Outbreaks of serogroup X meningococcal meningitis in Niger 1995-2000

In the African meningitis belt, the recurrent meningococcal meningitis epidemics are generally caused by serogroup A. In the past 20 years, other serogroups have been detected, such as X or W135, which have caused sporadic cases or clusters. We report here 134 meningitis cases caused by Neisseria meningitidis serogroup X that occurred in Niamey between 1995 and 2000. They represented 3.91% of the meningococcal isolates from all CSF samples, whereas 94.4% were of serogroup A. Meningococcal meningitis cases were detected using the framework of the routine surveillance system for reportable diseases organized by the Ministry of Public Health of Niger. The strains were isolated and determined by the reference laboratory for meningitis in Niamey (CERMES) and further typed at the WHO collaborating center of the Pharo in Marseille and at the National Reference Center for the Meningococci at the Institut Pasteur. Reference laboratories in Marseille and Paris characterized 47 isolates having the antigenic formula (serogroup:serotype:sero-subtype) X:NT:P1.5. Meningitis cases due to meningococcus serogroup X did not present any clinical or epidemiological differences to those due to serogroup A. The seasonal incidence was classical; 93.3% of the cases were recorded during the dry season. The mean age of patients was 9.2 years (+/- 6 years). The sex ratio M/F was 1.3. Case fatality rate was 11.9% without any difference related to age or sex. The increasing incidence of the serogroup X was not related to the decrease of serogroup A, but seemed cyclic, and evolved independently of the recurrence of both serogroups A and C.     

Interferon-alpha reduces insulin resistance and beta-cell secretion in responders among patients with chronic hepatitis B and C

This study aimed at elucidating the effects of interferon (IFN)-alpha on glucose metabolism in patients with chronic hepatitis B and C infections. Twenty-eight biopsy-proven patients with chronic hepatitis B (ten cases) and hepatitis C (18 cases) were given IFN-alpha for a total of 24 weeks. The patients received a 75 g oral glucose tolerance test (OGTT), glucagon stimulation test, tests for type 1 diabetes-related autoantibodies and an insulin suppression test before and after IFN-alpha therapy. Ten of the 28 patients responded to IFN-alpha therapy. Steady-state plasma glucose of the insulin suppression test decreased significantly in responders (13.32+/-1.48 (S.E.M.) vs 11.33+/-1.19 mmol/l, P=0.0501) but not in non-responders (12.29+/-1.24 vs 11.11+/-0.99 mmol/l, P=0.2110) immediately after completion of IFN-alpha treatment. In the oral glucose tolerance test, no significant difference was observed in plasma glucose in either responders (10.17+/-0.23 vs 10.03+/-0.22 mmol/l) or non-responders (10.11+/-0.22 vs 9.97+/-0.21 mmol/l) 3 Months after completion of IFN-alpha treatment. However, significant differences were noted in C-peptide in both responders (2.90+/-0.13 vs 2.20+/-0.09 nmol/l, P=0.0040) and non-responders (2.45+/-0.11 vs 2.22+/-0.08 nmol/l, P=0.0287) before vs after treatment. The changes of C-peptide in an OGTT between responders and non-responders were also significantly different (P=0.0028), with responders reporting a greater reduction in C-peptide. No case developed autoantibodies during the treatment. In patients who were successfully treated with IFN-alpha, insulin sensitivity improved and their plasma glucose stayed at the same level without secreting as much insulin from islet beta-cells.     

Relationship of clinical and virological factors with hepatitis activity in hepatitis B e antigen-negative chronic hepatitis B virus-infected patients

