Immune response to pertussis vaccine in COPD patients.

Exacerbation triggered by respiratory infection is an important cause of morbidity and mortality in chronic obstructive pulmonary disease (COPD) patients. Strategies aiming to preventing infection may have significant public health impact. Our previous study demonstrated decreased immunological response to seasonal flu vaccination in COPD patients, questioning the efficiency of other vaccines in this group of patients. We performed a prospective, monocenter, longitudinal study that evaluated the humoral and cellular responses upon pertussis vaccination. We included 13 patients with stable COPD and 8 healthy volunteers. No difference in circulating B and T cell subsets at baseline was noted. Both groups presented similar levels of TFH, plasmablasts and pertussis specific antibodies induction after vaccination. Moreover, monitoring T cell immunity after ex-vivo peptide stimulation revealed equivalent induction of functional and specific CD4+ T cells (IFNγ, TNFα and IL-2-expressing T cells) in both groups. Our results highlight the immunological efficiency of pertussis vaccination in this particularly vulnerable population and challenge the concept that COPD patients are less responsive to all immunization strategies. Healthcare providers should stress the necessity of decennial Tdap booster vaccination in COPD patients.

Colorectal cancer (CRC) monitoring by 6-monthly 18FDG-PET/CT: an open-label multicentre randomised trial.

Background: [18F]2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (18FDG-PET/CT) has high sensitivity for detecting recurrences of colorectal cancer (CRC). Our objective was to determine whether adding routine 6-monthly 18FDG-PET/CT to our usual monitoring strategy improved patient outcomes and to assess the effect on costs. Patients and methods: In this open-label multicentre trial, patients in remission of CRC (stage II perforated, stage III, or stage IV) after curative surgery were randomly assigned (1 : 1) to usual monitoring alone (3-monthly physical and tumour marker assays, 6-monthly liver ultrasound and chest radiograph, and 6-monthly whole-body computed tomography) or with 6-monthly 18FDG-PET/CT, for 3 years. A multidisciplinary committee reviewed each patient's data every 3 months and classified the recurrence status as yes/no/doubtful. Recurrences were treated with curative surgery alone if feasible and with chemotherapy otherwise. The primary end point was treatment failure defined as unresectable recurrence or death. Relative risks were estimated, and survival was analysed using the Kaplan-Meier method, log-rank test, and Cox models. Direct costs were compared. Results: Of the 239 enrolled patients, 120 were in the intervention arm and 119 in the control arm. The failure rate was 29.2% (31 unresectable recurrences and 4 deaths) in the intervention group and 23.7% (27 unresectable recurrences and 1 death) in the control group (relative risk = 1.23; 95% confidence interval, 0.80-1.88; P = 0.34). The multivariate analysis also showed no significant difference (hazards ratio, 1.33; 95% confidence interval, 0.8-2.19; P = 0.27). Median time to diagnosis of unresectable recurrence (months) was significantly shorter in the intervention group [7 (3-20) versus 14.3 (7.3-27), P = 0.016]. Mean cost/patient was higher in the intervention group (18 192 ± 27 679 € versus 11 131 ± 13 €, P < 0.033). Conclusion: 18FDG-PET/CT, when added every 6 months, increased costs without decreasing treatment failure rates in patients in remission of CRC. The control group had very close follow-up, and any additional improvement (if present) would be small and hard to detect. ClinicalTrials.gov identifier: NCT00624260.

Similar white matter but opposite grey matter changes in schizophrenia and high-functioning autism.

OBJECTIVE: High-functioning autism (HFA) and schizophrenia (SZ) are two of the main neurodevelopmental disorders, sharing several clinical dimensions and risk factors. Their exact relationship is poorly understood, and few studies have directly compared both disorders. Our aim was thus to directly compare neuroanatomy of HFA and SZ using a multimodal MRI design. METHODS: We scanned 79 male adult subjects with 3T MRI (23 with HFA, 24 with SZ and 32 healthy controls, with similar non-verbal IQ). We compared them using both diffusion-based whole-brain tractography and T1 voxel-based morphometry. RESULTS: HFA and SZ groups exhibited similar white matter alterations in the left fronto-occipital inferior fasciculus with a decrease in generalized fractional anisotropy compared with controls. In grey matter, the HFA group demonstrated bilateral prefrontal and anterior cingulate increases in contrast with prefrontal and left temporal reductions in SZ. CONCLUSION: HFA and SZ may share common white matter deficits in long-range connections involved in social functions, but opposite grey matter abnormalities in frontal regions that subserve complex cognitive functions. Our results are consistent with the fronto-occipital underconnectivity theory of HFA and the altered connectivity hypothesis of SZ and suggest the existence of both associated and diametrical liabilities to these two conditions.

