Validation of a clinical prediction score for ruling out coronary heart disease in primary care patients with chest pain.

Background: A patient's chest pain raises concern for the possibility of coronary heart disease (CHD). An easy to use clinical prediction rule has been derived from the TOPIC study in Lausanne. Our objective is to validate this clinical score for ruling out CHD in primary care patients with chest pain. Methods: This secondary analysis used data collected from a oneyear follow-up cohort study attending 76 GPs in Germany. Patients attending their GP with chest pain were questioned on their age, gender, duration of chest pain (1-60 min), sternal pain location, pain increases with exertion, absence of tenderness point at palpation, cardiovascular risks factors, and personal history of cardiovascular disease. Area under the curve (ROC), sensitivity and specificity of the Lausanne CHD score were calculated for patients with full data. Results: 1190 patients were included. Full data was available for 509 patients (42.8%). Missing data was not related to having CHD (p = 0.397) or having a cardiovascular risk factor (p = 0.275). 76 (14.9%) were diagnosed with a CHD. Prevalence of CHD were respectively of 68/344 (19.8%), 2/62 (3.2%), 6/103 (5.8%) in the high, intermediate and low risk category. ROC was of 72.9 (CI95% 66.8; 78.9). Ruling out patients with low risk has a sensitivity of 92.1% (CI95% 83.0; 96.7) and a specificity of 22.4% (CI95% 18.6%; 26.7%). Conclusion: The Lausanne CHD score shows reasonably good sensitivity and can be used to rule out coronary events in patients with chest pain. Patients at risk of CHD for other rarer reasons should nevertheless also be investigated.

L'athérosclérose est-elle une maladie gingivo-induite [Is atherosclerosis a periodontally-induced disease?]

Traditional risk factors do not explain all of cases of ischemic cardiovascular disease. The literature now identifies periodontal disease, a chronic oral infection, as a potential risk factor of atherosclerosis. Three plausible biologic pathways have been proposed to explain this link: a direct action of periodontal bacteria migrating by bacteriemia, an indirect action by inflammation, mediators an immunopathogenic pathway related to heat shock proteins. Clinical studies show an increase in the CRP or recirculating specific immunoglobulins in presence of advanced periodontal disease. Other interventional studies show a reduction in cardiovascular risk factors when intensive periodontal therapy is used in patients with advanced periodontal disease. Literature therefore confirms a modest link between periodontal and cardiovascular diseases even if causality is not confirmed so far.

Métastases pulmonaires: quelle place pour la chirurgie [Management pulmonary metastases: when operate?].

Thirty percent of patients suffering from malignant disease will develop pulmonary metastases. Effective chemotherapy is lacking for many of these tumors. Many studies suggest survival benefit in selected patients when pulmonary metastasectomy allows complete resection. Several operative approach may be offered in order to achieve complete resection and maximal lung sparring. Pre-operative workup must assess the control of the primary tumor and the possibility of performing complete resection. Minimally invasive approaches may offer better quality life and equivalent oncologic outcomes than open approach.

Cerebral and extracerebral cholesterol metabolism and CSF markers of Alzheimer's disease.

The disturbances of the cholesterol synthesis and metabolism described in Alzheimer's disease (AD) may be both a consequence of the neurodegenerative process and a contributor to the pathogenesis. These putative relationships and their underlying mechanisms are not well understood. The aim of this study was to evaluate the relationship between the cerebral and extracerebral cholesterol synthesis and metabolism, and the AD pathology as reflected by CSF markers in humans. We evaluated the relationships between the plasma and the cerebrospinal fluid (CSF) concentrations of cholesterol, the cholesterol precursors lanosterol, lathosterol and desmosterol, and the cholesterol elimination products 24S-hydroxycholesterol and 27-hydroxycholesterol, and the CSF markers for AD pathology Aβ1-42 and p-tau181 in 86 subjects with normal cognition and in 107 AD patients. CSF desmosterol, cholesterol and 24S-hydroxycholesterol in the AD group, and CSF 24S-hydroxycholesterol in the control group correlated with the p-tau181 levels. Neither CSF nor plasma concentrations of the included compounds correlated with the CSF Aβ1-42 levels. In multivariate regression tests including age, gender, albumin ratio, number of the APOEε4 alleles, and diagnosis, p-tau181 levels independently predicted the CSF desmosterol, cholesterol and 24S-hydroxycholesterol concentrations. The associations remained significant for CSF cholesterol and 24S-hydroxycholesterol when analyses were separately performed in the AD group. The results suggest that alterations of CNS cholesterol de novo genesis and metabolism are related to neurodegeneration and in particular to the cerebral accumulation of phosphorylated tau.

