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.

[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.

[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.

Auditory midbrain responses parallel spectral integration phenomena.

Resolving the frequency components of complex sound spectra including speech is an inherent, important accomplishment of the auditory nervous systems of vertebrates. The critical perceptual unit in the frequency domain, the critical bandwidth, has a simple functional equivalent within the principal midbrain auditory nucleus--the central nucleus of the inferior colliculus.

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.

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.

Quantitative analysis of nerve fibre densities in the cochlea of the house mouse (Mus musculus).

Transverse sections of the cochlear nerve, silver-stained surface preparations of the cochlea, and silver- and osmium-stained tangential sections of the cochlea of the house mouse were made to determine the number and density of nerve fibres entering the organ of Corti and their distribution to inner and outer hair cells along the cochlear spiral. A number of 12,578 +/- 819 fibres was counted within the cochlear nerve, which is almost equal to the total number of 12,350 +/- 810 fibres entering the organ of Corti. The 12,350 fibres divide into 9,780 (= 79%) fibres running to the inner hair cells, 703 (= 6%) basilar (afferent) fibres and 1,867 (= 15%) upper tunnel radial (efferent) fibres innervating the outer hair cells. About 93% of all afferent fibres are connected to the inner hair cells, and only 7% innervate outer hair cells. The density of fibres running to the inner hair cells varies considerably and has a significant (p less than 0.01) absolute and relative maximum 3.7 mm and 2.9 mm from the apex respectively (total length: 6.84 mm) and decreases toward apex and base. The density of afferent fibres running to the outer hair cells shows a slow increase up to 2 mm from the apex, and remains on a constant low level (5.5 fibres per 40 micrometer) down to the base. The density of efferent fibres running to the outer hair cells increases linearly up to about 2 mm from the apex, remains rather constant (10 fibres per 40 micrometer) from 2 mm to 4 mm, and then decreases toward the base. Generally, the outer hair cells show a convergent innervation pattern, the inner hair cells a divergent one. The significance of the present measurements is discussed in relation to respecitve results from other mammals and in relation to auditory thresholds.

Inferior colliculus of the house mouse. I. A quantitative study of tonotopic organization, frequency representation, and tone-threshold distribution.

Electrophysiological mapping was used to study frequency representation in the inferior colliculus (IC) of the mouse. In the lateral nucleus (LN) only part of the frequency range of hearing was represented and tonotopicity was separate from that in the rest of the IC. Highest frequencies occupied the medial part (M) of the central nucleus (CN). A single complete representation of the hearing range was present only if representations in the dorsal cortex (plus dorsomedial nucleus) and CN (including M) were combined. Continuous isofrequency planes making up these nuclei (without the lateral part of the CN) were reconstructed. They tilted from medial to lateral and from caudal to rostral. The steepness of the slopes increased from caudal to rostral and from dorsal to ventral (i.e., with increasing frequency). Isofrequency planes had similar angles of deviation from the horizontal plane as described for dendritic laminae in the CN. Differences of mapping in the lateral part of the CN from that in the rest of the CN could be explained by the different organization of laminae in this part. The relative amounts of IC depth and volume occupied by parts of the mouse audible frequency range were quantified. Frequency representation along IC depth was not proportional to that along cochlear length. Compared with the relative density of afferent nerve fiber supply within given frequency ranges represented along the basilar membrane, there is a relative under-representation in the IC up to 15-20 kHz and an over-representation of higher frequencies. Highest absolute tone sensitivity (lowest threshold) was found in neurons forming a column (running perpendicular to isofrequency planes) in the center of the IC. Results are discussed with regard to frequency representation, intrinsic neuronal organization, and functional segregation in the IC of mammals.

The auditory cortex of the mouse: connections of the ultrasonic field.

