A novel SCN5A mutation, F1344S, identified in a patient with Brugada syndrome and fever-induced ventricular fibrillation

OBJECTIVE: Brugada syndrome (BS) is an inherited electrical cardiac disorder characterized by right bundle branch block pattern and ST segment elevation in leads V1 to V3 on surface electrocardiogram that can potentially lead to malignant ventricular tachycardia and sudden cardiac death. About 20% of patients have mutations in the only so far identified gene, SCN5A, which encodes the alpha-subunit of the human cardiac voltage-dependent sodium channel (hNa(v)1.5). Fever has been shown to unmask or trigger the BS phenotype, but the associated molecular and the biophysical mechanisms are still poorly understood. We report on the identification and biophysical characterization of a novel heterozygous missense mutation in SCN5A, F1344S, in a 42-year-old male patient showing the BS phenotype leading to ventricular fibrillation during fever. METHODS: The mutation was reproduced in vitro using site-directed mutagenesis and characterized using the patch clamp technique in the whole-cell configuration. RESULTS: The biophysical characterization of the channels carrying the F1344S mutation revealed a 10 mV mid-point shift of the G/V curve toward more positive voltages during activation. Raising the temperature to 40.5 degrees C further shifted the mid-point activation by 18 mV and significantly changed the slope factor in Na(v)1.5/F1344S mutant channels from -6.49 to -10.27 mV. CONCLUSIONS: Our findings indicate for the first time that the shift in activation and change in the slope factor at a higher temperature mimicking fever could reduce sodium currents' amplitude and trigger the manifestation of the BS phenotype.

Unexplained syncope--is screening for carotid sinus hypersensitivity indicated in all patients aged >40 years?

OBJECTIVE: To determine the frequency, age distribution and clinical presentation of carotid sinus hypersensitivity (CSH) among 373 patients (age range 15-92 years) referred to two autonomic referral centres during a 10-year period. METHODS: Carotid sinus massage (CSM) was performed both supine and during 60 degree head-up tilt. Beat-to-beat blood pressure, heart rate and a three-lead electrocardiography were recorded continuously. CSH was classified as cardioinhibitory (asystole > or = 3 s), vasodepressor (systolic blood pressure fall > or = 50 mm Hg) or mixed. All patients additionally underwent autonomic screening tests for orthostatic hypotension and autonomic failure. RESULTS: CSH was observed in 13.7% of all patients. The diagnostic yield of CSM was nil in patients aged < 50 years (n = 65), 2.4% in those aged 50-59 years (n = 82), 9.1% in those aged 60-69 years (n = 77), 20.7% in those aged 70-79 years (n = 92) and reached 40.4% in those > 80 years (n = 57). Syncope was the leading clinical symptom in 62.8%. In 27.4% of patients falls without definite loss of consciousness was the main clinical symptom. Mild and mainly systolic orthostatic hypotension was recorded in 17.6%; evidence of sympathetic or parasympathetic dysfunction was found in none. CONCLUSIONS: CSH was confirmed in patients > 50 years, the incidence steeply increasing with age. The current European Society of Cardiology guidelines that recommend testing for CSH in all patients > 40 years with syncope of unknown aetiology may need reconsideration. Orthostatic hypotension was noted in some patients with CSH, but evidence of sympathetic or parasympathetic failure was not found in any of them.

Effects of an aging vascular model on healthy and diseased hearts

The vitamin D(3) and nicotine (VDN) model is a model of isolated systolic hypertension (ISH) due to arterial calcification raising arterial stiffness and vascular impedance similar to an aged and stiffened arterial tree. We therefore analyzed the impact of this aging model on normal and diseased hearts with myocardial infarction (MI). Wistar rats were treated with VDN (n = 9), subjected to MI by coronary ligation (n = 10), or subjected to a combination of both MI and VDN treatment (VDN/MI, n = 14). A sham-treated group served as control (Ctrl, n = 10). Transthoracic echocardiography was performed every 2 wk, whereas invasive indexes were obtained at week 8 before death. Calcium, collagen, and protein contents were measured in the heart and the aorta. Systolic blood pressure, pulse pressure, thoracic aortic calcium, and end-systolic elastance as an index of myocardial contractility were highest in the aging model group compared with MI and Ctrl groups (P(VDN) < 0.05, 2-way ANOVA). Left ventricular wall stress and brain natriuretic peptide (P(VDNxMI) = not significant) were highest, while ejection fraction, stroke volume, and cardiac output were lowest in the combined group versus all other groups (P(VDNxMI) < 0.05). The combination of ISH due to this aging model and MI demonstrates significant alterations in cardiac function. This model mimics several clinical phenomena of cardiovascular aging and may thus serve to further study novel therapies.

