Evaluation of machine learning methods to stroke outcome prediction using a nationwide disease registry.
Being able to predict functional outcomes after a stroke is highly desirable for clinicians. This allows clinicians to set reasonable goals with patients and relatives, and to reach shared after-care decisions for recovery or rehabilitation. The aim of this study was to apply various machine learning (ML) methods for 90-day stroke outcome predictions, using a nationwide disease registry. This study used the Taiwan Stroke Registry (TSR) which has prospectively collected data from stroke patients since 2006. Three known ML models (support vector machine, random forest, and artificial neural network), and a hybrid artificial neural network were implemented and evaluated by 10-time repeated hold-out with 10-fold cross-validation. ML techniques present over 0.94 AUC in both ischemic and hemorrhagic stroke using preadmission and inpatient data. By adding follow-up data, the prediction ability improved to 0.97 AUC. We screened 206 clinical variables to identify 17 important features from the ischemic stroke dataset and 22 features from the hemorrhagic stroke dataset without losing much performance. Error analysis revealed that most prediction errors come from more severe stroke patients. The study showed that ML techniques trained from large, cross-reginal registry datasets were able to predict functional outcome after stroke with high accuracy. The follow-up data is important which can further improve the predictive models' performance. With similar performances among different ML techniques, the algorithm's characteristics and performance on severe stroke patients will be the primary focus when we further develop inference models and artificial intelligence tools for potential medical.


Analysis of Mutations in AARS2 in a Series of CSF1R-Negative Patients With Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia.
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a frequent cause of adult-onset leukodystrophy known to be caused by autosomal dominant mutations in the CSF1R (colony-stimulating factor 1) gene. The discovery that CSF1R mutations cause ALSP led to more accurate prognosis and genetic counseling for these patients in addition to increased interest in microglia as a target in neurodegeneration. However, it has been known since the discovery of the CSF1R gene that there are patients with typical clinical and radiologic evidence of ALSP who do not carry pathogenic CSF1R mutations. These patients include those in whom the pathognomonic features of axonal spheroids and pigmented microglia have been found. Achieving a genetic diagnosis in these patients is important to our understanding of this disorder. To genetically characterize a group of patients with typical features of ALSP who do not carry CSF1R mutations. In this case series study, 5 patients from 4 families were identified with clinical, radiologic, or pathologic features of ALSP in whom CSF1R mutations had been excluded previously by sequencing. Data were collected between May 2014 and September 2015 and analyzed between September 2015 and February 2016. Focused exome sequencing was used to identify candidate variants. Family studies, long-range polymerase chain reaction with cloning, and complementary DNA sequencing were used to confirm pathogenicity. Of these 5 patients, 4 were men (80%); mean age at onset of ALSP was 29 years (range, 15-44 years). Biallelic mutations in the alanyl-transfer (t)RNA synthetase 2 (AARS2) gene were found in all 5 patients. Frameshifting and splice site mutations were common, found in 4 of 5 patients, and sequencing of complementary DNA from affected patients confirmed that the variants were loss of function. All patients presented in adulthood with prominent cognitive, neuropsychiatric, and upper motor neuron signs. Magnetic resonance imaging in all patients demonstrated a symmetric leukoencephalopathy with punctate regions of restricted diffusion, typical of ALSP. In 1 patient, brain biopsy demonstrated axonal spheroids and pigmented microglia, which are the pathognomonic signs of ALSP. This work indicates that mutations in the tRNA synthetase AARS2 gene cause a recessive form of ALSP. The CSF1R and AARS2 proteins have different cellular functions but overlap in a final common pathway of neurodegeneration. This work points to novel targets for research and will lead to improved diagnostic rates in patients with adult-onset leukoencephalopathy.


Localization of pain-related brain activation: a meta-analysis of neuroimaging data.
A meta-analysis of 140 neuroimaging studies was performed using the activation-likelihood-estimate (ALE) method to explore the location and extent of activation in the brain in response to noxious stimuli in healthy volunteers. The first analysis involved the creation of a likelihood map illustrating brain activation common across studies using noxious stimuli. The left thalamus, right anterior cingulate cortex (ACC), bilateral anterior insulae, and left dorsal posterior insula had the highest likelihood of being activated. The second analysis contrasted noxious cold with noxious heat stimulation and revealed higher likelihood of activation to noxious cold in the subgenual ACC and the amygdala. The third analysis assessed the implications of using either a warm stimulus or a resting baseline as the control condition to reveal activation attributed to noxious heat. Comparing noxious heat to warm stimulation led to peak ALE values that were restricted to cortical regions with known nociceptive input. The fourth analysis tested for a hemispheric dominance in pain processing and showed the importance of the right hemisphere, with the strongest ALE peaks and clusters found in the right insula and ACC. The fifth analysis compared noxious muscle with cutaneous stimuli and the former type was more likely to evoke activation in the posterior and anterior cingulate cortices, precuneus, dorsolateral prefrontal cortex, and cerebellum. In general, results indicate that some brain regions such as the thalamus, insula and ACC have a significant likelihood of activation regardless of the type of noxious stimuli, while other brain regions show a stimulus-specific likelihood of being activated.


Auditory motion processing after early blindness.
Studies showing that occipital cortex responds to auditory and tactile stimuli after early blindness are often interpreted as demonstrating that early blind subjects "see" auditory and tactile stimuli. However, it is not clear whether these occipital responses directly mediate the perception of auditory/tactile stimuli, or simply modulate or augment responses within other sensory areas. We used fMRI pattern classification to categorize the perceived direction of motion for both coherent and ambiguous auditory motion stimuli. In sighted individuals, perceived motion direction was accurately categorized based on neural responses within the planum temporale (PT) and right lateral occipital cortex (LOC). Within early blind individuals, auditory motion decisions for both stimuli were successfully categorized from responses within the human middle temporal complex (hMT+), but not the PT or right LOC. These findings suggest that early blind responses within hMT+ are associated with the perception of auditory motion, and that these responses in hMT+ may usurp some of the functions of nondeprived PT. Thus, our results provide further evidence that blind individuals do indeed "see" auditory motion.


Effect of angiotensin converting enzyme inhibition after acute myocardial infarction in patients with arterial hypertension. TRACE Study Group, Trandolapril Cardiac Event.
To evaluate the influence of a history of arterial hypertension on the efficacy of the angiotensin converting enzyme (ACE) inhibitor trandolapril in patients with acute myocardial infarction (AMI) and left ventricular dysfunction. A retrospective analysis of data from the Trandolapril Cardiac Event (TRACE) study. The TRACE study was a randomized, double-blind, placebo-controlled study in which patients with an enzyme-verified AMI and ejection fraction < or = 35% were assigned randomly to be administered oral trandolapril or placebo 3-7 days after the infarction. Of 1749 patients who entered the study, 400 (23%) had a history of arterial hypertension. The mean follow-up time was 26 months. Mortality from any cause. Secondary endpoints were sudden death, cardiovascular mortality, reinfarction and development of severe heart failure. Of the patients in the hypertensive group, 173 (43%) died during follow-up, versus 500 (37%) in the normotensive group. Treatment with trandolapril resulted in a relative risk of death from any cause for the hypertensive group of 0.59 (96% confidence interval 0.44-0.80), versus 0.85 (0.72-1.02) for normotensive patients. In a multivariate analysis, treatment with trandolapril was associated with a reduction in mortality among patients with a history of hypertension (P = 0.03). In this retrospective analysis, ACE inhibition after AMI complicated with left ventricular dysfunction was of greater benefit to patients with a history of arterial hypertension. ACE inhibition might be of particular importance in this group of patients but further studies to establish the clinical impact are necessary.


Acetyl-L-carnitine in diabetic polyneuropathy: experimental and clinical data.
Diabetic polyneuropathy (DPN) is the most common late complication of diabetes mellitus. The underlying pathogenesis is multifaceted, with partly interrelated mechanisms that display a dynamic course. The mechanisms underlying DPN in type 1 and type 2 diabetes mellitus show overlaps or may differ. The differences are mainly due to insulin deficiency in type 1 diabetes which exacerbates the abnormalities caused by hyperglycaemia. Experimental DPN in rat models have identified early metabolic abnormalities with consequences for nerve conduction velocities and endoneurial blood flow. When corrected, the early functional deficits are usually normalised. On the other hand, if not corrected, they lead to abnormalities in lipid peroxidation and expression of neurotrophic factors which in turn result in axonal, nodal and paranodal degenerative changes with worsening of nerve function. As the structural changes progress, they become increasingly less amendable to metabolic interventions. In the past several years, experimental drugs--such as aldose reductase inhibitors, antioxidants and protein kinase C inhibitors--have undergone clinical trials, with disappointing outcomes. These drugs, targeting a single underlying pathogenetic factor, have in most cases been initiated at the advanced stage of DPN. In contrast, substitution of acetyl-L-carnitine (ALC) or C-peptide in type 1 DPN target a multitude of underlying mechanisms and are therefore more likely to be effective on a broader spectrum of the underlying pathogenesis. Clinical trials utilising ALC have shown beneficial effects on nerve conduction slowing, neuropathic pain, axonal degenerative changes and nerve fibre regeneration, despite relatively late initiation in the natural history of DPN. Owing to the good safety profile of ALC, early initiation of ALC therapy would be justified, with potentially greater benefits.


Marine harmful algal blooms, human health and wellbeing: challenges and opportunities in the 21st century.
Microalgal blooms are a natural part of the seasonal cycle of photosynthetic organisms in marine ecosystems. They are key components of the structure and dynamics of the oceans and thus sustain the benefits that humans obtain from these aquatic environments. However, some microalgal blooms can cause harm to humans and other organisms. These harmful algal blooms (HABs) have direct impacts on human health and negative influences on human wellbeing, mainly through their consequences to coastal ecosystem services (fisheries, tourism and recreation) and other marine organisms and environments. HABs are natural phenomena, but these events can be favoured by anthropogenic pressures in coastal areas. Global warming and associated changes in the oceans could affect HAB occurrences and toxicity as well, although forecasting the possible trends is still speculative and requires intensive multidisciplinary research. At the beginning of the 21st century, with expanding human populations, particularly in coastal and developing countries, mitigating HABs impacts on human health and wellbeing is becoming a more pressing public health need. The available tools to address this global challenge include maintaining intensive, multidisciplinary and collaborative scientific research, and strengthening the coordination with stakeholders, policymakers and the general public. Here we provide an overview of different aspects of the HABs phenomena, an important element of the intrinsic links between oceans and human health and wellbeing.


