Ultra-Rapid serial visual presentation reveals dynamics of feedforward and feedback processes in the ventral visual pathway.
Human visual recognition activates a dense network of overlapping feedforward and recurrent neuronal processes, making it hard to disentangle processing in the feedforward from the feedback direction. Here, we used ultra-rapid serial visual presentation to suppress sustained activity that blurs the boundaries of processing steps, enabling us to resolve two distinct stages of processing with MEG multivariate pattern classification. The first processing stage was the rapid activation cascade of the bottom-up sweep, which terminated early as visual stimuli were presented at progressively faster rates. The second stage was the emergence of categorical information with peak latency that shifted later in time with progressively faster stimulus presentations, indexing time-consuming recurrent processing. Using MEG-fMRI fusion with representational similarity, we localized recurrent signals in early visual cortex. Together, our findings segregated an initial bottom-up sweep from subsequent feedback processing, and revealed the neural signature of increased recurrent processing demands for challenging viewing conditions.


The Application of a Hospital Medical Surge Preparedness Index to Assess National Pandemic and Other Mass Casualty Readiness.
This article describes the use and findings of the Hospital Medical Surge Preparedness Index (HMSPI) tool to improve the understanding of hospitals' ability to respond to mass casualty events such as the COVID-19 pandemic. For this investigation, data from the U.S. Census Bureau, the Dartmouth Atlas Project, and the 2005 to 2014 annual surveys of the American Hospital Association (AHA) were analyzed. The HMSPI tool uses variables from the AHA survey and the other two sources to allow facility, county, and referral area index calculations. Using the three data sets, the HMSPI also allows for an index calculation for per capita ratios and by political (state or county) boundaries. In this use case, the results demonstrated increases in county and state HMSPI scores through the period of analysis; however, no statistically significant difference was found in HMSPI scores between 2013 and 2014. The HMSPI builds on the limited scientific foundation of medical surge preparedness and could serve as an objective and standardized measure to assess the nation's medical readiness for crises such as the COVID-19 pandemic and other large-scale emergencies such as mass shootings. Future studies are encouraged to refine the score, assess the validity of the HMSPI, and evaluate its relevance in response to future legislative and executive policies that affect preparedness measures.


Biotic factors and occurrence of Lutzomyia longipalpis in endemic area of visceral leishmaniasis, Mato Grosso do Sul, Brazil.
The relationships between environmental exposure to risk agents and health conditions have been studied with the aid of remote sensing imagery, a tool particularly useful in the study of vegetation cover. This study aims to evaluate the influence of environmental variables on the spatial distribution of the abundance of Lutzomyia longipalpis and the reported canine and human visceral leishmaniasis (VL) cases at an urban area of Campo Grande, state of Mato Grosso do Sul. The sandfly captures were performed in 13 residences that were selected by raffle considering four residences or collection station for buffer. These buffers were generated from the central house with about 50, 100 and 200 m from it in an endemic area of VL. The abundance of sandflies and human and canine cases were georreferenced using the GIS software PCI Geomatica. The normalized difference vegetation index (NDVI) and percentage of land covered by vegetation were the environmental variables extracted from a remote sensing IKONOS-2 image. The average NDVI was considered as the complexity of habitat and the standard deviation as the heterogeneity of habitat. One thousand three hundred sixty-seven specimens were collected during the catch. We found a significant positive linear correlation between the abundance of sandflies and the percentage of vegetation cover and average NDVI. However, there was no significant association between habitat heterogeneity and the abundance of these flies.


Effects of modulators of N-methyl-D-aspartate receptor-mediated neurotransmission on diazepam discrimination in rats.
N-methyl-D-aspartate (NMDA) antagonists share a number of pharmacological effects with GABA(A) agonists, including anxiolytic and anticonvulsant effects. This study evaluated the effects of site-selective NMDA antagonists in rats trained to discriminate the benzodiazepine diazepam from vehicle. As expected, diazepam produced robust discriminative stimulus effects and dose-dependently substituted for the training dose. Mixed results were obtained with competitive NMDA antagonists: whereas NPC 17742 partially substituted for diazepam, SDZ EAA 494 did not elicit responding on the diazepam-associated lever. Other site-selective NMDA antagonists, including the open channel blocker phencyclidine, the glycine-site antagonists ACEA 1021 and MDL 102,288, the polyamine-site antagonist arcaine, and the glutamate release inhibitor riluzole, failed to substitute for diazepam. Agonists at nonbenzodiazepine sites of the GABA(A) receptor complex were also tested for comparison purposes. The barbiturate pentobarbital and the neurosteroid Co 2-1068 partially substituted for diazepam. In contrast, the anticonvulsant carbamazepine failed to substitute even at a dose that substantially reduced response rates. These results suggest that substitution of NMDA antagonists for GABA(A) agonists is dependent upon the site at which the NMDA antagonist binds. Further, they suggest that similarities between the stimulus properties of GABA(A) agonists and NMDA antagonists are at least as strong as similarities among agonists acting at different sites on GABA(A) receptors.


Retardation of experimental tumorigenesis and reduction in DNA adducts by turmeric and curcumin.
Turmeric and its active principle curcumin have been extensively investigated for their antimutagenic and antioxidant effects in bacterial and animal systems. Because oral cancers are common in India, an experimental model of 7,12-dimethylbenzanthracene-induced buccal pouch tumors in Syrian Golden hamsters was used to evaluate the tumor retardation effects of turmeric and curcumin. Turmeric and/or curcumin was administered in the diet and/or applied locally for 14 weeks along with 7,12-dimethylbenzanthracene. After the experimental period, the animals were sacrificed and oral pouches were examined for tumor number and size. DNA adducts were estimated by 32P postlabel assay in the cheek pouches. Neoplastic changes were graded by histopathology. The results of the study suggest that turmeric or curcumin in the diet and/or applied locally significantly reduced DNA adducts at the target site. Tumor number and tumor burden were significantly lower (p < 0.05) in the animals that received turmeric in the diet and applied locally. The histopathological examinations suggested that the neoplastic grading was least in the animals fed or painted with curcumin (p < 0.05). The current study demonstrates that turmeric or curcumin administered in the diet or applied as paint may have a plausible chemopreventive effect on oral precancerous lesions.


Effect of transverse magnetic fields on dose distribution and RBE of photon beams: comparing PENELOPE and EGS4 Monte Carlo codes.
The application of a strong transverse magnetic field to a volume undergoing irradiation by a photon beam can produce localized regions of dose enhancement and dose reduction. This study uses the PENELOPE Monte Carlo code to investigate the effect of a slice of uniform transverse magnetic field on a photon beam using different magnetic field strengths and photon beam energies. The maximum and minimum dose yields obtained in the regions of dose enhancement and dose reduction are compared to those obtained with the EGS4 Monte Carlo code in a study by Li et al (2001), who investigated the effect of a slice of uniform transverse magnetic field (1 to 20 Tesla) applied to high-energy photon beams. PENELOPE simulations yielded maximum dose enhancements and dose reductions as much as 111% and 77%, respectively, where most results were within 6% of the EGS4 result. Further PENELOPE simulations were performed with the Sheikh-Bagheri and Rogers (2002) input spectra for 6, 10 and 15 MV photon beams, yielding results within 4% of those obtained with the Mohan et al (1985) spectra. Small discrepancies between a few of the EGS4 and PENELOPE results prompted an investigation into the influence of the PENELOPE elastic scattering parameters C(1) and C(2) and low-energy electron and photon transport cut-offs. Repeating the simulations with smaller scoring bins improved the resolution of the regions of dose enhancement and dose reduction, especially near the magnetic field boundaries where the dose deposition can abruptly increase or decrease. This study also investigates the effect of a magnetic field on the low-energy electron spectrum that may correspond to a change in the radiobiological effectiveness (RBE). Simulations show that the increase in dose is achieved predominantly through the lower energy electron population.


GABA transport modulates the ethanol sensitivity of tonic inhibition in the rat dentate gyrus.
In recent years, the effect of ethanol on tonic inhibition mediated by extrasynaptic GABA(A) receptors (GABA(A)Rs) has become a topic of intensive investigation and some controversy. The high ethanol sensitivity of extrasynaptic GABA(A) receptors containing the δ subunit combined with the role of tonic inhibition in maintaining the background inhibitory "tone" in hippocampal circuits has suggested that they may play a key role mediating certain behavioral effects of ethanol, including those related to learning and memory. We have found that ethanol disrupts learning and learning-related hippocampal function more potently in adolescent animals than in adults and that ethanol promotes extrasynaptic receptor-mediated GABAergic tonic currents more potently in adolescents than in adults. However, there have been no studies of potential mechanisms that may underlie the enhanced ethanol sensitivity of the tonic current in adolescents. In this study, we recorded GABA(A) receptor-mediated tonic currents in dentate gyrus granule cells in hippocampal slices from adolescent and adult rats. As previously reported, we found that ethanol potentiated the currents more efficaciously in cells from adolescents than in those from adults. We also found that the GAT-1 blocker NO-711 eliminated this developmental difference in ethanol sensitivity. These findings suggest that regulation of ambient GABA by GABA transporters may contribute to the difference in ethanol sensitivity between adolescents and adults.


Calmodulin plays a pivotal role in cellular regulation.
The role of calcium ions (Ca2+) in cell function is beginning to be unraveled at the molecular level as a result of recent research on calcium-binding proteins and particularly on calmodulin. These proteins interact reversibly with Ca2+ to form a protein . Ca2+ complex, whose activity is regulated by the cellular flux of Ca2+. Many of the effects of Ca2+ appear to be exerted through calmodulin-regulated enzymes.


