Changes in biomarkers of liver disease during successful combination antiretroviral therapy in HIV-HCV-coinfected individuals.

BACKGROUND: We investigated changes in biomarkers of liver disease in HIV-HCV-coinfected individuals during successful combination antiretroviral therapy (cART) compared to changes in biomarker levels during untreated HIV infection and to HIV-monoinfected individuals. METHODS: Non-invasive biomarkers of liver disease (hyaluronic acid [HYA], aspartate aminotransferase-to-platelet ratio index [APRI], Fibrosis-4 [FIB-4] index and cytokeratin-18 [CK-18]) were correlated with liver histology in 49 HIV-HCV-coinfected patients. Changes in biomarkers over time were then assessed longitudinally in HIV-HCV-coinfected patients during successful cART (n=58), during untreated HIV-infection (n=59), and in HIV-monoinfected individuals (n=17). The median follow-up time was 3.4 years on cART. All analyses were conducted before starting HCV treatment. RESULTS: Non-invasive biomarkers of liver disease correlated significantly with the histological METAVIR stage (P<0.002 for all comparisons). The mean ±sd area under the receiver operating characteristic (AUROC) curve values for advanced fibrosis (≥F3 METAVIR) for HYA, APRI, FIB-4 and CK-18 were 0.86 ±0.05, 0.84 ±0.08, 0.80 ±0.09 and 0.81 ±0.07, respectively. HYA, APRI and CK-18 levels were higher in HIV-HCV-coinfected compared to HIV-monoinfected patients (P<0.01). In the first year on cART, APRI and FIB-4 scores decreased (-35% and -33%, respectively; P=0.1), mainly due to the reversion of HIV-induced thrombocytopaenia, whereas HYA and CK-18 levels remained unchanged. During long-term cART, there were only small changes (<5%) in median biomarker levels. Median biomarker levels changed <3% during untreated HIV-infection. Overall, 3 patients died from end-stage liver disease, and 10 from other causes. CONCLUSIONS: Biomarkers of liver disease highly correlated with fibrosis in HIV-HCV-coinfected individuals and did not change significantly during successful cART. These findings suggest a slower than expected liver disease progression in many HIV-HCV-coinfected individuals, at least during successful cART.

Bloc atrioventriculaire complet sur borréliose de Lyme: aspects etectrocardiographiques, diagnostiques et microbiologiques [Atrioventricular heart block in Lyme disease]

Lyme disease is the most common tick-borne disease in Europe and in the United States. In comparison to dermatological, neurological and rheumatological manifestations, heart disease is quite rare. Atrioventricular heart block is nevertheless the most frequent cardiological manifestation. We hereby report the case of a patient with high degree heart block due to Lyme disease. We focus on the electrocardiographical evolution during antibiotic therapy, as well as on microbiological and diagnostic aspects. Lyme disease is a rare cause of conduction disturbances but it is treatable and potentially reversible.

The ADVANCE trial: clarifying the role of perindopril/indapamide fixed-dose combination in the reduction of cardiovascular and renal events in patients with diabetes mellitus.

Patients with type 2 diabetes mellitus exhibit a marked increase in cardiovascular and renal risk. A number of interventional trials have shown that these patients benefit greatly from aggressive BP lowering, especially when the drug regimen comprises an inhibitor of the renin-angiotensin system. The results of the placebo-controlled ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) trial, conducted in patients with type 2 diabetes, are exemplary in this respect. The systematic use of a fixed-dose combination containing the ACE inhibitor perindopril and the diuretic indapamide afforded substantial protection against cardiovascular mortality and myocardial infarction, while providing important renoprotection, reducing the development of micro- and macroalbuminuria, and allowing regression of nephropathy. The beneficial effects were obtained regardless of baseline BP and whether or not the patients were receiving antihypertensive therapy.

In leishmaniasis due to Leishmania guyanensis infection, distinct intralesional interleukin-10 and Foxp3 mRNA expression are associated with unresponsiveness to treatment.

