Pharmacological stimulation of edar signaling in the adult enhances sebaceous gland size and function.

Impaired ectodysplasin A (EDA) receptor (EDAR) signaling affects ectodermally derived structures including teeth, hair follicles, and cutaneous glands. The X-linked hypohidrotic ectodermal dysplasia (XLHED), resulting from EDA deficiency, can be rescued with lifelong benefits in animal models by stimulation of ectodermal appendage development with EDAR agonists. Treatments initiated later in the developmental period restore progressively fewer of the affected structures. It is unknown whether EDAR stimulation in adults with XLHED might have beneficial effects. In adult Eda mutant mice treated for several weeks with agonist anti-EDAR antibodies, we find that sebaceous gland size and function can be restored to wild-type levels. This effect is maintained upon chronic treatment but reverses slowly upon cessation of treatment. Sebaceous glands in all skin regions respond to treatment, although to varying degrees, and this is accompanied in both Eda mutant and wild-type mice by sebum secretion to levels higher than those observed in untreated controls. Edar is expressed at the periphery of the glands, suggesting a direct homeostatic effect of Edar stimulation on the sebaceous gland. Sebaceous gland size and sebum production may serve as biomarkers for EDAR stimulation, and EDAR agonists may improve skin dryness and eczema frequently observed in XLHED.

Origin and outcome of multiple pregnancies in Bern, Switzerland, 1995-2006 and the current proposal of the Swiss parliament to revise the Swiss law of reproductive medicine: Switzerland quo vadis?

INTRODUCTION: Infertility treatments are a major source of the increase in multiple pregnancies (MPs). AIMS: The aims of the present study were (1.) to investigate the origin and maternal/neonatal outcomes of MP and (2.) to review the different measures that can be adopted to reduce these serious complications. METHODS: The study included all women with multiple births between 1 January 1995 and 31 December 2006 at the University Hospital of Bern, Switzerland. The outcomes associated with the various origins of MP (natural conception, ovarian stimulation [OS] ‒ in-vitro fertilisation [IVF-ICSI]) were analysed using a multinomial logistic regression model. An analysis of the Swiss law on reproductive medicine and its current proposed revision, as well as a literature review using Pubmed, was carried out. RESULTS: A total of 592 MP were registered, 91% (n = 537) resulted in live births. There was significantly more neonatal/maternal morbidity in MP after OS compared with natural conception and even with the IVF-ICSI group. With a policy of elective single embryo transfer (eSET), twin rates after IVF-ICSI can be reduced to <5% and triplets to <1%. CONCLUSIONS: After OS, more triplets are found and the outcome of MP is worse. MP is known to be associated with morbidity, mortality, and economic and social risks. To counteract these complications (1.) better training for physicians performing OS should be encouraged and (2.) the Swiss law on reproductive medicine needs to be changed, with the introduction of eSET policies. This would lead to a dramatic decrease in neonatal and maternal morbidity/mortality as well as significant cost reductions for the Swiss healthcare system.

Auditory-visual multisensory interactions in humans: timing, topography, directionality, and sources.

Current models of brain organization include multisensory interactions at early processing stages and within low-level, including primary, cortices. Embracing this model with regard to auditory-visual (AV) interactions in humans remains problematic. Controversy surrounds the application of an additive model to the analysis of event-related potentials (ERPs), and conventional ERP analysis methods have yielded discordant latencies of effects and permitted limited neurophysiologic interpretability. While hemodynamic imaging and transcranial magnetic stimulation studies provide general support for the above model, the precise timing, superadditive/subadditive directionality, topographic stability, and sources remain unresolved. We recorded ERPs in humans to attended, but task-irrelevant stimuli that did not require an overt motor response, thereby circumventing paradigmatic caveats. We applied novel ERP signal analysis methods to provide details concerning the likely bases of AV interactions. First, nonlinear interactions occur at 60-95 ms after stimulus and are the consequence of topographic, rather than pure strength, modulations in the ERP. AV stimuli engage distinct configurations of intracranial generators, rather than simply modulating the amplitude of unisensory responses. Second, source estimations (and statistical analyses thereof) identified primary visual, primary auditory, and posterior superior temporal regions as mediating these effects. Finally, scalar values of current densities in all of these regions exhibited functionally coupled, subadditive nonlinear effects, a pattern increasingly consistent with the mounting evidence in nonhuman primates. In these ways, we demonstrate how neurophysiologic bases of multisensory interactions can be noninvasively identified in humans, allowing for a synthesis across imaging methods on the one hand and species on the other.

Direct detection of a BRAF mutation in total RNA from melanoma cells using cantilever arrays.