Deep hiearchical multi-label classification applied to chest X-ray abnormality taxonomies.
Chest X-rays (CXRs) are a crucial and extraordinarily common diagnostic tool, leading to heavy research for computer-aided diagnosis (CAD) solutions. However, both high classification accuracy and meaningful model predictions that respect and incorporate clinical taxonomies are crucial for CAD usability. To this end, we present a deep hierarchical multi-label classification (HMLC) approach for CXR CAD. Different than other hierarchical systems, we show that first training the network to model conditional probability directly and then refining it with unconditional probabilities is key in boosting performance. In addition, we also formulate a numerically stable cross-entropy loss function for unconditional probabilities that provides concrete performance improvements. Finally, we demonstrate that HMLC can be an effective means to manage missing or incomplete labels. To the best of our knowledge, we are the first to apply HMLC to medical imaging CAD. We extensively evaluate our approach on detecting abnormality labels from the CXR arm of the Prostate, Lung, Colorectal and Ovarian (PLCO) dataset, which comprises over 198,000 manually annotated CXRs. When using complete labels, we report a mean area under the curve (AUC) of 0.887, the highest yet reported for this dataset. These results are supported by ancillary experiments on the PadChest dataset, where we also report significant improvements, 1.2% and 4.1% in AUC and average precision, respectively over strong "flat" classifiers. Finally, we demonstrate that our HMLC approach can much better handle incompletely labelled data. These performance improvements, combined with the inherent usefulness of taxonomic predictions, indicate that our approach represents a useful step forward for CXR CAD.


Participation of epididymal cysteine-rich secretory proteins in sperm-egg fusion and their potential use for male fertility regulation.
Rat protein DE is an androgen-dependent cysteine-rich secretory protein (CRISP) synthesized by proximal epididymal regions. DE, also known as CRISP-1, is localized on the equatorial segment of acrosome-reacted spermatozoa and participates in gamete fusion through binding to egg complementary sites. Immunization of rats with DE inhibits fertility and sperm fusion ability, suggesting that DE represents a good epididymal contraceptive target. Recombinant DE fragments and synthetic peptides revealed that DE binds to the egg via a 12-amino acid region of an evolutionarily conserved motif, Signature 2 (S2). The ability of other CRISP to bind to the rat egg was correlated with their S2 amino acid sequences. Although testicular protein Tpx-1 (CRISP-2) was capable of binding to rodent eggs, human epididymal AEG-related protein (ARP) and helothermine (from lizard saliva) were not. The S2 region presented only two substitutions in Tpx-1 and four in ARP and helothermine, compared with the DE S2, suggesting that this amino acid sequence was relevant for egg interaction. Studies with Tpx-1 and anti-Tpx-1 revealed the participation of this protein in gamete fusion through binding to complementary sites in the egg. In competition studies, DE reduced binding of Tpx-1 dose-dependently, indicating that both CRISP share the egg complementary sites. That anti-DE and anti-Tpx-1 inhibit sperm-egg fusion while recognizing only the corresponding proteins, suggests functional cooperation between these homologous CRISP to ensure fertilization success. These results increase our understanding of the molecular mechanisms of gamete fusion and contribute to the development of new and safer fertility regulating methods.


Cerebroprotective activity of Pentapetes phoenicea on global cerebral ischemia in rats.
The study was performed to evaluate the cerebroprotective activity of methanolic extract (ME) of Pentapetes phoenicea - a folk medicine used as anti-inflammatory and in central nervous system ailments. It has high phenolic and flavonoid contents including rutin. Global cerebral ischemia was induced in male albino Wistar rats by temporary bilateral carotid artery occlusion (BCAO) for 30 min, followed by 4 h reperfusion. Groups of rats were pretreated for 10 days with 100, 200, and 400 mg/kg of ME of P. phoenicea and 3 mg/kg of edaravone, a marketed cerebroprotective agent, as standard. Antioxidant enzymes such as, the levels of malondialdehyde (MDA), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), superoxide dismutase (SOD), catalase (CAT) and hydrogen peroxide (H2O2), protein content, brain water content, cerebral infarct size and the histopathological changes were measured. P. phoenicea-pretreated groups restored the biochemical parameters significantly in a dose-dependent manner. The ischemic changes were involved with an increase in the concentration of MDA and H2O2, followed by decreased SOD, CAT, GPx, GR, and GST activity in rat brain. The neurodegenaration and its attenuation by P. phoenicea were confirmed by examination of triphenyl tetrazolium chloride staining and histopathological changes in the cerebral ischemic rat brains. Similarly, P. phoenicea reversed the brain water content in the ischemia-reperfusion animals. The result of the study indicates that the treatment with P. phoenicea enhances the antioxidant defense against BCAO-induced global cerebral ischemia/reperfusion and exerts cerebroprotection.


Differences in the clinical spectrum of two adolescent male patients with Alström syndrome.
Alström syndrome is a rare disorder typified by early childhood obesity, neurosensory deficits, cardiomyopathy, progressive renal and hepatic dysfunction, and endocrinological features such as severe insulin resistance, type 2 diabetes, hyperlipidemia, and hypogonadism. Widespread fibrosis leads to multiple organ failure. Mutations in ALMS1 cause Alström syndrome. Two age-matched, unrelated adolescent males of Serbian descent with Alström syndrome underwent an extensive workup of blood chemistries, and ophthalmological, audiological, and genetic evaluations. Although both showed typical features of Alström syndrome in childhood, several differences were observed that have not been reported previously. Patient 1 was first studied at the age of 13 years for multisystemic disease and re-evaluated at the age of 15.5 years. Patient 2 is a 15-year-old boy who presented at birth with epilepsy and psychomotor developmental delay and generalized tonic-clonic seizures with severe cognitive impairment, features not documented previously in this syndrome. Sequencing analysis indicated two novel ALMS1 mutations in exon 8: p.E1055GfsX4 and p.T1386NfsX15. Metabolic and physiological similarities were observed in both patients, including severe insulin resistance, and truncal obesity with fat loss suggestive of partial lipodystrophy, supporting evidence for a role for ALMS1 in adipose tissue function. The unusual phenotypes of clonic-tonic seizures and severe cognitive abnormalities and lipodystrophy-like adiposity pattern have not been documented previously in Alström syndrome and may be an under-reported abnormality.


Synaptic asymmetry to go.
Cell polarity is critical for T lymphocyte movement during their hunt for antigen-bearing cells and for infected target cells. In this issue of Cell, Yeh et al. (2008) now reveal a direct link between T cell polarity and the production of proinflammatory cytokines in mice lacking the class I MHC-restricted T cell-associated molecule (Crtam).


Eplerenone and new-onset diabetes in patients with mild heart failure: results from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF).
No studies have examined the effect of mineralocorticoid receptor antagonist therapy on new-onset diabetes. In addition, though the combination of diabetes and chronic heart failure (CHF) carries a poor prognosis, few studies have examined predictors of new-onset diabetes in those with CHF. In patients with symptomatically mild CHF who participated in the placebo-controlled Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure, we examined the effect of the aldosterone antagonist, eplerenone, on physician-diagnosed diabetes using univariate Cox proportional hazard analysis. To identify predictors of new-onset diabetes (measures of glycaemia were not available), data from trial arms were combined and multivariate Cox proportional hazard analyses and receiver operating characteristic curve analyses were conducted. At baseline, the mean age of 1846 initially non-diabetic patients was 69 years and mean left ventricular ejection fraction was 26%. Over 21 months, 69 (3.7%) developed diabetes (33 on eplerenone, 36 on placebo). Eplerenone had no effect on new-onset diabetes [hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.59-1.52] and no effect on the composite of new-onset diabetes or mortality (HR 0.80, 95% CI 0.64-1.01). Independent predictors of new-onset diabetes included digoxin therapy, higher serum alanine aminotransferase, longer duration of heart failure, current or previous smoker, higher waist circumference, lower age, and higher systolic blood pressure with a combined c-statistic of 0.74. Eplerenone had no effect on new-onset diabetes in patients with CHF, but further large-scale studies are required to address this question comprehensively. Commonly recorded parameters provided useful information for predicting new-onset diabetes.


Electronic and vibrational coherences in resonance energy transfer along MEH-PPV chains at room temperature.
In this work we report a study of the role of coherence dynamics in the intermediate coupling regime of electronic energy transfer (EET). Starting from the idea that in the intermediate coupling regime the phase information should be partially retained in a transfer process from a donor to an acceptor, we designed a new ultrafast experiment based on anisotropy decay along two time axes, capable of probing the degree of coherence characterizing this transfer. Conjugated polymer (poly[2-methoxy-5-(2'-ethyl-hexoxy)-1,4-phenylenevinylene], MEH-PPV) samples with different chain conformations were examined as a model multichromophoric system. The data, recorded at room temperature, reveal coherent transfer associated with intrachain energy transfer. These results were extended using two-dimensional photon echo measurements, which revealed the presence of long-lived intrachain electronic and vibrational coherences. Our results suggest that, in the intermediate coupling regime, quantum transport effects can occur when chemical bonds connecting donor and acceptor help to correlate their energy gap fluctuations. Moreover, they influence the mechanism of EET, even at room temperature.


Assessment of the statistical significance of classifications in infrared spectroscopy based diagnostic models.
Fourier transform infrared (IR) spectroscopy in combination with multivariate data analysis is a versatile tool that can be applied to disease diagnosis. However, a rigorous validation of the obtained models is necessary in order to obtain robust results. This work evaluates the advantages of the use of permutation testing for determining the statistical significance of the misclassification errors obtained from IR based diagnostic models through cross validation (CV). The model performance, estimated by CV, is compared to a distribution of CV-performance values obtained using randomly permuted class labels. The distribution of 'random CV-values' is considered as a null distribution and used to establish the significance of the model estimators obtained using real class labels. ATR-FTIR spectra of serum samples were classified using random forest (RF) classifiers according to two criteria, the tag number (a randomly assigned pseudo class membership) and the level of urea (real class). CV errors obtained were compared to the null distribution of CV errors from a permutation test and an independent validation set. The procedure was evaluated testing typical conditions leading to overoptimistic estimations provided by the CV like e.g. the size of subsamples used during CV, variable selection and the use of replicates. Results show that for the tag number (pseudo class), CV indicated classification errors between 23 and 33% depending on the subsample size employed. Those values were even lower when variable selection or replicates were used. However, permutation testing indicated that those CV errors were non-significant. In contrast, for sample classification according to their levels of urea, all cross validation errors were found to be significant. Although the proposed method is computationally intensive, it provides a simple way of calculating an empirical p-value of the CV-estimator, thus establishing the statistical significance and providing a feasibility indicator especially useful for studies where the number of samples is limited.


