly improved the prognosis of patients with prosthetic valve endocarditis.

[Open lung biopsy in immunocompromised patients with diffuse pulmonary infiltrates]. / La biopsia pulmonar abierta en pacientes inmunocomprometidos con infiltrados pulmonares difusos.

In order to evaluate the diagnostic usefulness of open lung biopsy and to determine how could it influence the treatment and the evolution of the disease, the clinical histories of 19 immunocompromised patients with diffuse lung infiltrates were reviewed. One or more specific diagnosis were obtained in 14 patients (73%) by open lung biopsy. However, the initial treatment was modified, in view of the results of the biopsy only in 3 cases (15%). Only 5 patients survived and were discharged. There were no differences in the survival rate of patients with a specific or a nonspecific diagnosis (11 out of 14 deaths and 3 out of 5 respectively). 5 patients suffered severe complications from the surgical procedure. Open lung biopsy should not be used routinarily in the study of diffuse lung infiltrates in immunocompromised patients.

Q fever endocarditis on porcine bioprosthetic valves. Clinicopathologic features and microbiologic findings in three patients treated with doxycycline, cotrimoxazole, and valve replacement.

Three patients developed Q fever endocarditis on porcine bioprosthetic valves. They had a subacute or chronic course with nonspecific symptoms, enlargement of the liver and spleen, and cardiac failure due to destruction of the cusps, without disruption of the valve ring. High-phase I-specific IgG and IgA antibody titers against Coxiella burnetii were found. C. burnetii was isolated in each patient by inoculating suspensions of valve tissue into a human fetal diploid fibroblast cell line, which was grown as monolayers on slides contained inside rubber-stoppered tube cultures. Patients were treated successfully with doxycycline, cotrimoxazole, and valve replacement and were followed up for periods of 24 to 42 months; no evidence of deterioration was found. The human fetal diploid cell culture may be an expeditious, easy, and safe method to isolate C. burnetii from cardiac valves. Valve replacement seemed necessary to cure prosthetic-valve endocarditis due to C. burnetii infection. Combined therapy with doxycycline and cotrimoxazole may control the disease and prevent reinfection of the homografts replacing the valves.