To investigate the factors associated with active disease among hepatitis B surface antigen (HBsAg) positive/hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV) infection we studied chronic HBV infected patients who had undetectable HBeAg at the first visit. HBV DNA was determined by the cross-linking assay (NAXCOR) and polymerase chain reaction (PCR). Mutations in the core promoter and precore regions and viral genotypes were studied. Clinical outcome of these patients were followed and categorized as: (i) relapse (ALT > 200 IU/L or three times the previous levels); (ii) active hepatitis (elevated ALT < 200 IU/L with concomitant detectable HBV DNA); or (iii) remission. A total of eighty-five patients were followed up for 5.5 ± 1.0 years. At first visit, 31 (36.5%) patients had elevated ALT levels, 12 (14.1%) had measurable HBV DNA by the cross-linking assay and 26 (30.6%) by PCR. Sixteen (18.8%) patients had hepatitis relapse, 13 (15.3%) had active hepatitis, and 56 (65.9%) remained in remission. Core promoter and precore stop codon mutants were found in 27 and 12 patients, respectively. Eleven and 20 had genotype B and C HBV, respectively. Initial elevated ALT and detectable HBV DNA were associated with active liver disease. Patient demographics, viral mutants or genotypes failed to predict disease activity. Hence, serum ALT and HBV DNA levels offer the best prediction of natural course of HBeAg-negative chronic HBV infection.     

Evaluation of model for end-stage liver disease for prediction of mortality in decompensated chronic hepatitis B

OBJECTIVES: We aimed to study the predictive ability of model for end-stage liver disease (MELD) for short-term mortality in chronic hepatitis B. METHODS: All patients admitted from 1996 to 2003 because of chronic hepatitis B and its related complications were identified by electronic search of the hospital database. MELD and Child-Turcotte-Pugh (CTP) scores on initial admissions were calculated. Cox proportional hazard model was used to determine the factors associated with mortality. The area under receiver operator characteristics curve (AUC) was used to determine the predictive abilities of the two models for 3-month and 1-yr mortalities. RESULTS: A total of 2,073 patients was admitted because of liver-related problems and 506 patients had chronic hepatitis B-related complications. Two hundred fifty-six (51%) patients died and 16 (3%) patients underwent liver transplantation. In multivariate analysis, MELD and CTP scores were independent predictors of 3-month and 1-yr mortality. Other independent predictors of mortality included older age, hepatocellular carcinoma (HCC), lamivudine treatment, and lower serum sodium. At both 3 months and 1 yr, the AUC of the MELD score (0.65 and 0.63, respectively) was significantly lower than that of the CTP score (0.75 and 0.77, respectively) (p < 0.0001). The differences remained significant when only liver cirrhosis patients without HCC at presentation were analyzed, but the AUC of the two scores became comparable when patients on lamivudine were excluded. CONCLUSIONS: The MELD score is a valid prognostic model in decompensated chronic hepatitis B. Lamivudine treatment may affect the performance of MELD score. Other variables including those in CTP score may improve its predictive ability.     

BNP and echocardiography can predict the occurrence of acute cardiac decompensation during titration of bisoprolol in chronic systolic heart failure

OBJECTIVES: Based on the fact that NYHA class, plasma BNP level, and echocardiographic indices of left ventricular filling pressures are prognostic factors in chronic systolic heart failure, we evaluated their predictive value for acute decompensation following initiation and titration of bisoprolol in this illness. METHODS AND RESULTS: Bisoprolol was initiated and/or increased according to the ESC/ACC/AHA recommendations in 50 patients with stable chronic systolic heart failure (age: 60+/-2 years, males: 88%) in NYHA class? 2 with a left ventricular ejection fraction (LVEF)<40% and a plasma creatinine<250 micromol/l. The clinical parameters, plasma BNP levels and echocardiographic indices were measured blind on the same day, on admission and then once a week for three weeks. On admission, the NYHA was 2.9+/-0.1, mean plasma creatinine 99+/-3 micromol/l, plasma BNP 503+/-57 pg/ml, LVEF 29+/-1%, E/A ratio 1.9+/-0.2, E/Ea ratio 8.8+/-0.3, E wave deceleration time 155+/-9 ms, systolic pulmonary artery pressure 40+/-2 mmHg and the diameter of the inferior vena cava was 16+/-1 mm. Over the course of follow up, an episode of acute decompensation occurred in 16% of the patients (8/50). Using univariate analysis, age and initial (admission) values for NYHA class, blood pressure, plasma BNP level, E/A ratio, E wave deceleration time, E/Ea ratio and the systolic pulmonary arterial pressure allowed prediction of the occurrence of acute decompensation following initiation and titration of bisoprolol. The use of the initial value of NYHA class alone allowed prediction of the occurrence of acute decompensation in just 56% of the patients, and the absence of an occurrence of acute decompensation in 93% of them. Normal results for the echocardiographic indices (systolic pulmonary arterial pressure<40 mmHg or E/A ratio<1.4 or E wave deceleration time>145 ms) as recorded on admission were associated with the absence of an occurrence of acute decompensation is 100% of cases. The combined use of NYHA class>3 and either a BNP>398 pg/ml or echocardiographic indices in favour of an elevation in left ventricular filling pressures (systolic pulmonary arterial pressure>40 mmHg, E/A ratio>1.4 or E wave deceleration time<145 ms) allowed prediction of the occurrence of acute heart failure in 100% of cases CONCLUSION: The combined use of NYHA class, BNP level and echocardiographic indices for measuring left ventricular filling pressures is more pertinent than the isolated use of clinical parameters for predicting tolerance to bisoprolol in chronic heart failure with a LVEF<40%.     

