Influence of Genetic Polymorphisms of Tumor Necrosis Factor Alpha and Interleukin 10 Genes on the Risk of Liver Cirrhosis in HIV-HCV Coinfected Patients.

OBJECTIVE: Analysis of the contribution of genetic (single nucleotide polymorphisms (SNP) at position -238 and -308 of the tumor necrosis factor alpha (TNF-α) and -592 of the interleukin-10 (IL-10) promotor genes) and of classical factors (age, alcohol, immunodepression, antirretroviral therapy) on the risk of liver cirrhosis in human immunodeficiency (HIV)-hepatitis C (HCV) virus coinfected patients. PATIENTS AND METHODS: Ninety one HIV-HCV coinfected patients (50 of them with chronic hepatitis and 41 with liver cirrhosis) and 55 healthy controls were studied. Demographic, risk factors for the HIV-HCV infection, HIV-related (CD4+ T cell count, antiretroviral therapy, HIV viral load) and HCV-related (serum ALT concentration, HCV viral load, HCV genotype) characteristics and polymorphisms at position -238 and -308 of the tumor necrosis factor alfa (TNF- α) and -592 of the interleukin-10 (IL-10) promotor genes were studied. RESULTS: Evolution time of the infection was 21 years in both patients' groups (chronic hepatitis and liver cirrhosis). The group of patients with liver cirrhosis shows a lower CD4+ T cell count at the inclusion in the study (but not at diagnosis of HIV infection), a higher percentage of individuals with previous alcohol abuse, and a higher proportion of patients with the genotype GG at position -238 of the TNF-α promotor gene; polymorphism at -592 of the IL-10 promotor gene approaches to statistical significance. Serum concentrations of profibrogenic transforming growth factor beta1 were significantly higher in healthy controls with genotype GG at -238 TNF-α promotor gene. The linear regression analysis demonstrates that the genotype GG at -238 TNF-α promotor gene was the independent factor associated to liver cirrhosis. CONCLUSION: It is stressed the importance of immunogenetic factors (TNF-α polymorphism at -238 position), above other factors previously accepted (age, gender, alcohol, immunodepression), on the evolution to liver cirrhosis among HIV-infected patients with established chronic HCV infections.

Role of toll-like receptor 4 in mediating multiorgan dysfunction in mice with acetaminophen induced acute liver failure.

Strategies for the prevention of multiorgan dysfunction (MOD) in acetaminophen (APAP)-induced acute liver failure (ALF) are an unmet need. Our study tested the hypothesis that sterile inflammation induced by APAP in a mouse model would activate toll-like receptor 4 (TLR4) in the liver and extrahepatic organs and lead to the progression of ALF and MOD and that the administration of the novel TLR4 antagonist STM28 (a peptide formed of 17 amino-acids) would prevent liver injury and associated MOD. ALF and, subsequently, MOD were induced in TLR4-knockout (KO) mice (B6.B10ScN-Tlr4 (lpsdel) /JthJ) and wild-type (WT) mice (C57BL/6) with APAP (500 mg/kg). A second set of experiments was conducted to evaluate the effects of a pretreatment with a novel TLR4 antagonist, STM28, on APAP-induced MOD in CD1 mice. Animals were sacrificed at the coma stage, and plasma, peripheral blood cells, liver, kidneys, and brain were collected. Biochemistry values and cytokines were measured. Liver and kidneys were studied histologically and were stained for TLR4 and activated Kupffer cells, and the expression of nuclear factor kappa B-p65 was quantified with western blotting. Brain water was measured in the frontal cortex. After APAP administration, TLR4-KO (NFkBp65) mice were relatively protected from liver necrosis and end-organ dysfunction and had significantly better survival than WT controls (P < 0.01). STM28 attenuated liver injury and necrosis, reduced creatinine levels, and delayed the time to a coma significantly. The increases in cytokines in the plasma and liver, including TLR4 expression and the activation of Kupffer cells, after APAP administration were reduced significantly in the STM28-treated animals. The increased number of circulating myeloid cells was reduced significantly after STM28 treatment. In conclusion, these data provide evidence for an important role of the TLR4 antagonist in the prevention of the progression of APAP-induced ALF and MOD.

[Characteristics of tuberculosis in patients older than 65 years in the sanitary area of Cadiz (Spain)]. / Características de la tuberculosis en pacientes mayores de 65 años en el área sanitaria de Cádiz (España).

BACKGROUND: Tuberculosis in the elderly is an increasing public health problem. AIM: To describe the epidemiological, clinical and microbiological characteristics of tuberculosis in patients over 65 years old, as compared to younger patients. MATERIAL AND METHODS: We reviewed the case histories of tuberculosis, microbiologically diagnosed by Ziehl-Neelsen/auramine smear and Löwenstein-Jensen culture, in patients over 65 years old, in the sanitary area of Cadiz (Spain). RESULTS: We detected 49 new cases (37 males) of tuberculosis in elderly subjects. The infection rate in this age group (16.3/100,000 inhabitants) is lower than in people younger than 65 years old (21.1/100,000 inhabitants). The most common symptoms were cough (44.9%), fever (40.8%) and dyspnea (44.9%). Neither of them were infected by the human immunodeficiency virus nor were parenteral drug abusers. Thirty seven percent of cases had a history of previous tuberculosis, and in 75.5% the disease location was pulmonary. The Ziehl-Neelsen/auramine smear was negative in 53.1% of the samples. CONCLUSIONS: The number of patients older than 65 years old with tuberculosis has increased in the sanitary area of Cadiz (Spain). This group of patients shows different epidemiological and clinical characteristics than younger patients.

Características de la tuberculosis en pacientes mayores de 65 años en el área sanitaria de Cádiz (España) / Characteristics of tuberculosis in patients older than 65 years in the sanitary area of Cadiz (Spain)

Background : Tuberculosis in the elderly is an increasing public health problem. Aim: To describe the epidemiological, clinical and microbiological characteristics of tuberculosis in patients over 65 years old, as compared to younger patients. Material and methods: We reviewed the case histories of tuberculosis, microbiologically diagnosed by Ziehl-Neelsen/auramine smear and L÷wenstein-Jensen culture, in patients over 65 years old, in the sanitary area of Cadiz (Spain). Results: We detected 49 new cases (37 males) of tuberculosis in elderly subjects. The infection rate in this age group (16.3/100.000 inhabitants) is lower than in people younger than 65 years old (21.1/100.000 inhabitants). The most common symptoms were cough (44.9 percent), fever (40.8 percent) and dyspnea (44.9 percent). Neither of them were infected by the human immunodeficiency virus nor were parenteral drug abusers. Thirty seven percent of cases had a history of previous tuberculosis, and in 75.5 percent the disease location was pulmonary. The Ziehl-Neelsen/auramine smear was negative in 53.1 percent of the samples. Conclusions: The number of patients older than 65 years old with tuberculosis has increased in the sanitary area of Cadiz (Spain). This group of patients shows different epidemiological and clinical characteristics than younger patients (Rev MÚd Chile 2004; 132: 325-30).