Trans-ethnic analysis of metabochip data identifies two new loci associated with BMI.

OBJECTIVE: Body mass index (BMI) is commonly used to assess obesity, which is associated with numerous diseases and negative health outcomes. BMI has been shown to be a heritable, polygenic trait, with close to 100 loci previously identified and replicated in multiple populations. We aim to replicate known BMI loci and identify novel associations in a trans-ethnic study population. SUBJECTS: Using eligible participants from the Population Architecture using Genomics and Epidemiology consortium, we conducted a trans-ethnic meta-analysis of 102 514 African Americans, Hispanics, Asian/Native Hawaiian, Native Americans and European Americans. Participants were genotyped on over 200 000 SNPs on the Illumina Metabochip custom array, or imputed into the 1000 Genomes Project (Phase I). Linear regression of the natural log of BMI, adjusting for age, sex, study site (if applicable), and ancestry principal components, was conducted for each race/ethnicity within each study cohort. Race/ethnicity-specific, and combined meta-analyses used fixed-effects models. RESULTS: We replicated 15 of 21 BMI loci included on the Metabochip, and identified two novel BMI loci at 1q41 (rs2820436) and 2q31.1 (rs10930502) at the Metabochip-wide significance threshold (P<2.5 × 10-7). Bioinformatic functional investigation of SNPs at these loci suggests a possible impact on pathways that regulate metabolism and adipose tissue. CONCLUSION: Conducting studies in genetically diverse populations continues to be a valuable strategy for replicating known loci and uncovering novel BMI associations.

Copeptin and insulin resistance: effect modification by age and 11 ß-HSD2 activity in a population-based study.

PURPOSE: Arginine vasopressin (AVP) may be involved in metabolic syndrome (MetS) by altering liver glycogenolysis, insulin and glucagon secretion, and pituitary ACTH release. Moreover, AVP stimulates the expression of 11ß-hydroxysteroid-dehydrogenase-type 2 (11ß-HSD2) in mineralocorticosteroid cells. We explored whether apparent 11ß-HSD2 activity, estimated using urinary cortisol-to-cortisone ratio, modulates the association between plasma copeptin, as AVP surrogate, and insulin resistance/MetS in the general adult population. METHODS: This was a multicentric, family-based, cross-sectional sample of 1089 subjects, aged 18-90 years, 47% men, 13.4% MetS, in Switzerland. Mixed multivariable linear and logistic regression models were built to investigate the association of insulin resistance (HOMA-IR)/fasting glucose and MetS/Type 2 Diabetes with copeptin, while considering potential confounders or effect modifiers into account. Stratified results by age and 11ß-HSD2 activity were presented as appropriate. RESULTS: Plasma copeptin was higher in men [median 5.2, IQR (3.7-7.8) pmol/L] than in women [median 3.0, IQR (2.2-4.3) pmol/L], P < 0.0001. HOMA-IR was positively associated with copeptin after full adjustment if 11ß-HSD2 activity was high [ß (95% CI) = 0.32 (0.17-0.46), P < 0.001] or if age was high [ß (95% CI) = 0.34 (0.20-0.48), P < 0.001], but not if either 11ß-HSD2 activity or age was low. There was a positive association of type 2 diabetes with copeptin [OR (95% CI) = 2.07 (1.10-3.89), P = 0.024), but not for MetS (OR (95% CI) = 1.12 (0.74-1.69), P = 0.605), after full adjustment. CONCLUSIONS: Our data suggest that age and apparent 11ß-HSD2 activity modulate the association of copeptin with insulin resistance at the population level but not MeTS or diabetes. Further research is needed to corroborate these results and to understand the mechanisms underlying these findings.

Generalization and fine mapping of European ancestry-based central adiposity variants in African ancestry populations.