The presence of intralesional natural regulatory T cells, characterized by the expression of Foxp3 mRNA, was analyzed in patients with localized leishmaniasis due to Leishmania guyanensis infection that was unresponsive to treatment with pentamidine isethionate. Foxp3 mRNA levels were associated with unresponsiveness to treatment among patients with a lesion duration of 1 month, but this association was not observed among patients with a lesion duration of <1 month. In conclusion, high intralesional expression of Foxp3 might be an indicator of poor response to treatment, depending on the duration of lesions.

Effect of once-yearly zoledronic acid five milligrams on fracture risk and change in femoral neck bone mineral density.

CONTEXT: In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly - Pivotal Fracture Trial (HORIZON-PFT), zoledronic acid (ZOL) 5 mg significantly reduced fracture risk. OBJECTIVE: The aim of the study was to identify factors associated with greater efficacy during ZOL 5 mg treatment. DESIGN, SETTING, AND PATIENTS: We conducted a subgroup analysis (preplanned and post hoc) of a multicenter, double-blind, placebo-controlled, 36-month trial in 7765 women with postmenopausal osteoporosis. Intervention: A single infusion of ZOL 5 mg or placebo was administered at baseline, 12, and 24 months. MAIN OUTCOME MEASURES: Primary endpoints were new vertebral fracture and hip fracture. Secondary endpoints were nonvertebral fracture and change in femoral neck bone mineral density (BMD). Baseline risk factor subgroups were age, BMD T-score and vertebral fracture status, total hip BMD, race, weight, geographical region, smoking, height loss, history of falls, physical activity, prior bisphosphonates, creatinine clearance, body mass index, and concomitant osteoporosis medications. RESULTS: Greater ZOL induced effects on vertebral fracture risk were seen with younger age (treatment-by-subgroup interaction, P = 0.05), normal creatinine clearance (P = 0.04), and body mass index >or= 25 kg/m(2) (P = 0.02). There were no significant treatment-factor interactions for hip or nonvertebral fracture or for change in BMD. CONCLUSIONS: ZOL appeared more effective in preventing vertebral fracture in younger women, overweight/obese women, and women with normal renal function. ZOL had similar effects irrespective of fracture risk factors or femoral neck BMD.

Trends over time of virological and immunological characteristics in the Swiss HIV Cohort Study.

BACKGROUND: The long-term outcome of antiretroviral therapy (ART) is not assessed in controlled trials. We aimed to analyse trends in the population effectiveness of ART in the Swiss HIV Cohort Study over the last decade. METHODS: We analysed the odds of stably suppressed viral load (ssVL: three consecutive values <50 HIV-1 RNA copies/mL) and of CD4 cell count exceeding 500 cells/μL for each year between 2000 and 2008 in three scenarios: an open cohort; a closed cohort ignoring the influx of new participants after 2000; and a worst-case closed cohort retaining lost or dead patients as virological failures in subsequent years. We used generalized estimating equations with sex, age, risk, non-White ethnicity and era of starting combination ART (cART) as fixed co-factors. Time-updated co-factors included type of ART regimen, number of new drugs and adherence to therapy. RESULTS: The open cohort included 9802 individuals (median age 38 years; 31% female). From 2000 to 2008, the proportion of participants with ssVL increased from 37 to 64% [adjusted odds ratio (OR) per year 1.16 (95% CI 1.15-1.17)] and the proportion with CD4 count >500 cells/μL increased from 40 to >50% [OR 1.07 (95% CI 1.06-1.07)]. Similar trends were seen in the two closed cohorts. Adjustment did not substantially affect time trends. CONCLUSIONS: There was no relevant dilution effect through new participants entering the open clinical cohort, and the increase in virological/immunological success over time was not an artefact of the study design of open cohorts. This can partly be explained by new treatment options and other improvements in medical care.