Effects 4.5 years after an interactive GP educational seminar on antibiotic therapy for respiratory tract infections: a randomized controlled trial.

BACKGROUND: The few studies assessing long-term effects of educational interventions on antibiotic prescription have produced conflicting results. OBJECTIVES: Our aim was to assess the effects after 4.5 years of an interactive educational seminar designed for GPs and focused on antibiotic therapy in respiratory tract infections (RTIs). The seminar was expected to decrease antibiotic prescriptions for any diagnosis. METHODS: We conducted a randomized controlled parallel-group trial in a Paris suburb (France), with GPs as the randomization unit and prescriptions as the analysis unit. The intervention occurred in September 2004 and the final assessment in March 2009. Among 203 randomized GPs, 168 completed the study, 70 in the intervention group and 98 in the control group. Intervention GPs were randomized to attending only a 2-day interactive educational seminar on evidence-based guidelines about managing RTIs or also 1 day of problem-solving training. The primary outcome was the percentage of change in the proportion of prescriptions containing an antibiotic for any diagnosis in 2009 versus 2004. An intention-to-treat sensitivity analysis was performed using multiple imputation. RESULTS: After 4.5 years, absolute changes in the primary outcome measure were -1.1% (95% confidence interval: -2.2 to 0.0) in the intervention group and +1.4% (0.3-2.6) in the control group, yielding an adjusted between-group difference of -2.2% (-2.7 to -1.7; P < 0.001). Both intervention modalities had significant effects, and multiple imputation produced similar results. CONCLUSIONS: A single, standardized and interactive educational seminar targeting GPs significantly decreased antibiotic use for RTIs after 4.5 years.

[The Clinical Investigation Centers in France: Whatzat? What for? How does it work?]. / Les Centres d'Investigation Clinique (CIC): QUESACO? Qu'est-ce que c'est? D'où ça vient? A quoi ça (SA) sert? Comment ça marche?

For the last 15 years, French university-affiliated hospitals have dramatically modified how biomedical research is conducted in France. Multidisciplinary and technically complex research projects are increasingly difficult to conduct in clinical units. To ensure quality, good clinical practice, and security, platforms dedicated to clinical research with specific staff have been implanted. These units, called Clinical Investigation Centers (CICs), are open to academic and industrial investigators working in the medical fields involving patients and healthy volunteers. The CICs' activities are always closely related to the university hospital research programs and can also serve as a tool for locally implanted clinical and fundamental research teams (INSERM). Nowadays, clinical research requires specific tools and platforms. To enhance French university hospital research efficiency and provide a more open research environment, all investigators, on-site as well as from other institutions, are invited to use these cohesive research facilities and skills to conduct protocols that are fully adapted to their needs in optimal conditions of professional clinical research.

Tumor necrosis factor alpha and glutathione interplay in chronic heart failure.

The pro-inflammatory cytokine, tumor necrosis factor alpha (TNF alpha), in concert with neurohormones, contributes to chronic heart failure (CHF) progression. This implies that TNF a antagonism may constitute an important target for CHF therapy. However, clinical trials in CHF patients using compounds that trap TNF alpha, comprising infliximab, an antibody directed to TNF alpha, and etanercept, a soluble recombinant receptor of TNF alpha, gave disappointing results bringing back to light the dual, short-term beneficial and long-term harmful effect of TNF alpha. This review focuses on the dual, concentration- and time-related effects of TNF alpha, the yin and yang action of TNF alpha in cardiac ischemia/reperfusion and contraction. Importantly, the harmful effects of TNF a are related to glutathione deficiency, a common hallmark to several other chronic inflammatory diseases. Recently, in rat models of CHF, oral administration of the glutathione precursor, N-acetylcysteine (NAC), was shown to hinder pathways of TNF alpha harmful signalling and to rescue cardiac structure and function. These results suggest that glutathione deficiency in association with TNF alpha activation may play a role in the pathophysiology of CHF and that NAC may represent a potential therapy in CHF.

[Sleep apnoea syndrome and cardiac failure]. / Syndrome d'apnées du sommeil et insuffisance cardiaque.