Holt Oram syndrome: a registry-based study in Europe.

BACKGROUND: Holt-Oram syndrome (HOS) is an autosomal dominant disorder characterised by upper limb anomalies and congenital heart defects. We present epidemiological and clinical aspects of HOS patients using data from EUROCAT (European Surveillance of Congenital Anomalies) registries. METHODS: The study was based on data collected during 1990-2011 by 34 registries. The registries are population-based and use multiple sources of information to collect data on all types of birth using standardized definitions, methodology and coding. Diagnostic criteria for inclusion in the study were the presence of radial ray abnormalities and congenital heart disease (CHD), or the presence of either radial ray anomaly or CHD, with family history of HOS. RESULTS: A total of 73 cases of HOS were identified, including 11 (15.1%) TOPFA and 62 (84.9%) LB. Out of 73 HOS cases, 30.8% (20/65) were suspected prenatally, 55.4% (36/65) at birth, 10.7% (7/65) in the first week of life, and 3.1% (2/65) in the first year of life. The prenatal detection rate was 39.2% (20/51), with no significant change over the study period. In 55% (11/20) of prenatally detected cases, parents decided to terminate pregnancy. Thumb anomalies were reported in all cases. Agenesis/hypoplasia of radius was present in 49.2% (30/61), ulnar aplasia/hypoplasia in 24.6% (15/61) and humerus hypoplasia/phocomelia in 42.6% (26/61) of patients. Congenital heart defects (CHD) were recorded in 78.7% (48/61) of patients. Isolated septal defects were present in 54.2 (26/48), while 25% (12/48) of patients had complex/severe CHD. The mean prevalence of HOS diagnosed prenatally or in the early years of life in European registries was 0.7 per 100,000 births or 1:135,615 births. CONCLUSIONS: HOS is a rare genetic condition showing regional variation in its prevalence. It is often missed prenatally, in spite of the existence of major structural anomalies. When discovered, parents in 45% (9/20) of cases opt for the continuation of pregnancy. Although a quarter of patients have severe CHD, the overall first week survival is very good, which is important information for counselling purposes.

CSF1R mutations link POLD and HDLS as a single disease entity.

OBJECTIVE: Pigmented orthochromatic leukodystrophy (POLD) and hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) are rare neurodegenerative disorders characterized by cerebral white matter abnormalities, myelin loss, and axonal swellings. The striking overlap of clinical and pathologic features of these disorders suggested a common pathogenesis; however, no genetic or mechanistic link between POLD and HDLS has been established. Recently, we reported that mutations in the colony-stimulating factor 1 receptor (CSF1R) gene cause HDLS. In this study, we determined whether CSF1R mutations are also a cause of POLD. METHODS: We performed sequencing of CSF1R in 2 pathologically confirmed POLD families. For the largest family (FTD368), a detailed case report was provided and brain samples from 2 affected family members previously diagnosed with POLD were re-evaluated to determine whether they had HDLS features. In vitro functional characterization of wild-type and mutant CSF1R was also performed. RESULTS: We identified CSF1R mutations in both POLD families: in family 5901, we found c.2297T>C (p.M766T), previously reported by us in HDLS family CA1, and in family FTD368, we identified c.2345G>A (p.R782H), recently reported in a biopsy-proven HDLS case. Immunohistochemical examination in family FTD368 showed the typical neuronal and glial findings of HDLS. Functional analyses of CSF1R mutant p.R782H (identified in this study) and p.M875T (previously observed in HDLS), showed a similar loss of CSF1R autophosphorylation of selected tyrosine residues in the kinase domain for both mutations when compared with wild-type CSF1R. CONCLUSIONS: We provide the first genetic and mechanistic evidence that POLD and HDLS are a single clinicopathologic entity.

