Different methylation signatures at diagnosis in patients with high-risk myelodysplastic syndromes and secondary acute myeloid leukemia predict azacitidine response and longer survival.

BACKGROUND: Epigenetic therapy, using hypomethylating agents (HMA), is known to be effective in the treatment of high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients who are not suitable for intensive chemotherapy and/or allogeneic stem cell transplantation. However, response rates to HMA are low and there is an unmet need in finding prognostic and predictive biomarkers of treatment response and overall survival. We performed global methylation analysis of 75 patients with high-risk MDS and secondary AML who were included in CETLAM SMD-09 protocol, in which patients received HMA or intensive treatment according to age, comorbidities and cytogenetic. RESULTS: Unsupervised analysis of global methylation pattern at diagnosis did not allow patients to be differentiated according to the cytological subtype, cytogenetic groups, treatment response or patient outcome. However, after a supervised analysis we found a methylation signature defined by 200 probes, which allowed differentiating between patients responding and non-responding to azacitidine (AZA) treatment and a different methylation pattern also defined by 200 probes that allowed to differentiate patients according to their survival. On studying follow-up samples, we confirmed that AZA decreases global DNA methylation, but in our cohort the degree of methylation decrease did not correlate with the type of response. The methylation signature detected at diagnosis was not useful in treated samples to distinguish patients who were going to relapse or progress. CONCLUSIONS: Our findings suggest that in a subset of specific CpGs, altered DNA methylation patterns at diagnosis may be useful as a biomarker for predicting AZA response and survival.

Effect of hepatitis B virus on steatosis in hepatitis C virus co-infected subjects: A multi-centre study and systematic review.

It remains unclear whether hepatitis B virus (HBV) infection may modify the severity of viral steatosis in patients coinfected with chronic hepatitis C virus (HCV). We examined the influence of coinfection with HBV on prevalence of steatosis in chronic hepatitis C in a multi-centre cohort of HBV-HCV subjects, and by performing a systematic review and meta-analysis of the literature. We centrally and blindly assessed steatosis prevalence and severity in a cohort of HBV-HCV coinfected subjects compared to HCV and HBV monoinfected controls and we performed a systematic review of studies addressing the prevalence of steatosis in HBV-HCV subjects compared to HCV controls. In the clinical cohort, we included 85 HBV-HCV, 69 HBV and 112 HCV subjects from 16 international centres. There was no significant difference in steatosis prevalence between the HBV-HCV and the HCV groups (33% vs 45%, P = .11). In subgroup analysis, lean HBV-HCV subjects with detectable HBV DNA had less steatosis than lean HCV subjects matched for HCV viremia (15% vs 45%, P = .02). Our literature search identified 5 additional studies included in a systematic review. Overall, prevalence of steatosis > 5% was similar in HBV-HCV infection compared to HCV (pooled odds ratio [OR] 0.91, 95% CI 0.53-1.6) although there was significant heterogeneity (I2 69%, P = .007). In conclusion, although the prevalence of steatosis is similar in HBV-HCV compared to HCV subjects, our analysis suggests that there may be an inhibitory effect of HCV-induced steatogenesis by HBV in certain subgroups of patients.

Impact of common risk factors of fibrosis progression in chronic hepatitis C.

