Changes in antihypertensive drug treatment in the general population: the Colaus Study

Background and aims: there is little information regar ding changes in antihypertensive drug treatment in Switzerland. We aimed at assessing those changes in a population-based, prospective study. Methods: 768 hypertensive subjects (372 women, 397 men) followed for 5 years. Subjects were defined as continuers (no change), switchers (one antihypertensive class replace by another), combiners (one antihypertensive class added) and discontinuers (stopped treatment). Results: Analysis of all patients (mono or combination therapy) showed that 54.6% were continuers, 27.2% combiners, 12.9% switchers and 5.3 % discontinuers. Similar findings were obtained for participants on monotherapy only: 42.2% continuers, 36.7% combiners, 13.4% switchers and 7.7% discontinuers. Combiners had higher systolic and diastolic blood pressure values at baseline than the other groups (p<0.001), while no difference were found for personal and family history and other clinical and biological variables. Compared to continuers, combiners and switchers improved their blood pressure status at follow-up: 26.7% of combiners and 26.3% of switchers improved, versus 17.7% of continuers and 7.3% of discontinuers (p<0.001). Among participants on monotherapy at baseline, continuation was greatest for angiotensin II type 1 receptor blocking agents (ARBs, 53.1%), angiotensin-converting enzyme inhibitors (44.4%) and β-blockers (41.8%). Only one quarter of participants treated with diuretic or calcium channel blockers at baseline remained so at follow-up. Conclusion: Antihypertensivedrug treatment is very stable in Switzerland. There are no big differences in persistence between antihypertensive classes, even if ARBs had the most favorable utilization pattern. Changes are only due to blood pressure level and improve blood pressure status.

Atypical association of semantic dementia, corticobasal syndrome, and 4R tauopathy.

A 57-year-old male with no family history was diagnosed with semantic dementia. He also showed some unusual cognitive features such as episodic memory and executive dysfunctions, spatial disorientation, and dyscalculia. Rapidly progressive cognitive and physical decline occurred. About 1.5 years later, he developed clinical features of a corticobasal syndrome. He died at the age of 60. Brain autopsy revealed numerous 4R-tau-positive lesions in the frontal, parietal and temporal lobes, basal ganglia, and brainstem. Neuronal loss was severe in the temporal cortex. Such association of semantic dementia with tauopathy and corticobasal syndrome is highly unusual. These findings are discussed in the light of current knowledge about frontotemporal lobar degeneration.

The T-381C SNP in BNP gene may be modestly associated with type 2 diabetes: an updated meta-analysis in 49 279 subjects.

A recent study reported an association between the brain natriuretic peptide (BNP) promoter T-381C polymorphism (rs198389) and protection against type 2 diabetes (T2D). As replication in several studies is mandatory to confirm genetic results, we analyzed the T-381C polymorphism in seven independent case-control cohorts and in 291 T2D-enriched pedigrees totalling 39 557 subjects of European origin. A meta-analysis of the seven case-control studies (n = 39 040) showed a nominal protective effect [odds ratio (OR) = 0.86 (0.79-0.94), P = 0.0006] of the CC genotype on T2D risk, consistent with the previous study. By combining all available data (n = 49 279), we further confirmed a modest contribution of the BNP T-381C polymorphism for protection against T2D [OR = 0.86 (0.80-0.92), P = 1.4 x 10(-5)]. Potential confounders such as gender, age, obesity status or family history were tested in 4335 T2D and 4179 normoglycemic subjects and they had no influence on T2D risk. This study provides further evidence of a modest contribution of the BNP T-381C polymorphism in protection against T2D and illustrates the difficulty of unambiguously proving modest-sized associations even with large sample sizes.