Detection of Invisible Damages in 'Rojo Brillante' Persimmon Fruit at Different Stages Using Hyperspectral Imaging and Chemometrics.
The main cause of flesh browning in 'Rojo Brillante' persimmon fruit is mechanical damage caused during harvesting and packing. Innovation and research on nondestructive techniques to detect this phenomenon in the packing lines are necessary because this type of alteration is often only seen when the final consumer peels the fruit. In this work, we have studied the application of hyperspectral imaging in the range of 450-1040 nm to detect mechanical damage without any external symptoms. The fruit was damaged in a controlled manner. Later, images were acquired before and at 0, 1, 2 and 3 days after damage induction. First, the spectral data captured from the images were analysed through an algorithm based on principal component analysis (PCA). The aim was to automatically separate intact and damaged fruit, and to detect the damage in the PC images when present. With this algorithm, 90.0% of intact fruit and 90.8% of damaged fruit were correctly detected. A model based on partial least squares-discriminant analysis (PLS-DA), was later calibrated using the mean spectrum of the pixels detected as damaged, to determine the moment when the fruit was damaged. The model differentiated fruit corresponding correctly to 0, 1, 2 and 3 days after damage induction, achieving a total accuracy of 99.4%.


The (limited) contribution of early childcare arrangements to social and academic development among Canadian children.
This study examined the longitudinal contribution of four different childcare arrangements attended during the preschool years to social behaviors and academic achievement up to age 15 years. Children participating in a Canadian longitudinal survey with available information on childcare attendance between ages 3 and 5 years (N = 6,852) were measured on multiple social behaviors (hyperactivity/inattention, depression/anxiety, disruptive behaviors) and academic outcomes (mathematic skills, academic achievement) across both childhood and adolescence. We conducted a propensity score matching analysis to control the selection bias for childcare attendance and performed generalized estimating equation models for panel data among matched groups. Our results showed no clear social or academic long-term advantage for Canadian children of attending any childcare arrangement in comparison to children being exclusively cared for by their parents. In contrast, children attending daycare centers had higher levels of hyperactivity/inattention until the age of 15 years. Children also had lower mathematic skills if attending daycare centers or informal childcare at preschool age, but this effect dissipated from childhood to adolescence. Interestingly, children from low-income families had higher levels of depression/anxiety if being cared for at home by someone other than their parents or relatives. This finding supports the dual-risk hypothesis suggesting that children from already impoverished families and attending informal childcare in their own home are at greater risk for internalizing difficulties. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Impaired matching of perfusion and ventilation in heart failure detected by 133xenon.
In severe chronic heart failure (CHF) the ventilatory cost of CO2 elimination during exercise (VE/VCO2) is increased, suggesting ventilation/perfusion (V/Q) mismatch. The relationship of exercise VE/VCO2 regression slope m to deadspace ventilation was studied in 15 patients with CHF who underwent cardiopulmonary exercise testing and arterial blood gas monitoring. Regional lung ventilation and perfusion was studied, using 133xenon, at rest and peak exercise in a further group of 10 CHF patients and in five normal subjects. VE/VCO2 slope m correlated well with deadspace ventilation at peak exercise in the 15 patients with CHF. We therefore used exercise VE/VCO2 slope m to categorize CHF patients undergoing 133xenon imaging into groups with increased (slope m > 36) or normal (slope m < 36) exercise deadspace ventilation. In normals, resting V/Q determined by 133xenon showed a gravitational gradient, which improved on exercise as a result of relative increases and of relative reductions in regional perfusion; no significant changes in regional ventilation distribution were detected. In patients with CHF who had normal slope m (n = 5), rest and exercise V/Q were similar to the normal subjects. In CHF patients with increased slope m (n = 5) however, the resting gravitational gradient of V/Q was lost, and there were no significant changes in relative perfusion distribution on exercise. These findings suggest that the increased ventilatory cost of CO2 elimination found in certain patients with CHF is related to inability to coordinate and optimise the relative distribution of lung perfusion with respect to ventilation during exercise.


Microscopic approach to second harmonic generation in quantum cascade lasers.
Second harmonic generation is analyzed from a microscopical point of view using a non-equilibrium Green's function formalism. Through this approach the complete on-state of the laser can be modeled and results are compared to experiment with good agreement. In addition, higher order current response is extracted from the calculations and together with waveguide properties, these currents provide the intensity of the second harmonic in the structure considered. This power is compared to experimental results, also with good agreement. Furthermore, our results, which contain all coherences in the system, allow to check the validity of common simplified expressions.


Increased forebrain activations in youths with family histories of alcohol and other substance use disorders performing a Go/NoGo task.
Youths with a family history of alcohol and other drug use disorders (FH+) are at a greater risk of developing substance use disorders than their peers with no such family histories (FH-), and this increased risk may be related to impaired maturation of forebrain circuitry. FH+ individuals have shown altered forebrain activity at rest and while performing cognitive tasks. However, it is not fully understood how forebrain activity is altered in FH+ individuals, and ultimately how these alterations may contribute to substance use disorder risk. In this study, we tested 72 FH+ and 32 FH- youths performing a go/no-go task and examined activations in blocks with only go trials (Go Only), blocks with 50% go and 50% no-go trials (Go/NoGo), and a contrast of those 2 blocks. FH+ youths had significantly greater cerebral activations in both the Go and Go/NoGo blocks than FH- youths in regions including the posterior cingulate/precuneus, bilateral middle/superior temporal gyrus, and medial superior frontal gyrus with no significant group differences in the subtraction between Go Only and Go/NoGo blocks. Additionally, FH+ youths had moderately slower reaction times on go trials in the Go Only blocks. Our findings suggest that global activation increase in FH+ youths are modulated by FH density and are not specific to the inhibitory components of the task. This pattern of increased activations in FH+ youths may be at least partially due to impaired forebrain white matter development leading to greater activations/less efficient neural communication during task performance.


Complex multimodality central airway management of aspergillus pseudomembranous tracheobronchitis.
A 69-year-old woman developed central airway obstruction due to invasive Aspergillus infection resulting in pseudomembranous tracheobronchitis (PTB). Several challenges were encountered in the airway management of this patient including her having relatively smaller airways which were more prone to obstruction by pseudomembranes and made airway interventions difficult. The patient had clinical deterioration in spite of antifungal therapy and bronchoscopic debridement. The multimodality airway techniques included the use of smaller biliary balloons for dilatation, using a hybrid stent to slowly dilate and maintain patency of right main stem and finally the insertion of right secondary carina peripheral Y stent, which resulted in clinical improvement and allowed time for antifungal therapy to take effect. To the best of our knowledge, the use of a peripheral Y stent has never been described in the setting of PTB.


Stability of serotypes during nasopharyngeal carriage of Streptococcus pneumoniae.
Serotype changes among natural isolates of Streptococcus pneumoniae are well documented and occur by recombinational exchanges at the capsular biosynthetic locus. However, the frequency with which this phenomenon occurs within the nasopharynx of children is not clear and is likely to be highest in the nasopharynx of children, who have high rates of pneumococcal carriage. A birth cohort of 100 infants was studied, and pneumococci were recovered from nasopharyngeal samples taken at monthly intervals during the first 6 months of life and then at 2-monthly intervals until the age of 2 years. Among the 1,353 nasopharyngeal samples were 523 that contained presumptive pneumococci, and three colonies from each were serotyped. A total of 333 isolates, including all isolates of differing serotypes from the same child, were characterized by multilocus sequence typing. Sixty-eight children carried multiple serotypes during the first 2 years of life. Two children carried a typeable and a nonserotypeable pneumococcus of identical genotype, and five children carried genetically indistinguishable isolates of serotypes 15B and 15C. These isolates were considered, respectively, to be due to loss of capsule expression and the known ability of serotype 15B and 15C pneumococci to interconvert by loss or gain of an acetyl group on the capsular polysaccharide. In all other cases, isolates from the same children that differed in serotype also differed in genotype, indicating the acquisition of a different pneumococcal strain rather than a change in capsular type. There was therefore no evidence in this study for any change of serotype due to recombinational replacements at the capsular locus among the pneumococci carried within the nasopharynges of the children.


A review of fluid and hydration in competitive tennis.
Hypohydration is known to impair performance and increases the risk of heat injury. Therefore, the consumption of appropriate fluid volumes before, during, and after tennis play is important to maintain physiological homeostasis and performance. Tennis is a sport that typically has points lasting fewer than ten seconds, with short-to-moderate rest periods between each work bout. This sequence is repeated over hours. Most fluid and hydration research has focused on continuous aerobic exercise, which provides vastly different physiological strain compared with tennis practice and competition. Consequently, practical recommendations on maintaining hydration status for aerobic continuous exercise may not be appropriate for tennis athletes. Tennis players can sweat more than 2.5 L.h(-1) and replace fluids at a slower rate during competition than in practice. In warm and hot environments, electrolyte-enhanced fluid should be consumed at greater than >200 mL per changeover and ideally closer to 400 mL per changeover. Tennis scientists, coaches, and players need to individualize hydration protocols to arrive at the optimal hydration strategy.


Some problems with life event lists and health outcomes.
Lists of life events are widely used in health outcomes research. As part of a large cohort study of women's health in Australia, age- and gender-specific life events lists were developed and administered to women in different age groups over time. In this article, we provide empirical evidence that recall of life events is subject to telescoping (i.e., remote events are reported to have occurred more recently) and to mood (women with lower mental health scores report more life events, especially perceived rather than factual events). Nevertheless, even after adjustment for confounders, there is a clear association between poorer physical health and more life events. Therefore, these results demonstrate a continuing need for lists of life events in health research but also highlight the methodological challenges in using them.


Association of Preoperative Platelet-to-Lymphocyte Ratio with Atrial Fibrillation after Coronary Artery Bypass Graft Surgery.
The aim of this study was to investigate the association between platelet-to-lymphocyte ratio (PLR) and atrial fibrillation (AF) after coronary artery bypass graft (CABG) surgery. A total of 125 patients were retrospectively analyzed. AF was diagnosed using standard clinical criteria, and PLR was calculated as the ratio of the platelets to lymphocytes, obtained from the blood samples that were taken in the fasting state before CABG surgery. The association of different variables with postoperative AF and PLR was calculated using univariate and multivariate analysis. The receiver operating characteristics curve was used to determine the sensitivity and specificity of PLR and the optimal cutoff value for predicting post-CABG AF. Of the 125 patients, 50 with AF (mean age: 67.0 ± 9.5 years, 38 males and 12 females) and 75 patients without AF (mean age: 61.1 ± 9.1 years, 58 males and 17 females) were identified, and the difference in the mean age was statistically significant (p = 0.01). PLR was also significantly higher in those with AF (152.8 ± 82.2) than those without AF (118.2 ± 32.9) (p = 0.012). Univariate analysis showed that age and PLR were associated with AF after CABG surgery (p < 0.001 and p = 0.005, respectively). Using a multivariate logistic regression model with the backward elimination method, age and PLR remained as independent predictors of AF after CABG surgery (p < 0.001 and p = 0.005, respectively). PLR levels >119.3 predicted postoperative AF with 64% sensitivity and 56% specificity (AUC: 0.634, p = 0.012). In this study, age and PLR level were independent predictors of AF after CABG surgery. Patients with an elevated preoperative PLR were at higher risk of AF after CABG surgery.