Low health literacy and evaluation of online health information: a systematic review of the literature.
Recent years have witnessed a dramatic increase in consumer online health information seeking. The quality of online health information, however, remains questionable. The issue of information evaluation has become a hot topic, leading to the development of guidelines and checklists to design high-quality online health information. However, little attention has been devoted to how consumers, in particular people with low health literacy, evaluate online health information. The main aim of this study was to review existing evidence on the association between low health literacy and (1) people's ability to evaluate online health information, (2) perceived quality of online health information, (3) trust in online health information, and (4) use of evaluation criteria for online health information. Five academic databases (MEDLINE, PsycINFO, Web of Science, CINAHL, and Communication and Mass-media Complete) were systematically searched. We included peer-reviewed publications investigating differences in the evaluation of online information between people with different health literacy levels. After abstract and full-text screening, 38 articles were included in the review. Only four studies investigated the specific role of low health literacy in the evaluation of online health information. The other studies examined the association between educational level or other skills-based proxies for health literacy, such as general literacy, and outcomes. Results indicate that low health literacy (and related skills) are negatively related to the ability to evaluate online health information and trust in online health information. Evidence on the association with perceived quality of online health information and use of evaluation criteria is inconclusive. The findings indicate that low health literacy (and related skills) play a role in the evaluation of online health information. This topic is therefore worth more scholarly attention. Based on the results of this review, future research in this field should (1) specifically focus on health literacy, (2) devote more attention to the identification of the different criteria people use to evaluate online health information, (3) develop shared definitions and measures for the most commonly used outcomes in the field of evaluation of online health information, and (4) assess the relationship between the different evaluative dimensions and the role played by health literacy in shaping their interplay.


Molecular analysis of protein assembly in muscle development.
The challenge presented by myofibril assembly in striated muscle is to understand the molecular mechanisms by which its protein components are arranged at each level of organization. Recent advances in the genetics and cell biology of muscle development have shown that in vivo assembly of the myofilaments requires a complex array of structural and associated proteins and that organization of whole sarcomeres occurs initially at the cell membrane. These studies have been complemented by in vitro analyses of the renaturation, polymerization, and three-dimensional structure of the purified proteins.


Mechanisms of plumbagin action on guinea pig isolated atria.
In electrically driven guinea pig left atria, plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone; 0.5-10 microM) produced a marked positive inotropic effect that was about 65% that caused by isoprenaline in the same experimental conditions. The effect was mainly not dependent on catecholamine release from adrenergic stores. An EC50 of 3 microM was calculated from the concentration-response curves. The increase in force of contraction was followed by a nonreversible contracture. Plumbagin was reduced by cardiac mitochondrial and soluble reductases with consequent generation of large amounts of superoxide anion. The assay of reduced glutathione/oxidized glutathione content in atria, treated with 10 microM plumbagin and frozen at the appearance of increase in diastolic tension, showed a significant decrease in reduced glutathione (-52% with respect to control atria) and a 5-fold increase in oxidized glutathione levels. Moreover, in the same experimental conditions a significant decrease in adenosine triphosphate (-55% with respect to the controls) and in adenylate energy charge (from 0.92-0.64) was observed. Of the enzymes and transport systems involved in the control of the cardiac contractility, the sarcoplasmic reticulum Ca2+ pump seemed to be a specific target for plumbagin. After 30 min of incubation with cardiac sarcoplasmic reticulum membrane vesicles, plumbagin inhibited Ca2+ uptake by the pump in a concentration-dependent manner (IC50 = 3 microM). On the basis of these results, the increase in diastolic tension caused by plumbagin appears to be related to intracellular Ca2+ accumulation, due both to the low availability of adenosine triphosphate for ionic pumps and direct inhibition of Ca2+ reuptake in sarcoplasmic reticulum.


Diffusion Tensor Imaging: A Possible Biomarker in Severe Traumatic Brain Injury and Aneurysmal Subarachnoid Hemorrhage?
A great need exists in traumatic brain injury (TBI) and aneurysmal subarachnoid hemorrhage (aSAH) for objective biomarkers to better characterize the disease process and to serve as early endpoints in clinical studies. Diffusion tensor imaging (DTI) has shown promise in TBI, but much less is known about aSAH. To explore the use of whole-brain DTI tractography in TBI and aSAH as a biomarker and early endpoint. Of a cohort of 43 patients with severe TBI (n = 20) or aSAH (n = 23) enrolled in a prospective, observational, multimodality monitoring study, DTI data were acquired at approximately day 12 (median, 12 days; interquartile range, 12-14 days) after injury in 22 patients (TBI, n = 12; aSAH, n = 10). Whole-brain DTI tractography was performed, and the following parameters quantified: average fractional anisotropy, mean diffusivity, tract length, and the total number of reconstructed fiber tracts. These were compared between TBI and aSAH patients and correlated with mortality and functional outcome assessed at 6 months by the Glasgow Outcome Scale Extended. Significant differences were found for fractional anisotropy values (P = .01), total number of tracts (P = .03), and average tract length (P = .002) between survivors and nonsurvivors. A sensitivity analysis showed consistency of results between the TBI and aSAH patients for the various DTI measures. DTI parameters, assessed at approximately day 12 after injury, correlated with mortality at 6 months in patients with severe TBI or aSAH. Similar patterns were found for both TBI and aSAH patients. This supports a potential role of DTI as early endpoint for clinical studies and a predictor of late mortality. aSAH, aneurysmal subarachnoid hemorrhageDTI, diffusion tensor imagingFA, fractional anisotropyGOSE, Glasgow Outcome Scale ExtendedTBI, traumatic brain injuryTE, echo timeTR, repetition time.


Vitexin reduces epilepsy after hypoxic ischemia in the neonatal brain via inhibition of NKCC1.
Neonatal hypoxic-ischemic brain damage, characterized by tissue loss and neurologic dysfunction, is a leading cause of mortality and a devastating disease of the central nervous system. We have previously shown that vitexin has been attributed various medicinal properties and has been demonstrated to have neuroprotective roles in neonatal brain injury models. In the present study, we continued to reinforce and validate the basic understanding of vitexin (45 mg/kg) as a potential treatment for epilepsy and explored its possible underlying mechanisms. P7 Sprague-Dawley (SD) rats that underwent right common carotid artery ligation and rat brain microvascular endothelial cells (RBMECs) were used for the assessment of Na+-K+-Cl- co-transporter1 (NKCC1) expression, BBB permeability, cytokine expression, and neutrophil infiltration by western blot, q-PCR, flow cytometry (FCM), and immunofluorescence respectively. Furthermore, brain electrical activity in freely moving rats was recorded by electroencephalography (EEG). Our data showed that NKCC1 expression was attenuated in vitexin-treated rats compared to the expression in the HI group in vivo. Oxygen glucose deprivation/reoxygenation (OGD) was performed on RBMECs to explore the role of NKCC1 and F-actin in cytoskeleton formation with confocal microscopy, N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide, and FCM. Concomitantly, treatment with vitexin effectively alleviated OGD-induced NKCC1 expression, which downregulated F-actin expression in RBMECs. In addition, vitexin significantly ameliorated BBB leakage and rescued the expression of tight junction-related protein ZO-1. Furthermore, inflammatory cytokine and neutrophil infiltration were concurrently and progressively downregulated with decreasing BBB permeability in rats. Vitexin also significantly suppressed brain electrical activity in neonatal rats. Taken together, these results confirmed that vitexin effectively alleviates epilepsy susceptibility through inhibition of inflammation along with improved BBB integrity. Our study provides a strong rationale for the further development of vitexin as a promising therapeutic candidate treatment for epilepsy in the immature brain.


A crystalline AlPO4-5 intermediate: designed synthesis, structure, and phase transformation.
AlPO4-5 is the most extensively studied material in exploring the crystallization mechanism of aluminophosphate molecular sieves, and it can be synthesized using 4-dimethylaminopyridine (DMAP) as an organic structure-directing agent (OSDA). Achieving the AlPO4-5 intermediate in the crystalline form would be of great importance and significance for this purpose. In this study, we proposed a concept that by carefully regulating the synthesis conditions, crystalline alumimophosphate intermediates could be rationally prepared. A crystalline AlPO4-5 intermediate, (C7H11N2)2(H3O)(Al3P4O16)·(H2O)2.5 (1), was, therefore, synthesized by significantly increasing the amounts of orthophosphoric acid and DMAP. The intermediate 1 consists of alternating organic DMAP and inorganic [Al3P4O16]3- layers with abundant hydrogen bonds and can transform to the AlPO4-5 framework upon heating in air or through a steam-assisted conversion (SAC) method. To unravel the role of DMAP in the transformation, pure AlPO4-5 (2) was also synthesized by altering the synthesis conditions. The supramolecular assembly templating (SAT) effects of DMAP in 1 and 2 were verified via fluorescence spectra. Thus, the π-π stacking interactions between the DMAP molecules and the abundant hydrogen bonds between the adjacent layers are considered to be important for the phase transformation of 1. This crystalline intermediate would promote the understanding of the crystallization mechanism in the system of aluminophosphate molecular sieves.


Canadian demand for highly qualified personnel for therapeutic evaluation: an opportunity for academic institutions.
Achievement of optimal therapeutics requires individuals with analytic skills appropriate to the balancing of enterprise, innovation and the need for rigorous scientific validation. A synergistic convergence of discovery research, clinical investigation, evaluative, regulatory and implementation sciences will be essential. None of the needed research capacities are likely to prove obtainable on demand. On the contrary, they require accurate projection of future needs and careful planning of post-secondary training programs. A survey conducted for Health Canada in 2010 revealed significant shortfalls in research skills available outside government and industry. This commentary argues that such an environment represents an outstanding opportunity for the academic community to demonstrate that it is eager to meet the needs of the Canadian public. University leaders should be assertive about their commitment to the ideals of patient oriented research and all governments should be clear about deliverables anticipated in return for consistent post-secondary funding.