Acute coronary syndromes or myocarditis in young people: a difficult daily diagnostic challenge

Background: Chest pain (CP) represents about 5% of admissions to emergency departments (ED), even in young people. Acute coronary syndrome (ACS) and myocarditis are among the most important diagnoses to rule out. Clinical and ECG findings are not specific for either condition and separating both diagnoses is a challenge. Aim of the study: To evaluate the prevalence of ACS and myocarditis in young patients presenting with CP and elevated cardiac biomarkers to the ED and to determinate the differences in their clinical presentation. Methods: Retrospective study of all consecutive patients < 40 years old admitted to our ED from January 2009 to June 2011 for CP with elevated serum troponin concentration. All clinical, angiographic and cardiac magnetic resonance (CMR) data from the local database was reviewed. Clinical follow-up was obtained to assess all cause mortality, myocardial infarction and re-hospitalisation for CP. Results: 1588 patients < 40 years old were admitted to the ED with chest pain. 49 (3%) patients presenting with an elevated troponin I (> 0.09ug/l) were included in the study. 32.7% (16/49) were diagnosed with ACS (11 STEMI and 5 NSTEMI) and 59.2% (29/49) with myocarditis. Among the 29 patients with myocarditis, 17 presented with typical subepicardial late enhancement on CMR and 12 were diagnosed based on clinical presentation (6 had no complementary workup, 3 normal coronary angiogram and 3 inconclusive CMR). 8.1% (4/49) of patients had other diagnoses. Compared to patients with myocarditis, ACS patients were older (34.1±3.9 vs 26.9±6.4, p=0.0002) with significantly more cardiovascular risk factors (mean 2.06 vs 0.69, p<0.0001). Diabetes (18.8% vs 0%, p=0.004), dyslipidemia (56.3% vs 3.4%, p=0.0001) and family history of coronary artery disease (CAD) (37.5% vs 10.3%, p=0.050) were significantly associated with ACS. No significant association was found for smoking, hypertension and obesity. Fever (>38°C) or recent viral illness were present in 75.9% (22/29) of patients with myocarditis, and in 0% of ACS patients. During follow-up (mean 19.9 months ± 8.6), only 2 patients with myocarditis were re-admitted for chest pain. Conclusions: In this study, 32.7% of patients < 40 year old admitted to an ED with CP and elevated troponin had an ACS. Key clinical factors include diabetes, dyslipidemia, family history of CAD, fever or recent viral illness, and may help to differentiate ACS from myocarditis.

Epidemiologie der Osteoporose. [The epidemiology of osteoporosis].

Osteoporosis is characterized by low bone mass, micro architectural impairment of bone tissue, and a subsequent in crease in fracture risk. Fractures or the vertebrae and distal forearm, as well as the proximal femur, or hip fracture, are included. Hip fracture is associated with high mortality, morbidity and medical expenses. There is a dramatic increase in the incidence of hip fracture with age. Hip fracture incidence is 350 times higher in women aged 85 years and over comparatively to women between 35 and 44 years of age. In recent studies in Switzerland, it was observed that the annual age adjusted incidence rate of hip fracture was comparable with similar rates for white population in industrialized countries, although in men the rates were relatively high. Among the major risk factors for osteoporosis are age, female gender, white and Asian race, and menopause. Postmenopausal estrogen replacement therapy reduces bone resorption. Family history of osteoporosis, frail constitution, as well as excessive alcohol intake, cigarette smoking, chronic insufficient nutritional calcium intake and physical inactivity are other risk factors. A cardinal element is the peak bone mass reached in the third or fourth decade of life. Independently of osteoporosis, falls are a key agent in fractures; several medical conditions and drugs increase the risk of falling. There is an enormous social and financial cost of osteoporosis; the annual cost of medical treatment only for hip fracture is close to Fr. 200 million in Switzerland. The burden of osteoporosis is likely to increase in the future because of the demographic aging of the population unless large scale preventive interventions are undertaken.

Allelic variation in the VMD2 gene in best disease and age-related macular degeneration.

PURPOSE: To assess the allelic variation of the VMD2 gene in patients with Best disease and age-related macular degeneration (AMD). METHODS: Three hundred twenty-one AMD patients, 192 ethnically similar control subjects, 39 unrelated probands with familial Best disease, and 57 unrelated probands with the ophthalmoscopic findings of Best disease but no family history were screened for sequence variations in the VMD2 gene by single-strand conformation polymorphism (SSCP) analysis. Amplimers showing a bandshift were reamplified and sequenced bidirectionally. In addition, the coding regions of the VMD2 gene were completely sequenced in six probands with familial Best disease who showed no SSCP shift. RESULTS: Forty different probable or possible disease-causing mutations were found in one or more Best disease or AMD patients. Twenty-nine of these variations are novel. Of the 39 probands with familial Best disease, mutations were detected in all 39 (33 by SSCP and 6 by DNA sequencing). SSCP screening of the 57 probands with a clinical diagnosis of Best disease but no family history revealed 16 with mutations. Mutations were found in 5 of 321 AMD patients (1.5%), a fraction that was not significantly greater than in control individuals (0/192, 0%). CONCLUSIONS: Patients with the clinical diagnosis of Best disease are significantly more likely to have a mutation in the VMD2 gene if they also have a positive family history. These findings suggest that a small fraction of patients with the clinical diagnosis of AMD may actually have a late-onset variant of Best disease, whereas at the same time, a considerable fraction of isolated patients with the ophthalmoscopic features of Best disease are probably affected with some other macular disease.