Despite recent therapeutic advances, chronic cardiac failure is still associated with a significant morbidity and mortality. Sleep apnoea syndrome is common in this population, affecting almost half of these patients. However, it is rarely diagnosed and treated. There are two types of sleep apnoea syndrome, which can sometimes co-exist: the obstructive apnoea syndrome with collapse of the upper airways, and the central apnoea syndrome with cyclical Cheyne-Stokes respiration, linked with anomalies of central control. Apnoea leads to sympathetic stimulation and an increase in the left ventricular post-charge which can alter cardiac function and the prognosis. Diagnosis of sleep apnoea syndromes is now made with small ambulatory oxymeters which do not disturb sleep and which allow precise detection of episodes of desaturation. Treatment with positive pressure ventilation brings an improvement in daytime symptoms (fatigue, drowsiness) as well as an improvement in cardiac function. Screening for sleep apnoea is thus essential in patients with chronic heart failure, especially in those resistant to optimal drug treatment, in order to improve their management.

Modifier genes and heart failure.

Recent progress in genomic applications have led to a better understanding of the relationship between genetic background and cardiovascular diseases such as heart failure. A considerable component of the variability in heart failure outcome is due to modifier genes, i.e. genes that are not involve in the genesis of a disease but modify the severity of the phenotypic expression once the disease has developed. The strategy most commonly used to identify modifier genes is based on association studies between the severity of the phenotype of the disease (morbidity and/or mortality) and the sequence variation(s) of selected candidate gene(s). This strategy has showed that several polymorphisms of the beta1 and beta2 adrenergic receptors genes and the angiotensin converting enzyme gene are correlated to the prognosis of patients with heart failure. Recently, we have applied an experimental strategy, known as genome mapping, for the identification of heart failure modifier genes. Genome mapping has previously been used with success to identify the genes involved in the development of both monogenic and multifactorial diseases. We have showed that the prognosis of heart failure mice, induced through overexpressing calsequestrin, is linked to 2 Quantitative Trait Loci (QTL) localized on chromosome 2 and 3. Using both strategies (candidate gene and genome mapping) should allow us to identify a number of modifier genes that may provide a more rational approach to identify patients at risk for disease and response to therapy.

Impact of genetic polymorphisms on heart failure prognosis.

Recent progress in genomic applications have led to a better understanding of the relationship between genetic background and cardiovascular diseases such as heart failure. The broad variability in heart failure patient outcome is in part secondary to modifier genes, i.e. genes that are not involved in the genesis of a disease but modify the severity of the phenotypic expression once the disease has developed. The strategy most commonly used to identify modifier genes is based on association studies between the severity of the phenotype and the sequence variation(s) of selected candidate gene(s). Using this strategy, several polymorphisms of the beta 1 and beta 2-adrenergic receptors genes and the angiotensin converting enzyme gene have been correlated to the prognosis of patients with heart failure. Recently, we have applied an experimental strategy, known as genome mapping, for the identification of heart failure modifier genes. Genome mapping has previously been used with success to identify the genes involved in the development of both monogenic and multifactorial diseases. We have shown that the prognosis of heart failure mice, induced through calsequestrin overexpression, is linked to two Quantitative Trait Loci localized on chromosomes 2 and 3. Using both strategies (candidate gene and genome mapping) should allow us to identify a number of modifier genes that may provide a more rational approach to identify patients with the worst prognosis and to predict their response to therapy.

[Aldosterone and its antagonists in heart failure]. / L'aldostérone et ses antagonistes dans l'insuffisance cardiaque.

THE ROLE OF ALDOSTERONE: Aldosterone is the key hormone in salt-water homeostasis. In heart failure, it participates in the appearance and maintenance of signs of congestion. Predominantly synthesised in the glomerular area of the cortico-adrenal glands, extra adrenal production areas have recently been identified notably in the brain, the heart and the large artery trunks. Aldosterone is activated in the cells by the intracellular mineral corticoid receptor. IN CARDIOVASCULAR-PATHOLOGIES: In chronic heart failure, patients treated with conversion enzyme inhibitor may escape from the renin-angiotensin blockade and this may lead to increased aldosterone plasma levels. This increase can induce not only vascular lesions and myocardial fibrosis but also renal and cerebral lesions. THE EFFECTS OF SPIRONOLACTONE: In patients with NYHA stage III or IV heart failure, addition of spironolactone to the treatment with conversion enzyme inhibitor, diuretic and/or digitalis leads to a reduction in morbidity and mortality, as demonstrated in the RALES study. The mechanisms by which spironolactone has a beneficial effect remain discussed. IN CLINICAL PRACTICE: The prescription of spironolactone is limited by hormonal side effects it provokes. IN THE FUTURE: Eplerenone, a new competitive aldosterone receptor antagonist that appears to be devoid of such side effects and which, at least experimentally may well have the same beneficial effects, is presently under clinical assessment.