Unaltered glucose-induced thermogenesis in Graves' disease.

The thermogenic response to a 100-g oral glucose challenge was studied in 12 patients with Graves' disease using continuous indirect calorimetry. Seven hyperthyroid patients were reinvestigated under the same experimental conditions after medical therapy. The mean net increase in energy expenditure (delta EE) following the glucose challenge was the same in hyperthyroid patients as compared to a control group (delta EE = +0.15 +/- 0.02 and 0.15 +/- 0.01 kcal/min, respectively) and the treated patients (delta EE = +0.11 +/- 0.03 kcal/min ns). When expressed as a percentage of the energy content of the glucose challenge, the mean glucose induced thermogenesis was similar in all three groups: 7.0 +/- 1.0%, 7.4 +/- 0.5%, and 5.5 +/- 1.3% in hyperthyroid, control subjects, and treated patients, respectively. It is concluded that the high energy requirement of hyperthyroid patients is due primarily to an elevated resting energy expenditure. The postprandial thermogenesis in itself does not contribute to the elevated fuel utilization in Graves' disease.

Does less frequent routine monitoring of patients on a stable, fully suppressed cART regimen lead to an increased risk of treatment failure?

OBJECTIVE: To investigate whether HIV-infected patients on a stable and fully suppressive combination antiretroviral therapy (cART) regimen could safely be monitored less often than the current recommendations of every 3 months. DESIGN: Two thousand two hundred and forty patients from the EuroSIDA study who maintained a stable and fully suppressed cART regimen for 1 year were included in the analysis. METHODS: Risk of treatment failure, defined by viral rebound, fall in CD4 cell count, development of new AIDS-defining illness, serious opportunistic infection or death, in the 12 months following a year of a stable and fully suppressed regimen was assessed. RESULTS: One hundred thirty-one (6%) patients experienced treatment failure in the 12 months following a year of stable therapy, viral rebound occurred in 99 (4.6%) patients. After 3, 6 and 12 months, patients had a 0.3% [95% confidence interval (CI) 0.1-0.5], 2.2% (95% CI 1.6-2.8) and 6.0% (95% CI 5.0-7.0) risk of treatment failure, respectively. Patients who spent more than 80% of their time on cART with fully suppressed viraemia prior to baseline had a 38% reduced risk of treatment failure, hazard ratio 0.62 (95% CI 0.42-0.90, P = 0.01). CONCLUSION: Patients who have responded well to cART and are on a well tolerated and durably fully suppressive cART regimen have a low chance of experiencing treatment failure in the next 3-6 months. Therefore, in this subgroup of otherwise healthy patients, it maybe reasonable to extend visit intervals to 6 months, with cost and time savings to both the treating clinics and the patients.

Fibrose rétropéritonéale: cause rare d'insuffisance rénale postrénale, a ne pas méconnaître [Retroperitoneal fibrosis: a rare cause of postrenal kidney failure, no to be missed].

We report the observation of a fifty years old man, admitted in the emergency room for bilateral lumbar pain and hyperkaliemic metabolic acidosis, and postrenal kidney failure induced by bilateral hydronephrosis. Radiographic exploration and histologic studies of biopsy confirmed an idiopathic retroperitoneal fibrosis that clinically and biologicaly responded to three seances of hemodialysis, and insertion in each uretere of one double J stent, and long term corticotherapy. The retroperitoneal fibrosis is a little common inflammatory disease, characterized by the development of a fibrous mass around the retroperitoneal structures. His diagnostic means evolved. On the other hand, his treatment was the object of no checked controlled and randomized trial. This article proposes an updating of the knowledge on this subject.

Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial.