Who is at low risk for cardiovascular disease? An assessment of different definitions.

BACKGROUND: There is little information regarding the determinants and trends of the prevalence of low cardiovascular risk factor (RF) profile in the general population. The aim of this study was to assess the prevalence and trends of low RF profile in the Swiss population according to different definitions. METHODS: Population-based cross-sectional studies conducted in 1984-1986 (N=3300), 1988-1989 (N=3331), 1992-1993 (N=3133) and 2003-2006 (N=6170) and restricted to age group 35-75 years. Seven different definitions of low RF profile were used to assess determinants, while two definitions were used to assess trends. RESULTS: Prevalence of low RF profile varied between 6.5% (95% confidence interval: 5.9-7.1) and 9.7% (9.0-10.5) depending on the definition used. This prevalence was higher than in other countries. Irrespective of the definition used, the prevalence of low RF profile was higher in women and in physically active participants, and decreased with increasing age or in the presence of a family history of cardiovascular disease. Using one definition, the prevalence of low RF profile increased from 3.8% (3.1-4.5) in 1984-1986 to 6.7% (6.1-7.3) in 2003-2006; using another definition, the results were 5.9% (5.1-6.8) and 9.7% (9.0-10.5), respectively. CONCLUSION: Switzerland is characterized by a high and increasing prevalence of low RF profile within the age group 35 to 75, irrespective of the criteria used. This high prevalence might partly explain the low and decreasing trend in cardiovascular mortality rates.