Seasonal influenza vaccination coverage and its determinants among nursing homes personnel in western France.
Influenza-associated deaths is an important risk for the elderly in nursing homes (NHs) worldwide. Vaccination coverage among residents is high but poorly effective due to immunosenescence. Hence, vaccination of personnel is an efficient way to protect residents. Our objective was to quantify the seasonal influenza vaccination (IV) coverage among NH for elderly workers and identify its determinants in France. We conducted a cross-sectional study in March 2016 in a randomized sample of NHs of the Ille-et-Vilaine department of Brittany, in western France. A standardized questionnaire was administered to a randomized sample of NH workers for face-to-face interviews. General data about the establishment was also collected. Among the 33 NHs surveyed, IV coverage for the 2015-2016 season among permanent workers was estimated at 20% (95% Confidence Interval (CI) 15.3%-26.4%) ranging from 0% to 69% depending on the establishments surveyed. Moreover, IV was associated with having previously experienced a "severe" influenza episode in the past (Prevalence Ratio 1.48, 95% CI 1.01-2.17), and varied by professional categories (p < 0.004) with better coverage among administrative staff. Better knowledge about influenza prevention tools was also correlated (p < 0.001) with a higher IV coverage. Individual perceptions of vaccination benefits had a significant influence on the IV coverage (p < 0.001). Although IV coverage did not reach a high rate, our study showed that personnel considered themselves sufficiently informed about IV. IV coverage remains low in the NH worker population in Ille-et-Vilaine and also possibly in France. Strong variations of IV coverage among NHs suggest that management and working environment play an important role. To overcome vaccine "hesitancy", specific communication tools may be required to be adapted to the various NH professionals to improve influenza prevention.


Photonic quasi-crystal terahertz lasers.
Quasi-crystal structures do not present a full spatial periodicity but are nevertheless constructed starting from deterministic generation rules. When made of different dielectric materials, they often possess fascinating optical properties, which lie between those of periodic photonic crystals and those of a random arrangement of scatterers. Indeed, they can support extended band-like states with pseudogaps in the energy spectrum, but lacking translational invariance, they also intrinsically feature a pattern of 'defects', which can give rise to critically localized modes confined in space, similar to Anderson modes in random structures. If used as laser resonators, photonic quasi-crystals open up design possibilities that are simply not possible in a conventional periodic photonic crystal. In this letter, we exploit the concept of a 2D photonic quasi crystal in an electrically injected laser; specifically, we pattern the top surface of a terahertz quantum-cascade laser with a Penrose tiling of pentagonal rotational symmetry, reaching 0.1-0.2% wall-plug efficiencies and 65 mW peak output powers with characteristic surface-emitting conical beam profiles, result of the rich quasi-crystal Fourier spectrum.


Practice-linked online personal health records for type 2 diabetes mellitus: a randomized controlled trial.
Web-based personal health records (PHRs) have been advocated as a means to improve type 2 diabetes mellitus (DM) care. However, few Web-based systems are linked directly to the electronic medical record (EMR) used by physicians. We randomized 11 primary care practices. Intervention practices received access to a DM-specific PHR that imported clinical and medications data, provided patient-tailored decision support, and enabled the patient to author a "Diabetes Care Plan" for electronic submission to their physician prior to upcoming appointments. Active control practices received a PHR to update and submit family history and health maintenance information. All patients attending these practices were encouraged to sign up for online access. We enrolled 244 patients with DM (37% of the eligible population with registered online access, 4% of the overall population of patients with DM). Study participants were younger (mean age, 56.1 years vs 60.3 years; P < .001) and lived in higher-income neighborhoods (median income, $53,784 vs $49,713; P < .001) but had similar baseline glycemic control compared with nonparticipants. More patients in the intervention arm had their DM treatment regimens adjusted (53% vs 15%; P < .001) compared with active controls. However, there were no significant differences in risk factor control between study arms after 1 year (P = .53). Previsit use of online PHR linked to the EMR increased rates of DM-related medication adjustment. Low rates of online patient account registration and good baseline control among participants limited the intervention's impact on overall risk factor control. clinicaltrials.gov Identifier: NCT00251875.


Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease.
Apolipoprotein E (apoE) genotype has a major influence on the risk for Alzheimer disease (AD). Different apoE isoforms may alter AD pathogenesis via their interactions with the amyloid beta-peptide (Abeta). Mice lacking the lipid transporter ABCA1 were found to have markedly decreased levels and lipidation of apoE in the central nervous system. We hypothesized that if Abca1-/- mice were bred to the PDAPP mouse model of AD, PDAPP Abca1-/ mice would have a phenotype similar to that of PDAPP Apoe+/- and PDAPP Apoe-/- mice, which develop less amyloid deposition than PDAPP Apoe+/+ mice. In contrast to this prediction, 12-month-old PDAPP Abca -/- mice had significantly higher levels of hippocampal Abeta, and cerebral amyloid angiopathy was significantly more common compared with PDAPP Abca1+/+ mice. Amyloid precursor protein (APP) C-terminal fragments were not different between Abca1 genotypes prior to plaque deposition in 3-month-old PDAPP mice, suggesting that deletion of Abca1 did not affect APP processing or Abeta production. As expected, 3-month-old PDAPP Abca1-/- mice had decreased apoE levels, but they also had a higher percentage of carbonate-insoluble apoE, suggesting that poorly lipidated apoE is less soluble in vivo. We also found that 12-month-old PDAPP Abca1-/- mice had a higher percentage of carbonate-insoluble apoE and that apoE deposits co-localize with amyloid plaques, demonstrating that poorly lipidated apoE co-deposits with insoluble Abeta. Together, these data suggest that despite substantially lower apoE levels, poorly lipidated apoE produced in the absence of ABCA1 is strongly amyloidogenic in vivo.


Differential regulation of the α-globin locus by Krüppel-like Factor 3 in erythroid and non-erythroid cells.
Krüppel-like Factor 3 (KLF3) is a broadly expressed zinc-finger transcriptional repressor with diverse biological roles. During erythropoiesis, KLF3 acts as a feedback repressor of a set of genes that are activated by Krüppel-like Factor 1 (KLF1). Noting that KLF1 binds α-globin gene regulatory sequences during erythroid maturation, we sought to determine whether KLF3 also interacts with the α-globin locus to regulate transcription. We found that expression of a human transgenic α-globin reporter gene is markedly up-regulated in fetal and adult erythroid cells of Klf3-/- mice. Inspection of the mouse and human α-globin promoters revealed a number of canonical KLF-binding sites, and indeed, KLF3 was shown to bind to these regions both in vitro and in vivo. Despite these observations, we did not detect an increase in endogenous murine α-globin expression in Klf3-/- erythroid tissue. However, examination of murine embryonic fibroblasts lacking KLF3 revealed significant de-repression of α-globin gene expression. This suggests that KLF3 may contribute to the silencing of the α-globin locus in non-erythroid tissue. Moreover, ChIP-Seq analysis of murine fibroblasts demonstrated that across the locus, KLF3 does not occupy the promoter regions of the α-globin genes in these cells, but rather, binds to upstream, DNase hypersensitive regulatory regions. These findings reveal that the occupancy profile of KLF3 at the α-globin locus differs in erythroid and non-erythroid cells. In erythroid cells, KLF3 primarily binds to the promoters of the adult α-globin genes, but appears dispensable for normal transcriptional regulation. In non-erythroid cells, KLF3 distinctly binds to the HS-12 and HS-26 elements and plays a non-redundant, albeit modest, role in the silencing of α-globin expression.


Degradation of selected agrochemicals by the white rot fungus Trametes versicolor.
Use of agrochemicals is a worldwide practice that exerts an important effect on the environment; therefore the search of approaches for the elimination of such pollutants should be encouraged. The degradation of the insecticides imiprothrin (IP) and cypermethrin (CP), the insecticide/nematicide carbofuran (CBF) and the antibiotic of agricultural use oxytetracycline (OTC) were assayed with the white rot fungus Trametes versicolor. Experiments with fungal pellets demonstrated extensive degradation of the four tested agrochemicals, at rates that followed the pattern IP>OTC>CP>CBF. In vitro assays with laccase-mediator systems showed that this extracellular enzyme participates in the transformation of IP but not in the cases of CBF and OTC. On the other hand, in vivo studies with inhibitors of cytochrome P450 revealed that this intracellular system plays an important role in the degradation of IP, OTC and CBF, but not for CP. The compounds 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (DCCA) and 3-phenoxybenzoic acid (PBA) were detected as transformation products of CP, as a result of the breakdown of the molecule. Meanwhile, 3-hydroxycarbofuran was detected as a transformation product of CBF; this metabolite tended to accumulate during the process, nonetheless, the toxicity of the system was effectively reduced. Simultaneous degradation of CBF and OTC showed a reduction in toxicity; similarly, when successive additions of OTC were done during the slower degradation of CBF, the fungal pellets were able to degrade both compounds. The simultaneous degradation of the four compounds successfully took place with minimal inhibition of fungal activity and resulted in the reduction of the global toxicity, thus supporting the potential use of T. versicolor for the treatment of diverse agrochemicals.


Clinical trial discrimination of physical function instruments for psoriatic arthritis: A systematic review.
Physical function (PF) is a core domain to be measured in randomized controlled trials (RCTs) of psoriatic arthritis (PsA), yet the discriminative performance of patient reported outcome measures (PROMs) for PF in RCTs has not been evaluated systematically. In this systematic review, we aimed to evaluate the clinical trial discrimination of PF-PROMs in PsA RCTs. We searched PubMed and Scopus databases in English to identify all original RCTs on biological and targeted synthetic disease modifying anti-rheumatic drugs (DMARDs) conducted in PsA. We assessed quality in each article using the OMERACT good method checklist. Effect sizes (ES) for the PF-PROMs were calculated and appraised using a priori hypotheses. Evidence supporting clinical trial discrimination for each PF-PROM was summarized to derive recommendations. 35 articles from 31 RCTs were included. Four PF-PROMs had data for evaluation: HAQ-Disability Index (DI), HAQ-Spondyloarthritis (S), and Short Form 36-item Health Survey Physical Component Summary (SF-36 PCS) and Physical Functioning domain (SF-36 PF). As anticipated, higher ES values were observed for intervention groups than the control groups. Across all studies, for HAQ-DI, the median ES were -0.73 and -0.24 for intervention and control groups, respectively. Whereas for SF-36 PCS, the median ES were 0.77 and 0.23. For intervention and control groups, respectively. Clinical trial discrimination was supported for HAQ-DI and SF-36 PCS in PsA with low risk of bias; and for SF-36 PF and HAQ-S with some caution. More studies are required for HAQ-S.