BACKGROUND: Platinum-based doublet chemotherapy is recommended to treat advanced non-small-cell lung cancer (NSCLC) in fit, non-elderly adults, but monotherapy is recommended for patients older than 70 years. We compared a carboplatin and paclitaxel doublet chemotherapy regimen with monotherapy in elderly patients with advanced NSCLC. METHODS: In this multicentre, open-label, phase 3, randomised trial we recruited patients aged 70-89 years with locally advanced or metastatic NSCLC and WHO performance status scores of 0-2. Patients received either four cycles (3 weeks on treatment, 1 week off treatment) of carboplatin (on day 1) plus paclitaxel (on days 1, 8, and 15) or five cycles (2 weeks on treatment, 1 week off treatment) of vinorelbine or gemcitabine monotherapy. Randomisation was done centrally with the minimisation method. The primary endpoint was overall survival, and analysis was done by intention to treat. This trial is registered, number NCT00298415. FINDINGS: 451 patients were enrolled. 226 were randomly assigned monotherapy and 225 doublet chemotherapy. Median age was 77 years and median follow-up was 30.3 months (range 8.6-45.2). Median overall survival was 10.3 months for doublet chemotherapy and 6.2 months for monotherapy (hazard ratio 0.64, 95% CI 0.52-0.78; p<0.0001); 1-year survival was 44.5% (95% CI 37.9-50.9) and 25.4% (19.9-31.3), respectively. Toxic effects were more frequent in the doublet chemotherapy group than in the monotherapy group (most frequent, decreased neutrophil count (108 [48.4%] vs 28 [12.4%]; asthenia 23 [10.3%] vs 13 [5.8%]). INTERPRETATION: Despite increased toxic effects, platinum-based doublet chemotherapy was associated with survival benefits compared with vinorelbine or gemcitabine monotherapy in elderly patients with NSCLC. We feel that the current treatment paradigm for these patients should be reconsidered. FUNDING: Intergroupe Francophone de Cancérologie Thoracique, Institut National du Cancer.

Prognostic and predictive value of centrally reviewed Ki-67 labeling index in postmenopausal women with endocrine-responsive breast cancer: results from Breast International Group Trial 1-98 comparing adjuvant tamoxifen with letrozole.

PURPOSE: To evaluate the prognostic and predictive value of Ki-67 labeling index (LI) in a trial comparing letrozole (Let) with tamoxifen (Tam) as adjuvant therapy in postmenopausal women with early breast cancer. PATIENTS AND METHODS: Breast International Group (BIG) trial 1-98 randomly assigned 8,010 patients to four treatment arms comparing Let and Tam with sequences of each agent. Of 4,922 patients randomly assigned to receive 5 years of monotherapy with either agent, 2,685 had primary tumor material available for central pathology assessment of Ki-67 LI by immunohistochemistry and had tumors confirmed to express estrogen receptors after central review. The prognostic and predictive value of centrally measured Ki-67 LI on disease-free survival (DFS) were assessed among these patients using proportional hazards modeling, with Ki-67 LI values dichotomized at the median value of 11%. RESULTS: Higher values of Ki-67 LI were associated with adverse prognostic factors and with worse DFS (hazard ratio [HR; high:low] = 1.8; 95% CI, 1.4 to 2.3). The magnitude of the treatment benefit for Let versus Tam was greater among patients with high tumor Ki-67 LI (HR [Let:Tam] = 0.53; 95% CI, 0.39 to 0.72) than among patients with low tumor Ki-67 LI (HR [Let:Tam] = 0.81; 95% CI, 0.57 to 1.15; interaction P = .09). CONCLUSION: Ki-67 LI is confirmed as a prognostic factor in this study. High Ki-67 LI levels may identify a patient group that particularly benefits from initial Let adjuvant therapy.

Loss of penicillin tolerance by inactivating the carbon catabolite repression determinant CcpA in Streptococcus gordonii.