Retrospective study of allogeneic haematopoietic stem-cell transplantation for myelofibrosis

Allogeneic haematopoietic stem-cell transplantation (HSCT) is the only curative treatment for myelofibrosis. We retrospectively analyzed the outcome of patients who underwent allogeneic HSCT, 1994-2008, and the potential risk factors affecting non-relapse mortality (NRM), OS and relapse-free survival (RFS). A total of 39 patients, 15-65 (median 49) years old, diagnosed with primary (n=27) or secondary (n=12) myelofibrosis underwent HSCT (25 related and 14 unrelated). In ten patients, disease had transformed into acute leukaemia. Lille prognosis score was low for 9, intermediate for 16 and high for 14 patients. The conditioning regimen was myeloablative (MAC) for 15 and reduced-intensity (RIC) fludarabine-based for 24, with successful engraftment in 38 patients. A total of 31 patients developed grade I-IV GvHD; 19 developed chronic GvHD. The 3-year OS, RFS and NRM rates (95% confidence interval) were 60% (42-74), 54% (37-59) and 30% (30-45), respectively.     

Hypoxia appears at pre-arthritic stage and shows co-localization with early synovial inflammation in collagen induced arthritis

OBJECTIVE:The presence of hypoxia in rheumatoid synovium has been well known, but exact correlation between hypoxia and synovitis is unclear. The aim of our study was to investigate the time and spatial relationship and the correlation of severity between hypoxia and synovitis in pre-arthritic or early stage of inflammatory joint disease.METHODS:DBA/1J mice were injected intradermally with type II collagen and adjuvant solution to induce arthritis; mice injected with only adjuvant were used as a control group. CIA and control mice were sacrificed weekly after the injection to evaluate serial pathological changes. H&E stain and hydroxyprobe-1 stain were performed to look at the status of inflammation and hypoxia.RESULTS: In serial observations of tissue pathology, we could note the inflammation of synovium developing a week after the injection of type II collagen. Hypoxic change, measured by the hydroxyprobe-1 stain, was also identified in synovium as early as 1 week after the collagen injection, prior to clinically evident arthritis. In addition, we could observe that inflammation and hypoxia co-localize in the synovium and there was a positive correlation between the severity of hypoxia and the degree of synovitis.CONCLUSION:Our results demonstrate that hypoxia takes place in synovium at the pre-arthritic stage of disease and have a close spatial relationship and a positive severity correlation with synovitis.     