Malignant melanoma, the deadliest form of skin cancer, is characterized by a predominant mutation in the BRAF gene. Drugs that target tumours carrying this mutation have recently entered the clinic. Accordingly, patients are routinely screened for mutations in this gene to determine whether they can benefit from this type of treatment. The current gold standard for mutation screening uses real-time polymerase chain reaction and sequencing methods. Here we show that an assay based on microcantilever arrays can detect the mutation nanomechanically without amplification in total RNA samples isolated from melanoma cells. The assay is based on a BRAF-specific oligonucleotide probe. We detected mutant BRAF at a concentration of 500 pM in a 50-fold excess of the wild-type sequence. The method was able to distinguish melanoma cells carrying the mutation from wild-type cells using as little as 20 ng µl(-1) of RNA material, without prior PCR amplification and use of labels.

The history and role of long duration stimulation in fMRI.

During the past 20 years, BOLD fMRI has developed towards a central and fundamental tool in neuroscience. It has been shown that the BOLD response provides an indicator of neuronal activity in the brain. Consequently, for an accurate interpretation of findings in BOLD MRI experiments and to draw meaningful conclusions about the temporal evolution of neural events, a deep understanding of the nature of the BOLD contrast has become of essential importance. Since the dynamics of the major direct determinants of the BOLD signal (CBF, CBV and CMRO(2)) range between seconds and minutes, long duration stimulation was an early key strategy needed to study and understand the BOLD characteristics. This paper summarizes and discusses the thoughts and rationales of the long duration stimulation studies.

Transcranial Doppler after traumatic brain injury: is there a role?

PURPOSE OF REVIEW: To present the practical aspects of transcranial Doppler (TCD) and provide evidence supporting its use for the management of traumatic brain injury (TBI) patients. RECENT FINDINGS: TCD measures systolic, mean, and diastolic cerebral blood flow (CBF) velocities and calculates the pulsatility index from basal intracranial arteries. These variables reflect the brain circulation, provided there is control of potential confounding factors. TCD can be useful in patients with severe TBI to detect low CBF, for example, during intracranial hypertension, and to assess cerebral autoregulation. In the emergency room, TCD might complement brain computed tomography (CT) scan and clinical examination to screen patients at risk for further neurological deterioration after mild-to-moderate TBI. SUMMARY: The diagnostic value of TCD should be incorporated into other findings from multimodal brain monitoring and CT scan to optimize the bedside management of patients with TBI and help guide the choice of appropriate therapies.

Preperceptual and stimulus-selective enhancement of low-level human visual cortex excitability by sounds.

Evidence of multisensory interactions within low-level cortices and at early post-stimulus latencies has prompted a paradigm shift in conceptualizations of sensory organization. However, the mechanisms of these interactions and their link to behavior remain largely unknown. One behaviorally salient stimulus is a rapidly approaching (looming) object, which can indicate potential threats. Based on findings from humans and nonhuman primates suggesting there to be selective multisensory (auditory-visual) integration of looming signals, we tested whether looming sounds would selectively modulate the excitability of visual cortex. We combined transcranial magnetic stimulation (TMS) over the occipital pole and psychophysics for "neurometric" and psychometric assays of changes in low-level visual cortex excitability (i.e., phosphene induction) and perception, respectively. Across three experiments we show that structured looming sounds considerably enhance visual cortex excitability relative to other sound categories and white-noise controls. The time course of this effect showed that modulation of visual cortex excitability started to differ between looming and stationary sounds for sound portions of very short duration (80 ms) that were significantly below (by 35 ms) perceptual discrimination threshold. Visual perceptions are thus rapidly and efficiently boosted by sounds through early, preperceptual and stimulus-selective modulation of neuronal excitability within low-level visual cortex.

Current approaches and challenges for the metabolite profiling of complex natural extracts.

Metabolite profiling is critical in many aspects of the life sciences, particularly natural product research. Obtaining precise information on the chemical composition of complex natural extracts (metabolomes) that are primarily obtained from plants or microorganisms is a challenging task that requires sophisticated, advanced analytical methods. In this respect, significant advances in hyphenated chromatographic techniques (LC-MS, GC-MS and LC-NMR in particular), as well as data mining and processing methods, have occurred over the last decade. Together, these tools, in combination with bioassay profiling methods, serve an important role in metabolomics for the purposes of both peak annotation and dereplication in natural product research. In this review, a survey of the techniques that are used for generic and comprehensive profiling of secondary metabolites in natural extracts is provided. The various approaches (chromatographic methods: LC-MS, GC-MS, and LC-NMR and direct spectroscopic methods: NMR and DIMS) are discussed with respect to their resolution and sensitivity for extract profiling. In addition the structural information that can be generated through these techniques or in combination, is compared in relation to the identification of metabolites in complex mixtures. Analytical strategies with applications to natural extracts and novel methods that have strong potential, regardless of how often they are used, are discussed with respect to their potential applications and future trends.