Correct consideration of the index of refraction using blackbody radiation.
The correct consideration of the index of refraction when using blackbody radiators as standard sources for optical radiation is derived and discussed. It is shown that simply using the index of refraction of air at laboratory conditions is not sufficient. A combination of the index of refraction of the media used inside the blackbody radiator and for the optical path between blackbody and detector has to be used instead. A worst case approximation for the introduced error when neglecting these effects is presented, showing that the error is below 0.1 % for wavelengths above 200 nm. Nevertheless, for the determination of the spectral radiance for the purpose of radiation temperature measurements the correct consideration of the refractive index is mandatory. The worst case estimation reveals that the introduced error in temperature at a blackbody temperature of 3000 degrees C can be as high as 400 mk at a wavelength of 650 nm and even higher at longer wavelengths.


Delay interferometric single shot measurement of a petawatt-class laser longitudinal chromatism corrector.
In this paper we present a self-referenced interferometric single-shot measurement technique that we use to evaluate the longitudinal chromatism compensation made by a diffractive lens corrector. A diffractive lens with a delay of 1 ps is qualified for a 60 mm beam aperture. This corrector was implemented on the Alisé Nd:glass power chain. We qualify the corrector and the Alisé power chain chromatism, demonstrating the potential of this measuring principle as well as the interest of diffractive lenses to correct longitudinal chromatism of petawatt-class lasers.


Do health halos and conspicuous consumption influence the appeal and risk perceptions of e-cigarettes among young Cambodian men?
Reduced risk perceptions influence young people's consumption behaviours of e-cigarettes, suggesting that a health halo effect may be associated with these devices. Product, performative, and social factors contribute to the appeal of e-cigarettes, with young people using e-cigarettes with friends as part of social interactions. This study explored the factors that influence the appeal and risk perceptions associated with e-cigarettes among young Cambodian men. A mixed-method, interviewer-administered survey with 147 young men in Cambodia, who were aged between 18 and 24 years and identified as cigarette smokers. Participants described their attitudes and consumption behaviours surrounding e-cigarettes, recalled e-cigarette promotions, and described their risk perceptions towards e-cigarettes. Descriptive statistics were calculated for quantitative data, and thematic analysis was conducted for qualitative data. Some participants associated e-cigarettes with affluence and exclusivity, describing these devices as products that rich and/or younger people use. Participants also described product attributes that were appealing about e-cigarettes, such as variety of flavours, vapour, and performing smoke 'styles' with friends, which differentiated the product from combustible cigarettes. Participants also had reduced risk perceptions towards e-cigarettes, with some commenting that e-cigarettes were not harmful or might be health-enhancing. Some young people may perceive e-cigarettes as a form of conspicuous consumption, which they associated with social status and identity. A health halo effect appears to be associated with e-cigarettes among some young people. This may influence young people to underestimate the potential health risks associated with these devices.


Thiol oxidation and altered NR2B/NMDA receptor functions in in vitro and in vivo pilocarpine models: implications for epileptogenesis.
Hippocampal sclerosis, the main pathological sign of chronic temporal lobe epilepsy (TLE), is associated with oxidative injury, altered N-methyl d-aspartate receptor (NMDAR) stoichiometry, and loss of hippocampal neurons. However, the mechanisms that drive the chronic progression of TLE remain elusive. Our previous studies have shown that NADPH oxidase activation and ERK 1/2 phosphorylation are required for the up-regulation of the predominantly pre-synaptic NR2B subunit auto-receptor in both in vitro and in vivo pilocarpine (PILO) models of TLE. To provide further understanding of the cellular responses during the early-stages of hyper excitability, we investigated the role of oxidative damage and altered NR2B functions. In rat primary hippocampal cultures, we found that N-acetylcysteine (NAC) prevented PILO-mediated thiol oxidation, apoptosis, cell death and NR2B subunit over-expression. Interestingly, NAC did not block thiol oxidation when added to the neurons 6h after the PILO exposure, suggesting that disulfide formation could rapidly become an irreversible phenomenon. Moreover, NAC pre-treatment did not prevent PILO-induced NR2A subunit over-expression, a critical event in hippocampal sclerosis. Pre-treatment with the highly specific NR2B subunit inhibitor, ifenprodil, partially decreased PILO-mediated thiol oxidation and was not effective in preventing apoptosis and cell death. However, if acutely administered 48h after PILO exposure, ifenprodil blocked glutamate-induced aberrant calcium influx, suggesting the crucial role of NR2B over-expression in triggering neuronal hyper-excitability. Furthermore, ifenprodil treatment was able to prevent NR2A subunit over-expression by means of ERK1/2 phosphorylation. Our findings indicate oxidative stress and NR2B/NMDA signaling as promising therapeutic targets for co-treatments aimed to prevent chronic epilepsy following the seizure onset.


Pilotin-secretin recognition in the type II secretion system of Klebsiella oxytoca.
A crucial aspect of the functionality of bacterial type II secretion systems is the targeting and assembly of the outer membrane secretin. In the Klebsiella oxytoca type II secretion system, the lipoprotein PulS, a pilotin, targets secretin PulD monomers through the periplasm to the outer membrane. We present the crystal structure of PulS, an all-helical bundle that is structurally distinct from proteins with similar functions. Replacement of valine at position 42 in a charged groove of PulS abolished complex formation between a non-lipidated variant of PulS and a peptide corresponding to the unfolded region of PulD to which PulS binds (the S-domain), in vitro, as well as PulS function in vivo. Substitutions of other residues in the groove also diminished the interaction with the S-domain in vitro but exerted less marked effects in vivo. We propose that the interaction between PulS and the S-domain is maintained through a structural adaptation of the two proteins that could be influenced by cis factors such as the fatty acyl groups on PulS, as well as periplasmic trans-acting factors, which represents a possible paradigm for chaperone-target protein interactions.


Follow-up on misrepresentation of research activity by orthopaedic residency applicants: has anything changed?
In our previous study, published in 1999, we showed that 18% of research citations listed as published by orthopaedic residency applicants were misrepresented. Since our last report, we sought to determine whether there had been any change in the behavior of applicants wishing to pursue the field of orthopaedic surgery. We evaluated the research citations that were identified after a review of the Publications section of the Common Application Form from the Electronic Residency Application Service for all applicants to our orthopaedic residency program for 2005 and 2006. Inclusion and exclusion criteria were established for citations listed on candidate applications. Citations were required to be from journals listed in Ulrich's Periodicals Directory. The PubMed-MEDLINE database engine was used to search for citations. If searching failed to yield the cited publication, a review of the journal of alleged publication was undertaken and an interlibrary search was conducted with the use of several research databases. When no match was found, the citation was labeled as misrepresented. Misrepresentation was defined as either (1) nonauthorship of an existing article or (2) claimed authorship of a nonexistent article. One hundred and forty-two (35.9%) of 396 applicants during the 2005 and 2006 application periods listed publications. A total of 304 citations were claimed from these 142 applicants. Listings included articles that were in press or in print (thirty-four citations), articles in journals not found in Ulrich's Periodicals Directory (twenty-eight citations), book chapters (twenty-three citations), and articles recorded as having been submitted (eighty-eight citations). These 173 works were excluded from our analysis. One hundred and thirty-one citations were referenced as appearing in journals per our search criteria, and all were verified. Twenty-seven or 20.6% (95% confidence interval, 14.2% to 28.7%) of 131 citations were misrepresented. The prevalence of misrepresented research publications from orthopaedic surgery residency applicants increased modestly to 20.6% compared with that found in our original report (18%). As we recommended in our last report, we strongly urge residency programs to require applicants to submit reprints of their publications with their residency applications. Perhaps standardized guidelines should be developed to help to prevent misrepresentation through the Electronic Residency Application Service.


The effects of the global structure of the mask in visual backward masking.
The visibility of a target can be strongly affected by a trailing mask. Research on visual backward masking has typically focused on the temporal characteristics of masking, whereas non-basic spatial aspects have received much less attention. However, recently, it has been demonstrated that the spatial layout is an important determinant of the strength of a mask. Here, we show that not only local but also global aspects of the mask's spatial layout affect target processing. Particularly, it is the regularity of the mask that plays an important role. Our findings are of importance for theoretical research, as well as for applications of visual masking.


Extreme plasticity in thermoregulatory behaviors of free-ranging black-tailed prairie dogs.
In the natural environment, hibernating sciurids generally remain dormant during winter and enter numerous deep torpor bouts from the time of first immergence in fall until emergence in spring. In contrast, black-tailed prairie dogs (Cynomys ludovicianus) remain active throughout winter but periodically enter short and shallow bouts of torpor. While investigating body temperature (T(b)) patterns of black-tailed prairie dogs from six separate colonies in northern Colorado, we observed one population that displayed torpor patterns resembling those commonly seen in hibernators. Five individuals in this population experienced multiple torpor bouts in immediate succession that increased in length and depth as winter progressed, whereas 16 prairie dogs in five neighboring colonies remained euthermic for the majority of winter and entered shallow bouts of torpor infrequently. Our results suggest that these differences in torpor patterns did not result from differences in the physiological indicators that we measured because the prairie dogs monitored had similar body masses and concentrations of stored lipids across seasons. Likewise, our results did not support the idea that differences in overwinter T(b) patterns between prairie dogs in colonies with differing torpor patterns resulted from genetic differences between populations; genetic analyses of prairie dog colonies revealed high genetic similarity between the populations and implied that individuals regularly disperse between colonies. Local environmental conditions probably played a role in the unusual T(b) patterns experienced by prairie dogs in the colony where hibernation-like patterns were observed; this population received significantly less rainfall than neighboring colonies during the summer growing seasons before, during, and after the year of the winter in which they hibernated. Our study provides a rare example of extreme plasticity in thermoregulatory behaviors of free-ranging prairie dogs and provides evidence contrary to models that propose a clear delineation between homeothermy, facultative torpor, and hibernation.