Application of allele-specific RNAi in hepatitis B virus lamivudine resistance

Understanding the consequences of mutation in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of hepatitis B virus (HBV) genome on replication is critical for treating chronic hepatitis B with lamivudine. Allele-specific gene silencing by RNAi (allele-specific RNAi: ASP-RNAi) is an advanced application of RNAi techniques. Use of this strategy as a means for specifically inhibiting an allele expression of interest suggested that it can specifically suppress the expression of alleles causing disease without inhibiting the expression of corresponding wild-type alleles. However, no studies have used ASP-RNAi to address the issue of HBV lamivudine resistance. In this study, we applied ASP-RNAi into two long-term eukaryotic cell lines of full-length HBV containing either lamivudine-resistant mutants (HBV-YIDD) or wild type (HBV-WT) which we generated in previously. The designed siRNAs were also used in this eukaryotic expression system together with lamivudine. ELISA and real-time PCR were performed to monitor virus-specific protein synthesis and viral DNA replication. The results showed that the base substitutions conferring marked ASP-RNAi appeared to be largely present in positions 1, 3, 6, 11, 12, 15 and 19 of the sense strand of siRNAs which were different from the most sensitive positions of this application in eukaryotes. In addition, siRNA-lamivudine combinations did not possess the prominent anti-HBV activity we expected because of some unknown mechanisms. These findings recapitulated many of the features of ASP-RNAi in hepadnaviruses which provided a new insight into the development of a potent strategy against HBV drug resistance.     

Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma

BACKGROUND: Identification of risk factors for the development of hepatocellular carcinoma (HCC) is important for HCC surveillance in chronic hepatitis B virus (HBV) infection. Our aim was to study the independent risk factors and effect of HBV genotypes on HCC development in a prospective longitudinal cohort of chronic hepatitis B patients. PATIENTS AND METHODS: Chronic hepatitis B patients recruited since 1997 were prospectively followed up for the development of HCC. HCC was diagnosed by a combination of alpha fetoprotein, imaging, and histology. Liver cirrhosis was defined as ultrasonic features of cirrhosis together with hypersplenism, ascites, varices, and/or encephalopathy. RESULTS: In total, 426 patients were followed up for 1664 person years; median 225 (range 12-295) weeks. Forty nine (11%) patients had underlying clinical liver cirrhosis. A total of 242 (57%) and 179 (42%) patients had HBV genotypes C and B, respectively. Twenty five patients developed HCC in a median follow up of 121 (range 14-236) weeks. The overall incidence of HCC was 1502 cases per 100 000 person years. On multivariate analysis, clinical liver cirrhosis and HBV genotype C infection were independently associated with HCC development, with an adjusted relative risk of 10.24 (95% confidence interval (CI) 4.39-23.89; p<0.001) and 2.84 (95% CI 1.05-7.72; p = 0.040), respectively. Patient age, sex, hepatitis B e antigen (HBeAg) status, alanine aminotransferase (ALT) levels, and basal core promoter mutations did not predict HCC development. Patients infected with HBV genotype C tended to have persistently positive HBeAg or fluctuating HBeAg status and higher ALT levels during the follow up period. CONCLUSION: Genotype C HBV infection is an independent risk factor for HCC development in addition to liver cirrhosis.     

Expression level of lipoprotein lipase in Chinese patients with chronic lymphocytic leukemia and its correlation with other prognostic factors

Chronic lymphocytic leukemia (CLL) is the most common adult form of leukemia in the Western world, however, infrequent in the Eastern. It shows a remarkable heterogeneity, with some patients having an almost normal lifespan, others surviving only several years after diagnosis despite intensive therapy. To investigate lipoprotein lipase (LPL) expression level in Chinese patients with CLL and its correlation with other prognostic factors, including immunoglobulin heavy-chain variable region (IgVH) mutation status, Binet stages, ZAP-70 protein and CD38 expression level, semiquantitative RT-PCR was used to detect LPL expression in peripheral blood samples of 58 Chinese patients with CLL. LPL expression level was significantly correlated with IgVH mutational status (r = 0.348, P = 0.010), Binet stages (r = 0.276, P = 0.036), ZAP-70 protein (r = 0.431, P = 0.001) and CD38 (r = 0.546, P < 0.001). Patients with unmutated IgVH genes had higher expression of LPL than patients with IgVH mutations. The higher expression level of LPL was also associated with higher level of ZAP-70 and CD38, and more aggressive Binet stage. We also analyzed LPL expression in different cytogenetic subgroups. Higher LPL level was found in patients with unfavorable cytogenetic aberrations (deletion in 17p13 or 11q22) in contrast to lower level in good risk cytogenetics (deletion in 13q as the sole abnormality) (r = 0.404, P = 0.002). It was showed that LPL expression correlates with IgVH mutational status and other clinical or laboratory prognostic factors, and might be applied for the assessment of prognosis in patients with CLL.