Increased inspired oxygen concentration as a factor in improved brain tissue oxygenation and tissue lactate levels after severe human head injury

OBJECT: Early impairment of cerebral blood flow in patients with severe head injury correlates with poor brain tissue O2 delivery and may be an important cause of ischemic brain damage. The purpose of this study was to measure cerebral tissue PO2, lactate, and glucose in patients after severe head injury to determine the effect of increased tissue O2 achieved by increasing the fraction of inspired oxygen (FiO2). METHODS: In addition to standard monitoring of intracranial pressure and cerebral perfusion pressure, the authors continuously measured brain tissue PO2, PCO2, pH, and temperature in 22 patients with severe head injury. Microdialysis was performed to analyze lactate and glucose levels. In one cohort of 12 patients, the PaO2 was increased to 441+/-88 mm Hg over a period of 6 hours by raising the FiO2 from 35+/-5% to 100% in two stages. The results were analyzed and compared with the findings in a control cohort of 12 patients who received standard respiratory therapy (mean PaO2 136.4+/-22.1 mm Hg). The mean brain PO2 levels increased in the O2-treated patients up to 359+/-39% of the baseline level during the 6-hour FiO2 enhancement period, whereas the mean dialysate lactate levels decreased by 40% (p < 0.05). During this O2 enhancement period, glucose levels in brain tissue demonstrated a heterogeneous course. None of the monitored parameters in the control cohort showed significant variations during the entire observation period. CONCLUSIONS: Markedly elevated lactate levels in brain tissue are common after severe head injury. Increasing PaO2 to higher levels than necessary to saturate hemoglobin, as performed in the O2-treated cohort, appears to improve the O2 supply in brain tissue. During the early period after severe head injury, increased lactate levels in brain tissue were reduced by increasing FiO2. This may imply a shift to aerobic metabolism.

Effect of interferon-beta and atorvastatin on Th1/Th2 cytokines in multiple sclerosis

Beneficial effects by both interferon-beta and statin treatment in patients with multiple sclerosis (MS) may be linked to interference with the Th1/Th2 cytokine balance. We determined patterns of Th1/Th2 cytokines (interleukin (IL)-1beta, IL-2, IL-6, IL-12p70, tumor-necrosis factor (TNF)-alpha and interferon-gamma, and IL-4, IL-5 and IL-10, respectively) in the serum of patients with relapsing-remitting MS treated with 250microg interferon-beta 1b or with interferon-beta plus 40mg atorvastatin. In treatment naïve patients with MS, a trend for lower TNF-alpha serum levels compared to controls was detected (P=0.08). Interferon-beta treatment increased TNF-alpha levels, while a trend for lowering of IL-5 serum levels was found (P=0.07). Addition of atorvastatin raised IL-12p70 serum levels (P<0.05). Mean levels of two Th2 cytokines (IL-4, IL-10) showed a non-significant increase after addition of atorvastatin. We conclude that interferon-beta and atorvastatin exert divergent action on Th1/Th2 serum cytokines levels in MS. Supplemental atorvastatin might promote a Th1-type response by raising IL-12p70. Further studies are required to support a Th2 cytokine shift by atorvastatin in patients with MS.

Dementia with lewy bodies--diagnosis and treatment

Dementia with Lewy bodies (DLB) accounts for 15-20% of all autopsy confirmed dementias in old age. Characteristic histopathological changes are intracellular Lewy bodies and Lewy neurites, with abundant senile plaques but sparse neurofibrillary tangles. Core clinical features are fluctuating cognitive impairment, persistent visual hallucinations and extrapyramidal motor symptoms (parkinsonism). One of these core features has to be present for a diagnosis of possible DLB, and two for probable DLB. Supportive features are repeated falls, syncope, transient loss of consciousness, neuroleptic sensitivity, delusions and hallucinations in other modalities. DLB is clinically under-diagnosed and frequently misclassified as systemic delirium or dementia due to Alzheimer's disease or cerebrovascular disease. Therapeutic approaches to DLB can pose difficult dilemmas in pharmacological management. Neuroleptic medication is relatively contraindicated because some patients show severe neuroleptic sensitivity, which is associated with increased morbidity and mortality. Antiparkinsonian medication has the potential to exacerbate psychotic symptoms and may be relatively ineffective at relieving extrapyramidal motor symptoms. Recently there is converging evidence that treatment with cholinesterase inhibitors can offer a safe alternative for the symptomatic treatment of cognitive and neuropsychiatric features in DLB. This review will focus on the clinical characteristics of DLB, its differential diagnosis and on possible management strategies.

