Cerebrofaciothoracic dysplasia: four new patients with a recurrent TMCO1 pathogenic variant.

Biallelic loss of function variants in the TMCO1 gene have been previously demonstrated to result in cerebrofaciothoracic dysplasia (CFTD; MIM #213980). The phenotype of this condition includes severe intellectual disability, as well as distinctive craniofacial features, including brachycephaly, synophrys, arched eyebrows, "cupid's bow" upper lip, and microdontia. In addition, nonspecific skeletal anomalies are common, including bifid ribs, scoliosis, and spinal fusion. Only 19 molecularly confirmed patients have been previously described. Here, we present four patients with CFTD, including three brothers from a Pakistani background and an additional unrelated white Scottish patient. All share the characteristic craniofacial appearance, with severe intellectual disability and skeletal abnormalities. We further define the phenotype with comparison to the published literature, and present images to define the dysmorphic features in a previously unreported ethnic group. All of our patient series are homozygous for the same c.292_293del (p.Ser98*) TMCO1 pathogenic variant, which has been previously reported only in an isolated Amish population. Thus we provide evidence that CFTD may be more common than previously thought. The patients presented here further delineate the phenotypic spectrum of CFTD and provide evidence for a recurrent pathogenic variant in TMCO1

Determination of micro-scale plastic strain caused by orthogonal cutting

An electron beam lithography technique has been used to produce microgrids in order to measure local plastic strains, induced during an orthogonal cutting process, at the microscopic scale in the shear zone and under the machined surface. Microgrids with a 10 μm pitch and a line width less than 1 μm have been printed on the polished surface of an aluminium alloy AA 5182 to test the applicability of the technique in metal cutting operations. Orthogonal cutting tests were carried out at 40 mm/s. Results show that the distortion of the grids could successfully be used to compute plastic strains due to orthogonal cutting with higher accuracy compared to other techniques reported in the literature. Strain maps of the machined specimens have been produced and show high-strain gradients very close to the machined surface with local values reaching 2.2. High-resolution strain measurements carried out in the primary deformation zone also provide new insight into the material deformation during the chip formation process

Ex-Vivo 13 C NMR Spectroscopy of Rodent Brain: TNF Restricts Neuronal Utilization of Astrocyte-Derived Metabolites

Tumor necrosis factor (TNF) has well-established roles in neuroinflammatory disorders, but the effect of TNF on the biochemistry of brain cells remains poorly understood. Here, we microinjected TNF into the brain to study its impact on glial and neuronal metabolism (glycolysis, pentose phosphate pathway, citric acid cycle, pyruvate dehydrogenase, and pyruvate carboxylase pathways) using 13C NMR spectroscopy on brain extracts following intravenous [1,2-13C]-glucose (to probe glia and neuron metabolism), [2-13C]-acetate (probing astrocyte-specific metabolites), or [3-13C]-lactate. An increase in [4,5-13C]-glutamine and [2,3-13C]-lactate coupled with a decrease in [4,5-13C]-glutamate was observed in the [1,2-13C]-glucose-infused animals treated with TNF. As glutamine is produced from glutamate by astrocyte-specific glutamine synthetase the increase in [4,5-13C]-glutamine reflects increased production of glutamine by astrocytes. This was confirmed by infusion with astrocyte substrate [2-13C]-acetate. As lactate is metabolized in the brain to produce glutamate, the simultaneous increase in [2,3-13C]-lactate and decrease in [4,5-13C]-glutamate suggests decreased lactate utilization, which was confirmed using [3-13C]-lactate as a metabolic precursor. These results suggest that TNF rearranges the metabolic network, disrupting the energy supply chain perturbing the glutamine-glutamate shuttle between astrocytes and the neurons. These insights pave the way for developing astrocyte-targeted therapeutic strategies aimed at modulating effects of TNF to restore metabolic homeostasis in neuroinflammatory disorders

Numerical methods for non-LTE line radiative transfer: Performance and convergence characteristics

Comparison is made between a number of independent computer programs for radiative transfer in molecular rotational lines. The test models are spherically symmetric circumstellar envelopes with a given density and temperature profile. The first two test models have a simple power law density distribution, constant temperature and a fictive 2-level molecule, while the other two test models consist of an inside-out collapsing envelope observed in rotational transitions of HCO+. For the 2-level molecule test problems all codes agree well to within 0.2%, comparable to the accuracy of the individual codes, for low optical depth and up to 2% for high optical depths (tau=4800). The problem of the collapsing cloud in HCO+ has a larger spread in results, ranging up to 12% for the J=4 population. The spread is largest at the radius where the transition from collisional to radiative excitation occurs. The resulting line profiles for the HCO+ J=4-3 transition agree to within 10%, i.e., within the calibration accuracy of most current telescopes. The comparison project and the results described in this paper provide a benchmark for future code development, and give an indication of the typical accuracy of present day calculations of molecular line transfer.Comment: Accepted for publication in A&

Lower cardiorespiratory fitness contributes to increased insulin resistance and fasting glycaemia in middle-aged South Asian compared with European men living in the UK