BACKGROUND/OBJECTIVES: Central adiposity measures such as waist circumference (WC) and waist-to-hip ratio (WHR) are associated with cardiometabolic disorders independently of body mass index (BMI) and are gaining clinically utility. Several studies report genetic variants associated with central adiposity, but most utilize only European ancestry populations. Understanding whether the genetic associations discovered among mainly European descendants are shared with African ancestry populations will help elucidate the biological underpinnings of abdominal fat deposition. SUBJECTS/METHODS: To identify the underlying functional genetic determinants of body fat distribution, we conducted an array-wide association meta-analysis among persons of African ancestry across seven studies/consortia participating in the Population Architecture using Genomics and Epidemiology (PAGE) consortium. We used the Metabochip array, designed for fine-mapping cardiovascular-associated loci, to explore novel array-wide associations with WC and WHR among 15 945 African descendants using all and sex-stratified groups. We further interrogated 17 known WHR regions for African ancestry-specific variants. RESULTS: Of the 17 WHR loci, eight single-nucleotide polymorphisms (SNPs) located in four loci were replicated in the sex-combined or sex-stratified meta-analyses. Two of these eight independently associated with WHR after conditioning on the known variant in European descendants (rs12096179 in TBX15-WARS2 and rs2059092 in ADAMTS9). In the fine-mapping assessment, the putative functional region was reduced across all four loci but to varying degrees (average 40% drop in number of putative SNPs and 20% drop in genomic region). Similar to previous studies, the significant SNPs in the female-stratified analysis were stronger than the significant SNPs from the sex-combined analysis. No novel associations were detected in the array-wide analyses. CONCLUSIONS: Of 17 previously identified loci, four loci replicated in the African ancestry populations of this study. Utilizing different linkage disequilibrium patterns observed between European and African ancestries, we narrowed the suggestive region containing causative variants for all four loci.

Analysis of a random modulation single photon counting differential absorption lidar system for space-borne atmospheric CO2 sensing.

The ability to observe the Earth's carbon cycles from space provides scientists an important tool to analyze climate change. Current proposed systems are mainly based on pulsed integrated path differential absorption lidar, in which two high energy pulses at different wavelengths interrogate the atmosphere sequentially for its transmission properties and are back-scattered by the ground. In this work an alternative approach based on random modulation single photon counting is proposed and analyzed; this system can take advantage of a less power demanding semiconductor laser in intensity modulated continuous wave operation, benefiting from a better efficiency, reliability and radiation hardness. Our approach is validated via numerical simulations considering current technological readiness, demonstrating its potential to obtain a 1.5 ppm retrieval precision for 50 km averaging with 2.5 W average power in a space-borne scenario. A major limiting factor is the ambient shot noise, if ultra-narrow band filtering technology could be applied, 0.5 ppm retrieval precision would be attainable.

Ultrasonic vocalizations of adult male Foxp2-mutant mice: behavioral contexts of arousal and emotion.

Adult mouse ultrasonic vocalizations (USVs) occur in multiple behavioral and stimulus contexts associated with various levels of arousal, emotion and social interaction. Here, in three experiments of increasing stimulus intensity (water; female urine; male interacting with adult female), we tested the hypothesis that USVs of adult males express the strength of arousal and emotion via different USV parameters (18 parameters analyzed). Furthermore, we analyzed two mouse lines with heterozygous Foxp2 mutations (R552H missense, S321X nonsense), known to produce severe speech and language disorders in humans. These experiments allowed us to test whether intact Foxp2 function is necessary for developing full adult USV repertoires, and whether mutations of this gene influence instinctive vocal expressions based on arousal and emotion. The results suggest that USV calling rate characterizes the arousal level, while sound pressure and spectrotemporal call complexity (overtones/harmonics, type of frequency jumps) may provide indices of levels of positive emotion. The presence of Foxp2 mutations did not qualitatively affect the USVs; all USV types that were found in wild-type animals also occurred in heterozygous mutants. However, mice with Foxp2 mutations displayed quantitative differences in USVs as compared to wild-types, and these changes were context dependent. Compared to wild-type animals, heterozygous mutants emitted mainly longer and louder USVs at higher minimum frequencies with a higher occurrence rate of overtones/harmonics and complex frequency jump types. We discuss possible hypotheses about Foxp2 influence on emotional vocal expressions, which can be investigated in future experiments using selective knockdown of Foxp2 in specific brain circuits.

[Screening and management of hypertension in elderly]. / Dépistage et prise en charge de l'hypertension artérielle chez la personne âgée.