Epidemiology of Brucellosis and Q Fever in Linked Human and Animal Populations in Northern Togo

BACKGROUND: Although brucellosis (Brucella spp.) and Q Fever (Coxiella burnetii) are zoonoses of global importance, very little high quality data are available from West Africa. METHODS/PRINCIPAL FINDINGS: A serosurvey was conducted in Togo's main livestock-raising zone in 2011 in 25 randomly selected villages, including 683 people, 596 cattle, 465 sheep and 221 goats. Additionally, 464 transhumant cattle from Burkina Faso were sampled in 2012. The serological analyses performed were the Rose Bengal Test and ELISA for brucellosis and ELISA and the immunofluorescence assay (IFA) for Q Fever Brucellosis did not appear to pose a major human health problem in the study zone, with only 7 seropositive participants. B. abortus was isolated from 3 bovine hygroma samples, and is likely to be the predominant circulating strain. This may explain the observed seropositivity amongst village cattle (9.2%, 95%CI:4.3-18.6%) and transhumant cattle (7.3%, 95%CI:3.5-14.7%), with an absence of seropositive small ruminants. Exposure of livestock and people to C. burnetii was common, potentially influenced by cultural factors. People of Fulani ethnicity had greater livestock contact and a significantly higher seroprevalence than other ethnic groups (Fulani: 45.5%, 95%CI:37.7-53.6%; non-Fulani: 27.1%, 95%CI:20.6-34.7%). Appropriate diagnostic test cut-off values in endemic settings requires further investigation. Both brucellosis and Q Fever appeared to impact on livestock production. Seropositive cows were more likely to have aborted a foetus during the previous year than seronegative cows, when adjusted for age. This odds was 3.8 times higher (95%CI: 1.2-12.1) for brucellosis and 6.7 times higher (95%CI: 1.3-34.8) for Q Fever. CONCLUSIONS: This is the first epidemiological study of zoonoses in Togo in linked human and animal populations, providing much needed data for West Africa. Exposure to Brucella and C. burnetii is common but further research is needed into the clinical and economic impact.

Comparison of iron isotope variations in modern and Ordovician siliceous Fe oxyhydroxide deposits

Formation pathways of ancient siliceous iron formations and related Fe isotopic fractionation are still not completely understood. Investigating these processes, however, is difficult as good modern analogues to ancient iron formations are scarce. Modern siliceous Fe oxyhydroxide deposits are found at marine hydrothermal vent sites, where they precipitate from diffuse, low temperature fluids along faults and fissures on the seafloor. These deposits exhibit textural and chemical features that are similar to some Phanerozoic iron formations, raising the question as to whether the latter could have precipitated from diffuse hydrothermal fluids rather than from hydrothermal plumes. In this study, we present the first data on modern Fe oxyhydroxide deposits from the Jan Mayen hydrothermal vent fields, Norwegian-Greenland Sea. The samples we investigated exhibited very low δ56Fe values between -2.09‰ and -0.66‰. Due to various degrees of partial oxidation, the Fe oxyhydroxides are with one exception either indistinguishable from low-temperature hydrothermal fluids from which they precipitated (-1.84‰ and -1.53‰ in δ56Fe) or are enriched in the heavy Fe isotopes. In addition, we investigated Fe isotope variations in Ordovician jasper beds from the Løkken ophiolite complex, Norway, which have been interpreted to represent diagenetic products of siliceous ferrihydrite precursors that precipitated in a hydrothermal plume, in order to compare different formation pathways of Fe oxyhydroxide deposits. Iron isotopes in the jasper samples have higher δ56Fe values (-0.38‰ to +0.89‰) relative to modern, high-temperature hydrothermal vent fluids (ca. -0.40‰ on average), supporting the fallout model. However, formation of the Ordovician jaspers by diffuse venting cannot be excluded, due to lithological differences of the subsurface of the two investigated vent systems. Our study shows that reliable interpretation of Fe isotope variations in modern and ancient marine Fe oxyhydroxide deposits depends on comprehensive knowledge of the geological context. Furthermore, we demonstrate that very negative δ56Fe values in such samples might not be the result of microbial dissimilatory iron reduction, but could be caused instead by inorganic reactions.