Apport de la psychanalyse en oncogénétique prédictive

La médecine prédictive évalue la probabilité que des personnes portant des mutations génétiques constitutionnelles puissent développer une maladie donnée, comme par exemple une tumeur maligne (oncogénétique). Dans le cas des prédispositions génétiques au cancer, des mesures particulières de surveillance et de prévention sont discutées en fonction de l'évaluation des risques et des résultats de l'analyse génétique, y compris certains traitements préventifs allant, à l'extrême, jusqu'à l'intervention chirurgicale prophylactique (ex : mastectomie et/ou ovariectomie). Cette étude est basée sur une interprétation psychanalytique du récit de sujets ayant entrepris une démarche en oncogénétique et vise à analyser l'impact psychique : a) du résultat de l'analyse génétique et b) de la construction de l'arbre généalogique. Elle a été conduite dans l'Unité d'oncogénétique et de prévention des cancers (UOPC) du Service d'oncologie des Hôpitaux Universitaires de Genève (HUG). L'UOPC assure des consultations de conseil génétique spécialisé pour les personnes ayant des antécédents personnels et/ou familiaux de maladies tumorales suggestifs de l'existence de prédispositions génétiques au cancer. La population de cette étude comprend 125 sujets suivis lors des différentes étapes du dépistage, pour un total de 289 consultations et 50 entretiens individuels. Cette recherche montre que les sujets asymptomatiques réélaborent de façon personnelle, soit le résultat génétique (négatif ou positif), soit l'acte de prédiction. En revanche, ceux qui ont développé un cancer expriment des sentiments d'angoisse, comme s'ils subissaient les effets d'un destin inéluctable qui s'est effectivement réalisé. Par ailleurs, l'arbre généalogique est réinterprété de façon personnelle, laissant apparaître des aspects refoulés ou niés qui peuvent resurgir. Lorsque d'autres membres de la famille sont sollicités pour préciser les liens génétiques et/ou être soumis en première intention à l'analyse génétique, le sujet exprime sa difficulté de dépendre d'autres personnes pour connaître son propre statut biologique. D'une façon générale, on constate que là où la médecine prédictive réalise son acte de prévision, le sujet répond de façon imprévisible. Dans l'optique de la psychanalyse, cette imprévisibilité est liée aux aspects du « désir inconscient ». Cette étude montre aussi qu'on ne peut pas considérer le dépistage génétique comme étant la cause directe du traumatisme. L'effort doit porter sur le fait que le sujet puisse se réapproprier ce qui lui arrive, et exprimer progressivement sa souffrance spécifique en jeu dans le processus de prédiction pour créer un écart entre la vérité médicale et la sienne. L'espace de la parole devient ainsi le lieu d'un travail privilégié. La psychanalyse opère donc pour que le résultat génétique se détache de l'acte de prédiction, c'est-à-dire qu'il redevienne un moment de la vie du sujet qui puisse s'articuler comme sa propre histoire personnelle. The aim of predictive medicine is to assess the probability that individuals carrying germ-line mutations will develop certain diseases, for instance cancer (oncogenetics). In predictive oncology, particular surveillance and prevention measures are discussed with these patients in relation to risk assessment and results of genetic testing, including preventive care which can, in extremes cases, lead to prophylactic surgery (i.e. mastectomy and/or ovariectomy). This study is based on a psychoanalytic interpretation of subjects' narration of the oncogenetic process and aims at analyzing the psychological impact of a) genetic testing and b) the construction of the family tree. It was carried out at the Oncogenetics and cancer prevention unit (Unité d'oncogénétique et de prévention des cancers) from the Geneva University Hospitals (Hôpitaux Universitaires de Genève, HUG) which organizes genetic counselling for individuals having personal and/or family history suggestive of genetic predisposition to cancer. The study population comprises 125 patients followed during the successive steps of genetic counselling, for a total of 289 consultations and 50 personal interviews. This research shows that asymptomatic subjects re-elaborate in a personal way either the results of genetic testing (negative or positive) or the act of prediction. Conversely, those having developed cancer express feelings of anguish, as if they were undergoing the effects of a destiny which effectively happened. Its sight remains a difficult step of the oncogenetic process, as psychological aspects which were repressed or denied can re-appear. When some family members are solicited to help reconstructing the genetic relationships, sometimes being themselves submitted first to genetic testing, the study subject expresses the difficulty to depend on other persons to learn more about his own biological status. In this study, we observe that, in parallel to predictions delivered by the process of predictive medicine, the subject actually answers unpredictably. With a psychoanalytic perspective, this unpredictability is related to an "unconscious desire". We also find that we cannot consider that genetic screening is a direct cause of psychological trauma. Our efforts must rely on allowing the subject to re-appropriate himself what is happening, to let him progressively express his own suffering of the prediction in order to create a gap between the medical reality and his own. In this process, "speech" is needed to let this happening. Psychoanalysis works in such a way that the genetic testing's result becomes distinct from the act of prediction, a moment of the subject's life expressed as his own personal history.

Results from a multicentre international registry of familial Mediterranean fever: impact of environment on the expression of a monogenic disease in children.

BACKGROUND AND AIM: Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by mutations of the MEFV gene. We analyse the impact of ethnic, environmental and genetic factors on the severity of disease presentation in a large international registry. METHODS: Demographic, genetic and clinical data from validated paediatric FMF patients enrolled in the Eurofever registry were analysed. Three subgroups were considered: (i) patients living in the eastern Mediterranean countries; (ii) patients with an eastern Mediterranean ancestry living in western Europe; (iii) Caucasian patients living in western European countries. A score for disease severity at presentation was elaborated. RESULTS: Since November 2009, 346 FMF paediatric patients were enrolled in the Eurofever registry. The genetic and demographic features (ethnicity, age of onset, age at diagnosis) were similar among eastern Mediterranean patients whether they lived in their countries or western European countries. European patients had a lower frequency of the high penetrance M694V mutation and a significant delay of diagnosis (p<0.002). Patients living in eastern Mediterranean countries had a higher frequency of fever episodes/year and more frequent arthritis, pericarditis, chest pain, abdominal pain and vomiting compared to the other two groups. Multivariate analysis showed that the variables independently associated with severity of disease presentation were country of residence, presence of M694V mutation and positive family history. CONCLUSIONS: Eastern Mediterranean FMF patients have a milder disease phenotype once they migrate to Europe, reflecting the effect of environment on the expression of a monogenic disease.