OBJECTIVE: The natural course of chronic hepatitis C varies widely. To improve the profiling of patients at risk of developing advanced liver disease, we assessed the relative contribution of factors for liver fibrosis progression in hepatitis C. DESIGN: We analysed 1461 patients with chronic hepatitis C with an estimated date of infection and at least one liver biopsy. Risk factors for accelerated fibrosis progression rate (FPR), defined as ≥ 0.13 Metavir fibrosis units per year, were identified by logistic regression. Examined factors included age at infection, sex, route of infection, HCV genotype, body mass index (BMI), significant alcohol drinking (≥ 20 g/day for ≥ 5 years), HIV coinfection and diabetes. In a subgroup of 575 patients, we assessed the impact of single nucleotide polymorphisms previously associated with fibrosis progression in genome-wide association studies. Results were expressed as attributable fraction (AF) of risk for accelerated FPR. RESULTS: Age at infection (AF 28.7%), sex (AF 8.2%), route of infection (AF 16.5%) and HCV genotype (AF 7.9%) contributed to accelerated FPR in the Swiss Hepatitis C Cohort Study, whereas significant alcohol drinking, anti-HIV, diabetes and BMI did not. In genotyped patients, variants at rs9380516 (TULP1), rs738409 (PNPLA3), rs4374383 (MERTK) (AF 19.2%) and rs910049 (major histocompatibility complex region) significantly added to the risk of accelerated FPR. Results were replicated in three additional independent cohorts, and a meta-analysis confirmed the role of age at infection, sex, route of infection, HCV genotype, rs738409, rs4374383 and rs910049 in accelerating FPR. CONCLUSIONS: Most factors accelerating liver fibrosis progression in chronic hepatitis C are unmodifiable.

Two cases of interferon-alpha-induced sarcoidosis Koebnerized along venous drainage lines: new pathogenic insights and review of the literature of interferon-induced sarcoidosis.

Sarcoidosis is a systemic granulomatous disorder of unknown origin commonly affecting the lung, the lymphoid system and the skin. We report here two cases of cutaneous sarcoidosis in two former intravenous drug users following interferon (IFN)-α and ribavirin therapy for chronic hepatitis C. Both patients developed skin sarcoidosis along venous drainage lines of both forearms, coinciding with the areas of prior drug injections. The unique distribution of the skin lesions suggests that tissue damage induced by repeated percutaneous drug injections represents a trigger for the local skin manifestation of sarcoidosis. Interestingly, skin damage was recently found to induce the local expression IFN-α, a well-known trigger of sarcoidosis in predisposed individuals. Here we review the literature on sarcoidosis elicited in the context of IFN-α therapy and propose a new link between the endogenous expression of IFN-α and the induction of disease manifestations in injured skin.

[Infectious diseases]. / Maladies infectieuses.

Cranberry containing products can protect against recurrent UTIs. The duration of treatment for uncomplicated pyelonephritis can be safely shortened to 7 days when using ciprofloxacin. Early surgical treatment for infective endocarditis in patients with large vegetations (> 10 mm) and valve dysfunction should be considered, even in the absence of urgent indications for surgery. Enterobacteriaceae with ESBL are less transmitted in hospital than in households. Tattoo ink-related mycobacterial infections are increasingly reported, even in Western Switzerland. Differentiating acute bacterial from viral rhinosinusitis on clinical criteria remains difficult. Antibiotic and non-antibiotic prevention of acute exacerbations of COPD is still a hot topic, we propose to discuss here.

Expression profiling of genes involved in the formation of aroma in two peach genotypes.

The expression profile of flavour-related genes during ripening was investigated in two peach genotypes, Bolero and OroA, which have been selected for their contrasting aroma/ripening behaviour. A new peach microarray containing 4776 oligonucleotide probes corresponding to a set of ESTs specifically enriched in secondary metabolism (µPEACH2.0) was designed to investigate transcriptome changes during three fruit ripening stages, revealing 1807 transcripts differentially expressed within and between the two genotypes. Differences in the expression of genes involved in the biosynthesis of aroma compounds were detected during the ripening process within and between the two genotypes. In particular, a subset of 12 transcripts involved in metabolism of esters, norisoprenoids, phenylpropanoids and lactones, varied in expression during ripening and between Bolero and OroA.

Impact of international consensus guidelines on antiviral therapy of chronic hepatitis C patients in Switzerland.

