Apolipoprotein-AII Concentrations are Associated With Liver Steatosis in Patients With Chronic Hepatitis C

It has been shown that the hepatitis C virus (HCV) core protein reduces the activity of the microsomal triglyceride transfer protein (MTP) and could lead to steatosis in HCV-infected patients. Experimentally, apolipoprotein-AII (apoAII), which restores triglyceride secretion altered by the HCV core protein, could be protective against HCV steatosis. On the other hand, increasing plasma concentrations of mouse apoAII in transgenic mice produced several aspects of insulin-resistance syndrome, which also is implicated in the pathogenesis of HCV steatosis. This study was designed to investigate the role of apoAII in HCV-related steatosis in humans. Sixty-five hospitalized patients with chronic HCV were included in this study to assess the effects of apoAII, body mass index (BMI), age, insulin sensibility (HOMA), and leptin level on steatosis. Steatosis was observed in 55.3% of patients. Apo-AII was significantly associated with HOMA and with leptin concentrations. In univariate analyses, age, BMI, increased leptin level, increased HOMA, and increased apoAII concentration were associated with steatosis. In multivariate analysis, steatosis was associated with apoAII concentration, age, gender, and BMI. Contrary to previous hypotheses, apoAII is not a protective factor against HCV steatosis but is significantly associated with the development of liver steatosis. The fact that the plasma levels of apoAII correlate with HOMA and leptin levels in HCV-infected patients suggests that apoAII may contribute to hepatic steatosis progression in relationship to visceral obesity, insulin resistance, and metabolism of triglyceride-rich lipoproteins. Supported by the Centre Hospitalier Universitaire de Dijon (PHRC 2001).     

Frequency of going outdoors predicts long-range functional change among ambulatory frail elders living at home

The purpose of the study was to investigate the relationships between frequency of going outdoors and subsequent functional and psychosocial changes over a 20-month period. Data were collected from community-dwelling 107 frail elders who could walk independently but who still needed some assistance to live on their own. Functional and psychosocial status at baseline and follow-up were compared among three groups defined by the frequency of going outdoors: (1) four or more times a week, (2) one to three times a week and (3) less than once a week. At baseline, elders going outdoors more often were less functionally impaired, more socially active, and less depressed than elders going outdoors less often. There was a significant difference in change over time of activities of daily living (ADLs) (p=0.002) among the three groups, even when controlling for baseline differences, and the scores of those who went outdoors almost daily were least likely to decline. More of those going outdoors four or more times a week at baseline were still living at home at follow-up than those in the other two groups (p=0.048). These results suggest that the frequency of going outdoors can predict changes in ADLs over at least a 20-month period.     

3' Mutation of the APC gene and family history of FAP in a patient with apparently sporadic desmoid tumors

Desmoid tumors may occur sporadically or as part of the extraintestinal manifestations of familial adenomatous polyposis. Different phenotypes have been described and some genotype-phenotype correlations have been raised, associated with different sites of germline mutations in the adenomatous polyposis coli (APC) gene. We report on a 42-year-old woman ascertained for a large desmoid tumor of the anterior chest wall with pleural involvement, which persistently recurred despite a decade of treatment including hormone therapy, chemotherapy, and surgery. Spontaneous disappearance of the tumor was later noted after 1 year without any treatment and confirmed after 4 years of regular follow-up. Repeated colonoscopies were normal in the proband and DNA sequencing showed a frameshift mutation due to a single adenosine deletion at position 5772 (codon 1924). This mutation, located in the exon 15 at the 3' end of the APC gene, leads to an unusual and late onset phenotype. The pedigree revealed other isolated or familial adenomatous polyposis-associated cases of desmoid tumors. This family report shows that a molecular analysis of the APC gene should be performed in familial desmoid tumors for accurate genetic counseling and follow-up.     