When should clinicians search for GLUT1 deficiency syndrome in childhood generalized epilepsies?

UNLABELLED: GLUT1 deficiency (GLUT1D) has recently been identified as an important cause of generalized epilepsies in childhood. As it is a treatable condition, it is crucial to determine which patients should be investigated. METHODS: We analyzed SLC2A1 for mutations in a group of 93 unrelated children with generalized epilepsies. Fasting lumbar puncture was performed following the identification of a mutation. We compared our results with a systematic review of 7 publications of series of patients with generalized epilepsies screened for SLC2A1 mutations. RESULTS: We found 2/93 (2.1%) patients with a SLC2A1 mutation. One, carrying a novel de novo deletion had epilepsy with myoclonic-atonic seizures (MAE), mild slowing of head growth, choreiform movements and developmental delay. The other, with a paternally inherited missense mutation, had childhood absence epilepsy with atypical EEG features and paroxysmal exercise-induced dyskinesia (PED) initially misdiagnosed as myoclonic seizures. Out of a total of 1110 screened patients with generalized epilepsies from 7 studies, 2.4% (29/1110) had GLUT1D. This rate was higher (5.6%) among 303 patients with early onset absence epilepsy (EOAE) from 4 studies. About 50% of GLUT1D patients had abnormal movements and 41% a family history of seizures, abnormal movements or both. CONCLUSION: GLUT1D is most likely to be found in MAE and in EOAE. The probability of finding GLUT1D in the classical idiopathic generalized epilepsies is very low. Pointers to GLUT1D include an increase in seizures before meals, cognitive impairment, or PED which can easily be overlooked.

Who is at low risk for cardiovascular disease?: an assessment of different definitions

Purpose: to assess the prevalence and trends of low cardiovascular risk factor (RF) profile in the Swiss population according to different definitions. Methods: Population-based cross-sectional study of 6170 subjects (3241 women) aged 35-75 years living in Lausanne, Switzerland. Trends were assessed using data from the Swiss MONICA population surveys conducted in 1984-6 (N = 3300), 1988-9 (N = 3331) and 1992-3 (N = 3133) and restricted to the same age group. Seven different definitions of low RF profile were used. Results: prevalence of low RF profile varied between 6.5% (95% confidence interval: 5.9-7.1) and 9.7% (9.0-10.5) depending on the definition used (see fig. 1). The prevalence was inversely related to the number of criteria used and higher than in other countries. Irrespective of the definition used, the prevalence of low RF profile was higher in women and in physically active participants, and decreased with increasing age or in the presence of a family history of cardiovascular disease. The prevalence of low RF profile increased from 3.8% (3.1- 4.5) in 1984-6 to 6.7% (6.1-7.3) in 2003-6; using another definition, the results were 5.9% (5.1-6.8) and 9.7% (9.0-10.5), respectively (see fig. 2). Conclusion: the prevalence of low RF profile varies according to the criteria used; this prevalence is relatively high and increasing in the Swiss population, which might partly explain the low and decreasing trend in cardiovascular mortality rates.

Investigating the genetic variation underlying episodicity in major depressive disorder: Suggestive evidence for a bipolar contribution.

BACKGROUND: Highly recurrent major depressive disorder (MDD) has reportedly increased risk of shifting to bipolar disorder; high recurrence frequency has, therefore, featured as evidence of 'soft bipolarity'. We aimed to investigate the genetic underpinnings of total depressive episode count in recurrent MDD. METHODS: Our primary sample included 1966 MDD cases with negative family history of bipolar disorder from the RADIANT studies. Total episode count was adjusted for gender, age, MDD duration, study and center before being tested for association with genotype in two separate genome-wide analyses (GWAS), in the full set and in a subset of 1364 cases with positive family history of MDD (FH+). We also calculated polygenic scores from the Psychiatric Genomics Consortium MDD and bipolar disorder studies. RESULTS: Episodicity (especially intermediate episode counts) was an independent index of MDD familial aggregation, replicating previous reports. The GWAS produced no genome-wide significant findings. The strongest signals were detected in the full set at MAGI1 (p=5.1×10(-7)), previously associated with bipolar disorder, and in the FH+ subset at STIM1 (p=3.9×10(-6) after imputation), a calcium channel signaling gene. However, these findings failed to replicate in an independent Munich cohort. In the full set polygenic profile analyses, MDD polygenes predicted episodicity better than bipolar polygenes; however, in the FH+ subset, both polygenic scores performed similarly. LIMITATIONS: Episode count was self-reported and, therefore, subject to recall bias. CONCLUSIONS: Our findings lend preliminary support to the hypothesis that highly recurrent MDD with FH+ is part of a 'soft bipolar spectrum' but await replication in larger cohorts.