An overview of positive and negative effects of gender-fair language use

The basic principle of gender-fair language is symmetric linguistic treatment of women and men. Depending on the structure of the respective language, two principle strategies can be deployed to make a language gender-fair. In languages with few gender-differentiating forms, such as English, there is a tendency towards neutralization. Here, gender-unmarked forms such as police officer or chairperson are used to substitute the male-biased policeman or chairman. The second strategy, feminization, implies that feminine forms of human nouns are used more frequently and systematically to make female referents visible.Since the 1970s, gender-fair language has been suggested, if not prescribed, for both scientific and official texts and its positive effects are widely documented. The use of gender-fair language increases the cognitive availability of feminine exemplars. Also in an applied context women responding to job advertisements formulated in gender-fair language feel more motivated to apply for the position. However, "side effects" of gender-fair language have also been observed: For instance, women referred to with a gender-fair title (e.g. chairperson) were evaluated as lower in status than women referred to with a masculine generic (e.g. chairman). Similarily, social initiatives framed with the use of gender-fair language were evaluated less-favourably than initiatives using traditional language. This presentation presents the gender-fair language use in the framework of a social dilemma. In order to protect themselves (or initiatives they stand for) from being ascribed incompetence or a lower status, women may avoid feminine forms and thus contribute to the perpetuation of gender-unfair language, which may be detrimental for women in general. Raising awareness for this social concern, and framing it both in terms of group and individual interest can direct the discussion about gender-fair language into a broader perspective of gender equality.

High-Sensitive Troponin Measurement in Emergency Department Patients Presenting with Syncope: A Retrospective Analysis

OBJECTIVE To study the relevance of high-sensitive troponin measurements in the acute workup in patients admitted to the emergency department of a large university hospital due to syncope. METHODS In this retrospective study all patients admitted to the emergency department because of syncope of the Inselspital, University Hospital Bern between 01 August 2010 and 31 October 2012, with serial determination of high-sensitive troponin (baseline and three hours control) were included. Of all identified patients we obtained data on demographics, laboratory data, ECG as well as on outcome. A change in high-sensitive troponin in the three hours control of +/-30% compared to baseline was considered significant. RESULTS A total of 121 patients with a mean age of 67 years (SD 16) were included in the study. 79 patients (65%) were male and 42 (35%) were female. There was no significant difference in the median high sensitive-troponin level at baseline and in the three hours control (0.01 mcg/L [0.003 to 0.022] versus 0.011 mcg/L [0.003 to 0.022], p = 0.47). Median percent change in high-sensitive troponin level between baseline and control was 0% (-9.1 to 5). 51 patients (42%) had elevated high-sensitive troponin levels at baseline with 7 patients (6%) showing a dynamic of +/-30% change from the baseline measurement in the 3 hours control. 3 of these patients received coronary angiography due to the dynamic in high-sensitive troponin, none of whom needed intervention for coronary revascularization. CONCLUSIONS On basis of the current study, where no single patient took benefit from determination of high-sensitive troponin, measurement of cardiac troponins should be reserved for patients with syncope presenting with symptoms suggestive for the presence of an acute cardiac syndrome.

Reconstruction of a flash flood with large wood transport and its influence on hazard patterns in an ungauged mountain basin

The reconstruction of past flash floods in ungauged basins leads to a high level of uncertainty, which increases if other processes are involved such as the transport of large wood material. An important flash flood occurred in 1997 in Venero Claro (Central Spain), causing significant economic losses. The wood material clogged bridge sections, raising the water level upstream. The aim of this study was to reconstruct this event, analysing the influence of woody debris transport on the flood hazard pattern. Because the reach in question was affected by backwater effects due to bridge clogging, using only high water mark or palaeostage indicators may overestimate discharges, and so other methods are required to estimate peak flows. Therefore, the peak discharge was estimated (123 ± 18 m3 s–1) using indirect methods, but one-dimensional hydraulic simulation was also used to validate these indirect estimates through an iterative process (127 ± 33 m3 s–1) and reconstruct the bridge obstruction to obtain the blockage ratio during the 1997 event (~48%) and the bridge clogging curves. Rainfall–Runoff modelling with stochastic simulation of different rainfall field configurations also helped to confirm that a peak discharge greater than 150 m3 s–1 is very unlikely to occur and that the estimated discharge range is consistent with the estimated rainfall amount (233 ± 27 mm). It was observed that the backwater effect due to the obstruction (water level ~7 m) made the 1997 flood (~35-year return period) equivalent to the 50-year flood. This allowed the equivalent return period to be defined as the recurrence interval of an event of specified magnitude, which, where large woody debris is present, is equivalent in water depth and extent of flooded area to a more extreme event of greater magnitude. These results highlight the need to include obstruction phenomena in flood hazard analysis.