AIM OF THE STUDY: To assess the impact of international consensus conference guidelines on the attitude of Swiss specialists when facing the decision to treat chronic hepatitis C patients. METHODS: Questionnaires focusing on the personal situation and treatment decisions were mailed to 165 patients who were newly diagnosed with hepatitis C virus (HCV) infection and enrolled into the Swiss Hepatitis C Cohort Study during the years 2002-2004. RESULTS: Survey respondents (n = 86, 52.1%) were comparable to non-respondents with respect to severity of liver disease, history of substance abuse and psychiatric co-morbidities. Seventy percent of survey respondents reported having been offered antiviral treatment. Patients deferred from treatment had less advanced liver fibrosis, were more frequently infected with HCV genotypes 1 or 4 and presented more often with a history of depression. There were no differences regarding age, socio-economic background, alcohol abuse, intravenous drug abuse or methadone treatment when compared with patients to whom treatment was proposed. Ninety percent of eligible patients agreed to undergo treatment. Overall, 54.6% of respondents and 78.3% of those considered eligible had actually received antiviral therapy by 2007. Ninety-five percent of patients reported high satisfaction with their own hepatitis C management. CONCLUSIONS: Consistent with latest international consensus guidelines, patients enrolled in the Swiss Hepatitis C Cohort with a history of substance abuse were not withheld antiviral treatment. A multidisciplinary approach is warranted to provide antiviral treatment to patients suffering from depression.

Effect of antiviral therapy on circulating cytokeratin-18 fragments in patients with chronic hepatitis C.

Hepatocellular apoptosis plays a major role in the pathogenesis of chronic hepatitis C. It can be measured noninvasively by determining the circulating levels of cytokeratin-18 fragments. We hypothesized that the effect of antiviral therapy on this parameter will be different in patients with a sustained virological response, relapse (REL) and nonresponse (NR). We quantified cytokeratin-18 fragments in plasma of patients participating in the Swiss Hepatitis C cohort, who received antiviral therapy without stopping because of sides effects. A total of 315 patients were included, 183 with a sustained response, 64 with NR and 68 who relapsed. Mean levels ±SD of circulating cytokeratin-18 fragments before therapy were 174 ± 172 U/L for responsders, 188 ± 145 for nonresponders and 269 ± 158 U/L for patients who relapsed. The values were significantly higher in the REL group (ANOVA P < 0.006). A sustained response was associated with a significant improvement of the plasma levels (94 ± 92 U/L, paired test P < 0.000001), whereas there was no improvement in the nonresponder group (183 ± 158 U/L) and in the relapser group (158 ± 148 U/L). There was a weak correlation between alanine aminotransferase (ALT) and cytokeratin-18 fragment levels (r² = 0.35, P < 0.000001) before therapy but not after therapy and none with hepatitis C virus (HCV) viremia. Successful antiviral therapy results in a significant decrease in circulating levels of cytokeratin-18 fragments arguing for a reduction in hepatocellular apoptosis after clearance of the HCV. Baseline cytokeratin-18 fragment levels are higher in relapsers. Correlations with ALT are weak, suggesting that these two tests measure different but related processes.

[The management of asymptomatic bacteriuria in different patient population]. / Bactériurie asymptomatique chez l'adulte: prise en charge différenciée.

Who should be screened for asymptomatic bacteriuria (AB) and who should be treated? This review updates some aspects of the management of AB in different patient populations. A systematic screening for AB is recommended for pregnant women because of a significant risk of complications. In these cases as well as before any uro-gynecologic surgical procedure treatment of AB is strongly recommended. The management of AB in immunosuppressed or transplanted patients is more controversial. In other populations treating AB is not recommended and the outcome seems to be worse in case of treatment due to possible side effects and selection of resistant organisms. Recent studies have shown a considerable gap between clinical practice and recommendations.

Diagnostic markers for diseases: SELDI-TOF profiling of pig sera for PRRS.