Differential effects of glutamate transporter inhibitors on the global electrophysiological response of astrocytes to neuronal stimulation

Astrocytes are responsible for regulating extracellular levels of glutamate and potassium during neuronal activity. Glutamate clearance is handled by glutamate transporter subtypes glutamate transporter 1 and glutamate-aspartate transporter in astrocytes. DL-threo-beta-benzyloxyaspartate (TBOA) and dihydrokainate (DHK) are extensively used as inhibitors of glial glutamate transport activity. Using whole-cell recordings, we characterized the effects of both transporter inhibitors on afferent-evoked astrocyte currents in acute cortical slices of 3-week-old rats. When neuronal afferents were stimulated, passive astrocytes responded by a rapid inward current followed by a persistent tail current. The first current corresponded to a glutamate transporter current. This current was inhibited by both inhibitors and by tetrodotoxin. The tail current is an inward potassium current as it was blocked by barium. Besides inhibiting transporter currents, TBOA strongly enhanced the tail current. This effect was barium-sensitive and might be due to a rise in extracellular potassium level and increased glial potassium uptake. Unlike TBOA, DHK did not enhance the tail current but rather inhibited it. This result suggests that, in addition to inhibiting glutamate transport, DHK prevents astrocyte potassium uptake, possibly by blockade of inward-rectifier channels. This study revealed that, in brain slices, glutamate transporter inhibitors exert complex effects that cannot be attributed solely to glutamate transport inhibition.

Direct Fourier Tomographic Reconstruction Image-To-Image Filter

We present an open-source ITK implementation of a directFourier method for tomographic reconstruction, applicableto parallel-beam x-ray images. Direct Fourierreconstruction makes use of the central-slice theorem tobuild a polar 2D Fourier space from the 1D transformedprojections of the scanned object, that is resampled intoa Cartesian grid. Inverse 2D Fourier transform eventuallyyields the reconstructed image. Additionally, we providea complex wrapper to the BSplineInterpolateImageFunctionto overcome ITKâeuro?s current lack for image interpolatorsdealing with complex data types. A sample application ispresented and extensively illustrated on the Shepp-Loganhead phantom. We show that appropriate input zeropaddingand 2D-DFT oversampling rates together with radial cubicb-spline interpolation improve 2D-DFT interpolationquality and are efficient remedies to reducereconstruction artifacts.

Triiodothyronine stimulation of oligodendroglial differentiation and myelination. A developmental study.

The biochemical development of rotation-mediated aggregating brain cell cultures was studied in a serum-free chemically defined medium in the presence (complete medium) or the absence of triiodothyronine (T3). The expression of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) and myelin basic protein (MBP), two myelin components, was temporally dissociated in brain cell aggregating cultures grown in a complete medium. CNP increased from day 8 and reached a plateau around day 25. MBP accumulated rapidly from the third until the fourth week in culture. The total protein content increased gradually until day 25. The activity of ornithine decarboxylase (ODC) used as an index of cell growth and differentiation, showed two well-defined peaks of activity. The first peak reached a maximum at day 6 and correlated with both the highest DNA content and the peak of [3H]-thymidine incorporation. The second peak of ODC activity (from day 19 to 35) coincided with the differentiation of oligodendrocytes. These results confirm that aggregating fetal rat brain cells cultured in a serum-free chemically defined medium undergo extensive differentiation. Addition of T3 to the culture medium doubled the CNP activity by day 16. In contrast, MBP was only slightly increased by day 16, reaching at 25 and 35 days 8 to 10-fold higher values than the untreated cultures. When T3 was removed between day 16 and 25, CNP decreased almost to control values and MBP failed to accumulate. Moreover, when T3 was reintroduced into the medium (between day 25 and 35), CNP activity was restored and MBP content was partially corrected. T3 treatment produced a concentration-dependent increase in ODC activity which was observed only around day 19. The first peak of ODC activity observed at culture day 6 was independent of the presence of T3. These results obtained in brain cell cultures emphasize the direct effect of T3 on myelination.

Prise en charge actuelle de l'incontinence anale [Current management of anal incontinence]

Even though anal incontinence affects a significant proportion of the population, causing a major burden to both patient and society, it still remains "the last closet issue". Less than a third of patients will share this problem with their physician. Consequently, the incidence of anal incontinence is difficult to determine, varying from 2-50%. Since this disabling condition is often associated with urinary incontinence and/or pelvic organ prolapse, a multidisciplinary team approach is required. A wide range of therapeutic options are available. When dietary, medical and rehabilitative treatments have failed, sacral neuromodulation should be considered in selected cases. More invasive surgery is usually undertaken in the presence of major structural defects. The aim of this article is to suggest a comprehensive way of identifying and treating anal incontinence.

Electrical colonic stimulation reduces mean transit time in a porcine model.