Allograft rejection mediated by memory T cells is resistant to regulation

Alloreactive memory T cells may be refractory to many of the tolerance-inducing strategies that are effective against naive T cells and thus present a significant barrier to long-term allograft survival. Because CD4(+)CD25(+) regulatory T cells (Tregs) are critical elements of many approaches to successful induction/maintenance of transplantation tolerance, we used MHC class I and II alloreactive TCR-transgenic models to explore the ability of antigen-specific Tregs to control antigen-specific memory T cell responses. Upon coadoptive transfer into RAG-1(-/-) mice, we found that Tregs effectively suppressed the ability of naive T cells to reject skin grafts, but neither antigen-unprimed nor antigen-primed Tregs suppressed rejection by memory T cells. Interestingly, different mechanisms appeared to be active in the ability of Tregs to control naive T cell-mediated graft rejection in the class II versus class I alloreactive models. In the former case, we observed decreased early expansion of effector cells in lymphoid tissue. In contrast, in the class I model, an effect of Tregs on early proliferation and expansion was not observed. However, at a late time point, significant differences in cell numbers were seen, suggesting effects on responding T cell survival. Overall, these data indicate that the relative resistance of both CD4(+) and CD8(+) alloreactive memory T cells to regulation may mediate resistance to tolerance induction seen in hosts with preexisting alloantigen-specific immunity and further indicate the multiplicity of mechanisms by which Tregs may control alloimmune responses in vivo.     

Valproic acid induces apoptosis in chronic lymphocytic leukemia cells through activation of the death receptor pathway and potentiates TRAIL response

OBJECTIVE: Chronic lymphocytic leukemia (CLL) cells develop chemoresistance over time associated with defects in apoptosis pathway. Novel treatment strategies are required to overcome resistance of cells to commonly used agents. The effects of valproic acid (VPA), an antiepileptic drug with histone deacetylase inhibitory activity, on mononuclear cells isolated from 40 CLL patients were evaluated. METHODS: CLL cells were treated with increasing doses of VPA (0.5, 1, 2, and 5 mM). The mode of cytotoxic drug action was determined by annexin binding, DNA fragmentation, and caspase activation. RESULTS: Exposure of CLL cells to VPA resulted in dose-dependent cytotoxicity and apoptosis in the 40 CLL patients. VPA treatment induced apoptotic changes in CLL cells including phosphatidylserine externalization and DNA fragmentation. The mean apoptotic rates were similar between IgV(H) mutated and unmutated patients, the latter presenting a more aggressive clinical course. VPA induced apoptosis via the extrinsic pathway involving engagement of the caspase-8-dependent cascade. Although CLL cells are commonly resistant to death receptor-induced apoptosis, VPA significantly increased sensitivity of leukemic cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and led to downregulation of c-FLIP (L) expression. VPA caused no potentialization of TRAIL-induced apoptosis on normal B cells. In addition, VPA overcame the prosurvival effects of bone marrow stromal cells. CONCLUSION: These findings point out that the combination of TRAIL and VPA, at clinically relevant concentration, may be valuable in the treatment of CLL.     

Mesenteric ischemia in giant cell arteritis: 6 cases and a systematic review

OBJECTIVE: To report the main features of mesenteric ischemia related to giant cell arteritis (GCA). METHODS: We screened 13 French internal medicine tertiary care centers for their cases of patients exhibiting GCA-associated mesenteric ischemia during a 16-year period (1990-2006). Patients were included if they reported newly developed abdominal symptoms associated with histological proof of GCA-associated mesenteric vasculitis and/or radiological abnormalities consistent with GCA-associated mesenteric vasculitis. We performed a Medline search to identify previously reported cases of GCA-associated mesenteric ischemia. RESULTS: We included 6 original cases and 22 cases identified in the literature (mean age of the 28 patients: 72.4 +/- 7.1 yrs; women: 79%). GCA was histologically proven for all patients. In 12 patients GCA diagnosis preceded mesenteric inflammatory arteritis. Mesenteric ischemia occurred either soon after initiation of steroid therapy (n = 6, mean time to onset after starting steroid 12 +/- 11 days) or with a low-dose steroid regimen (n = 6, dosage 0-10 mg/day). In 16 other patients, the mesenteric involvement was the first manifestation of GCA. Only 6 patients (21%) reported cardiovascular risk factors. Clinical manifestations of GCA-associated mesenteric ischemia, as well as biological markers (mean C-reactive protein level 91 +/- 50 mg/l), were very nonspecific. Imaging explorations were performed for 14 patients and showed specific signs of vasculitis on the mesenteric artery in 10 (71%). Nineteen patients (68%) required laparotomy and 9 patients (33%) died. CONCLUSION: Early diagnosis and medical management of mesenteric GCA may ameliorate the severe prognosis of this possibly underdiagnosed complication.     