Porcine reproductive and respiratory syndrome (PRRS) is a highly infectious viral disease causing severe losses to the pig industry. Most weaning piglets are likely to be exposed to the infection and show at least asymptomatic PRRS viremia strongly related to productive performance. The aims of this study were to set up experimental conditions for pig sera proteomic profiling and to identify biomarkers that differentiate weaning asymptomatic piglets positive to PRRS viremia from negative controls (PCR tested) with potential predictive value for the subsequent occurrence of clinical PRRS. Protein profiles were generated by SELDI-TOF MS using the Bio-Rad Chips WCX, IMAC30 and H50. The discovery phase revealed that a consistent number of highly significant protein peaks can be detected by the WCX and IMAC30 surfaces; however none of these peaks were statistically confirmed by the subsequent validation phase, highlighting that serum concentration of the contaminant and most abundant proteins is a crucial parameterfor SELDI-TOF MS studies. Current protocols are being furtheroptimized and adapted to pig sera to reduce the unfavourable effects of the most abundant proteins and to increase the number of potential detectable biomarkers. Furthermore, proteomic fingerprint profiling has been shown to be a promising diagnostic tool that, in the future, may be useful to provide also insights into the mechanisms of early viral infection in vivo.

Host- rather than virus-related factors reduce health-related quality of life in hepatitis C virus infection.

BACKGROUND: Hepatitis C virus (HCV) infection is associated with decreased health-related quality of life (HRQOL). Although HCV has been suggested to directly impair neuropsychiatric functions, other factors may also play a role. PATIENTS AND METHODS: In this cross-sectional study, we assessed the impact of various host-, disease- and virus-related factors on HRQOL in a large, unselected population of anti-HCV-positive subjects. All individuals (n = 1736) enrolled in the Swiss Hepatitis C Cohort Study (SCCS) were asked to complete the Short Form 36 (SF-36) and the Hospital Anxiety Depression Scale (HADS). RESULTS: 833 patients (48%) returned the questionnaires. Survey participants had significantly worse scores in both assessment instruments when compared to a general population. By multivariable analysis, reduced HRQOL (mental and physical summary scores of SF-36) was independently associated with income. In addition, a low physical summary score was associated with age and diabetes, whereas a low mental summary score was associated with intravenous drug use. HADS anxiety and depression scores were independently associated with income and intravenous drug use. In addition, HADS depression score was associated with diabetes. None of the SF-36 or HADS scores correlated with either the presence or the level of serum HCV RNA. In particular, SF-36 and HADS scores were comparable in 555 HCV RNA-positive and 262 HCV RNA-negative individuals. CONCLUSIONS: Anti-HCV-positive subjects have decreased HRQOL compared to controls. The magnitude of this decrease was clinically important for the SF-36 vitality score. Host and environmental, rather than viral factors, seem to impact on HRQOL level.

Outbreak of human listeriosis associated with tomme cheese in northwest Switzerland, 2005.

During an eight week period in spring 2005, 10 cases of listeriosis were reported in a small area of northwest Switzerland (150,000 inhabitants). Eight cases were in older immunocompromised patients who became ill with bacteraemia (three deaths), and two cases were in pregnant women who had septic abortion. All cases were due to a serotype 1/2a isolate with one of two pulsovars found by PFGE. Patient interviews quickly revealed that a locally made and distributed soft cheese (known as 'tomme') was the food source responsible for the outbreak. Samples of this cheese, and of butter made in the same factory, revealed Listeria monocytogenes sv 1/2a of the same pulsovar in amounts of 1000-10 000 and 10-100 cfu/g, respectively. The prompt suspension of production, the market recall of the product, and a public alert terminated the outbreak. However, two cases of febrile gastroenteritis due to the same strains were reported within 10 days of product recall. The restricted distribution area of the contaminated cheese and the collaboration of local physicians, medical microbiologists and food health services all contributed to a rapid and successful investigation. This small outbreak of listeriosis reinforces the need for a laboratory-based surveillance system with rapid typing, as well as collaboration between physicians and microbiologists.

Outbreak of human listeriosis associated with tomme cheese in northwest Switzerland, 2005.

During an eight week period in spring 2005, 10 cases of listeriosis were reported in a small area of northwest Switzerland (150 000 inhabitants). Eight cases were in older immunocompromised patients who became ill with bacteraemia (three deaths), and two cases were in pregnant women who had septic abortion.