Abstract Electrical stimulation is a new way to treat digestive disorders such as constipation. Colonic propulsive activity can be triggered by battery operated devices. This study aimed to demonstrate the effect of direct electrical colonic stimulation on mean transit time in a chronic porcine model. The impact of stimulation and implanted material on the colonic wall was also assessed. Three pairs of electrodes were implanted into the caecal wall of 12 anaesthetized pigs. Reference colonic transit time was determined by radiopaque markers for each pig before implantation. It was repeated 4 weeks after implantation with sham stimulation and 5 weeks after implantation with electrical stimulation. Aboral sequential trains of 1-ms pulse width (10 V; 120 Hz) were applied twice daily for 6 days, using an external battery operated stimulator. For each course of markers, a mean value was computed from transit times obtained from individual pig. Microscopic examination of the caecum was routinely performed after animal sacrifice. A reduction of mean transit time was observed after electrical stimulation (19 +/- 13 h; mean +/- SD) when compared to reference (34 +/- 7 h; P = 0.045) and mean transit time after sham stimulation (36 +/- 9 h; P = 0.035). Histological examination revealed minimal chronic inflammation around the electrodes. Colonic transit time measured in a chronic porcine model is reduced by direct sequential electrical stimulation. Minimal tissue lesion is elicited by stimulation or implanted material. Electrical colonic stimulation could be a promising approach to treat specific disorders of the large bowel.

A CT-based study investigating the relationship between pedicle screw placement and stimulation threshold of compound muscle action potentials measured by intraoperative neurophysiological monitoring.

PURPOSE: Neurophysiological monitoring aims to improve the safety of pedicle screw placement, but few quantitative studies assess specificity and sensitivity. In this study, screw placement within the pedicle is measured (post-op CT scan, horizontal and vertical distance from the screw edge to the surface of the pedicle) and correlated with intraoperative neurophysiological stimulation thresholds. METHODS: A single surgeon placed 68 thoracic and 136 lumbar screws in 30 consecutive patients during instrumented fusion under EMG control. The female to male ratio was 1.6 and the average age was 61.3 years (SD 17.7). Radiological measurements, blinded to stimulation threshold, were done on reformatted CT reconstructions using OsiriX software. A standard deviation of the screw position of 2.8 mm was determined from pilot measurements, and a 1 mm of screw-pedicle edge distance was considered as a difference of interest (standardised difference of 0.35) leading to a power of the study of 75 % (significance level 0.05). RESULTS: Correct placement and stimulation thresholds above 10 mA were found in 71 % of screws. Twenty-two percent of screws caused cortical breach, 80 % of these had stimulation thresholds above 10 mA (sensitivity 20 %, specificity 90 %). True prediction of correct position of the screw was more frequent for lumbar than for thoracic screws. CONCLUSION: A screw stimulation threshold of >10 mA does not indicate correct pedicle screw placement. A hypothesised gradual decrease of screw stimulation thresholds was not observed as screw placement approaches the nerve root. Aside from a robust threshold of 2 mA indicating direct contact with nervous tissue, a secondary threshold appears to depend on patients' pathology and surgical conditions.

Direct Effect of Birth Weight on Childhood Blood Pressure: a Causal Mediation Analysis

Background: Numerous studies have shown a negative association between birth weight (BW) and blood pressure (BP) later in life. To estimate the direct effect of BW on BP, it is conventional to condition on current weight (CW). However, such conditioning can induce collider stratification bias in the estimate of the direct effect. Objective: To bound the potential bias due to U, an unmeasured common cause of CW and BP, on the estimate of the (controlled) direct effect of BW on BP. Methods: Data from a school based study in Switzerland were used (N = 4,005; 2,010 B/1,995 G; mean age: 12.3 yr [range: 10.1-14.9]). Measured common causes of BW-BP (SES, smoking, body weight, and hypertension status of the mother) and CW-BP (breastfeeding and child's physical activity and diet) were identified with DAGs. Linear regression models were fitted to estimate the association between BW and BP. Sensitivity analyses were conducted to assess the potential effect of U on the association between BW and BP. U was assumed 1) to be a binary variable that affected BP by the same magnitude in low BWand in normal BW children and 2) to have a different prevalence in low BW children and in normal BW children for a given CW. Results: A small negative association was observed between BW and BP [beta: -0.3 mmHg/kg (95% CI: -0.9 to 0.3)]. The association was strengthened upon conditioning for CW [beta: -1.5 mmHg/kg (95% CI: -2.1 to -0.9)]. Upon further conditioning on common causes of BW-BP and CW-BP, the association did not change substantially [beta: -1.4 mmHg/kg (95% CI: -2.0 to -0.8)]. The negative association could be explained by U only if U was strongly associated with BP and if there was a large difference in the prevalence of U between low BWand normal BW children. Conclusion: The observed negative association between BW and BP upon adjustment for CW was not easily explained by an unmeasured common cause of CWand BP.