The prevalence of hypertension in elderly is extremely high. Because of the burden of ageing of population, this condition considered as the most important risk factor for mortality is supposed to increase. There are some specific pitfalls in the diagnosis and management of hypertension in elderly. The definition of hypertension is the same in all age groups, however the phenotype is different in the elderly: white coat effect, non-dipping pattern, orthostatic hypotension, dysautonomia and pseudohypertension. The hallmark of hypertension in the elderly is pure systolic hypertension and an increased variability of blood pressure. The diagnosis is often difficult to establish. The elderly can be overtreated with undesirable effects of falls or hypoperfusion, particularly when there is frailty, or polymedication.

[My patient is too old for a lipid-lowering therapy: myths and reality]. / Mon patient est trop âgé pour une statine: mythes et réalités.

Lipid-lowering treatment in the elderly patient is conditioned by a high incidence and prevalence of cardiovascular disease in the setting of a limited remaining life span. The clinical benefit of statin therapy can be seen after a few months, thus supporting use in secondary prevention even when the lifespan is restricted to a few years. Recent guidelines propose the use of moderate doses in the elderly > 75 years. The evidence for treatment in primary prevention is weaker and the evaluation of the total cardiovascular risk is complicated by the high baseline risk of many elderly. Rational treatment decisions should be based on biologic rather than chronologic age. Statins are generally well tolerated in the elderly, requiring clinical monitoring only, with particular attention to pharmacokinetic interactions and renal failure.

The structure of innate vocalizations in Foxp2-deficient mouse pups.

Heterozygous mutations of the human FOXP2 gene are implicated in a severe speech and language disorder. Aetiological mutations of murine Foxp2 yield abnormal synaptic plasticity and impaired motor-skill learning in mutant mice, while knockdown of the avian orthologue in songbirds interferes with auditory-guided vocal learning. Here, we investigate influences of two distinct Foxp2 point mutations on vocalizations of 4-day-old mouse pups (Mus musculus). The R552H missense mutation is identical to that causing speech and language deficits in a large well-studied human family, while the S321X nonsense mutation represents a null allele that does not produce Foxp2 protein. We ask whether vocalizations, based solely on innate mechanisms of production, are affected by these alternative Foxp2 mutations. Sound recordings were taken in two different situations: isolation and distress, eliciting a range of call types, including broadband vocalizations of varying noise content, ultrasonic whistles and clicks. Sound production rates and several acoustic parameters showed that, despite absence of functional Foxp2, homozygous mutants could vocalize all types of sounds in a normal temporal pattern, but only at comparably low intensities. We suggest that altered vocal output of these homozygotes may be secondary to developmental delays and somatic weakness. Heterozygous mutants did not differ from wild-types in any of the measures that we studied (R552H ) or in only a few (S321X ), which were in the range of differences routinely observed for different mouse strains. Thus, Foxp2 is not essential for the innate production of emotional vocalizations with largely normal acoustic properties by mouse pups.

[Resistant hypertension]. / Hypertension artérielle résistante.

Resistant hypertension (rHTN) is a frequent problem with a high impact on cardiovascular risk. The preferred diagnostic approach is to systematically evaluate risk factors for rHTN and the presence of secondary hypertension. The follow-up of several key elements will often allow an improvement of blood pressure. Four therapeutic classes or even more are often used in these patients. Adding an aldosterone antagonist is often beneficial. Monitoring of patient compliance by electronic medication event monitoring systems can be helpful. Several new therapeutic approaches are currently in development: antagonists of the endothelin receptor and two interventional methods, carotid sinus stimulators and catheter-based renal sympathetic denervation therapy, have shown some promise.

Systemic allergic reaction and diffuse bone pain after exposure to a preparation of betamethasone.