The neonatal progeroid syndrome (Wiedemann-Rautenstrauch) and its relationship to Pelizaeus-Merzbacher's disease.

The neuropathology of a clinically well-documented case of the neonatal progeroid syndrome Wiedemann-Rautenstrauch is described. The most striking feature was a nearly complete absence of mature myelin in the brain. When immunohistochemistry for myelin basic protein was applied, some subcortical nerve fibres were accompanied by immature myelin sheaths. The neuropathology corresponds exactly to that of Pelizaeus-Merzbacher disease (Seitelberger type). Furthermore, this morphology, with the presence of myelin basic protein in the absence of mature myelin sheaths is reminiscent of the early stages of myelination in the newborn. From a brief review of the literature on Wiedemann-Rautenstrauch syndrome, we conclude, that the neuropathology of the syndrome is heterogeneous, and that there is relationship between the progeroid aspect and pathological myelination.

Rapid cohort generation and analysis of disease spectrum of large animal model of cone dystrophy.

Large animal models are an important resource for the understanding of human disease and for evaluating the applicability of new therapies to human patients. For many diseases, such as cone dystrophy, research effort is hampered by the lack of such models. Lentiviral transgenesis is a methodology broadly applicable to animals from many different species. When conjugated to the expression of a dominant mutant protein, this technology offers an attractive approach to generate new large animal models in a heterogeneous background. We adopted this strategy to mimic the phenotype diversity encounter in humans and generate a cohort of pigs for cone dystrophy by expressing a dominant mutant allele of the guanylate cyclase 2D (GUCY2D) gene. Sixty percent of the piglets were transgenic, with mutant GUCY2D mRNA detected in the retina of all animals tested. Functional impairment of vision was observed among the transgenic pigs at 3 months of age, with a follow-up at 1 year indicating a subsequent slower progression of phenotype. Abnormal retina morphology, notably among the cone photoreceptor cell population, was observed exclusively amongst the transgenic animals. Of particular note, these transgenic animals were characterized by a range in the severity of the phenotype, reflecting the human clinical situation. We demonstrate that a transgenic approach using lentiviral vectors offers a powerful tool for large animal model development. Not only is the efficiency of transgenesis higher than conventional transgenic methodology but this technique also produces a heterogeneous cohort of transgenic animals that mimics the genetic variation encountered in human patients.

Sniff nasal inspiratory pressure in patients with chronic obstructive pulmonary disease.

In subjects with normal lung mechanics, inspiratory muscle strength can be reliably and easily assessed by the sniff nasal inspiratory pressure (SNIP), which is the pressure measured in an occluded nostril during a maximal sniff performed through the contralateral nostril. The aim of this study was to assess the validity of the SNIP in patients with chronic obstructive pulmonary disease (COPD), where pressure transmission from alveoli to upper airways is likely to be dampened. Twenty eight patients with COPD were studied (mean forced expiratory volume in one second (FEV1) = 36% of predicted). The SNIP and the sniff oesophageal pressure (sniff Poes) were measured simultaneously during maximal sniffs, and were compared to the maximal inspiratory pressure obtained against an occlusion (MIP). All measurements were performed from functional residual capacity in the sitting position. The ratio SNIP/sniff Poes was 0.80, and did not correlate with the degree of airflow limitation. The ratio MIP/sniff Poes was 0.87, and the ratio SNIP/MIP was 0.97. Inspiratory muscle weakness, as defined by a low sniff Poes, was present in 17 of the 28 patients. A false diagnosis of weakness was made in eight patients when MIP was considered alone, in four when SNIP was considered alone, and in only three patients when MIP and SNIP were combined. We conclude that both the sniff nasal inspiratory pressure and the maximal inspiratory pressure moderately underestimate sniff oesophageal pressure in chronic obstructive pulmonary disease. Although suboptimal in this condition, the sniff nasal inspiratory pressure appears useful to complement the maximal inspiratory pressure for assessing inspiratory muscle strength in patients with chronic obstructive pulmonary disease.