Isomorphous crystal structures of Escherichia coli dihydrofolate reductase complexed with folate, 5-deazafolate, and 5,10-dideazatetrahydrofolate: mechanistic implications.
Crystal structures of Escherichia coli dihydrofolate reductase (ecDHFR, EC 188.8.131.52) in binary complexes with folate, 5-deazafolate (5dfol), and 5,10-dideazatetrahydrofolate (ddTHF) have been refined to R-factors of 13.7%, 14.9%, and 14.5%, respectively, all at 1.9 A. All three are isomorphous with a previously reported binary complex of ecDHFR with methotrexate (MTX), in space group P6(1), two molecules per asymmetric unit [Bolin, J. T., Filman, D. J., Matthews, D. A., Hamlin, R. C., & Kraut, J. (1982) J. Biol. Chem. 257, 13650-13662]. A hitherto unobserved water molecule is hydrogen bonded to the pteridine N5 and O4 in both molecules of the asymmetric unit of the folate complex (but not the 5dfol or ddTHF complexes), supporting the hypothesis that N5 protonation of bound substrate, an important step of the DHFR reaction, occurs by way of such a water molecule. There is no indication of a hydrogen bond between N8 of 5dfol and the backbone carbonyl of Ile-5, suggesting that the bacterial enzyme, unlike the human enzyme [Davies, J. F., II, Delcamp, T. J., Prendergast, N. J., Ashford, V. A., Freisheim, J. H., & Kraut, J. (1990) Biochemistry 29, 9467-9479], does not favor protonation at N8. Perhaps this explains why bacterial DHFR is much less effective than vertebrate DHFR in folate reduction. When the ecDHFR.NADPH complex (space group P3221; M. R. Sawaya, in preparation) is superimposed on the folate and 5dfol complexes, the distances from pteridine C6 to nicotinamide C4 were found to be 2.9 and 2.8 A, respectively, in close agreement with the theoretically calculated optimal distance in the transition state for hydride transfer [Wu, Y. D., & Houk, K. N. (1987) J. Am. Chem. Soc. 109, 906-908, 2226-2227]. In contrast to the planar ring system of folate or 5dfol, the reduced pteridine ring of ddTHF is severely puckered and bent toward the nicotinamide pocket, with the reduced pyridine ring assuming a half-chair type of conformation. This change in shape causes the pteridine ring to bind with O4 closer to Trp-22(N epsilon 1) by over 0.5 A, so that an invariant water molecule now bridges these two atoms with ideal hydrogen bonds. Furthermore, while the pABA rings of folate and 5dfol are nearly coincident and closer to the alpha C helix than to the alpha B helix, those of MTX and ddTHF are displaced along the binding crevice by approximately 1.1 and 0.6 A, respectively, and are equidistant from alpha B and alpha C.(ABSTRACT TRUNCATED AT 400 WORDS)


Prospective Identification of Oligoclonal/Abnormal Band of the Same Immunoglobulin Type as the Malignant Clone by Differential Location of M-Spike and Oligoclonal Band.
Serum and urine protein electrophoreses and immunofixation electrophoreses are the gold standards in diagnosing monoclonal gammopathy. Identification of oligoclonal bands in post-treatment patients has emerged as an important issue and recording the location of the malignant monoclonal peak may facilitate prospective identification of a new "monoclonal" spike as being distinct from the malignant peak. We recorded the locations of monoclonal spikes in descriptive terms, such as being in the cathodal region, mid-gamma region, anodal region, and beta region. The location of monoclonal or restricted heterogeneity bands in subsequent protein electrophoreses was compared to the location of the original malignant spike. In a patient with plasma cell myeloma, the original monoclonal IgG kappa band was located at the anodal end of gamma region. Post-treatment, an IgG kappa band was noted in mid-gamma region and the primary malignant clone was not detectable by serum protein immunofixation electrophoresis (SIFE) in post-treatment sample. Even though the κ/λ ratio remained abnormal, we were able to recognize stringent complete response by noting the different location of the new IgG kappa band as a benign regenerative process. Recording the location of the malignant monoclonal spike facilitates the identification of post-treatment oligoclonal bands, prospectively. Recognizing the regenerative, benign, bands in post-transplant patients facilitates the determination of stringent complete response despite an abnormal κ/λ ratio.


Predictive and prognostic angiogenic markers in a gynecologic oncology group phase II trial of bevacizumab in recurrent and persistent ovarian or peritoneal cancer.
Potential predictive/prognostic angiogenic markers were prospectively examined in a phase II trial of bevacizumab in epithelial ovarian cancer (EOC)/primary peritoneal cancer (PPC). Recurrent/persistent EOC/PPC patients were treated with bevacizumab (15 mg/kg IV q21days) until disease progression. Validated-immunohistochemistry (IHC) assays were performed on pre-cycle 1/4 tumor biopsies for CD31-microvessel density (MVD), VEGF-histoscore (HS), p53-HS, and TSP1 image analysis score (IA). Pre-cycle 1/4 serum and plasma VEGF were quantified using a validated-ELISA. CD31-MVD and serum VEGF, evaluated pre-cycle 1 in 41/61 and 51/61 eligible patients, respectively, did not appear to be correlated. High CD31-MVD, categorized at the median, appeared to be associated with tumor response, a 13-month shorter median survival, and an increased risk of death (unadjusted hazard ratio [HR] = 2.2, 95% confidence interval [CI] = 1.067-4.467). In addition, each standard deviation (SD) increase in CD31-MVD appeared to be associated with worse survival in unadjusted and adjusted analyses. IHC and plasma biomarkers did not change with bevacizumab treatment except for serum VEGF, which appeared to decrease during bevacizumab treatment. This decrease was not associated with response. High pre-cycle 1 serum VEGF, categorized at the median, was associated with 22-month shorter median survival and an increased risk of death (unadjusted HR = 2.7, 95% CI = 1.369-5.191). Categorized p53 appeared to be associated with unadjusted survival and each SD increase in TSP1-IA appeared to be associated with a decreased risk of progression in unadjusted and adjusted analyses. Despite the limitations in sample size and exploratory nature of the study, angiogenic markers in tumor and serum may provide prognostic value in recurrent/persistent EOC/PPC, and are being prospectively evaluated in the GOG phase III trial of carboplatin, paclitaxel and bevacizumab/placebo in previously untreated EOC/PPC.


Differing risk factor profiles of ischemic stroke subtypes: evidence for a distinct lacunar arteriopathy?
Differences in risk factor profiles between lacunar and other ischemic stroke subtypes may provide evidence for a distinct lacunar arteriopathy, but existing studies have limitations. We overcame these by pooling individual data on 2875 patients with first-ever ischemic stroke from 5 collaborating prospective stroke registers that used similar, unbiased methods to define risk factors and classify stroke subtypes. We compared risk factors between lacunar and nonlacunar ischemic strokes, altering the comparison groups in sensitivity analyses, and incorporated these data into a meta-analysis of published studies. Unadjusted and adjusted analyses gave similar results. We found a lower prevalence of cardioembolic source (adjusted odds ratio, 0.33; 95% CI, 0.24 to 0.46), ipsilateral carotid stenosis (odds ratio, 0.21; 95% CI, 0.14 to 0.30), and ischemic heart disease (odds ratio, 0.75; 95% CI, 0.58 to 0.97) in lacunar compared with nonlacunar patients but no difference for hypertension, diabetes, or any other risk factor studied. Results were robust to sensitivity analyses and largely confirmed in our meta-analysis. Hypertension and diabetes appear equally common in lacunar and nonlacunar ischemic stroke, but lacunar stroke is less likely to be caused by embolism from the heart or proximal arteries, and the lower prevalence of ischemic heart disease in lacunar stroke provides additional support for a nonatherosclerotic arteriopathy causing many lacunar ischemic strokes. Our findings have implications for how clinicians classify ischemic stroke subtypes and highlight the need for additional research into the specific causes of and treatments for lacunar stroke.


Management of sexual disorders in spinal cord injured patients.
Spinal cord injured (SCI) patients have sexual disorders including erectile dysfunction (ED), impotence, priapism, ejaculatory dysfunction and infertility. Treatments for erectile dysfunction include four steps. Step 1 involves smoking cessation, weight loss, and increasing physical activity. Step 2 is phosphodiesterase type 5 inhibitors (PDE5I) such as Sildenafil (Viagra), intracavernous injections of Papaverine or prostaglandins, and vacuum constriction devices. Step 3 is a penile prosthesis, and Step 4 is sacral neuromodulation (SNM). Priapism can be resolved spontaneously if there is no ischemia found on blood gas measurement or by Phenylephrine. For anejaculatory dysfunction, massage, vibrator, electrical stimulation and direct surgical biopsy can be used to obtain sperm which can then be used for intra-uterine or in-vitro fertilization. Infertility treatment in male SCI patients involves a combination of the above treatments for erectile and anejaculatory dysfunctions. The basic approach to and management of sexual dysfunction in female SCI patients are similar as for men but do not require treatment for erectile or ejaculatory problems.


Theoretical waveguide optimization in a Ti:LiNb0(3) Mach-Zehnder modulator by Mg diffusion.
Magnesium diffusion can be used to optimize the characteristics and performance of a Ti:LiNbO(3) Mach-Zehnder modulator. Suitable use of titanium/magnesium double diffusion reduces fiber-waveguide coupling loss, minimizes the modulator size by increasing the bend radius of curvature without increasing bend losses, and decreases separation of the modulator arms. The proposed method also makes it possible to reduce the modulating voltage by improvement of guided-wave lateral confinement. Secondary ion mass spectrometry and 771-line techniques are used to characterize Ti/Mg:LiNbO(3) waveguides. A numerical optimization procedure based on the full vectorial beam-propagation method is presented.