The cortical and subcortical connections of the ultrasonic field (UF) of the auditory cortex of the house mouse (Mus musculus) were studied by using retrograde and anterograde transport of horseradish peroxidase (HRP). Small amounts of HRP were locally injected into the electrophysiologically defined UF. Superficial (layer I-IV) and deep (layer IV-VI) injections were prepared. Superficial injections led to labelling of both cells (retrograde) and terminals (anterograde) in areas of the ipsilateral primary and secondary auditory cortex and in its dorsoposterior field, in an ipsilateral dorsal association area (patches of label), probably in ipsilateral secondary somatosensory cortex, in the contralateral homotopic UF, and in the ipsilateral medial geniculate body (MGBv, MGBd, and MGBm) and caudal posterior nucleus complex. Deep injections showed the same connectivities as superficial ones and, in addition, terminals in the very caudal caudatoputamen, in the nucleus limitans and the nucleus reticularis of the thalamus, in the rostral pole, the dorsomedial, and lateral nucleus of the inferior colliculus, in the stratum griseum intermediale of the superior colliculus, and in a pontine nucleus ventromedial of the lateral lemniscus. All these projections occurred only ipsilaterally. The majority of connections, except those with the nucleus limitans, superior colliculus and pontine nucleus, suggest that UF is part of the primary anditory cortex (AI) and/or of the anterior anditory field (AAF) of the auditory cortex. Since UF has no regular tonotopy, this has important implications for the functional role that AI/AAF can have in communication-sound analysis.

Haloperidol- and apomorphine-induced changes in pup searching behaviour of house mice.

Maternal pup searching behaviour of lactating house mice treated with apomorphine, haloperidol or saline was examined on a running board with a central depression as a nest. Pup searching was elicited by artificial ultrasonic stimuli: a female moved out from the nest either towards a 50 kHz tone (key stimulus) which is adequate to activate species specific pup searching behaviour or towards a 20 kHz tone (neutral stimulus), thus showing her preference for one of these stimuli. Under apomorphine (0.00625; 0.0125; 0.025 mg/kg) the females preferred the key stimulus. Nevertheless apomorphine (0.00625-0.025 mg/kg) prolonged response latencies and shortened the duration of pup searching. At the highest dose (0.05 mg/kg), apomorphine induced stereotyped sniffing. Haloperidol (0.025; 0.05; 0.1 mg/kg) had opposite effects to apomorphine: it lowered the threshold for elicitation, shortened response latencies and prolonged the duration of pup searching. Females treated with haloperidol (0.025-0.1 mg/kg) did not prefer the key stimulus. Changes in response elicitation and in the performance of pup searching induced by apomorphine and haloperidol, respectively, were assumed to be due to i) a reduced and an increased responsiveness to external stimuli respectively, ii) an enhanced and a reduced tendency for response switching respectively, and iii) a preference for spontaneous behaviour in apomorphine-treated females, with an increased dependence on exteroceptive stimuli following haloperidol.

Perception and recognition discriminated in the mouse auditory cortex by c-Fos labeling.

The functions of the fields of the mammalian auditory cortex in sound perception and recognition are unknown. We used Fos (a protein of the inducible immediate-early gene c-fos) as a cellular marker of activated brain areas to show in the mouse (Mus domesticus) that sound is processed differentially in auditory cortical fields according to its actual significance in a behavioral context. Recognition, compared with perception of exactly the same sound, produced significantly less but well focused Fos-positive cells in a primary auditory cortical field and significantly more labeling in higher auditory and association fields. Thus, recognition means a state of distinctive spatial distribution of activity in auditory cortical fields with a predominance of activation in higher-order fields.

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.

Oestrogen receptor occurrence in the male mouse brain: modulation by paternal experience.

Paternal behaviour (pup-searching and retrieving of pups) was studied in male house mice with different experience in pup care and oestrogen receptor immunoreactive (ER-IR) cells were localized and quantified in their brains. Experience with pups induced paternal behaviour and correlated with (a) the occurrence of ER-IR cells in the bed nucleus of the stria terminalis, hippocampus, subiculum, lateral septal nuclei, entorhinal and piriform cortex, (b) increased numbers of ER-IR cells in the medial preoptic area and arcuate nucleus of the hypothalamus, and (c) decreased presence of ER-IR cells in the periventricular grey of the midbrain. The data indicate oestrogen receptor modulation in the male brain and suggest that oestrogen binding in distinct brain areas is involved in the regulation of paternal behaviour.