AIMS/HYPOTHESIS: This study aimed to determine the extent to which increased insulin resistance and fasting glycaemia in South Asian men, compared with white European men, living in the UK, was due to lower cardiorespiratory fitness (maximal oxygen uptake [[Formula: see text]]) and physical activity. METHODS: One hundred South Asian and 100 age- and BMI-matched European men without diagnosed diabetes, aged 40–70 years, had fasted blood taken for measurement of glucose concentration, HOMA-estimated insulin resistance (HOMA(IR)), plus other risk factors, and underwent assessment of physical activity (using accelerometry), [Formula: see text], body size and composition, and demographic and other lifestyle factors. For 13 South Asian and one European man, HbA(1c) levels were >6.5% (>48 mmol/mol), indicating potential undiagnosed diabetes; these men were excluded from the analyses. Linear regression models were used to determine the extent to which body size and composition, fitness and physical activity variables explained differences in HOMA(IR) and fasting glucose between South Asian and European men. RESULTS: HOMA(IR) and fasting glucose were 67% (p < 0.001) and 3% (p < 0.018) higher, respectively, in South Asians than Europeans. Lower [Formula: see text], lower physical activity and greater total adiposity in South Asians individually explained 68% (95% CI 45%, 91%), 29% (11%, 46%) and 52% (30%, 80%), respectively, and together explained 83% (50%, 119%) (all p < 0.001) of the ethnic difference in HOMA(IR). Lower [Formula: see text] and greater total adiposity, respectively, explained 61% (9%, 111%) and 39% (9%, 76%) (combined effect 63% [8%, 115%]; all p < 0.05) of the ethnic difference in fasting glucose. CONCLUSIONS/INTERPRETATION: Lower cardiorespiratory fitness is a key factor associated with the excess insulin resistance and fasting glycaemia in middle-aged South Asian, compared with European, men living in the UK. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-013-2969-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users

Anatomical and surgical study of volume determination of the anterolateral epidural space nerve root L5/S1 under the aspect of epidural perineural injection in minimal invasive treatment of lumbar nerve root compression

Herniated intervertebral disc causes in a great number of cases of lumbar nerve root compression, especially in the segment L5/S1. Other reasons responsible for stress to the lumbar spinal root are the spinal canal stenosis and the postdiscotomy syndrome. For patients without neurological deficiencies, the conservative treatment includes different epidural injection techniques. Steroids are often applied. A specific injection technique needing only a small drug amount is the epidural perineural approach using a special two-needle technique. The anatomical spaces of the nerve roots have received little attention in therapy. We have determined the anterolateral epidural space nerve volume of the nerve root L5/S1, and compared the data collected in an anatomical study with operative measurements during discectomy. The volume determination in the human cadavers was performed with liquid silicone filling the anterolateral space after dissection. The in vivo measurements were performed during surgery at the site of the anterolateral space after discectomy. The anatomical studies showed us a mean value volume of 1.1 ml. The surgical volume determinations result in a mean volume of 0.9 ml. A better understanding of the anterolateral epidural space may allow a reduction of the injection volume in the conservative nerve root compression treatment, especially using the epidural perineural technique, avoiding the risk of side effects of high doses of steroids

Effects of intrauterine exposure to synthetic glucocorticoids on fetal, newborn, and infant hypothalamic-pituitary-adrenal axis function in humans : a systematic review

BACKGROUND: Synthetic glucocorticoids are commonly used in reproductive medicine. Fetal organ systems are highly sensitive to changes in the intrauterine environment, including overexposure to glucocorticoids. Structural and functional alterations resulting from such changes may persist throughout life and have been associated with diverse diseases. One system that could be particularly sensitive to fetal glucocorticoid overexposure is the hypothalamic-pituitary-adrenal (hpa) axis. Many human studies have investigated this possibility, but a systematic review to identify consistent, emergent findings is lacking. METHODS: We systematically review 49 human studies, assessing the effects of intrauterine exposure to synthetic glucocorticoids on fetal, neonate, and infant hpa function. RESULTS: Study quality varied considerably, but the main findings held true after restricting the analyses to higher-quality studies: intrauterine exposure to synthetic glucocorticoids reduces offspring hpa activity under unstimulated conditions after pain but not pharmacological challenge. Although reduced unstimulated hpa function appears to recover within the first 2 wk postpartum, blunted hpa reactivity to pain is likely to persist throughout the first 4 months of life. There is some evidence that the magnitude of the effects is correlated with the total amount of glucocorticoids administered and varies with the time interval between glucocorticoid exposure and hpa assessment. CONCLUSIONS: This systematic review has allowed the demonstration of the way in which intrauterine exposure to various regimens of synthetic glucocorticoids affects various forms of hpa function. As such, it guides future studies in terms of which variables need to be focused on in order to further strengthen the understanding of such therapy, whilst continuing to profit from its clinical benefits

Can Antiviral Drugs Contain Pandemic Influenza Transmission?

Antiviral drugs dispensed during the 2009 influenza pandemic generally failed to contain transmission. This poses the question of whether preparedness for a future pandemic should include plans to use antiviral drugs to mitigate transmission