Effects of 6-Weeks High-Intensity Interval Training in Schoolchildren with Insulin Resistance: Influence of Biological Maturation on Metabolic, Body Composition, Cardiovascular and Performance Non-responses.
Background: Previous studies have observed significant heterogeneity in the magnitude of change in measures of metabolic response to exercise training. There are a lack of studies examining the prevalence of non-responders (NRs) in children while considering other potential environmental factors involved such as biological maturation. Aim: To compare the effects and prevalence of NRs to improve the insulin resistance level (by HOMA-IR), as well as to other anthropometric, cardiovascular, and performance co-variables, between early (EM) and normal maturation (NM) in insulin-resistance schoolchildren after 6-weeks of HIIT. Methods: Sedentary children (age 11.4 ± 1.7 years) were randomized to either HIIT-EM group (n = 12) or HIIT-NM group (n = 17). Fasting glucose (FGL), fasting insulin (FINS) and homeostasis model assessment of insulin resistant (HOMA-IR) were assessed as the main outcomes, as well as the body composition [body mass, body mass index (BMI), waist circumference (WC), and tricipital (TSF), suprailiac (SSF) and abdominal skinfold (AbdSF)], cardiovascular systolic (SBP) and diastolic blood pressure (DBP), and muscular performance [one-repetition maximum strength leg-extension (1RMLE) and upper row (1RMUR) tests] co-variables were assessed before and after intervention. Responders or NRs to training were defined as a change in the typical error method from baseline to follow-up for the main outcomes and co-variables. Results: There were no significant differences between groups in the prevalence of NRs based on FGL, FINS, and HOMA-IR. There were significant differences in NRs prevalence to decrease co-variables body mass (HIIT-EM 66.6% vs. HIIT-NM 35.2%) and SBP (HIIT-EM 41.6% vs. HIIT-NM 70.5%). A high risk [based on odds ratios (OR)] of NRs cases was detected for FGL, OR = 3.2 (0.2 to 5.6), and HOMA-IR, OR = 3.2 (0.2 to 6.0). Additionally, both HIIT-EM and HIIT-NM groups showed significant decreases (P < 0.05) in TSF, SSF, and AbdSF skinfold, and similar decreases in fasting insulin and HOMA-IR. The HIIT-EM group showed significant decreases in SBP. The HIIT-NM group showed significant increases in 1RMLE and 1RMUR. A large effect size was observed for pre-post changes in TSF in both groups, as well as in SSF in the HIIT-NM group. Conclusion: Although there were no differences in the prevalence of NRs to metabolic variables between groups of insulin resistance schoolchildren of different maturation starting, other NRs differences were found to body mass and systolic BP, suggesting that anthropometric and cardiovascular parameters can be playing a role in the NRs prevalence after HIIT. These results were displayed with several metabolic, body composition, blood pressure, and performance improvements independent of an early/normal maturation or the prevalence of NRs.


Asymmetric superradiant scattering and abnormal mode amplification induced by atomic density distortion.
The superradiant Rayleigh scattering using a pump laser incident along the short axis of a Bose-Einstein condensate with a density distortion is studied, where the distortion is formed by shocking the condensate utilizing the residual magnetic force after the switching-off of the trapping potential. We find that very small variation of the atomic density distribution would induce remarkable asymmetrically populated scattering modes by the matter-wave superradiance with long time pulse. The optical field in the diluter region of the atomic cloud is more greatly amplified, which is not an ordinary mode amplification with the previous cognition. Our numerical simulations with the density envelop distortion are consistent with the experimental results. This supplies a useful method to reflect the geometric symmetries of the atomic density profile by the superradiance scattering.


Bcl-2 overexpression delays caspase-3 activation and rescues cerebellar degeneration in prion-deficient mice that overexpress amino-terminally truncated prion.
Prnp knockout mice that overexpress an amino-truncated form of PrPc (deltaPrP) are ataxic and display cerebellar cell loss and premature death. Studies on the molecular and intracellular events that trigger cell death in these mutants may contribute to elucidate the functions of PrPc and to the design of treatments for prion disease. Here we examined the effects of Bcl-2 overexpression in neurons on the development of the neurological syndrome and cerebellar pathology of deltaPrP. We show that deltaPrP overexpression activates the stress-associated kinases ERK1-2 in reactive astroglia, p38 and the phosphorylation of p53, which leads to the death of cerebellar neurons in mutant mice. We found that the expression of deltaPrP in cell lines expressing very low levels of PrPc strongly induces the activation of apoptotic pathways, thereby leading to caspase-3 activation and cell death, which can be prevented by coexpressing Bcl-2. Finally, we corroborate in vivo that neuronal-directed Bcl-2 overexpression in deltaPrP mice (deltaPrP Bcl-2) markedly reduces caspase-3 activation, glial activation, and neuronal cell death in cerebellum by improving locomotor deficits and life expectancy.


Association between Dental Caries and BMI in Children: A Systematic Review and Meta-Analysis.
Research on the association between dental caries and body mass index (BMI) in children has shown contradictory results; thus we aimed to examine the association between dental caries and the full range of BMI classes among children. We comprehensively searched PubMed, Embase, and the Cochrane Library for studies published prior to March 2017. Articles comparing dental caries among the full range of BMI classes for children below 18 years of both genders were included. Fourteen studies were eligible for this study. Basic information - i.e., first author, published year, study design, country, sample size, age, type of dental caries index and BMI, main results and conclusions, and means and standard deviations of the dental caries indexes used - was pooled. The weighted mean differences and corresponding 95% confidence intervals for dental caries between children with abnormal weight and those with normal weight were analyzed. Generally, no significant differences in caries were found between any abnormal-weight group and the normal-weight group for both primary and permanent teeth. Sensitivity analyses showed that the obese group had more caries than the normal-weight group in their primary teeth. Significantly more caries was found among the overweight and obese children in both primary and permanent teeth in high-income countries, but not in low- and middle-income countries. We recommend that further studies use suitable sample sizes, unify the criteria for BMI categorization and the dental caries index, and investigate the confounding factors that might influence dental caries and BMI.


Motivational interviewing to increase physical activity in long-term cancer survivors: a randomized controlled trial.
Physical activity can confer many benefits on cancer survivors, including relief of persistent symptoms related to cancer treatment. To evaluate the effect of a motivational interviewing (MI) intervention on increasing physical activity (Community Healthy Activities Model Program for Seniors questionnaire) and improving aerobic fitness (6-minute walk), health (Medical Outcomes Study Short-Form 36), and fatigue (Schwartz Cancer Fatigue Scale) in cancer survivors. A secondary purpose was to evaluate whether the effect of MI on physical activities depended on self-efficacy. Fifty-six physically inactive adult cancer survivors (mean=42 months since completion of treatment) were assigned randomly to intervention and control groups. The MI intervention consisted of one in-person counseling session followed by two MI telephone calls over 6 months. Control group participants received two telephone calls without MI content. Outcomes were measured at baseline, 3 months, and 6 months, and were analyzed using multilevel modeling. The results of the MI intervention explained significant group differences in regular physical activities (measured in caloric expenditure per week), controlling for time since completion of cancer treatment (p<.05). Aerobic fitness, physical and mental health, and fatigue were not different between groups. In the intervention group, individuals with high self-efficacy for exercise at baseline increased their physical activity more than those with low self-efficacy (p<.05). In the control group, increases in physical activity did not depend on self-efficacy. Use of MI may increase physical activity in long-term cancer survivors, especially in persons with high self-efficacy for exercise. Multilevel modeling analysis revealed individual changes that would not have been shown by analysis of group means. Future studies with larger samples or more intense MI interventions may show changes in aerobic fitness, physical and mental health, and fatigue.


Depression in Men and Women One Year Following Traumatic Brain Injury (TBI): A TBI Model Systems Study.
In the general population, females experience depression at significantly higher rates than males. Individuals with traumatic brain injury (TBI) are at substantially greater risk for depression compared to the overall population. Treatment of, and recovery from, TBI can be hindered by depression; comorbid TBI and depression can lead to adverse outcomes and negatively affect multiple aspects of individuals' lives. Gender differences in depression following TBI are not well understood, and relevant empirical findings have been mixed. Utilizing the Patient Health Questionnaire-9 (PHQ-9) 1 year after TBI, we examined whether women would experience more severe depressive symptoms, and would endorse higher levels of depression within each category of depression severity, than would men. Interestingly, and contrary to our hypothesis, men and women reported mild depression at equal rates; PHQ-9 total scores were slightly lower in women than in men. Men and women did not differ significantly in any PHQ-9 depression severity category. Item analyses, yielded significant gender differences on the following items: greater concentration difficulties (cognitive problems) in men and more sleep disturbances (psychosomatic issues) in women per uncorrected two-sample Z-test for proportions analyses; however, these results were not significant after the family-wise Bonferroni correction. Our results indicate that, in contrast to the general population, mild depression in persons with moderate to severe TBI may not be gender-specific. These findings underscore the need for early identification, active screening, and depression treatment equally for men and women to improve emotional well-being, promote recovery, and enhance quality of life following TBI.


Reliability of AcuGraph system for measuring skin conductance at acupoints.
There are many commercially available instruments for measuring electrical conductance, but there is little information about their reliability. The aim of this study was to quantify measurement variability and assess reliability of the AcuGraph system-a commonly used electrodermal screening device. Four experiments were conducted to measure variability in electrical conductance readings obtained by the AcuGraph system. The first involved measuring known resistors. The second measured non-human organic matter. The third was a test-retest assessment of the Yuan-Source and Jing-Well points in 30 healthy volunteers who were measured by a single operator. The fourth was an interoperator reliability evaluation of seven acupuncturists at the Yuan-Source and Jing-Well acupoints on four individuals at two time points. Against known resistors, the AcuGraph had an average coefficient of variability (CV) of 1.8% between operators and test-retests. On non-human organic material the AcuGraph had an average CV of 0.9% and 2.8%. When a single operator tested 30 participants, the average reliability for the Yuan-Source points was 0.86 and 0.76 for Jing-Well points with a CV of 23.2% and 25.9% respectively. The average CV for the seven acupuncturists was 24.5% on Yuan-Source points and 23.7% on Jing-Well points. The AcuGraph measures known resistors and organic matter accurately and reliably. Skin conductance at acupoints recorded by one operator was also reliable. There was less consistency in electrodermal recordings obtained by seven different operators. Operator training and technical improvements to the AcuGraph may improve consistency among operators.