Estrogen-receptor occurrence in the female mouse brain: effects of maternal experience, ovariectomy, estrogen and anosmia.

Maternal behavior (ultrasound-induced pup-searching and retrieving) was studied in eight groups of female house mice with various hormonal backgrounds, experience with pups and function of the olfactory system. In their brains, estrogen receptor immunoreactive (ER-IR) cells were localized and quantified. All animals of all groups had ER-IR cells in a 'reliable subset' of brain areas, the medial preoptic area (MPOA) and ventromedial (VMH) and arcuate nucleus (ARH) of the hypothalamus. In another subset of brain areas, the anterior hypothalamic area (AHA) and cortical (CA) and medial (MA) amygdaloid nucleus, ER-IR cells can be expected in at least some animals of all experimental groups ('expected subset'). In a variable subset of additional brain areas (bed nucleus of the stria terminalis, BNST; suprachiasmatic nucleus, SC; lateral septal nuclei, LS; paraventricular nucleus of the hypothalamus, PVH; entorhinal and piriform cortex, ENT, PIR; subiculum, SUB; hippocampus, HPC; periventricular gray of the midbrain, PVG), ER-IR cells occurred only in some animals of some groups. Numbers of ER-IR cells in a given brain area, volumes occupied by these cells, and cell densities varied considerably among the groups. A covariation of cell counts and volumes was significant for most brain areas indicating that increases of numbers of ER-IR cells relate mainly to volume increases within a given brain area. Experience with pups correlated with an increase of ER presence in the AHA, VMH, ENT, PIR, SUB, HPC and PVG, however, only in the presence of estrogen. Estrogen and pup-experience together led to an increased ER presence in mainly the VMH, ENT and PIR, however, only in females with intact olfaction. Full maternal behavior (retrieving, ultrasound recognition) occurred after the high pregnancy- or experience-induced ER content was reduced to lower levels. The ER occurrence in lactating and experienced virgin females differed, however, in the AHA, BNST, SC, PVH, ENT, PIR, SUB, HPC and PVG showing that the maintenance of maternal behavior can run under different profiles of ER content in the brain. Ovariectomy and/or prolonged high blood-estrogen levels correlated significantly with decreased levels of ER-IR cells in most brain areas which could not be increased by pup-experience.

Parental behavior in the mouse: effects of lesions in the entorhinal/piriform cortex.

The effects of bilateral radiofrequency lesions in the region of the entorhinal and piriform cortex (ENT/PIR cortex) on pup-retrieving and ultrasound-elicited pup-searching behavior were investigated in ovariectomized estrogen-treated female mice, which were sensitized to pups by co-caring for a litter for 5 days together with the mother (FoEBex), as well as in primiparous lactating females (Flact). A further group of FoEBex were rendered anosmic by an intranasal treatment with zinc sulfate-solution before the sensitization period and tests for parental motivation. Both pup-retrieving and pup-searching behavior were disturbed to the same extent by ENT/PIR lesions and ZnSO4-induced anosmia in FoEBex. In Flact, however, pup-retrieving was not affected by the lesion, while ultrasound-recognition leading to pup-searching was disrupted. The present data suggest sensitization to pups as a case of olfactory learning and thus, the effects of the ENT/PIR lesions are regarded as anterograde olfactory amnesia. From the present data and results reported in the literature, it is suggested to differentiate between the neural substrates processing stimuli relevant for the appetitive component (pup-searching) of parental behavior (among others, the region of the entorhinal and piriform cortex), and the mechanisms regulating the consummatory component (pup-retrieving).

Neuronal activity and tonotopy in the auditory system visualized by c-fos gene expression.

Responsiveness in the cochlear nucleus complex and inferior colliculus of the mouse to tonal stimulation is labelled via immunocytochemically stained Fos protein that is expressed by c-fos gene activation in excited neurons. The locations of Fos-positive neurons closely reproduce the tonotopic maps in the dorsal cochlear nucleus and inferior colliculus. Thus, the c-fos method can demonstrate stimulus-related local neuronal activation on a single-cell level and may be useful to complement other mapping techniques such as electrophysiological recording or 2-deoxyglucose autoradiography.