Alternate task inhibits single-neuron category-selective responses in the human hippocampus while preserving selectivity in the amygdala.
One fifth of neurons in the medial-temporal lobe of human epilepsy patients respond selectively to categories of images, such as faces or cars. Here we show that responses of hippocampal neurons are rapidly modified as subjects alternate (over 60 sec) between two tasks (1) identifying images from a category, or (2) playing a simple video game superimposed on the same images. Category-selective responses, present when a subject identifies categories, are eliminated when the subject shifts to playing the game for 87% of category-selective hippocampal neurons. By contrast, responses in the amygdala are present during both tasks for 72% of category-selective amygdalar neurons. These results suggest that attention to images is required to evoke selective responses from single neurons in the hippocampus, but is not required by neurons in the amygdala.


Intraventricular topotecan for the treatment of neoplastic meningitis: five case studies.
Many systemic cytotoxic agents cannot penetrate the blood-brain barrier. Because of this, in approximately 5% of cancer cases, metastatic disease is seen in the leptomeninges. Without treatment, patients with neoplastic meningitis (NM) generally survive for only a matter of weeks. In the treatment of NM, intraventricular (IVT) topotecan results in progression-free and overall survival outcomes similar to those seen with other IVT chemotherapies, while being particularly well tolerated by most patients. In this article, we present the case studies of five patients with NM, with various primary malignancies, who received treatment with IVT topotecan.


Accommodating Autistics and Treating Autism: Can We Have Both?
One of the central claims of the neurodiversity movement is that society should accommodate the needs of autistics, rather than try to treat autism. People have variously tried to reject this accommodation thesis as applicable to all autistics. One instance is Pier Jaarsma and Stellan Welin, who argue that the thesis should apply to some but not all autistics. They do so via separating autistics into high- and low-functioning, on the basis of IQ and social effectiveness or functionings. I reject their grounds for separating autistics. IQ is an irrelevant basis for separating autistics. Charitably rendering it as referring to more general capacities still leaves us mistaken about the roles they play in supporting the accommodation thesis. The appeal to social effectiveness or functionings relies on standards that are inapplicable to autistics, and which risks being deaf to the point of their claims. I then consider if their remaining argument concerning autistic culture may succeed independently of the line they draw. I argue that construing autistics' claims as beginning from culture mistakes their status, and may even detract from their aims. Via my discussion of Jaarsma and Welin, I hope to point to why the more general strategy of separating autistics, in response to the accommodation thesis, does not fully succeed. Finally, I sketch some directions for future discussions, arguing that we should instead shift our attention to consider another set of questions concerning the costs and extent of change required to accommodate all autistics.


Functionalizing a dentin bonding resin to become bioactive.
To investigate chemo-mechanical effects of incorporating alkaline bioactive glass nanoparticles into a light-curable dental resin matrix. An unfilled Bis-GMA/TEGDMA material was infiltrated with up to 20 wt% of ultrafine SiO2-Na2O-CaO-P2O5-Bi2O3 particles. The unfilled and filled resins were investigated regarding their viscosity before setting and compared to commercially available materials. Set specimens were immersed for 21 days in phosphate buffered saline at 37°C. Water uptake, pH, Knoop hardness, and degree of conversion of freshly polymerized and stored samples were investigated. Resin surfaces were viewed and mapped in a scanning electron microscope for the formation of calcium phosphate (Ca/P) precipitates. In addition, Raman spectroscopy was performed. Numeric values were statistically compared (p<0.01). Viscosity increased with particle loading, but remained below that of a flowable dental composite material. Water uptake into and pH induction from the polymerized samples also increased with particle loading (p<0.01). The addition of 20 wt% nanoparticles had no significant influence on microhardness, yet it slightly (p<0.01) increased the degree of conversion after 21 days. Ca/P precipitates formed on specimens filled with 20 wt% of the particles, while they were scarce on counterparts loaded with 10 wt%, and absent on unfilled resin surfaces. The results of the current study show that a Bis-GMA-based resin can be functionalized using alkaline nanoparticles. A material with bioactive properties and similar hardness as the unfilled resin was obtained by incorporating 20wt% of ultrafine SiO2-Na2O-CaO-P2O5-Bi2O3 particles into the resin matrix.


An analysis of India's 2017 National Ethical Guidelines for Biomedical and Health Research Involving Human Participants: The Social and Behavioural Sciences aspect.
In this commentary on Section 9 (Social and Behavioural Sciences Research for Health) of the National Ethical Guidelines for Biomedical and Health Research Involving Human Participants (2017) by the Indian Council of Medical Research (ICMR), we appreciate that the guidelines clarify that human beings are "research participants" and not merely "subjects". Further, we appreciate and commend the ICMR for: i) contextualising the guidelines to India's unique sociocultural and economic situation and ii) affirming the multidisciplinary nature of health research and the wide scope of social and behavioural research. However, we question the prominence given to the difference between biomedical research and other aspects of health research and the description of social and psychological risks and discomforts as minor risks. Finally, we suggest that the guidelines would express greater value and diversity of the social aspects of health if they recommended wider representation of these aspects in the composition of research ethics committees.


Regulation by calcium of proliferation and morphology of normal human tracheobronchial epithelial cell cultures.
Human tracheobronchial epithelial cells have been serially passaged in serum-free medium. This serum-free model was employed to investigate the effects of different concentrations of Ca2+ (0.1, 1.0 and 2.0 mM) on multiplication and morphology of the cells. The responses were analysed in terms of growth kinetics, histochemical and ultrastructural alterations. Culturing of the cells in high Ca2+ (1.0-2.0 mM) medium stimulated cell multiplication characterized by increased colony forming efficiency, greater number of cells per colony and cell population doublings per day. Additionally, the high Ca2+ concentrations induced proliferation in cultures grown to confluency in low Ca2+ (0.1 mM) medium. Cells propagated in low Ca2+ medium consisted of relatively heterogeneous cell populations, with most cells staining positive with periodic acid-Schiff (PAS) reagent. Ultrastructurally the cells exhibited secretory vesicles and microvilli on their surfaces, small desmosomes and intercellular interdigitation between cells and numerous large secretory vesicles in the cytoplasm. The cells grown in high Ca2+ medium acquired characteristics of a highly proliferative phenotype. The cultures consisted of closely packed, relatively homogeneous cells that did not stain with PAS reagent. Their characteristic features were: absence of surface secretory vesicles, reductions of microvilli and intercellular interdigitations, and increases in size and number of desmosomal junctions. The results show that low Ca2+ in the culture medium inhibits cell multiplication and favors the secretory cell phenotype, while high Ca2+ levels stimulate cell multiplication and inhibit the secretory cell phenotype.


Rates and Covariates of Recent Sexual and Physical Violence Against HIV-Infected Outpatient Drinkers in Western Kenya.
Victimization from physical and sexual violence presents global health challenges. Partner violence is higher in Kenya than Africa. Violence against drinkers and HIV-infected individuals is typically elevated, so dual vulnerabilities may further augment risk. Understanding violence risks can improve interventions. Participants were 614 HIV-infected outpatient drinkers in western Kenya enrolled in a randomized trial to reduce alcohol use. At baseline, past 90-day partner physical and sexual violence were examined descriptively and in gender-stratified regression models. We hypothesized higher reported violence against women than men, and positive violence association with HIV stigma and alcohol use across gender. Women reported significantly more current sexual (26.3 vs. 5.7%) and physical (38.9 vs. 24.8%) victimization than men. Rates were generally higher than Kenyan lifetime national averages. In both regression models, HIV stigma and alcohol-related sexual expectations were significantly associated with violence while alcohol use was not. For women, higher violence risk was also conferred by childhood violence, past-year transactional sex, and younger age. HIV-infected Kenyan drinkers, particularly women, endorse high current violence due to multiple risk factors. Findings have implications for HIV interventions. Longitudinal research is needed to understand development of risk.


How effective are antioxidant supplements in obesity and diabetes?
Obesity is a central health issue due to its epidemic prevalence and its association with type 2 diabetes and other comorbidities. Obesity is not just being overweight. It is a metabolic disorder due to the accumulation of excess dietary calories into visceral fat and the release of high concentrations of free fatty acids into various organs. It represents a state of chronic oxidative stress and low-grade inflammation whose intermediary molecules may include leptin, adiponectin and cytokines. It may progress to hyperglycemia, leading to type 2 diabetes. Whether or not dietary antioxidant supplements are useful in the management of obesity and type 2 diabetes is discussed in this review. Only the benefits for obesity and diabetes are examined here. Other health benefits of antioxidants are not considered. There are difficulties in comparing studies in this field because they differ in the time frame, participants' ethnicity, administration of antioxidant supplements, and even in how obesity was measured. However, the literature presents reasonable evidence for marginal benefits of supplementation with zinc, lipoic acid, carnitine, cinnamon, green tea, and possibly vitamin C plus E, although the evidence is much weaker for omega-3 polyunsaturated fatty acids, coenzyme Q10, green coffee, resveratrol, or lycopene. Overall, antioxidant supplements are not a panacea to compensate for a fast-food and video-game way of living, but antioxidant-rich foods are recommended as part of the lifestyle. Such antioxidant foods are commonly available.


Guide to the Management of Clozapine-Related Tolerability and Safety Concerns.
Clozapine is a highly effective antipsychotic medication, which provides a range of significant benefits for patients with schizophrenia, and is the standard of care for treatment-resistant schizophrenia as well as for reducing the risk of suicidal behaviors in schizophrenia and schizoaffective disorder. However, clozapine is widely underutilized, largely because prescribing clinicians lack experience in prescribing it and managing its adverse events (AEs). Clozapine is associated with three uncommon but immediately dangerous AEs-agranulocytosis, myocarditis/cardiomyopathy, and seizures-as well as AEs that may become dangerous if neglected, including weight gain, metabolic syndrome and constipation, and others that are annoying or distressing such as sedation, nighttime enuresis and hypersalivation. Because of the risk of agranulocytosis, clozapine formulations are available only through restricted distribution via a patient registry, with mandatory, systematized monitoring for absolute neutrophil count using a specific algorithm. We identified articles on managing clozapine-associated AEs by searching PubMed using appropriate key words and search techniques for each topic. A review of the prevalence and clinical characteristics of clozapine-associated AEs shows that these risks can be managed efficiently and effectively. The absolute risks for both agranulocytosis and myocarditis/cardiomyopathy are low, diminish after the first six months, and are further reduced with appropriate monitoring. Weight gain/metabolic disorders and constipation, which develop more gradually, can be mitigated with regular monitoring and timely interventions. Sedation, hypersalivation, and enuresis are common but manageable with ameliorative measures and/or medications.