Impact of Obesity on Orthodontic Tooth Movement in Adolescents: A Prospective Clinical Cohort Study.
Obesity is a widespread chronic inflammatory disorder characterized by an increased overall disease burden and significant association with periodontitis. The aim of this prospective clinical cohort study was to investigate the effect of obesity on orthodontic tooth movement. Fifty-five adolescent patients (27 males, 28 females) with a mean (SD) age of 15.1 (1.7) years and mean (SD) body mass index (BMI) of 30.2 (3.5) kg/m2 in obese and 19.4 (2.2) kg/m2 in normal-weight groups were followed from start of treatment to completion of tooth alignment with fixed orthodontic appliances. Primary outcome was time taken to complete tooth alignment, while secondary outcomes included rate of tooth movement and change in clinical parameters (plaque/gingival indices, unstimulated whole-mouth salivary flow rate, gingival crevicular fluid biomarkers). Data collection took place at baseline (start of treatment: appliance placement), 1 h and 1 wk following appliance placement, and completion of alignment. Results were analyzed by descriptive statistics followed by generalized estimating equation regression modeling. There were no significant differences between groups in time taken to achieve tooth alignment (mean [SD] 158.7 [75.3] d; P = 0.486). However, at 1 wk, initial tooth displacement was significantly increased in the obese group ( P < 0.001), and after adjusting for confounders, obese patients had a significantly higher rate of tooth movement compared with normal-weight patients (+0.017 mm/d; 95% confidence interval, 0.008-0.025; P < 0.001) over the period of alignment. Explorative analyses indicated that levels of the adipokines leptin and resistin, the inflammatory marker myeloperoxidase (MPO), and the cytokine receptor for nuclear factor kappa-B ligand (RANKL) were significantly different between obese- and normal-weight patients and associated with observed rates of tooth movement. This represents the first prospective data demonstrating a different response in obese patients compared with normal-weight patients during early orthodontic treatment. These differences in the response of periodontal tissues to orthodontic force in the presence of obesity have potential short- and long-term clinical implications.


Investigation of cardiac function in children with suspected obstructive sleep apnea.
To assess the prevalence of cardiac failure in a group of children with suspected obstructive sleep apnea (OSA) and to assess the need for preoperative electrocardiograms (ECGs) and chest radiographs (CXRs) in children with OSA. Case record review of 271 children having (adeno)tonsillectomy for symptoms of OSA. Preoperative ECGs and CXRs were assessed for signs of right atrial or ventricular hypertrophy or failure. Case records were assessed for evidence of cardiac failure during anaesthesia. One child with congenital heart disease had signs of cardiac failure preoperatively. No other cases of atrial or ventricular hypertrophy or failure were found. Cardiac failure appears to be uncommon in children with symptoms of OSA. Preoperative ECG and CXR are essential in only selected cases.


Medicaid enrollment and health services access by Latino children in inner-city Los Angeles.
To understand the role of parental immigration status on Medicaid enrollment and access to health services for young Latino children. A cross-sectional household survey of the parents of inner-city Latino children. South Central and East Los Angeles, Calif, 1992. Children 12 to 36 months old and their parents from 817 Latino families. Continuous Medicaid enrollment, continuity of care, deferral of care, and number of visits. Univariate analysis, logistic and linear regression by demographic and socioeconomic characteristics, residency status, and language use. Children were primarily born in the United States (96%), but most parents were not citizens (80%). Only 40.0% of eligible children had continuous Medicaid coverage since birth, 18.6% had never been insured, and 20.7% had received episodic Medicaid coverage. Continuous Medicaid coverage was negatively associated with either the caregiver (odds ratio [OR],0.32; 95% confidence interval [CI], 0.19-0.56) or their partner (OR=0.33, 95% CI =0.20-0.55) working. Residency status, language preference, and length of US residency were not associated with continuous Medicaid enrollment. Insurance coverage was associated with more physician visits, greater continuity of care, and fewer deferrals of care. While most (84%) young Latino children in inner-city Los Angeles were eligible for Medicaid, a substantial proportion (39.3%) have episodic or no coverage. Insurance status and provider type were more consistently associated with access rather than residency and language preference. In the aftermath of California's Proposition 187 and federal welfare reform, insurance status and access are likely to worsen for these young children unless the wave of antiimmigration sentiments is held in check.


Genetic Diversity of O-Antigens in Hafnia alvei and the Development of a Suspension Array for Serotype Detection.
Hafnia alvei is a facultative and rod-shaped gram-negative bacterium that belongs to the Enterobacteriaceae family. Although it has been more than 50 years since the genus was identified, very little is known about variations among Hafnia species. Diversity in O-antigens (O-polysaccharide, OPS) is thought to be a major factor in bacterial adaptation to different hosts and situations and variability in the environment. Antigenic variation is also an important factor in pathogenicity that has been used to define clones within a number of species. The genes that are required to synthesize OPS are always clustered within the bacterial chromosome. A serotyping scheme including 39 O-serotypes has been proposed for H. alvei, but it has not been correlated with known OPS structures, and no previous report has described the genetic features of OPS. In this study, we obtained the genome sequences of 21 H. alvei strains (as defined by previous immunochemical studies) with different lipopolysaccharides. This is the first study to show that the O-antigen gene cluster in H. alvei is located between mpo and gnd in the chromosome. All 21 of the OPS gene clusters contain both the wzx gene and the wzy gene and display a large number of polymorphisms. We developed an O serotype-specific wzy-based suspension array to detect all 21 of the distinct OPS forms we identified in H. alvei. To the best of our knowledge, this is the first report to identify the genetic features of H. alvei antigenic variation and to develop a molecular technique to identify and classify different serotypes.


Toll-like receptors in atherosclerosis.
Atherosclerosis, the leading cause of cardiovascular disease (CVD), is driven by inflammation. Increasing evidence suggests that toll-like receptors (TLRs) are key orchestrators of the atherosclerotic disease process. Interestingly, a distinct picture is being revealed for individual receptors in atherosclerosis. TLRs exhibit a complex nature enabling the detection of multiple motifs named danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). Activation of these receptors triggers an intracellular signalling cascade mediated through MyD88 or TRIF, leading to the production of pro- and anti-inflammatory cytokines. In this review we explore key novel findings pertaining to TLR signalling in atherosclerosis, including recently described endosomal TLRs and future directions in TLR research.


Morphometric analysis of canine in gender determination: revisited in India.
Teeth are excellent material for anthropological, genetic and odontologic investigations in both living and dead population. Canines are the ideal teeth for identification of sex, due to its sexual dimorphism and durability in the oral cavity. This study tests the effectiveness of the canine tooth in predicting sex of an individual. This study involved 60 males and 60 females between the age group of 20-30 years. Mesio-distal (MD) widths of maxillary and mandibular right and left canines and inter-canine distance of both arches were measured clinically and on cast for all patients. Standard canine indices were derived from these dimensions and tested for sexual dimorphism and reliability of canine teeth in gender determination by comparison with the known gender of the population under investigation. All measurements showed significant sexual dimorphism. Standard mandibular canine index (CI) was found to be more reliable in gender estimation than the MD width of canine and CI values. Use of the standard mandibular CI in gender determination is recommended for forensic procedures as it was found to have an acceptable accuracy. MD width of canine may be used in a setup when only the single tooth or a fragment of a jaw is available for analysis, with due consideration to its relatively low accuracy.


Level of Fluoride in Soil, Grain and Water in Jalgaon District, Maharashtra, India.
Fluoride has an influence on both oral as well as systemic health. The major source of fluoride to body is through drinking water as well as through diet. Staple diet mainly depends on local environmental factors, food grains grown locally, its availability etc. Determination of fluoride level in these food grains is important. So, estimation of the amount of fluoride in grains and its relation to the sources of fluoride used for their cultivation viz., soil and water is important. To estimate the relation of fluoride concentration in grains (Jowar) with respect to that of soil and water used for their cultivation. Fifteen samples each of soil, water and grains were collected using standardized method from the same farm fields of randomly selected villages of Jalgaon district. Fluoride ion concentration was determined in laboratory using SPADNS technique. Mean difference in fluoride levels in between the groups were analyzed using ANOVA and Post-Hoc Tukey test. Linear regression method was applied to analyse the association of the fluoride content of grain with water and soil. There was a significant difference in between mean fluoride levels of soil and water (p<0.001) and in between soil and grain (p<0.001); however, difference in between mean fluoride levels of water and grain was found to be non significant (p=0.591). Also fluoride levels in all the three groups showed significant association with each other. Fluoride level of soil, grains and water should be adjusted to an optimum level. Soil has positive correlation with respect to uptake of fluoride by Jowar grains. So, Jowar grains with optimum fluoride content should be made available in the commercial markets so that oral and general health can be benefitted.


Design and fabrication of Ni nanowires having periodically hollow nanostructures.
We propose a concept for the design and fabrication of metal nanowires having periodically hollow nanostructures inside the pores of an anodic aluminum oxide (AAO) membrane using a sacrificial metal. In this study, nickel (Ni) and silver (Ag) were used as the base metal and the sacrificial metal, respectively. Alternating an applied potential between -0.4 and -1.0 V provided alternatively deposited Ni and Ag segments in a Ni-Ag 'barcode' nanowire with a diameter of 18 or 35 nm. After etching away the Ag segments, we fabricated Ni nanowires with nanopores of 12 ± 5.3 nm. Such nanostructure formation is explained by the formation of a Ni shell layer over the surface of the Ag segments due to the strong affinity of Ni(2+) for the interior surfaces of AAO. The Ni shell layer allows the Ni segments to remain even after dissolution of the Ag segments. Because the electroplating conditions can be easily controlled, we could carefully adjust the size and pitch of the periodically hollow nanospaces. We also describe a method for the fabrication of Ni nanorods by forming an Ag shell instead of a Ni shell on the Ni-Ag barcode nanowire, in which the interior of the AAO surfaces was modified with a compound bearing a thiol group prior to electroplating.