[Urinary tract infections and antibiotic resistance]. / Harnwegsinfektionen und Antibiotikaresistenz.

Urinary tract infections (UTI) are diseases which differ considerably regarding pathogenesis, natural history and management. Complicated UTI as well as uncomplicated acute pyelonephritis in women are managed with pretherapy urine and, possibly, blood culture. This is not the case, however, with the most frequent UTI, acute uncomplicated cystitis in women. Empirical management strategies, without pretherapy culture, are well established and widely used. The treatment of choice is trimethoprim-sulfamethoxazole (TMP-SMZ) and fluoroquinolones. E. coli cause the vast majority of these infections, and resistance to TMP-SMZ has been observed to increase considerably during the last decade. Data from Europe and Switzerland regarding resistance of etiologic agents causing acute uncomplicated cystitis are very limited. Indeed, these empirical management strategies have resulted in poor microbiological information, since only selected groups of women with UTI undergo urine culture. Data derived from laboratory isolates usually lack the necessary clinical and epidemiological correlations. Preliminary data allow some estimates of the clinical and microbiological success rates when treating TMP-SMZ resistant uropathogens with TMP-SMZ. TMP-SMZ should probably no longer be used if the prevalence of TMP-SMZ resistance among uropathogens causing acute uncomplicated cystitis is 20% or higher. In these cases, a fluoroquinolone during three days, amoxicillin-clavulanate during three to five days or nitrofurantoin during seven days should be given empirically. Non-antibiotic means of preventing UTI, such as increasing colonization resistance with lactobacilli, or the use of vaccines which provide inhibition of adherence of uropathogens to uroepithelial cells, show very promising experimental results. In order to survey and correct the value of our empirical strategies, more appropriate data on antimicrobial resistance and risk factors in the community are needed. This data can only be produced by a strong collaboration effort with networks of general practitioners.

Combined therapy with saquinavir, ritonavir and stavudine in moderately to severely immunosuppressed HIV-infected protease inhibitor-naive patients.

OBJECTIVE: To assess the short-term and long-term effect of a combination of saquinavir, ritonavir and stavudine in moderately to severely immunosuppressed protease inhibitor-naive patients. DESIGN: Prospective open-label multicentre study. PATIENTS AND METHODS: A total of 64 protease inhibitor-naive and stavudine-naive HIV-infected patients with a CD4 count of < 250 cells/microL and > 10 000 HIV-1 RNA copies/mL received saquinavir hard-gelatin capsules, ritonavir and stavudine. Full (drop in viraemia of > 2 log10 and/or < 500 copies/mL) and partial responders (drop to between 500 and 5000 viraemia copies/mL) at week 9 (end of phase I) entered the second phase (additional 12-month period). RESULTS: Fifty-six patients completed phase I, 45 (70%) full responders and nine (14%) partial responders by intent-to-treat analysis. Thirty-nine patients completed phase II, 33 (52%) full responders and two (3%) partial responders. Six patients had < 50 HIV-1 RNA copies/mL at week 9, and 20 (31%) patients at month 12 of phase II. Mean CD4 cell counts increased significantly in the 56 patients from 89 to 184 cells/microL after 9 weeks and from 100 to 292 cells/microL in the 39 patients treated for another 12 months. Higher baseline viraemia and lower baseline CD4 cell counts were not associated with an unfavourable virological response at week 9 and month 12 of phase II. HIV DNA in peripheral blood monocytes decreased substantially (- 1.5 log10) but was detectable in all except one patient at the end of phase II. CONCLUSION: In protease- and stavudine-naive HIV-infected patients with moderate to severe immunosuppression, saquinavir in combination with ritonavir and stavudine caused a substantial long-term decrease in plasma viral load in approximately half the participants and a substantial increase in CD4 cell counts.

Economic evaluation of systemic treatments for cytomegalovirus retinitis in patients with AIDS.