Opposite effects of leptin on bone metabolism: a dose-dependent balance related to energy intake and insulin-like growth factor-I pathway

Published data describing leptin effects on bone are at variance with both positive and negative consequences reported. These findings are consistent with a bimodal threshold response to serum leptin levels. To test this theory, two groups of female rats (tail-suspended and unsuspended) were treated with ip leptin at two different doses or vehicle for 14 d. In tail-suspended rats, low-dose leptin compensated the decrease in serum leptin levels observed with suspension and was able to prevent the induced bone loss at both the trabecular and cortical level (assessed by three-dimensional microtomography). In contrast, high-dose leptin inhibited femoral bone growth and reduced bone mass by decreasing bone formation rate and increasing bone resorption in both tail-suspended and unsuspended groups. High- and low-dose leptin administration resulted in a reduced medullar adipocytic volume in all groups. High-dose leptin (but not low) induced a decrease in body-weight abdominal fat mass and serum IGF-I levels. Thus, the observed bone changes at high-dose leptin are at least partly mediated by a leptin-induced energy imbalance. In conclusion, a balance between negative and positive leptin effects on bone is dependent on a bimodal threshold that is triggered by leptin serum concentration. Also, the negative effects of high leptin levels are likely induced by reduced energy intake and related hormonal changes. The respective part of each pathway will be unraveled by additional studies.     

HIV and malaria: interactions and implications

PURPOSE OF REVIEW: This review summarizes accumulating evidence of interactions between HIV and malaria and implications related to prevention and treatment of coinfection. RECENT FINDINGS: HIV-infected persons are at increased risk for clinical malaria; the risk is greatest when immune suppression is advanced. Adults with advanced HIV may be at risk for failure of malaria treatment, especially with sulfa-based therapies. Malaria is associated with increases in HIV viral load that, while modest, may impact HIV progression or the risk of HIV transmission. Cotrimoxazole prophylaxis greatly reduces the risk of malaria in people with HIV; the risk can be further reduced with antiretroviral treatment and the use of insecticide treated mosquito nets. Increased numbers of doses of intermittent preventive treatment during pregnancy can reduce the risk of placental malaria in women with HIV. SUMMARY: Interactions between malaria and HIV have important public health implications. People with HIV should use cotrimoxazole and insecticide treated mosquito nets. Malaria prevention is particularly important for pregnant women with HIV, although more information is needed about the best combination of strategies for prevention. In people with HIV, malaria diagnoses should be confirmed, highly effective drugs should be used for treatment, and possible drug interactions should be considered.     

Long-term safety, effectiveness and quality of a generic fixed-dose combination of nevirapine, stavudine and lamivudine

We assessed the long-term safety, effectiveness and quality of a fixed-dose combination of nevirapine, stavudine and lamivudine (triomune). HIV-1-infected adults initially enrolled in a one-year, open-label, single-arm, multicentre trial in Cameroon were followed for 2 years. Our results support the safety and effectiveness of the triomune combination for first-line treatment of HIV infection. Virological effectiveness appeared to wane somewhat during the second year of treatment, however, and plasma nevirapine concentrations were relatively high.