A phase 0 trial of riluzole in patients with resectable stage III and IV melanoma.
Ectopic expression of GRM1 in murine melanocytes results in transformation into a form of melanoma, and more than 60% of human melanoma samples tested ectopically express GRM1. Stimulation of this receptor in vitro results in up-regulation of activated extracellular signal-regulated kinase (ERK). Furthermore, a xenograft model of melanoma treated with riluzole, an oral GRM1 blocking agent, showed decreased tumor growth compared with the untreated controls. We have now completed a phase 0 trial of riluzole in patients with melanoma. Patients enrolled on this trial underwent a pretreatment biopsy, took 200 mg of oral riluzole per day for 14 days, and then underwent resection of their remaining tumor. We compared the levels of pERK and pAKT in the pretreatment and post-treatment samples and assessed the metabolic activity of pretreatment and post-treatment tumors using fluorodeoxyglucose positron emission tomography (FDG-PET) scanning. We accrued 12 patients and all expressed GRM1. We found a significant decrease in pAKT and/or pERK in post-treatment tumor samples as compared with pretreatment samples in 4 (34%) patients. These four patients had a significant decrease in FDG-PET intensity post-treatment as well. Two other patients had a clinical response with no corresponding metabolic response; five patients had similar pretreatment and post-treatment FDG-PET scan findings; and one patient had progressive disease. Our data show that glutamate blockade with riluzole can inhibit signaling through the mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT pathways and suppress the metabolic activity of melanoma. The ectopic expression of metabotropic glutamate receptors may be important in the pathogenesis of human melanoma, and targeting this pathway may be an effective therapy.


Assessing the influence of music on wine perception among wine professionals.
Several recent studies have demonstrated that music can significantly influence the eating/drinking experience. It is not clear, however, whether this influence would be moderated by the expertise of the taster. In the experiments reported here, we tested a large group (N = 154) of very experienced wine tasters-the majority of whom were professionals working in the wine business-at a winemaking conference. The first study assessed the impact of putatively "sweet" and "sour" soundtracks on taste evaluation, whereas the second study assessed more subtle wine-specific terminology such as length, balance, and body. The results revealed that the effect of music on wine perception can indeed be demonstrated in wine experts. Moreover, the amount of wine tasting experience, as measured in years, did not moderate the influence of music on sensory and hedonic wine evaluation. This result suggests that the aforementioned auditory modulation of drinking experience is not influenced by the increased analytical abilities afforded by traditional wine tasting expertise.


Factors influencing access of pregnant women and their infants to their local healthcare system: a prospective, multi-centre, observational study.
The successful implementation of maternal vaccination relies on results of clinical trials, considering the prenatal and postnatal attendance at selected healthcare institutions. This study evaluated factors influencing maternal/infant access to healthcare facilities to identify potential barriers to participation in future clinical trials on maternal vaccination. In this prospective, multi-centre, observational study, pregnant women (N = 3243) were enrolled at ten sites across Panama, the Dominican Republic, South Africa, and Mozambique between 2012 and 2014. They completed questionnaires at enrolment, delivery, and infant follow-up (90 days post-partum) visits, including questions on transportation, phone accessibility, alternative childcare, gestational age at enrolment, delivery location, and health status of their infant. Logistic regression was used to identify factors significantly associated with return to study site for delivery or infant follow-up visits. Among 3229 enrolled women with delivery information, 63.6% (range across sites: 25.3-91.5%) returned to study site for delivery. Older women and those at later gestational age at enrolment were more likely to deliver at the study site. While heterogeneities were observed at site level, shorter travel time at delivery and increased transportation costs at enrolment were associated with increased likelihood of women returning to study site for delivery. Among 3145 women with live-born infants, 3077 (95.3%) provided 90-day follow-up information; of these, 68.9% (range across sites: 25.6-98.9%) returned to study site for follow-up visits. Women with other children and with lower transportation costs at delivery were more likely to return to study site for follow-up visits. Among 666 infants reported sick, 94.3% were taken to a healthcare facility, with only 41.9% (range across sites: 4.9-77.3%) to the study site. Although high retention was observed from enrolment through 90 days after delivery, post-partum surveillance should be broadened beyond the study sites and additional follow-up visits should be planned within the neonatal period. The factors influencing maternal/infant access to healthcare facilities and the issues identified in this study should be taken into consideration in planning future clinical studies on maternal immunisation in low- and middle-income countries. The study was registered at ClinicalTrial.gov ( NCT01734434 ) on November 22, 2012.


Ultrasound in the diagnosis of ectopic pregnancy.
The majority of ectopic pregnancies can be diagnosed on transvaginal scan before treatment. Diagnosis should be based on positive visualization of an ectopic pregnancy rather the inability to visualize an intrauterine pregnancy. The majority of ectopic pregnancies will be visible on the initial transvaginal scan performed. Those who do not have their ectopic pregnancies visualized on the first examination will be initially classified as having a pregnancy of unknown location. They will then need follow-up until a diagnosis of ectopic pregnancy is confirmed. This review discusses the use of ultrasound in the diagnosis of ectopic pregnancy and the specific criteria for diagnosis of the different types of ectopic pregnancy.


Death certification in patients whose primary treatment for oral and oropharyngeal carcinoma was operation: 1992-1997.
The aim of this study was to report the cause and place of death of patients with oral cancer as recorded by death certification and their survival with regard to comorbidity and age. From the departmental head and neck oncology database, 322 patients were identified with previously untreated oral and oropharyngeal squamous cell carcinoma diagnosed between 1992 and 1997 inclusive. Three-hundred were matched with the Office for National Statistics (ONS) and copies of death certificates generated on 6 March 1999. Of the 286 patients primarily treated by operation, 203 were alive and 83 had died. In 56 (68%), oral cancer was a contributory factor to the patient's death. Patients with a medical history recorded on their admission for operation had similar survival curves compared to those having no problems recorded. Although most patients (n= 46 55%) died in hospital, only 13 (16%) died in the Regional Maxillofacial Unit. Almost half of those patients who died were not recorded as dead on the departmental oncology database. This study shows that it is useful to link with the ONS to obtain accurate data on date and place of death. The death certificate also gives a useful indication of the cause of death and this seems unrelated to preoperative comorbidity.


Efficacy of Pulsed Radiofrequency in Herpetic Neuralgia: A Meta-Analysis of Randomized Controlled Trials.
Herpes zoster and postherpetic neuralgia (PHN) are often refractory to current standard treatments and can reduce patients' quality of life (QoL). Pulsed radiofrequency (PRF) effectively controls intractable neurological pain. The aim of the study was to conduct a systematic review and meta-analysis to evaluate the efficacy of PRF in PHN management. We searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs) published up to October 2019. The primary outcomes were pain levels and rescue analgesia at different postintervention time intervals. The secondary outcomes were QoL and sleep quality. We reviewed 6 RCTs involving 420 patients. The meta-analysis revealed that the PRF group exhibited significantly lower pain scores in PHN than did the control group at 2 to 3 days (weighted mean differences [WMD]=-2.82; 95% confidence interval [CI]: -5.08 to -0.55), 1 week (WMD=-2.95; 95% CI: -4.53 to -1.37), 2 weeks (WMD=-3.17; 95% CI: -4.11 to -2.23), 4 weeks (WMD=-2.59; 95% CI: -3.40 to -1.79), 8 weeks (WMD=-3.02; 95% CI: -4.17 to -1.88), and 6 months (WMD=-1.94; 95% CI: -2.85 to -1.03). After intervention, QoL was significantly higher in the PRF group than in the control group. No major complications were reported. PRF safely and effectively reduced pain scores and improved QoL in patients with herpes zoster in the cervical to lumbosacral areas. PRF could be considered during refractory PHN treatment. Future studies require standardized PRF settings and outcome assessment tools, including physical and emotional function assessments.


Studies on the pathophysiology of diabetic retinopathy. The blood-retinal barrier in diabetes.
A review of the pathologic picture of diabetic retinopathy shows that available clinical methods of examination demonstrate the alteration of the blood-retinal barrier (leakage), microaneurysms, capillary closure, preferential channels, preretinal neovascularization and gross extravascular lesions. All of these changes may be shown by fluorescein angiography. The value of this method, however, is fundamentally related to the morphologic demonstration of these lesions and not their quantification. Quantitative evaluation of retinal involvement in diabetes is needed in order to delineate more clearly its natural history, criteria for prognosis, and effect of treatment. Vitreous fluorophotometry, a quantitative and sensitive method of evaluating the permeability of the blood-retinal barrier, has opened new perspectives for the evaluation of retinal involvement in diabetes. Vitreous fluorophotometry has shown that a disturbance of the blood-retinal barrier, possibly functional, appears in diabetic eyes before any lesion is clinically visible in the fundus, and that there is a close correlation between the severity of the vascular lesions and higher vitreous fluorophotometry readings. Recent studies also indicate an interesting correlation with metabolic control, particularly, glycosylated hemoglobin levels and insulin treatment. Finally, on the basis of these findings a working hypothesis for the pathogenesis of diabetic retinopathy is presented.


The third national Japanese antimicrobial susceptibility pattern surveillance program: Bacterial isolates from complicated urinary tract infection patients.
The antimicrobial susceptibility patterns of bacterial pathogens isolated from patients with complicated urinary tract infections were analyzed using national surveillance data. The data consisted of 881 bacterial strains from eight clinically relevant species. The data were collected for the third national surveillance project from January 2015 to March 2016 by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Disease, and the Japanese Society of Clinical Microbiology. Surveillance was undertaken with the cooperation of 41 medical institutions throughout Japan. Fluoroquinolone required a MIC90 of 2-64 mg/L to inhibit the 325 Escherichia coli strains tested and the proportion of levofloxacin resistant E. coli strains increased to 38.5% from 29.6% in 2011 and 28.6% in 2008. The proportion of levofloxacin resistant strains of Pseudomonas aeruginosa and Enterococcus faecalis decreased from previous reports and the proportion of multidrug-resistant P. aeruginosa and carbapenem-resistant Enterobacteriaceae remained low. Among methicillin-resistant Staphylococcus aureus (MRSA) strains, strains with reduced susceptibility to vancomycin (minimum inhibitory concentration, 2 μg/mL) increased to 14.7% from 5.5%. Bacterial strains that produced extended-spectrum β-lactamase included E. coli (79 of 325 strains, 24.3%), Klebsiella pneumoniae (9 of 177 strains, 7.7%), and Proteus mirabilis (6 of 55 strains, 10.9%). The proportion of extended-spectrum β-lactamase producing E. coli and K. pneumoniae strains increased from previous surveillance reports.