Monitoring Disease Activity and Progression in Crohn's Disease. A Swiss Perspective on the IBD Ahead 'Optimised Monitoring' Recommendations.

BACKGROUND AND AIMS: The structured IBD Ahead 'Optimised Monitoring' programme was designed to obtain the opinion, insight and advice of gastroenterologists on optimising the monitoring of Crohn's disease activity in four settings: (1) assessment at diagnosis, (2) monitoring in symptomatic patients, (3) monitoring in asymptomatic patients, and (4) the postoperative follow-up. For each of these settings, four monitoring methods were discussed: (a) symptom assessment, (b) endoscopy, (c) laboratory markers, and (d) imaging. Based on literature search and expert opinion compiled during an international consensus meeting, recommendations were given to answer the question 'which diagnostic method, when, and how often'. The International IBD Ahead Expert Panel advised to tailor this guidance to the healthcare system and the special prerequisites of each country. The IBD Ahead Swiss National Steering Committee proposes best-practice recommendations adapted for Switzerland. METHODS: The IBD Ahead Steering Committee identified key questions and provided the Swiss Expert Panel with a structured literature research. The expert panel agreed on a set of statements. During an international expert meeting the consolidated outcome of the national meetings was merged into final statements agreed by the participating International and National Steering Committee members - the IBD Ahead 'Optimized Monitoring' Consensus. RESULTS: A systematic assessment of symptoms, endoscopy findings, and laboratory markers with special emphasis on faecal calprotectin is deemed necessary even in symptom-free patients. The choice of recommended imaging methods is adapted to the specific situation in Switzerland and highlights the importance of ultrasonography and magnetic resonance imaging besides endoscopy. CONCLUSION: The recommendations stress the importance of monitoring disease activity on a regular basis and by objective parameters, such as faecal calprotectin and endoscopy with detailed documentation of findings. Physicians should not rely on symptoms only and adapt the monitoring schedule and choice of options to individual situations. © 2014 S. Karger AG, Basel.

Le cancer est-il une maladie nouvelle? A propos du diagnostic des maladies tumorales dans le De Medicina de Celse [Is cancer a new disease? Apropos of diagnosis of tumor diseases in De Medicina by Celsus]

Cancer is a particularly common disease in modern societies. Moreover, epidemiology considers it typical of contemporary pathology. Nevertheless, the abundant ancient literature-in the De Medicina by Celsus, among others-leads us to believe that numerous benign and malignant tumours were observed if not identified as such. Hence, it is possible that both the change in medical conceptualization and the real increase in the prevalence are responsible for the actual importance of cancer

Does fructose consumption contribute to non-alcoholic fatty liver disease?

Fructose is mainly consumed with added sugars (sucrose and high fructose corn syrup), and represents up to 10% of total energy intake in the US and in several European countries. This hexose is essentially metabolized in splanchnic tissues, where it is converted into glucose, glycogen, lactate, and, to a minor extent, fatty acids. In animal models, high fructose diets cause the development of obesity, insulin resistance, diabetes mellitus, and dyslipidemia. Ectopic lipid deposition in the liver is an early occurrence upon fructose exposure, and is tightly linked to hepatic insulin resistance. In humans, there is strong evidence, based on several intervention trials, that fructose overfeeding increases fasting and postprandial plasma triglyceride concentrations, which are related to stimulation of hepatic de novo lipogenesis and VLDL-TG secretion, together with decreased VLDL-TG clearance. However, in contrast to animal models, fructose intakes as high as 200 g/day in humans only modestly decreases hepatic insulin sensitivity, and has no effect on no whole body (muscle) insulin sensitivity. A possible explanation may be that insulin resistance and dysglycemia develop mostly in presence of sustained fructose exposures associated with changes in body composition. Such effects are observed with high daily fructose intakes, and there is no solid evidence that fructose, when consumed in moderate amounts, has deleterious effects. There is only limited information regarding the effects of fructose on intrahepatic lipid concentrations. In animal models, high fructose diets clearly stimulate hepatic de novo lipogenesis and cause hepatic steatosis. In addition, some observations suggest that fructose may trigger hepatic inflammation and stimulate the development of hepatic fibrosis. This raises the possibility that fructose may promote the progression of non-alcoholic fatty liver disease to its more severe forms, i.e. non-alcoholic steatohepatitis and cirrhosis. In humans, a short-term fructose overfeeding stimulates de novo lipogenesis and significantly increases intrahepatic fat concentration, without however reaching the proportion encountered in non-alcoholic fatty liver diseases. Whether consumption of lower amounts of fructose over prolonged periods may contribute to the pathogenesis of NAFLD has not been convincingly documented in epidemiological studies and remains to be further assessed.