OBJECTIVE: To determine the cost of using systemic therapy to treat newly diagnosed cytomegalovirus (CMV) retinitis in persons with AIDS. DESIGN: Incidence-based simulation model of CMV treatment from a government payer perspective. SETTING: Swiss healthcare system. PATIENTS AND PARTICIPANTS: Patients with AIDS and newly diagnosed CMV retinitis. INTERVENTIONS: Patients were assigned to 1 of 4 treatment regimens for induction and maintenance therapy: (i) intravenous (IV) cidofovir induction and maintenance (cidofovir IV/IV); (ii) IV foscarnet induction and maintenance (foscarnet IV/IV); (iii) IV ganciclovir induction and maintenance (ganciclovir IV/IV); and (iv) IV ganciclovir induction and oral (PO) ganciclovir maintenance (ganciclovir IV/PO). Following a second relapse, patients were assigned to one of the other regimens. MAIN OUTCOME MEASURES: Time to first and subsequent progression, duration of maintenance treatment and direct medical expenditures [1998 Swiss francs (SwF)] . RESULTS: The median time to first progression was longest for cidofovir IV/IV, followed by foscarnet IV/IV, ganciclovir IV/IV and ganciclovir IV/PO. Mean survival was 13 months and mean costs for this period in the base case were lowest in those initially treated with cidofovir (SwF146,742), followed by initial treatment with foscarnet IV/IV (SwF194,809), ganciclovir IV/PO (SwF195,190) and ganciclovir IV/IV (SwF243,964). Costs were most sensitive to changes in efficacy estimates. CONCLUSIONS: Of the regimens studied, initiation of treatment with systemic cidofovir appears least costly over a 13-month period.

Long-term hydroxyurea in combination with didanosine and stavudine for the treatment of HIV-1 infection. Swiss HIV Cohort Study.

OBJECTIVE AND METHODS: In 1998 we reported on a randomized comparison between stavudine plus didanosine plus placebo versus stavudine plus didanosine plus hydroxyurea (HU), in patients with a CD4 count of 200-500 x 10(6) cells/l. After 3 months, the HU group had a higher proportion of patients with viral load < 200 x 10 cells/l. At the end of the 3 months blinded period, patients in the placebo group had the option to add HU if their viral load remained > 200 x 10(6) cells/l. We report results after 24 months. RESULTS: Seventy-two patients were randomized to the HU arm, and a further 30 elected to add HU after 12 weeks. Twenty-four months after the start of the trial, only 25% of the 72 patients originally randomized to HU, and 20% of the 30 who added HU after week 12, were still taking it. The reasons for stopping HU were: lack of efficacy (45%), adverse events (37%) and patient or physician preference (18%). Side effects were more frequent in the didanosine/stavudine/HU group than in the didanosine/stavudine group: neuropathy (35 versus 15%, P< 0.02), fatigue (22 versus 7%, P< 0.01), and nausea or vomiting (26 versus 9%, P< 0.01). Of those who had discontinued HU, 73% were taking three drugs including a protease inhibitor. Patients who had started HU were compared with similar patients who had started protease inhibitors in the Swiss cohort. The probability of stopping HU was higher than the probability of stopping nelfinavir or indinavir, and similar to the probability of stopping ritonavir. CONCLUSION: HU increased the antiviral effect of stavudine plus didanosine. However, side effects were more frequent, and after 24 months the majority of patients had switched to protease inhibitor regimens.

Effect of azithromycin plus rifampin versus amoxicillin alone on eradication and inflammation in the chronic course of Chlamydia pneumoniae pneumonitis in mice.

The effects of treatment with azithromycin plus rifampin (A+R), amoxicillin (A), or placebo (P) on the chronic course of experimental Chlamydia pneumoniae pneumonitis in mice were assessed by culture, PCR, and immunocytochemistry as well as by degree of inflammation in lung tissue. Eradication of the pathogen was significantly more frequent and inflammation in tissue was significantly reduced after treatment with A+R compared to after treatment with A or P. Combination therapy with azithromycin plus rifampin showed favorable effects in the chronic course of C. pneumoniae pneumonitis.