Allergic reactions to corticosteroids are unexpected as they seem to contradict their pharmacodynamic action. Nevertheless, they are not infrequent, with an estimated incidence of up to 4% for cutaneous reactions. Systemic reactions are rarely reported, but their incidence might be underestimated. We report here an unusual allergic reaction to betamethasone presenting with diffuse bone pain, erythema, and bronchoconstriction, which was confirmed by a positive rechallenge in a double-blind procedure. This is the first case report of a systemic reaction to betamethasone confirmed by a positive rechallenge. An impurity in betamethasone diproprionate cannot be excluded. As this substance is frequently used in rheumatologic soft-tissue injections, it is important to recognize this potentially life-threatening side effect.

[Measurement of noise protection in functional magnetic resonance imaging]. / Messungen zum Lärmschutz bei der funktionellen MR-Tomographie.

BACKGROUND: Functional magnetic resonance imaging (fMRI) can detect changes in oxygen saturation of the brain. Fast changing high gradient fields are necessary which produce high levels of noise. In studies of the auditory cortex, auditory stimuli have to be perceived and discriminated against the noise level of the activated tomograph. MATERIAL AND METHODS: The generated frequency bands and their intensities during fMRI with a Siemens Magnetom Vision, 1.5 T, EPI sequence were measured in the outer ear canal of a dummy head. Noise attenuation was evaluated with four different noise muffs (simple/inexpensive products, quality product, specialized fMRI muffs). RESULTS: Without protection, peak noise levels reached up to 111 dB(A) near 1000 Hz in the dummy ear canal. Major noise attenuation was only found at higher frequencies (4000 Hz by about 25 dB; 8000 Hz by about 35 dB) with the quality product and the specialized fMRI muffs. CONCLUSION: Only quality noise products can sufficiently protect patients from high sound pressure levels of tomograph noise. If in the future higher gradient fields are applied at faster slew rates, acoustic stimuli can safely be applied only in combination with increased hearing protection systems in order to minimize the risk of noise trauma.

Synthesis of CoFe2O4 nanowire in carbon nanotubes. A new use of the confinement effect.

Cobalt ferrite nanowires with an average diameter of 50 nm and lengths up to several micrometers were synthesized inside carbon nanotubes under mild reaction conditions using the confinement effect provided by the carbon tubular template.

Local lattice distortions in spherical carbon nanoparticles as studied by HRTEM image analysis.

The study of lattice distortions in structures with spherical or cylindrical geometry is of growing interest in the field of carbon nanoparticles (onions, nanotubes, etc.). We report an image analysis procedure entirely performed in reciprocal space which provides a global map of the inter-shell distances in carbon nanoparticles. This procedure is applied to carbon nanoparticles with a size of 100 nm that are generated under CVD conditions and exhibit positive as well as negative curvature of the basal lattice planes. These nanoparticles are subjected to intense electron irradiation under the beam of a high-voltage electron microscope with an acceleration voltage of 1.25 MeV. We observe a compression in their centre and a dilation of the outer shells. The reciprocal-space analysis of the high-resolution electron microscopy images opens the way to investigate the stability and equilibrium structure of carbon nanoparticles and to conclude on the formation mechanism.

Corticofugal reorganization of the midbrain tonotopic map in mice.

Previous studies have indicated that frequency maps (tonotopies) in mammalian auditory brain centers are plastic. Here, we examined this plasticity in the mouse auditory midbrain through focal stimulation of the primary auditory cortex. Cortical activation shifted midbrain frequency tunings toward the best frequencies of the stimulated cortical neurons if these were either higher or lower than the cortical ones. Such corticofugal adjustments appear to minimize the difference between cortical and collicular frequency tuning within the critical bandwidths of the auditory system. Consequently, the neural representation is enhanced for the frequencies to which the cortical neurons were tuned. Our data suggest that the auditory cortex reorganizes midbrain tonotopy on the basis of which cortical frequencies are stimulated, mostly probably through corticofugal projections.

Frequency response areas of neurons in the mouse inferior colliculus. I. Threshold and tuning characteristics.

