Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders

Background Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families. Methods Here we present data that refine this locus to a 0.5 cM region, flanked by the microsatellite markers D2S2345 and D2S326. The minimal region contains the candidate gene GAD1, which encodes a glutamate decarboxylase isoform (GAD67), involved in conversion of the amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Results A novel amino acid mis-sense mutation in GAD67 was detected, which segregated with CP in affected individuals. Conclusions This result is interesting because auto-antibodies to GAD67 and the more widely studied GAD65 homologue encoded by the GAD2 gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. Further investigation seems merited of the possibility that variation in the GAD1 sequence, potentially affecting glutamate/GABA ratios, may underlie this form of spastic CP, given the presence of anti-GAD antibodies in SPS and the recognised excitotoxicity of glutamate in various contexts

Choice of activity-intensity classification thresholds impacts upon accelerometer-assessed physical activity-health relationships in children

It is unknown whether using different published thresholds (PTs) for classifying physical activity (PA) impacts upon activity-health relationships. This study explored whether relationships between PA (sedentary [SED], light PA [LPA], moderate PA [MPA], moderate-to-vigorous PA, vigorous PA [VPA]) and health markers differed in children when classified using three different PTs

Ferromagnetic Semiconductors: Moving Beyond (Ga,Mn)As

The recent development of MBE techniques for growth of III-V ferromagnetic semiconductors has created materials with exceptional promise in spintronics, i.e. electronics that exploit carrier spin polarization. Among the most carefully studied of these materials is (Ga,Mn)As, in which meticulous optimization of growth techniques has led to reproducible materials properties and ferromagnetic transition temperatures well above 150 K. We review progress in the understanding of this particular material and efforts to address ferromagnetic semiconductors as a class. We then discuss proposals for how these materials might find applications in spintronics. Finally, we propose criteria that can be used to judge the potential utility of newly discovered ferromagnetic semiconductors, and we suggest guidelines that may be helpful in shaping the search for the ideal material.Comment: 37 pages, 4 figure

Combined effects of time spent in physical activity, sedentary behaviors and sleep on obesity and cardio-metabolic health markers: a novel compositional data analysis approach

<div><p>The associations between time spent in sleep, sedentary behaviors (SB) and physical activity with health are usually studied without taking into account that time is finite during the day, so time spent in each of these behaviors are codependent. Therefore, little is known about the combined effect of time spent in sleep, SB and physical activity, that together constitute a composite whole, on obesity and cardio-metabolic health markers. Cross-sectional analysis of NHANES 2005–6 cycle on N = 1937 adults, was undertaken using a compositional analysis paradigm, which accounts for this intrinsic codependence. Time spent in SB, light intensity (LIPA) and moderate to vigorous activity (MVPA) was determined from accelerometry and combined with self-reported sleep time to obtain the 24 hour time budget composition. The distribution of time spent in sleep, SB, LIPA and MVPA is significantly associated with BMI, waist circumference, triglycerides, plasma glucose, plasma insulin (all p<0.001), and systolic (p<0.001) and diastolic blood pressure (p<0.003), but not HDL or LDL. Within the composition, the strongest positive effect is found for the proportion of time spent in MVPA. Strikingly, the effects of MVPA replacing another behavior and of MVPA being displaced by another behavior are asymmetric. For example, re-allocating 10 minutes of SB to MVPA was associated with a lower waist circumference by 0.001% but if 10 minutes of MVPA is displaced by SB this was associated with a 0.84% higher waist circumference. The proportion of time spent in LIPA and SB were detrimentally associated with obesity and cardiovascular disease markers, but the association with SB was stronger. For diabetes risk markers, replacing SB with LIPA was associated with more favorable outcomes. Time spent in MVPA is an important target for intervention and preventing transfer of time from LIPA to SB might lessen the negative effects of physical inactivity.</p></div

Diagnostic potential of near-infrared Raman spectroscopy in the stomach: differentiating dysplasia from normal tissue

Raman spectroscopy is a molecular vibrational spectroscopic technique that is capable of optically probing the biomolecular changes associated with diseased transformation. The purpose of this study was to explore near-infrared (NIR) Raman spectroscopy for identifying dysplasia from normal gastric mucosa tissue. A rapid-acquisition dispersive-type NIR Raman system was utilised for tissue Raman spectroscopic measurements at 785 nm laser excitation. A total of 76 gastric tissue samples obtained from 44 patients who underwent endoscopy investigation or gastrectomy operation were used in this study. The histopathological examinations showed that 55 tissue specimens were normal and 21 were dysplasia. Both the empirical approach and multivariate statistical techniques, including principal components analysis (PCA), and linear discriminant analysis (LDA), together with the leave-one-sample-out cross-validation method, were employed to develop effective diagnostic algorithms for classification of Raman spectra between normal and dysplastic gastric tissues. High-quality Raman spectra in the range of 800–1800 cm−1 can be acquired from gastric tissue within 5 s. There are specific spectral differences in Raman spectra between normal and dysplasia tissue, particularly in the spectral ranges of 1200–1500 cm−1 and 1600–1800 cm−1, which contained signals related to amide III and amide I of proteins, CH3CH2 twisting of proteins/nucleic acids, and the C=C stretching mode of phospholipids, respectively. The empirical diagnostic algorithm based on the ratio of the Raman peak intensity at 875 cm−1 to the peak intensity at 1450 cm−1 gave the diagnostic sensitivity of 85.7% and specificity of 80.0%, whereas the diagnostic algorithms based on PCA-LDA yielded the diagnostic sensitivity of 95.2% and specificity 90.9% for separating dysplasia from normal gastric tissue. Receiver operating characteristic (ROC) curves further confirmed that the most effective diagnostic algorithm can be derived from the PCA-LDA technique. Therefore, NIR Raman spectroscopy in conjunction with multivariate statistical technique has potential for rapid diagnosis of dysplasia in the stomach based on the optical evaluation of spectral features of biomolecules