Differential effects of eNOS uncoupling on conduit and small arteries in GTP-cyclohydrolase I-deficient hph-1 mice.
In the present study, we used the hph-1 mouse, which displays GTP-cyclohydrolase I (GTPCH I) deficiency, to test the hypothesis that loss of tetrahydrobiopterin (BH(4)) in conduit and small arteries activates compensatory mechanisms designed to protect vascular wall from oxidative stress induced by uncoupling of endothelial nitric oxide synthase (eNOS). Both GTPCH I activity and BH(4) levels were reduced in the aortas and small mesenteric arteries of hph-1 mice. However, the BH(4)-to-7,8-dihydrobiopterin ratio was significantly reduced only in hph-1 aortas. Furthermore, superoxide anion and 3-nitrotyrosine production were significantly enhanced in aortas but not in small mesenteric arteries of hph-1 mice. In contrast to the aorta, protein expression of copper- and zinc-containing superoxide dismutase (CuZnSOD) was significantly increased in small mesenteric arteries of hph-1 mice. Protein expression of catalase was increased in both aortas and small mesenteric arteries of hph-1 mice. Further analysis of endothelial nitric oxide synthase (eNOS)/cyclic guanosine monophosphate (cGMP) signaling demonstrated that protein expression of phosphorylated Ser(1177)-eNOS as well as basal cGMP levels and hydrogen peroxide was increased in hph-1 aortas. Increased production of hydrogen peroxide in hph-1 mice aortas appears to be the most likely mechanism responsible for phosphorylation of eNOS and elevation of cGMP. In contrast, upregulation of CuZnSOD and catalase in resistance arteries is sufficient to protect vascular tissue from increased production of reactive oxygen species generated by uncoupling of eNOS. The results of our study suggest that anatomical origin determines the ability of vessel wall to cope with oxidative stress induced by uncoupling of eNOS.


Evaluation of the safety of fenbendazole in cats.
To evaluate the safety of fenbendazole in domestic cats. 28 six- to seven-month old domestic short-hair cats. Cats were randomly assigned to 1 of 3 treatment groups or a control group (n = 7/group). Cats in the treatment groups were given fenbendazole at a dosage of 50, 150, or 250 mg/kg, PO, every 24 hours for 9 days; control cats were given a placebo. A fecal examination, coagulation tests, serum biochemical analyses, CBC, and urinalyses were performed before and 5, 9, and 21 days after initiation of treatment; cats were closely monitored for adverse reactions. After the last dose of fenbendazole was given, 4 control cats and 4 cats given fenbendazole at the highest dosage were euthanatized, and necropsies were performed. None of the cats developed any adverse reactions. For cats in the control and all treated groups, laboratory test results were within reference limits, and there were no significant differences in results of laboratory tests among groups. No gross or histologic lesions were identified in the control or treated cats that were euthanatized. Fenbendazole administered to healthy cats at a dosage 5 times the dosage and 3 times the duration approved for use in dogs and wild felids did not cause any acute or subacute adverse reactions or pathologic changes. Results suggest that cats may be safely treated with fenbendazole.


Oil refinery experience with the assessment of refinery effluents and receiving waters using biologically based methods.
The trend in discharges of petroleum-related substances from refineries in Europe shows a consistent picture of declining emissions, since first measured in 1969. This decline coincides with enhanced internal capture or recycling procedures and increasing use of physical and biological treatments. At the same time, and partly in response to legislative drivers, there has been an increase in the use of chronic (long-term) toxicity tests and alternative methods for assessing the quality of effluent discharges. The Whole Effluent Assessment (WEA) approach has also driven the increased conduct of studies addressing the fate of effluent constituents. Such studies have included the use of biodegradation and solid-phase micro-extraction-biomimetic extraction (SPME-BE) methods to address potentially bioaccumulative substances (PBS). In this way, it is then possible to address the persistence and toxicity of these PBS constituents of an effluent. The data collected in various case studies highlights the advantages and pitfalls of using biologically-based methods to assess the potential for refinery effluents to cause environmental impacts.


Mueller matrices in fluorescence scattering.
A reappraisal of the 1929 analysis of luminescence by Soleillet reveals the form of the Mueller matrix for fluorescence scattering whose parameters are directly defined in terms of the now-familiar fluorescence anisotropy parameter. If the scattering analyte is optically active, it is further shown how fluorescence detected circular dichroism and circularly polarized luminescence can be recovered, simultaneously and free of artifacts.


Impact of active drug use on antiretroviral therapy adherence and viral suppression in HIV-infected drug users.
Despite a burgeoning literature on adherence to HIV therapies, few studies have examined the impact of ongoing drug use on adherence and viral suppression, and none of these have utilized electronic monitors to quantify adherence among drug users. We used 262 electronic monitors to measure adherence with all antiretrovirals in 85 HIV-infected current and former drug users, and found that active cocaine use, female gender, not receiving Social Security benefits, not being married, screening positive for depression, and the tendency to use alcohol or drugs to cope with stress were all significantly associated with poor adherence. The strongest predictor of poor adherence and, in turn, failure to maintain viral suppression, was active cocaine use. Overall adherence among active cocaine users was 27%, compared to 68% among subjects who reported no cocaine use during the 6-month study period. Consequently, 13% of active cocaine users maintained viral suppression, compared to 46% of nonusers. Interventions to improve adherence should focus on reducing cocaine use, developing adaptive coping skills, and identifying and treating depression.


Mosquito genomics. Extensive introgression in a malaria vector species complex revealed by phylogenomics.
Introgressive hybridization is now recognized as a widespread phenomenon, but its role in evolution remains contested. Here, we use newly available reference genome assemblies to investigate phylogenetic relationships and introgression in a medically important group of Afrotropical mosquito sibling species. We have identified the correct species branching order to resolve a contentious phylogeny and show that lineages leading to the principal vectors of human malaria were among the first to split. Pervasive autosomal introgression between these malaria vectors means that only a small fraction of the genome, mainly on the X chromosome, has not crossed species boundaries. Our results suggest that traits enhancing vectorial capacity may be gained through interspecific gene flow, including between nonsister species.


Online Multiperson Tracking-by-Detection from a Single, Uncalibrated Camera.
In this paper, we address the problem of automatically detecting and tracking a variable number of persons in complex scenes using a monocular, potentially moving, uncalibrated camera. We propose a novel approach for multiperson tracking-by-detection in a particle filtering framework. In addition to final high-confidence detections, our algorithm uses the continuous confidence of pedestrian detectors and online-trained, instance-specific classifiers as a graded observation model. Thus, generic object category knowledge is complemented by instance-specific information. The main contribution of this paper is to explore how these unreliable information sources can be used for robust multiperson tracking. The algorithm detects and tracks a large number of dynamically moving people in complex scenes with occlusions, does not rely on background modeling, requires no camera or ground plane calibration, and only makes use of information from the past. Hence, it imposes very few restrictions and is suitable for online applications. Our experiments show that the method yields good tracking performance in a large variety of highly dynamic scenarios, such as typical surveillance videos, webcam footage, or sports sequences. We demonstrate that our algorithm outperforms other methods that rely on additional information. Furthermore, we analyze the influence of different algorithm components on the robustness.


Adjuvant chemotherapy for elderly patients with stage I non-small-cell lung cancer ≥4 cm in size: an SEER-Medicare analysis.
The role of adjuvant chemotherapy for non-small-cell lung cancer (NSCLC) stage I patients with tumors size ≥4 cm is not well established in the elderly. We identified 3289 patients with stage I NSCLC (T2N0M0 and tumor size ≥4 cm) who underwent lobectomy from the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database diagnosed from 1992 to 2009. Overall survival and rates of serious adverse events (defined as those requiring admission to hospital) were compared between patients treated with resection alone, platinum-based adjuvant chemotherapy, or postoperative radiation (PORT) with or without adjuvant chemotherapy. Propensity scores for receiving each treatment were calculated and survival analyses were conducted using inverse probability weights based on the propensity score. Overall, 84% patients were treated with resection alone, 9% received platinum-based adjuvant chemotherapy, and 7% underwent PORT with or without adjuvant chemotherapy. Adjusted analysis showed that adjuvant chemotherapy [hazard ratio (HR), 0.82; 95% confidence interval (CI) 0.68-0.98] was associated with improved survival compared with resection alone. Conversely, the use of PORT with or without adjuvant chemotherapy (HR 1.91; 95% CI 1.64-2.23) was associated with worse outcomes. Patients receiving adjuvant chemotherapy had more serious adverse events compared with those treated with resection alone, with neutropenia (odds ratio, 21.2; 95% CI 5.8-76.6) being most significant. No significant difference was observed in rates of fever, cytopenias, nausea, and renal dysfunction. Platinum-based adjuvant chemotherapy is associated with reduced mortality and increased serious adverse events in elderly patients with stage I NSCLC and tumor size ≥4 cm.


Left ventricular hypertrophy and arterial wall thickening in children with essential hypertension.
Our aim was to determine the prevalence of left ventricular hypertrophy (LVH) and increased intima-media thickness (IMT) in Caucasian children with newly diagnosed, untreated essential hypertension (EH). Our study cohort consisted of 72 children with EH (mean age: 14.5 years; range: 5-18 years). The control groups consisted of 103 age-matched, healthy children. We evaluated the left ventricular mass (LVM), intima-media thickness in the carotid (cIMT) and superficial femoral (fIMT) arteries, 24-h ambulatory blood pressure, and biochemical cardiovascular risk factors. Of the hypertensive children examined, 41.6% had LVM above the 95th percentile, and 13.2% had LVM above 51 g/m2.7. Of the hypertensive subjects, the cIMT was above 2 SDS of normal values in 38.8%, and the flMT was above 2 SDS of normal values in 17.5%. Patients with LVM above 51 g/m2.7 had a higher birth weight than other patients. LVM, cIMT, and fIMT correlated with 24-h SBP and pulse pressure; LVM also correlated with homocysteine and serum uric acid concentrations. fIMT correlated with low Aprotein A1 (ApoA1), higher ApoB and C reactive protein, and daily sodium excretion. Step-wise regression analysis revealed that serum uric acid and higher birth weight were predictors for LVM, pulse pressure was a predictor for cIMT, and ApoB was a predictor for fIMT. A significant number of adolescents with EH already had cardiovascular damage at diagnosis. LVM and markers of arterial injury correlate with SBP, biochemical, and perinatal cardiovascular risk factors. Serum uric acid and higher birth weight are predictors of LVM.