Stereologic estimates of total spinophilin-immunoreactive spine number in area 9 and the CA1 field: Relationship with the progression of Alzheimer's disease

The loss of presynaptic markers is thought to represent a strong pathologic correlate of cognitive decline in Alzheimer's disease (AD). Spinophilin is a postsynaptic marker mainly located to the heads of dendritic spines. We assessed total numbers of spinophilin-immunoreactive puncta. in the CA I and CA3 fields of hippocampus and area 9 in 18 elderly individuals with various degrees of cognitive decline. The decrease in spinophilin-immunoreactivity was significantly related to both Braak neurofibrillary tangle (NFT) staging and clinical severity but not A beta deposition staging. The total number of spinophilin-immunoreactive puncta in CA I field and area 9 were significantly related to MMSE scores and predicted 23.5 and 61.9% of its variability. The relationship between total number of spinophilin-immunoreactive puncta in CA I field and MMSE scores did not persist when adjusting for Braak NFT staging. In contrast, the total number of spinophilin-immunoreactive puncta in area 9 was still significantly related to the cognitive outcome explaining an extra 9.6% of MMSE and 25.6% of the Clinical Dementia Rating scores variability. Our data suggest that neocortical dendritic spine loss is an independent parameter to consider in AD clinicopathologic correlations.

Previous thyroid disease and risk of thyroid cancer in Switzerland

A hospital-based case-control study of 86 cases of thyroid cancer and 317 controls was done in the Swiss Canton of Vaud. Patients with thyroid cancer tended to be better educated (odds ratio [OR] 2.1 for greater than or equal to 14 vs. less than or equal to 8 years of education 95% CI 1.1-4.1) and of higher social class than controls. Cases more often had a history of benign thyroid nodules (OR 25.2, 95% CI 7.6-83.6) and non-toxic goitre (OR 5.3, 95% CI 2.5-11.2). Furthermore, patients with thyroid cancer were more likely to have resided in endemic goitre areas (OR 1.7, 95% CI 1.0-3.0) and to have had first-degree relatives affected by benign thyroid disease (OR 3.9, 95% CI 2.1-7.1). Therefore, this study offers quantitative evidence of the association between various thyroid diseases and the risk of thyroid cancer which, despite difficulties in the classification of benign and malignant thyroid diseases, is remarkably consistent in studies from different countries.

How demography, life history, and kinship shape the evolution of genomic imprinting.

How phenomena like helping, dispersal, or the sex ratio evolve depends critically on demographic and life-history factors. One phenotype that is of particular interest to biologists is genomic imprinting, which results in parent-of-origin-specific gene expression and thus deviates from the predictions of Mendel's rules. The most prominent explanation for the evolution of genomic imprinting, the kinship theory, originally specified that multiple paternity can cause the evolution of imprinting when offspring affect maternal resource provisioning. Most models of the kinship theory do not detail how population subdivision, demography, and life history affect the evolution of imprinting. In this work, we embed the classic kinship theory within an island model of population structure and allow for diverse demographic and life-history features to affect the direction of selection on imprinting. We find that population structure does not change how multiple paternity affects the evolution of imprinting under the classic kinship theory. However, if the degree of multiple paternity is not too large, we find that sex-specific migration and survival and generation overlap are the primary factors determining which allele is silenced. This indicates that imprinting can evolve purely as a result of sex-related asymmetries in the demographic structure or life history of a species.