Excitatory and inhibitory frequency response areas of 130 neurons of the central nucleus of the mouse inferior colliculus (ICC) were mapped by extracellular single-unit recordings and quantitatively evaluated with regard to thresholds, steepness of slopes of excitatory tuning, characteristic frequencies of excitation (CF(E)), inhibition (CFI), and bandwidths of response areas (sharpness of tuning). Two-tone stimuli were used to determine the shapes of inhibitory response areas. Class I neurons (n=54) had asymmetrical (with regard to the CF(E)) excitatory and inhibitory response areas, with inhibition above CF(E) having lower thresholds and covering larger areas than inhibition below CF(E). Quantitative relationships between CF(E) and CF(I) thresholds, and sharpness of tuning showed that the receptive fields of about two-thirds of these neurons had properties similar to auditory nerve fibers. Class II neurons (n=36) had small symmetrical or tilted excitatory areas of rather constant bandwidths and broad inhibitory areas reaching far into and often through the excitatory area, leading to closed excitatory areas in ten neurons. Class III neurons (n=32) had higher excitatory thresholds and the highest proportions of unilateral inhibitory areas compared with neurons of the other classes. Their excitatory area often widened symmetrically with increasing sound level. Their inhibitory areas did not overlap with the excitatory area. Class IV neurons (n=8) had two branches of excitatory areas (two-CFs(E)) and six of the neurons had a central inhibitory area in addition to the low- and high-frequency inhibitory areas. In most neurons, the shapes of excitatory response areas predicted the shapes of inhibitory areas. Altogether, 15 neurons from all 4 classes had areas of facilitation in addition to inhibitory areas. Facilitation in six class IV neurons occurred between the two branches of the excitatory area. All 130 neurons had large inhibitory areas, 106 of them on both sides of the excitatory area. That is, sound processing in the ICC shows strong inhibitory components. The close relationships between excitatory and inhibitory CFs found here indicate that inhibitory projections to and interactions within the ICC are tonotopically organized comparable to the excitatory ones.

DNA binding specificity of different STAT proteins. Comparison of in vitro specificity with natural target sites.

STAT transcription factors are expressed in many cell types and bind to similar sequences. However, different STAT gene knock-outs show very distinct phenotypes. To determine whether differences between the binding specificities of STAT proteins account for these effects, we compared the sequences bound by STAT1, STAT5A, STAT5B, and STAT6. One sequence set was selected from random oligonucleotides by recombinant STAT1, STAT5A, or STAT6. For another set including many weak binding sites, we quantified the relative affinities to STAT1, STAT5A, STAT5B, and STAT6. We compared the results to the binding sites in natural STAT target genes identified by others. The experiments confirmed the similar specificity of different STAT proteins. Detailed analysis indicated that STAT5A specificity is more similar to that of STAT6 than that of STAT1, as expected from the evolutionary relationships. The preference of STAT6 for sites in which the half-palindromes (TTC) are separated by four nucleotides (N(4)) was confirmed, but analysis of weak binding sites showed that STAT6 binds fairly well to N(3) sites. As previously reported, STAT1 and STAT5 prefer N(3) sites; however, STAT5A, but not STAT1, weakly binds N(4) sites. None of the STATs bound to half-palindromes. There were no specificity differences between STAT5A and STAT5B.

Regional variations of noise-induced changes in operating range in cat AI.

Regional differences in spectral integration of neurons in cat primary auditory cortex (AI) suggest that regions differ in effects of background noise on operating characteristics of neurons. Therefore, tone-response threshold, best level (peak-rate intensity), dynamic range, and sharpness of tuning in quiet and in continuous broadband noise were mapped for single neurons along the isofrequency domain of AI. Neurons did not show an excitatory response to the noise. Noise invariably increased the tone-response threshold and best levels. Consequently, the dynamic ranges and receptive fields shifted to higher intensity levels without changes of average sharpness of tuning. These shifts were linearly related to noise level and showed little inter-neuronal variability for neurons in the central, mostly sharply tuned part of AI. In more dorsal and ventral parts of AI, neurons were more variable in tone-response threshold, dynamic range and best level, and no systematic relationship between increase in noise level, threshold increase and best-level increase was observed. We conclude that linear shifts in the operating range of neurons in central AI in the presence of continuous noise backgrounds do not affect other response properties and may relate to the unaltered analysis and representation of spectral components of sounds. In contrast, neurons in dorsal and ventral AI change response properties in a non-predictable way in the presence of noise in accordance with the more complex receptive field properties in those areas.