The Citizen Nurse: An Educational Innovation for Change.
Nursing education needs to provide the necessary tools for students to develop leadership skills and to practice civic agency to create meaningful change in the shifting health care field. This article focuses on facilitating a student's role in becoming a citizen nurse through curricular modifications. Through an ongoing partnership, nursing faculty and community organizers implemented a year-long pilot project to discover the deeper insights into the role of a citizen nurse and to analyze the skills students need to be effective agents of change. Pilot lectures and workshops were held throughout the academic year, and curricular changes were implemented. Based on input from pilot class experiences, student reflections, and faculty workshop feedback, the decision to implement ongoing curricular changes was made by the department. The development of citizen nurses in nursing education will pave the way for praxis embedded in meaningful work with just solutions, enhancing the agency of all involved in promoting health and well-being. [J Nurs Educ. 2017;56(4):247-250.].


Outcomes and quality of life assessment in patients undergoing endoscopic surgery for pituitary adenomas.
The endoscopic technique is increasingly being used for the resection of pituitary adenomas. Its efficacy and safety have been generally accepted, but its impact on the quality of life of the patients treated has not been previously addressed. Most of the studies assessing the quality of life after long-term cure of pituitary adenomas suggest a significantly impaired quality of life (QoL) in all subgroups of pituitary tumours. In our study we analyse QoL data following endoscopic surgery, and attempt comparisons with normative and data from standard approaches. The validated health questionnaire SF-36 was sent to 80 patients who had undergone pure endoscopic resection of a pituitary adenoma. Fifty-four patients returned the completed questionnaire. Outcomes were compared with normative data for the Short Form-36 (SF-36) Heath survey for the general Canadian population. We also compared the results amongst different types of adenomas. We attempted a comparison to previous studies on quality of life for patients who underwent conventional trans-sphenoidal surgery. Our study suggests only minimal impairment of quality of life in patients after successful treatment of pituitary adenomas using the endoscopic approach. There were only very few differences in the perceived quality of life within the different subgroups of adenomas. There was a trend to improved scores in the endoscopic group compared with previous studies in patients treated by conventional approaches. Whilst our data suggest minimal impact on the quality of life for patients after endoscopic removal of pituitary adenomas, further studies with larger number of patients and longer follow-up are required to encourage this finding.


NfL and pNfH are increased in Friedreich's ataxia.
To assess neurofilaments as neurodegenerative biomarkers in serum of patients with Friedreich's ataxia. Single molecule array measurements of neurofilament light (NfL) and heavy chain (pNfH) in 99 patients with genetically confirmed Friedreich's ataxia. Correlation of NfL/pNfH serum levels with disease severity, disease duration, age, age at onset, and GAA repeat length. Median serum levels of NfL were 21.2 pg/ml (range 3.6-49.3) in controls and 26.1 pg/ml (0-78.1) in Friedreich's ataxia (p = 0.002). pNfH levels were 23.5 pg/ml (13.3-43.3) in controls and 92 pg/ml (3.1-303) in Friedreich's ataxia (p = 0.0004). NfL levels were significantly increased in younger patients (age 16-31 years, p < 0.001) and patients aged 32-47 years (p = 0.008), but not in patients of age 48 years and older (p = 0.41). In a longitudinal assessment, there was no difference in NfL levels in 14 patients with repeated sampling 2 years after baseline measurement. Levels of NfL correlated inversely with GAA1 repeat length (r = - 0.24, p = 0.02) but not with disease severity (r = - 0.13, p = 0.22), disease duration (r = - 0.06, p = 0.53), or age at onset (r = 0.05, p = 0.62). Serum levels of NfL and pNfH are elevated in Friedreich's ataxia, but differences to healthy controls decrease with increasing age. Long-term longitudinal data are required to explore whether this reflects a selection bias from early death of more severely affected individuals or a slowing down of the neurodegenerative process with age. In a pilot study over 2 years of follow-up-a period relevant for biomarkers indicating treatment effects-we found NfL levels to be stable.


Feline non-erosive immune-mediated polyarthritis: a multicentre, retrospective study of 20 cases (2009-2020).
Cats with non-erosive immune-mediated polyarthritis (IMPA) were identified from seven referral hospitals between 2009 and 2020 for a multicentre retrospective case series. Data were obtained from hospital records and referring veterinarians were contacted for follow-up. Twenty cases were identified: 12 castrated males (60%), one entire male (5%) and seven spayed females (35%). Common clinical signs included lameness (n = 20/20) and pyrexia (n = 10/18). Three cats presented with and two cats developed ligament laxity during treatment. Thirteen cats (65%) were diagnosed with non-associative IMPA and seven (35%) with associative IMPA. Comorbidities identified included chronic enteropathy (n = x/7), feline immunodeficiency virus (n = x/7) feline herpesvirus (n = x/7), bronchopneumonia (n = x/7) and discospondylitis (n = x/7). Sampling of the tarsal joints most frequently identified an increased proportion of neutrophils, consistent with IMPA. Eighteen cats (90%) received immunosuppressants. Eleven cats were started on prednisolone; eight had a poor response resulting in the addition of a second agent, euthanasia or acceptance of the persisting signs. One cat received ciclosporin and required an alternative second agent owing to adverse effects. Five cats were started on prednisolone and ciclosporin; three had a poor response and required an alternative second agent. One cat received prednisolone and chlorambucil and had a good response. Two cats (10%) received meloxicam and had a good response, although the clinical signs recurred when medication was tapered. A good outcome was achieved in 14/20 cats (70%) with IMPA. In the cats with a poor outcome 4/6 were euthanased and 2/6 had chronic lameness. Prognosis for feline IMPA can be good. Multimodal immunosuppression was often required. IMPA should be considered in lame cats, with or without pyrexia, when there is no evidence of trauma or infection. The tarsal joints should be included in the multiple joints chosen for sampling. Ligament laxity can occur in non-erosive feline IMPA.


Antibody to hepatitis C virus and liver disease in volunteer blood donors.
To evaluate the specificity of antibodies to hepatitis C virus (anti-HCV) and their relation to liver disease in blood donors. Case series of consecutive blood donors found positive for anti-HCV by enzyme-linked immunosorbent assay (ELISA). Patients were evaluated for antibody specificity using a recombinant immunoblotting assay (RIBA) and were evaluated for biochemical evidence of liver disease. Patients showing increased alanine aminotransferase (ALT) levels had a liver biopsy. University hospital. Fifty consecutive blood donors found to be anti-HCV positive on both an initial and repeat ELISA. Inclusion criteria were as follows: an absence of hepatitis B surface antigens and non-organ-specific autoantibodies; a daily alcohol intake of less than 50 g; no history of recent hepatotoxic drug use; and normal serum levels of alpha 1 antitrypsin, ceruloplasmin, and copper. Anti-HCV positivity was confirmed by RIBA in only 13 of 50 donors (26%) who had positive ELISA results. These 13 donors had an elevated ALT level and histologic evidence of chronic hepatitis, which was active in 8 patients (62%) and had already produced cirrhosis in 2 patients (15%). In contrast, the 17 donors with an intermediate RIBA pattern had only mild and often nonspecific histologic liver abnormalities. The 20 patients with a negative RIBA result had normal ALT levels. In blood donors, the anti-HCV RIBA is not only more specific than the anti-HCV ELISA, but is also useful in identifying patients who have an underlying chronic liver disease.


MET in human cancer: germline and somatic mutations.
Since the initial discovery of missense MET mutations in hereditary papillary renal carcinoma (HPRC), activating MET mutations have been identified in a diverse range of human cancers. MET mutations have been identified in several functional domains including the kinase, juxtamembrane, and Sema domains. Studies of these mutations have been invaluable for our understanding of the tumor initiating activity of MET, receptor tyrosine kinase (RTK) recycling and regulation, and mechanisms of resistance to kinase inhibition. These studies also demonstrate that mutationally activated MET plays a significant role in a wide range of cancers and RTKs can promote tumor progression through diverse mechanisms. This review will cover the various MET mutations that have been identified, their mechanism of action, and the significant role that mutationally-activated MET plays in tumor initiation, progression, and therapeutic resistance.


Unmet needs of outpatients with late-life depression; a comparison of patient, staff and carer perceptions.
There is evidence that late life depression is associated with high levels of unmet needs. Only a minority of the depressed patients appears to be adequately treated. Ninety-nine older patients (58-92 years), 96 informal carers and 85 health-care professionals were recruited from six outpatient facilities for old age psychiatry in the Netherlands and interviewed to identify met and unmet needs, using the Camberwell Assessment of Needs for the Elderly (CANE). The severity of depression was measured with the Montgomery Åsberg Depression Rating Scale (MADRS). On average patients scored more unmet needs than staff and carers. On item level, patients and staff showed the highest agreement in the psychological needs category. Patient and carers showed the highest agreement on physical health needs. Logistic regression showed that severe depression is a significant predictor of low concordance between stakeholders on a substantial number of CANE items. Kappa coefficients were computed to determine agreement between parties involved. However, Kappa coefficients should be interpreted with caution, especially when obvious disparity in unmet needs scores between groups of interest can be observed. Home dwelling older patients with major depressive disorder, their practitioners and their informal carers have different perceptions of the older patients unmet needs.Practitioners should be aware of the negative impact of depression severity on reaching agreement regarding unmet needs and its possible consequences for mutual goal setting and compliance.


Elevated plasma homocysteine is associated with increased brain atrophy rates in older subjects with mild hypertension.
We determined using serial MR imaging whether raised plasma homocysteine levels are associated with increased brain atrophy, white matter lesion (WML) progression or incidence of silent brain infarcts (SBIs) in older hypertensive subjects. Brain atrophy rates (0.58 ± 0.48% per year, mean ± SD) were significantly correlated with homocysteine (β = 0.46, p = 0.001 homocysteine; β = 0.44, p = 0.007 homocysteine/folate/B12 models) but not with folate or B12 levels. Progression of WML (0.08 ± 0.16%) was not associated with homocysteine level (B = 0.01, p = 0.29). New SBIs were uncommon. In older hypertensive individuals, plasma homocysteine levels are associated with increased rates of whole-brain atrophy but not WML progression.