Presentation of neurogenic shock within the emergency department.
Injury to the spinal cord can result in loss of sympathetic innervation causing a drop in BP and HR, this condition is known as neurogenic shock. There is debate among the literature on how and when neurogenic shock presents and what values of HR and BP should be used to define it. Previous studies do not take into account multiple prehospital and emergency department recordings. To improve understanding of how neurogenic shock presents in humans, allowing better identification and treatment. The Trauma Audit and Research Network database for an adult major trauma centre was used to isolate patients with a spinal cord injury. Qualifying patients had all available BPs and HRs collated into a database. Patients with neurogenic shock were isolated, allowing data analysis. Out of 3069 trauma patients, 33 met the inclusion criteria, of which 15 experienced neurogenic shock. 87% of the patients who had neurogenic shock experienced it within 2 hours of injury. Neurogenic shock below the T6 level was less common (p=0.009); however, there were still four cases in the cohort. More patients with complete spinal cord injury had neurogenic shock (p=0.039). Neurogenic shock is variable and unpredictable. It can present in the prehospital environment and without warning in a patient with previously normal vital signs. The medical team should be aware of it in all patients with spinal cord injury regardless of injury level.


Suppression of RNA interference by adenovirus virus-associated RNA.
We show that human adenovirus inhibits RNA interference (RNAi) at late times of infection by suppressing the activity of two key enzyme systems involved, Dicer and RNA-induced silencing complex (RISC). To define the mechanisms by which adenovirus blocks RNAi, we used a panel of mutant adenoviruses defective in virus-associated (VA) RNA expression. The results show that the virus-associated RNAs, VA RNAI and VA RNAII, function as suppressors of RNAi by interfering with the activity of Dicer. The VA RNAs bind Dicer and function as competitive substrates squelching Dicer. Further, we show that VA RNAI and VA RNAII are processed by Dicer, both in vitro and during a lytic infection, and that the resulting short interfering RNAs (siRNAs) are incorporated into active RISC. Dicer cleaves the terminal stem of both VA RNAI and VA RNAII. However, whereas both strands of the VA RNAI-specific siRNA are incorporated into RISC, the 3' strand of the VA RNAII-specific siRNA is selectively incorporated during a lytic infection. In summary, our work shows that adenovirus suppresses RNAi during a lytic infection and gives insight into the mechanisms of RNAi suppression by VA RNA.


A Survey on Dietary Supplement Consumption in Amateur and Professional Rugby Players.
the aim of the present study was to analyse the pattern of dietary supplements (DS) consumption on federated rugby players, including the analysis of differences based on the sex and competitive level (professional vs. amateurs). 144 rugby players (83 male and 61 female), of whom 69 were professionals and 75 amateurs, were recruited for the study. All the participants filled out a specific questionnaire about DS consumption including questions related to the consumption of DS and their effects on sport performance and health status. 65.3% of participants declared consuming at least one DS, with a higher prevalence in males than females (77.1% vs. 49.2%) and in professionals thanin amateur players (79.7% vs. 52.0%). The main reason for consumption was to enhance sport performance (62.3%) with differences only based on sex (74.3% males vs. 43.2% females). The most common purchase sites were the Internet (45.6%) and specialised stores (39.8%). As to the moment of ingestion, professionals did this most frequently during competition and training (56.4% vs. 28.2%), whereas amateur players did so only during competition (20.5% vs. 3.6%). Moreover, professional player intake most frequently in post-exercise (65.5% vs. 35.9%), whereas amateur during pre-exercise (30.8% vs. 5.5%). The DS most consumed included whey protein (44%), caffeine (42%), sports drinks (38%), energy bars (34%) and creatine monohydrate (31%), with a higher prevalence in male and professional players of whey protein and creatine monohydrate. The main reason for DS consumption is for enhancing sports performance). Professional players more frequently purchase them on the Internet and consume DS during training and competition period and in the post-exercise, whereas amateur players consume during competition and pre-exercise. Related to the main form of DS consumption, it is observed that a moderate consumption of DS could be considered ergogenic, such as whey protein, sport bar and creatine, while an absence of other DS could be considered ergogenic.


The effect of tofacitinib on pneumococcal and influenza vaccine responses in rheumatoid arthritis.
To evaluate tofacitinib's effect upon pneumococcal and influenza vaccine immunogenicity. We conducted two studies in patients with rheumatoid arthritis using the 23-valent pneumococcal polysaccharide vaccine (PPSV-23) and the 2011-2012 trivalent influenza vaccine. In study A, tofacitinib-naive patients were randomised to tofacitinib 10 mg twice daily or placebo, stratified by background methotrexate and vaccinated 4 weeks later. In study B, patients already receiving tofacitinib 10 mg twice daily (with or without methotrexate) were randomised into two groups: those continuing ('continuous') or interrupting ('withdrawn') tofacitinib for 2 weeks, and then vaccinated 1 week after randomisation. In both studies, titres were measured 35 days after vaccination. Primary endpoints were the proportion of patients achieving a satisfactory response to pneumococcus (twofold or more titre increase against six or more of 12 pneumococcal serotypes) and influenza (fourfold or more titre increase against two or more of three influenza antigens). In study A (N=200), fewer tofacitinib patients (45.1%) developed satisfactory pneumococcal responses versus placebo (68.4%), and pneumococcal titres were lower with tofacitinib (particularly with methotrexate). Similar proportions of tofacitinib-treated and placebo-treated patients developed satisfactory influenza responses (56.9% and 62.2%, respectively), although fewer tofacitinib patients (76.5%) developed protective influenza titres (≥1:40 in two or more of three antigens) versus placebo (91.8%). In study B (N=183), similar proportions of continuous and withdrawn patients had satisfactory responses to PPSV-23 (75.0% and 84.6%, respectively) and influenza (66.3% and 63.7%, respectively). Among patients starting tofacitinib, diminished responsiveness to PPSV-23, but not influenza, was observed, particularly in those taking concomitant methotrexate. Among existing tofacitinib users, temporary drug discontinuation had limited effect upon influenza or PPSV-23 vaccine responses. NCT01359150, NCT00413699.


Feasibility of a Mindfulness-Based Intervention for Surgical Intensive Care Unit Personnel.
Surgical intensive care unit personnel are exposed to catastrophic situations as they care for seriously injured or ill patients. Few interventions have been developed to reduce the negative effects of work stress in this environment. This pilot study evaluated the feasibility of a workplace intervention for increasing resilience to stress. The intervention was implemented within the unique constraints characteristic of surgical intensive care units. Participants were randomly assigned to an intervention or control group. The mindfulness-based intervention included meditation, mild yoga movement, and music and was conducted in a group format 1 hour a week for 8 weeks in a surgical intensive care unit during work hours. Assessments were performed 1 week before and 1 week after the intervention. The intervention was well received, with a 97% overall retention rate and 100% retention in the intervention group. Work satisfaction, measured with the Utrecht Work Engagement Scale, increased significantly in the intervention group with no change in the control group. Negative correlations were found between the vigor subscale scores of the Utrecht Work Engagement Scale and scores for emotional exhaustion on the Maslach Burnout Inventory and scores for burnout on the Professional Quality of Life scale. Participants rated recognizing their stress response as a main benefit of the intervention. Workplace group interventions aimed at decreasing the negative effects of stress can be applied within hospital intensive care units. Despite many constraints, attendance at weekly sessions was high. Institutional support was critical for implementation of this program.


Intraarticular steroids as DMARD-sparing agents for juvenile idiopathic arthritis flares: Analysis of the Childhood Arthritis and Rheumatology Research Alliance Registry
Children with juvenile idiopathic arthritis (JIA) who achieve a drug free remission often experience a flare of their disease requiring either intraarticular steroids (IAS) or systemic treatment with disease modifying anti-rheumatic drugs (DMARDs). IAS offer an opportunity to recapture disease control and avoid exposure to side effects from systemic immunosuppression. We examined a cohort of patients treated with IAS after drug free remission and report the probability of restarting systemic treatment within 12 months. We analyzed a cohort of patients from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry who received IAS for a flare after a period of drug free remission. Historical factors and clinical characteristics and of the patients including data obtained at the time of treatment were analyzed. We identified 46 patients who met the inclusion criteria. Of those with follow up data available 49% had restarted systemic treatment 6 months after IAS injection and 70% had restarted systemic treatment at 12 months. The proportion of patients with prior use of a biologic DMARD was the only factor that differed between patients who restarted systemic treatment those who did not, both at 6 months (79% vs 35%, p < 0.01) and 12 months (81% vs 33%, p < 0.05). While IAS are an option for all patients who flare after drug free remission, it may not prevent the need to restart systemic treatment. Prior use of a biologic DMARD may predict lack of success for IAS. Those who previously received methotrexate only, on the other hand, are excellent candidates for IAS.


Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease.
A reduction in dietary saturated fat has generally been thought to improve cardiovascular health. The objective of this meta-analysis was to summarize the evidence related to the association of dietary saturated fat with risk of coronary heart disease (CHD), stroke, and cardiovascular disease (CVD; CHD inclusive of stroke) in prospective epidemiologic studies. Twenty-one studies identified by searching MEDLINE and EMBASE databases and secondary referencing qualified for inclusion in this study. A random-effects model was used to derive composite relative risk estimates for CHD, stroke, and CVD. During 5-23 y of follow-up of 347,747 subjects, 11,006 developed CHD or stroke. Intake of saturated fat was not associated with an increased risk of CHD, stroke, or CVD. The pooled relative risk estimates that compared extreme quantiles of saturated fat intake were 1.07 (95% CI: 0.96, 1.19; P = 0.22) for CHD, 0.81 (95% CI: 0.62, 1.05; P = 0.11) for stroke, and 1.00 (95% CI: 0.89, 1.11; P = 0.95) for CVD. Consideration of age, sex, and study quality did not change the results. A meta-analysis of prospective epidemiologic studies showed that there is no significant evidence for concluding that dietary saturated fat is associated with an increased risk of CHD or CVD. More data are needed to elucidate whether CVD risks are likely to be influenced by the specific nutrients used to replace saturated fat.