OBJECTIVES: Antibiotic tolerance is a phenomenon allowing bacteria to withstand drug-induced killing. Here, we studied a penicillin-tolerant mutant of Streptococcus gordonii (Tol1), which was shown to be deregulated in the expression of the arginine deiminase operon (arc). arc was not directly responsible for tolerance, but is controlled by the global regulator CcpA. Therefore, we sought whether CcpA might be implicated in tolerance. METHODS: The ccpA gene was characterized and subsequently inactivated by PCR ligation mutagenesis in both the susceptible wild-type (WT) and Tol1. The minimal inhibitory concentration and time-kill curves for the strains were determined and the outcome of penicillin treatment in experimental endocarditis assessed. RESULTS: ccpA sequence and expression were similar between the WT and Tol1 strains. In killing assays, the WT lost 3.5 +/- 0.6 and 5.3 +/- 0.6 log(10) cfu/mL and Tol1 lost 0.4 +/- 0.2 and 1.4 +/- 0.9 log(10) cfu/mL after 24 and 48 h of penicillin exposure, respectively. Deletion of ccpA almost totally restored Tol1 kill susceptibility (loss of 2.5 +/- 0.7 and 4.9 +/- 0.7 log(10) cfu/mL at the same endpoints). In experimental endocarditis, penicillin treatment induced a significant reduction in vegetation bacterial densities between Tol1 (4.1 log(10) cfu/g) and Tol1DeltaccpA (2.4 log(10) cfu/g). Restitution of ccpA re-established the tolerant phenotype both in vitro and in vivo. CONCLUSIONS: CcpA, a global regulator of the carbon catabolite repression system, is implicated in penicillin tolerance both in vitro and in vivo. This links antibiotic survival to bacterial sugar metabolism. However, since ccpA sequence and expression were similar between the WT and Tol1 strains, other factors are probably involved in tolerance.

Management of faecal incontinence and constipation in adults with central neurological diseases.

BACKGROUND: People with neurological disease have a much higher risk of both faecal incontinence and constipation than the general population. There is often a fine line between the two conditions, with any management intended to ameliorate one risking precipitating the other. Bowel problems are observed to be the cause of much anxiety and may reduce quality of life in these people. Current bowel management is largely empirical with a limited research base. OBJECTIVES: To determine the effects of management strategies for faecal incontinence and constipation in people with neurological diseases affecting the central nervous system. SEARCH STRATEGY: We searched the Cochrane Incontinence Group Specialised Trials Register (searched 26 January 2005), the Cochrane Central Register of Controlled Trials (Issue 2, 2005), MEDLINE (January 1966 to May 2005), EMBASE (January 1998 to May 2005) and all reference lists of relevant articles. SELECTION CRITERIA: All randomised or quasi-randomised trials evaluating any types of conservative or surgical measure for the management of faecal incontinence and constipation in people with neurological diseases were selected. Specific therapies for the treatment of neurological diseases that indirectly affect bowel dysfunction were also considered. DATA COLLECTION AND ANALYSIS: Two reviewers assessed the methodological quality of eligible trials and two reviewers independently extracted data from included trials using a range of pre-specified outcome measures. MAIN RESULTS: Ten trials were identified by the search strategy, most were small and of poor quality. Oral medications for constipation were the subject of four trials. Cisapride does not seem to have clinically useful effects in people with spinal cord injuries (three trials). Psyllium was associated with increased stool frequency in people with Parkinson's disease but did not alter colonic transit time (one trial). Prucalopride, an enterokinetic did not demonstrate obvious benefits in this patient group (one study). Some rectal preparations to initiate defaecation produced faster results than others (one trial). Different time schedules for administration of rectal medication may produce different bowel responses (one trial). Mechanical evacuation may be more effective than oral or rectal medication (one trial). There appears to be a benefit to patients in one-off educational interventions from nurses. The clinical significance of any of these results is difficult to interpret. AUTHORS' CONCLUSIONS: There is still remarkably little research on this common and, to patients, very significant condition. It is not possible to draw any recommendation for bowel care in people with neurological diseases from the trials included in this review. Bowel management for these people must remain empirical until well-designed controlled trials with adequate numbers and clinically relevant outcome measures become available.