VEGF attenuates development from cardiac hypertrophy to heart failure after aortic stenosis through mitochondrial mediated apoptosis and cardiomyocyte proliferation

<p>Abstract</p> <p>Background</p> <p>Aortic stenosis (AS) affects 3 percent of persons older than 65 years and leads to greater morbidity and mortality than other cardiac valve diseases. Surgery with aortic valve replacement (AVR) for severe symptomatic AS is currently the only treatment option. Unfortunately, in patients with poor ventricular function, the mortality and long-term outcome is unsatisfied, and only a minority of these patients could bear surgery. Our previous studies demonstrated that vascular endothelial growth factor (VEGF) protects cardiac function in myocardial infarction model through classic VEGF-PI3k-Akt and unclear mitochondrial anti-apoptosis pathways; promoting cardiomyocyte (CM) proliferation as well. The present study was designed to test whether pre-operative treatment with VEGF improves AS-induced cardiac dysfunction, to be better suitable for AVR, and its potential mechanism.</p> <p>Methods</p> <p>Adult male mice were subjected to AS or sham operation. Two weeks later, adenoviral VEGF (Ad-VEGF), enhanced green fluorescence protein (Ad-EGFP, as a parallel control) or saline was injected into left ventricle free wall. Two weeks after delivery, all mice were measured by echocardiography and harvested for further detection.</p> <p>Results</p> <p>AS for four weeks caused cardiac hypertrophy and left ventricular dysfunction. VEGF treatment increased capillary density, protected mitochondrial function, reduced CMs apoptosis, promoted CMs proliferation and eventually preserved cardiac function.</p> <p>Conclusions</p> <p>Our findings indicate that VEGF could repair AS-induced transition from compensatory cardiac hypertrophy to heart failure.</p

The pharmacological regulation of cellular mitophagy

Small molecules are pharmacological tools of considerable value for dissecting complex biological processes and identifying potential therapeutic interventions. Recently, the cellular quality-control process of mitophagy has attracted considerable research interest; however, the limited availability of suitable chemical probes has restricted our understanding of the molecular mechanisms involved. Current approaches to initiate mitophagy include acute dissipation of the mitochondrial membrane potential (ΔΨm) by mitochondrial uncouplers (for example, FCCP/CCCP) and the use of antimycin A and oligomycin to impair respiration. Both approaches impair mitochondrial homeostasis and therefore limit the scope for dissection of subtle, bioenergy-related regulatory phenomena. Recently, novel mitophagy activators acting independently of the respiration collapse have been reported, offering new opportunities to understand the process and potential for therapeutic exploitation. We have summarized the current status of mitophagy modulators and analyzed the available chemical tools, commenting on their advantages, limitations and current applications

Raman spectroscopy in head and neck cancer

In recent years there has been much interest in the use of optical diagnostics in cancer detection. Early diagnosis of cancer affords early intervention and greatest chance of cure. Raman spectroscopy is based on the interaction of photons with the target material producing a highly detailed biochemical 'fingerprint' of the sample. It can be appreciated that such a sensitive biochemical detection system could confer diagnostic benefit in a clinical setting. Raman has been used successfully in key health areas such as cardiovascular diseases, and dental care but there is a paucity of literature on Raman spectroscopy in Head and Neck cancer. Following the introduction of health care targets for cancer, and with an ever-aging population the need for rapid cancer detection has never been greater. Raman spectroscopy could confer great patient benefit with early, rapid and accurate diagnosis. This technique is almost labour free without the need for sample preparation. It could reduce the need for whole pathological specimen examination, in theatre it could help to determine margin status, and finally peripheral blood diagnosis may be an achievable target

The rate of cellular hydrogen peroxide removal shows dependency on GSH: Mathematical insight into in vivo H2O2 and GPx concentrations

Although its concentration is generally not known, glutathione peroxidase-1 (GPx-1) is a key enzyme in the removal of hydrogen peroxide (H2O2) in biological systems. Extrapolating from kinetic results obtained in vitro using dilute, homogenous buffered solutions, it is generally accepted that the rate of elimination of H2O2 in vivo by GPx is independent of glutathione concentration (GSH). To examine this doctrine, a mathematical analysis of a kinetic model for the removal of H2O2 by GPx was undertaken to determine how the reaction species (H2O2, GSH, and GPx-1) influence the rate of removal of H2O2. Using both the traditional kinetic rate law approximation (classical model) and the generalized kinetic expression, the results show that the rate of removal of H2O2 increases with initial GPxr, as expected, but is a function of both GPxr and GSH when the initial GPxr is less than H2O2. This simulation is supported by the biological observations of Li et al.. Using genetically altered human glioma cells in in vitro cell culture and in an in vivo tumour model, they inferred that the rate of removal of H2O2 was a direct function of GPx activity × GSH (effective GPx activity). The predicted cellular average GPxr and H2O2 for their study are approximately GPxr ≤ 1 μm and H2O2 ≈ 5 μm based on available rate constants and an estimation of GSH. It was also found that results from the accepted kinetic rate law approximation significantly deviated from those obtained from the more generalized model in many cases that may be of physiological importance