External K activation of Kir1.1 depends on the pH gate.
The inward rectifier Kir1.1 (ROMK) family is gated by both internal pH and external K, where the putative pH gate is formed by the convergence of leucine side chains, near the inner helical bundle crossing at L160-Kir1.1. However, it is unclear whether K activation is mediated at the pH gate or by another gate in the permeation path. In this study, we used the whole-cell conductance increase during rapid K elevation as a measure of K activation, assuming that activation is inherently slower than changes in channel conduction. Results indicate that structural disruption of the Kir1.1 bundle-crossing pH gate prevents both inactivation by low external K and reactivation by high external K.


Casein kinase 2 associates with and phosphorylates dishevelled.
The dishevelled (dsh) gene of Drosophila melanogaster encodes a phosphoprotein whose phosphorylation state is elevated by Wingless stimulation, suggesting that the phosphorylation of Dsh and the kinase(s) responsible for this phosphorylation are integral parts of the Wg signaling pathway. We found that immunoprecipitated Dsh protein from embryos and from cells in tissue culture is associated with a kinase activity that phosphorylates Dsh in vitro. Purification and peptide sequencing of a 38 kDa protein co-purifying with this kinase activity showed it to be identical to Drosophila Casein Kinase 2 (CK2). Tryptic phosphopeptide mapping indicates that identical peptides are phosphorylated by CK2 in vitro and in vivo, suggesting that CK2 is at least one of the kinases that phosphorylates Dsh. Overexpression of Dfz2, a Wingless receptor, also stimulated phosphorylation of Dsh, Dsh-associated kinase activity, and association of CK2 with Dsh, thus suggesting a role for CK2 in the transduction of the Wg signal.


Changing the paradigm for hospital outbreak detection by leading with genomic surveillance of nosocomial pathogens.
The current paradigm for hospital outbreak detection and investigation is based on methodology first developed over 150 years ago. Daily surveillance to detect patients positive for pathogens of particular importance for nosocomial infection is supported by epidemiological investigation to determine their relationship in time and place, and to identify any other factor that could link them. The antibiotic resistance pattern is commonly used as a surrogate for bacterial relatedness, although this lacks sensitivity and specificity. Typing may be used to define bacterial relatedness, although routine methods lack sufficient discriminatory power to distinguish relatedness beyond the level of bacterial clones. Ultimately, the identification of an outbreak remains a predominately subjective process reliant on the intuition of experienced infection control professionals. Here, we propose a redesign of hospital outbreak detection and investigation in which bacterial species associated with nosocomial transmission and infection undergo routine prospective whole-genome sequencing. Further investigation is based on the probability that isolates are associated with an outbreak, which is based on the degree of genetic relatedness between isolates. Evidence is provided that supports this model based on studies of MRSA (methicillin-resistant Staphylococcus aureus), together with the benefits of a 'Sequence First' approach. The feasibility of implementation is discussed, together with residual barriers that need to be overcome prior to implementation.


Vitagenes, dietary antioxidants and neuroprotection in neurodegenerative diseases.
The ability of a cell to counteract stressful conditions, known as cellular stress response, requires the activation of pro-survival pathways and the production of molecules with anti-oxidant, anti-apoptotic or pro-apoptotic activities. Among the cellular pathways conferring protection against oxidative stress, a key role is played by vitagenes, which include heat shock proteins (Hsps) heme oxygenase-1 and Hsp70, as well as the thioredoxin/thioredoxin reductase system. Heat shock response contributes to establish a cytoprotective state in a wide variety of human diseases, including inflammation, cancer, aging and neurodegenerative disorders. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing stress responses. Dietary antioxidants, such as curcumin, L-carnitine/acetyl-L-carnitine and carnosine have recently been demonstrated in vitro to be neuroprotective through the activation of hormetic pathways, including vitagenes. In the present review we discuss the importance of vitagenes in the cellular stress response and analyse, from a pharmacological point of view, the potential use of dietary antioxidants in the treatment of neurodegenerative disorders in humans.


A quantitative-trait locus on chromosome 6p influences different aspects of developmental dyslexia.
Recent application of nonparametric-linkage analysis to reading disability has implicated a putative quantitative-trait locus (QTL) on the short arm of chromosome 6. In the present study, we use QTL methods to evaluate linkage to the 6p25-21.3 region in a sample of 181 sib pairs from 82 nuclear families that were selected on the basis of a dyslexic proband. We have assessed linkage directly for several quantitative measures that should correlate with different components of the phenotype, rather than using a single composite measure or employing categorical definitions of subtypes. Our measures include the traditional IQ/reading discrepancy score, as well as tests of word recognition, irregular-word reading, and nonword reading. Pointwise analysis by means of sib-pair trait differences suggests the presence, in 6p21.3, of a QTL influencing multiple components of dyslexia, in particular the reading of irregular words (P=.0016) and nonwords (P=.0024). A complementary statistical approach involving estimation of variance components supports these findings (irregular words, P=.007; nonwords, P=.0004). Multipoint analyses place the QTL within the D6S422-D6S291 interval, with a peak around markers D6S276 and D6S105 consistently identified by approaches based on trait differences (irregular words, P=.00035; nonwords, P=.0035) and variance components (irregular words, P=.007; nonwords, P=.0038). Our findings indicate that the QTL affects both phonological and orthographic skills and is not specific to phoneme awareness, as has been previously suggested. Further studies will be necessary to obtain a more precise localization of this QTL, which may lead to the isolation of one of the genes involved in developmental dyslexia.


Image-guided stereotactic radiosurgery for treatment of spinal hemangioblastoma.
OBJECTIVE Stereotactic radiosurgery (SRS) has been an attractive treatment option for hemangioblastomas, especially for lesions that are surgically inaccessible and in patients with von Hippel-Lindau (VHL) disease and multiple lesions. Although there has been a multitude of studies examining the utility of SRS in intracranial hemangioblastomas, SRS has only recently been used for spinal hemangioblastomas due to technical limitations. The purpose of this study is to provide a long-term evaluation of the effectiveness of image-guided radiosurgery in halting tumor progression and providing symptomatic relief for spinal hemangioblastomas. METHODS Between 2001 and 2011, 46 spinal hemangioblastomas in 28 patients were treated using the CyberKnife image-guided radiosurgery system at the authors' institution. Fourteen of these patients also had VHL disease. The median age at treatment was 43.5 years (range 19-85 years). The mean prescription radiation dose to the tumor periphery was 21.6 Gy (range 15-35 Gy). The median tumor volume was 0.264 cm3 (range 0.025-70.9 cm3). Tumor response was evaluated on serial, contrast-enhanced CT and MR images. Clinical response was evaluated by clinical and imaging evaluation. RESULTS The mean follow-up for the cohort was 54.3 months. Radiographic follow-up was available for 19 patients with 34 tumors; 32 (94.1%) tumors were radiographically stable or displayed signs of regression. Actuarial control rates at 1, 3, and 5 years were 96.1%, 92.3%, and 92.3%, respectively. Clinical evaluation on follow-up was available for 13 patients with 16 tumors; 13 (81.2%) tumors in 10 patients had symptomatic improvement. No patient developed any complications related to radiosurgery. CONCLUSIONS Image-guided SRS is safe and effective for the primary treatment of spinal hemangioblastomas and is an attractive alternative to resection, especially for those with VHL disease.


Efficiency clustering for low-density microarrays and its application to QPCR.
Pathway-targeted or low-density arrays are used more and more frequently in biomedical research, particularly those arrays that are based on quantitative real-time PCR. Typical QPCR arrays contain 96-1024 primer pairs or probes, and they bring with it the promise of being able to reliably measure differences in target levels without the need to establish absolute standard curves for each and every target. To achieve reliable quantification all primer pairs or array probes must perform with the same efficiency. Our results indicate that QPCR primer-pairs differ significantly both in reliability and efficiency. They can only be used in an array format if the raw data (so called CT values for real-time QPCR) are transformed to take these differences into account. We developed a novel method to obtain efficiency-adjusted CT values. We introduce transformed confidence intervals as a novel measure to identify unreliable primers. We introduce a robust clustering algorithm to combine efficiencies of groups of probes, and our results indicate that using n < 10 cluster-based mean efficiencies is comparable to using individually determined efficiency adjustments for each primer pair (N = 96-1024). Careful estimation of primer efficiency is necessary to avoid significant measurement inaccuracies. Transformed confidence intervals are a novel method to assess and interpret the reliability of an efficiency estimate in a high throughput format. Efficiency clustering as developed here serves as a compromise between the imprecision in assuming uniform efficiency, and the computational complexity and danger of over-fitting when using individually determined efficiencies.


Study of the selective cytotoxic properties of cationic, lipophilic mitochondrial-specific compounds in gynecologic malignancies.
Cationic lipophilic compounds have a unique cytotoxic mechanism of action which is dependent on mitochondrial-specific localization of these fluorescent dyes. We have demonstrated in vitro that carcinoma cells, which have a higher negative mitochondrial membrane potential than normal cells, have an increased accumulation and retention of two of these compounds. The compounds tested were rhodamine 123 and dequalinium (DECA). After the development of a reproducible murine intraperitoneal (ip) human ovarian cancer model, which maintained the biologic characteristics of the parent cell line, we undertook in vivo evaluation of DECA. Mice with intraperitoneal tumor inoculations were treated with cisplatin, and/or DECA. When compared to cisplatin, a chemotherapeutic agent known to be effective in the treatment of clinical ovarian cancer, DECA was significantly more efficacious and seemed less toxic in the murine model. Cisplatin and DECA used together were possibly synergistic. Cationic lipophilic compounds may prove to be an exciting new class of antineoplastic agents which exploit intracellular, mitochondrial differences between normal cells and cancer cells.