[Future molecules in heart failure]. / Molécules du futur dans l'insuffisance cardiaque.

TODAY: The management of heart failure (HF) has considerably progressed over the last two decades. Treatment today relies on prevention and treatment of congestion (limited salt intake, diuretics, converting enzyme inhibitors) and limiting neurohormone stimulation (converting enzyme inhibitors +/- aldactone, beta-blockers). IN THE YEARS TO COME: Based on new concepts, several therapeutic strategies are interesting: blocking over vasoconstrictor systems which have not been taking into account; stimulation of vasodilator and natriuretic systems; modulation of cardiac remodelling; modulation of the immune and inflammatory systems; modification in intrinsic contractility; prevention of rhythm disorders. Among these differing strategies and molecules, it is not easy to predict those that will change the HF prognosis. In any event, their efficacy and safety remain to be demonstrated with large cohort randomised studies. THE PRINCIPLES: To reduce the number of drugs administered, two options appear particularly interesting: measurement of hormone levels (BNP) in order to adjust treatment and administration of molecules with greatest efficacy and safety profiles; limit cardiac remodelling by using new imaging techniques to detect it more precisely and select the molecule(s) exerting the required effect. To target the new molecules better, patients should be classified according to their etiology, stage and progressive profile of their disease, cardiac remodelling, expression of principle endocrine systems and pro-inflammatory cytokines, expression of inflammatory and immune systems and inherent genetic characteristics and response to treatment. This would permit the adaptation of treatment to each individual patient with heart failure.

[Hospital mortality in cardiology. Analysis of deaths occurring in the Federation of Cardiology of a university hospital center]. / Mortalité hospitalière en cardiologie. Analyse des décès survenus au sein de la fédération de cardiologie d'un centre hospitalo-universitaire.

The aim of this study was to examine the nature of cardiovascular deaths occurring in a University Hospital. All the hospital files of 1999 of the Federation of Cardiology of Henri Mondor Hospital, Creteil, of patients who died in the department or after transfer to the intensive care unit or cardiac surgery department, were analysed. Myocardial ischaemia was the leading cause of death, occurring either in the acute phase of transmural infarction or in patients with chronic cardiac failure. Deaths occurring during acute myocardial infarction were associated with late treatment and/or non-reperfusion of the culprit artery. The delay of diagnosis seemed to be secondary to late consultation or difficulty in diagnosis. This resulted in severe left ventricular dysfunction and, in a quarter of cases, mechanical complications. They led to the early death of the patients (2.9 +/- 3.5 days after admission). Campaigns of patient information and education of doctors who see these patients would seem to be the most appropriate approach to reduce the delay before hospital admission in order to reduce mortality related to myocardial infarction. Cardiac failure is a common cause of death in cardiology departments. The deaths of patients occurred after a long follow-up and several days after hospital admission (11 +/- 10 days). Optimisation of the treatment of cardiac failure, the investigation of ischaemic heart disease, the search for new therapeutic strategies of acute cardiac failure and information of patients about their disease, seem to be the principal measures to take to improve the poor prognosis of this disease.

[Role of nitric oxide in heart failure]. / Rôle du monoxyde d'azote dans l'insuffisance cardiaque.

The benefit effects of nitric oxide (NO) donors in acute heart failure have led to the development of vasodilators as treatment of chronic heart failure. However, the mechanisms involved in the effects of NO are complex and still discussed. In chronic heart failure, the eNOS downregulation in vascular endothelium explains the alteration of endothelial function. In addition, in the myocardium, cytokines induce the expression of inducible nitric oxide synthase (iNOS) which increase NO production by myocytes and surrounding cells. This excess of NO production, associated with anion superoxide synthesis, limits the inotropic properties of catecholamines and exert proapoptotic effects. The role of NO donors in heart failure treatment is still controversial but by reducing preload they improve patient's symptoms. Beside blockade of the renin-angiotensin system, the angiotensin converting enzyme inhibitors act via the inhibition of bradykinin degradation which increase NO levels. Finally, vascular endothelial NO expression is improved by exercise training and participates in the improvement of exercise capacity in patients with chronic heart failure involved in cardiac readaptation program.