Awareness of headache and of National Headache Society activities among primary care physicians - a qualitative study

BACKGROUND Headache is one of the most common symptoms in primary care. To improve the quality of headache diagnosis and management with the largest possible benefit for the general population, headache and pain societies around the world have recently been devoting more attention to headache in primary care.The aim of the study was to investigate the potential contribution that national societies can make toward raising the awareness of primary headaches in general practice. FINDINGS In a qualitative telephone survey, targeting primary care practices (PCP), we asked about the frequency of headache patients in their practices and inquired about their treatment and referral strategies.A total of 1000 telephone interviews with PCP have been conducted. Three-hundred and fifty physicians have been directly interviewed, 95% of them see headache patients every week, 23% daily. Direct MRI referral is done by 84%. Sixty-two per cent of the physicians knew the Swiss headache society, 73% were interested in further education about headaches. CONCLUSION The survey yielded information about the physicians' awareness of the Swiss Headache Society and its activities, and about their desire for continuing education in the area of headache. National headache societies should work to improve the cooperation between headache specialists and PCP, aiming for a better care for our patients with headache.

Dusty punch cards and an eternal enigma: high-density lipoproteins and atherosclerosis

Epidemiological, clinical, and experimental evidence has accumulated during the last decades suggesting that high-density lipoproteins (HDLs) may protect from atherosclerosis and its clinical consequences. However, more than 55 years after the first description of the link between HDL and heart attacks, many facets of the biochemistry, function, and clinical significance of HDL remain enigmatic. This applies particularly to the completely unexpected results that became available from some recent clinical trials of nicotinic acid and of inhibitors of cholesteryl ester transfer protein (CETP). The concept that raising HDL cholesterol by pharmacological means would decrease the risk of vascular disease has therefore been challenged.

Vulnerability to Heatwaves, Floods and Mass Movements in Mountainous Terrain: Test Cases in South Tyrol

South Tyrol is a region that has been often affected by various mountain hazards such as floods, flash floods, debris flows, rock falls, and snow avalanches. Furthermore, areas located in lower altitudes are often influenced by high temperatures and heat waves. Climate change is expected to influence the frequency, magnitude, and spatial extent of these natural phenomena. For this reason, local authorities and other stakeholders are in need of tools that can enable them to reduce the risk posed by these processes. In the present study, a variety of methods are applied at local level in different places in South Tyrol that aim at: (1) the assessment of future losses caused by the occurrence of debris flows by using a vulnerability curve, (2) the assessment of social vulnerability based on the risk awareness of the exposed people to floods, and (3) the assessment of spatial exposure and social vulnerability of the exposed population to heat waves. The results show that, in South Tyrol, the risk to a number of hazards can be reduced by: (1) improving documentation for past events in order to improve existing vulnerability curves and the assessment of future losses, (2) raising citizens' awareness and responsibility to improve coping capacity to floods, and (3) extending heat wave early warning systems to more low-lying areas of South Tyrol.

Three essays on prices and selection

Competitive Market Segmentation Abstract In a two-firm model where each firm sells a high-quality and a low-quality version of a product, customers differ with respect to their brand preferences and their attitudes towards quality. We show that the standard result of quality-independent markups crucially depends on the assumption that the customers' valuation of quality is identical across firms. Once we relax this assumption, competition across qualities leads to second-degree price discrimination. We find that markups on low-quality products are higher if consuming a low-quality product involves a firm-specific disutility. Likewise, markups on high-quality products are higher if consuming a high-quality product creates a firm-specific surplus. Selection upon Wage Posting Abstract We discuss a model of a job market where firms announce salaries. Thereupon, they decide through the evaluation of a productivity test whether to hire applicants. Candidates for a job are locked in once they have applied at a given employer. Hence, such a market exhibits a specific form of the bargain-then-ripoff principle. With a single firm, the outcome is efficient. Under competition, what might be called "positive selection" leads to market failure. Thus our model provides a rationale for very small employment probabilities in some sectors. Exclusivity Clauses: Enhancing Competition, Raising Prices Abstract In a setting where retailers and suppliers compete for each other by offering binding contracts, exclusivity clauses serve as a competitive device. As a result of these clauses, firms addressed by contracts only accept the most favorable deal. Thus the contract-issuing parties have to squeeze their final customers and transfer the surplus within the vertical supply chain. We elaborate to what extent the resulting allocation depends on the sequence of play and discuss the implications of a ban on exclusivity clauses.