Comparing Bone Microarchitecture by Trabecular Bone Score (TBS) in Caucasian American Women with and Without Osteoporotic Fractures.

Several cross-sectional studies have shown the ability of the TBS to discriminate between those with and without fractures in European populations. The aim of this study was to assess the ability of TBS to discriminate between those with and without fractures in a large female Caucasian population in the USA. This was a case-control study of 2,165 Caucasian American women aged 40 and older. Patients with illness or taking medications known to affect bone metabolism were excluded. Those in the fracture group (n = 289) had at least one low-energy fracture. BMD was measured at L1-L4, TBS calculated directly from the same DXA image. Descriptive statistics and inferential tests for difference were used. Univariate and multivariate logistic regression models were created to investigate possible association between independent variables and the status of fracture. Odds ratios per standard deviation decrease (OR) and areas under the ROC curve were calculated for discriminating parameters. Weak correlations were observed between TBS and BMD and between TBS and BMI (r = 0.33 and -0.17, respectively, p < 0.01). Mean age, weight, BMD and TBS were significantly different between control and fracture groups (all p ≤ 0.05), whereas no difference was noted for BMI or height. After adjusting for age, weight, BMD, smoking, and maternal and family history of fracture, TBS (but not BMD) remained a significant predictor of fracture: OR 1.28[1.13-1.46] even after adjustment. In a US female population, TBS again was able to discriminate between those with and those without fractures, even after adjusting for other clinical risk factors.

PFAPA syndrome is not a sporadic disease.

OBJECTIVES: To determine whether PFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) patients have a positive family history (FH) for recurrent fever syndromes. METHOD: For all patients with PFAPA seen in two paediatric rheumatology centres (Romandy, Switzerland and Bordeaux, France), parents were interviewed to record the FH for periodic fever. As controls, we interviewed a group of children without history of recurrent fever. RESULTS: We recruited 84 patients with PFAPA and 47 healthy children. The FH for recurrent fever (without an infectious cause and recurring for at least half a year) was positive in 38/84 (45%), and was positive for PFAPA (diagnosis confirmed by a physician) in 10/84 (12%) of the PFAPA patients. For 29 of the 38 patients with positive FH, the affected person was a sibling or a parent. None of the healthy children had a positive FH for recurrent fever or PFAPA. A positive FH for rheumatological diseases was seen in both groups of children. CONCLUSION: These data show that a significant percentage of PFAPA patients present a positive FH of recurrent fever and PFAPA. This familial susceptibility suggests a potential genetic origin for this syndrome.

Gene organization of the mating type regions in the ectomycorrhizal fungus Laccaria bicolor reveals distinct evolution between the two mating type loci

In natural conditions, basidiomycete ectomycorrhizal fungi such as Laccaria bicolor are typically in the dikaryotic state when forming symbioses with trees, meaning that two genetically different individuals have to fuse or 'mate'. Nevertheless, nothing is known about the molecular mechanisms of mating in these ecologically important fungi. Here, advantage was taken of the first sequenced genome of the ectomycorrhizal fungus, Laccaria bicolor, to determine the genes that govern the establishment of cell-type identity and orchestrate mating. The L. bicolor mating type loci were identified through genomic screening. The evolutionary history of the genomic regions that contained them was determined by genome-wide comparison of L. bicolor sequences with those of known tetrapolar and bipolar basidiomycete species, and by phylogenetic reconstruction of gene family history. It is shown that the genes of the two mating type loci, A and B, are conserved across the Agaricales, but they are contained in regions of the genome with different evolutionary histories. The A locus is in a region where the gene order is under strong selection across the Agaricales. By contrast, the B locus is in a region where the gene order is likely under a low selection pressure but where gene duplication, translocation and transposon insertion are frequent.