Difficulties in the Prognostic Study of Oral Leukoplakia: Standardisation Proposal of Follow-Up Parameters.
Oral leukoplakia is the most prevalent potentially malignant disorder of the oral cavity. To evaluate its potential for malignancy, appropriate documentation of the biological parameters is crucial, allowing the patients' progression to be assessed. We hypothesized a lack of standardization in the parameters employed for the prognostic study of oral leukoplakia; our aims were to determine the different parameters used for follow-up according to definition, importance, and frequency of use, and to provide a standardization proposal of follow-up research. We made a scoping review to identify papers with the keywords "leukoplakia," "oral," and "follow-up" published until June 2019 in English, Spanish and Portuguese literature through an online search in PUBMED, SCIELO, and SCOPUS databases. In total, 514 articles were initially identified, and fifty-nine publications were selected, of which 37 were retrospective. The reports included a total of 18,660 patients between 13 and 98 years old, with a mean age of 57.6 years. Tobacco and alcohol habits were positive for 77 and 37% of the patients, respectively. Our results showed that reported leukoplakias were predominantly located on buccal mucosa (40.4%), were homogeneous (60.8%), multiple (59.9%), smaller than 2 cm (74.4%) and histopathologically non-dysplastic (71%). The mean follow-up time was 55 months, with a 13% malignant transformation rate. The categorization and definition of multiple variables were notably diverse. Age, sex, habits (tobacco and alcohol), site, size, distribution, morphology, degree of dysplasia, and evolution were the chosen parameters for our proposal. The current study reflected the lack of consensus found in the literature regarding parameters for diagnosis or follow-up, impacting negatively on clinical and research results. standardization comprises an efficient way to facilitate the prognosis assessment of oral leukoplakia, being beneficial for clinical practice, and enabling better quality information to apply in research.


Caching in the presence of competitors: Are Cape ground squirrels (Xerus inauris) sensitive to audience attentiveness?
When social animals cache food close to their burrow, the potential for an audience member to observe the event is significantly increased. As a consequence, in order to reduce theft it may be advantageous for animals to be sensitive to certain audience cues, such as whether they are attentive or not to the cache event. In this study, observations were made on three groups of Cape ground squirrels (Xerus inauris) in their natural habitat when they cached provisioned food items. When individuals cached within 10 m of conspecifics, we recorded the attentiveness (i.e. whether any audience members were orientated towards the cacher, had direct line of site and were not engaged in other activities) and identity of audience members. Overall, there was a preference to cache when audience members were inattentive rather than attentive. Additionally, we found rank effects related to cache avoidance whereby high-ranked individuals showed less avoidance to cache when audience members were attentive compared to medium- and low-ranked individuals. We suggest this audience sensitivity may have evolved in response to the difference in competitive ability amongst the ranks in how successful individuals are at winning foraging competitions. This study demonstrates that Cape ground squirrels have the ability to not only monitor the presence or absence of conspecifics but also discriminate individuals on the basis of their attentive state.


Radiosurgery to the spinal dorsal root ganglion induces fibrosis and inhibits satellite glial cell activation while preserving axonal neurotransmission.
Stereotactic radiosurgery (SRS) has been used to treat trigeminal neuralgia by targeting the cisternal segment of the trigeminal nerve, which in turn triggers changes in the gasserian ganglion. In the lumbar spine, the dorsal root ganglion (DRG) is responsible for transmitting pain sensitivity and is involved in the pathogenesis of peripheral neuropathic pain. Therefore, radiosurgery to the DRG might improve chronic peripheral pain. This study evaluated the clinical and histological effects of high-dose radiosurgery to the DRG in a rodent model. Eight Sprague-Dawley rats received either 40- or 80-Gy SRS to the fifth and sixth lumbar DRGs using the Leksell Gamma Knife Icon. Animals were euthanized 3 months after treatment, and the lumbar spine was dissected and taken for analysis. Simple histology was used to assess collagen deposition and inflammatory response. GFAP, Neu-N, substance P, and internexin were used as a measure of peripheral glial activation, neurogenesis, pain-specific neurotransmission, and neurotransmission in general, respectively. The integrity of the spinothalamic tract was assessed by means of the von Frey test. The animals did not exhibit any signs of motor or sensory deficits during the experimentation period. Edema, fibrosis, and vascular sclerotic changes were present on the treated, but not the control, side. SRS reduced the expression of GFAP without affecting the expression of Neu-N, substance P, or internexin. The von Frey sensory perception elicited equivalent results for the control side and both radiosurgical doses. SRS did not alter sensory or motor function but reduced the activation of satellite glial cells, a pathway for DRG-mediated pain perpetuation. Radiosurgery provoked changes equivalent to the effects of focal radiation on the trigeminal ganglion after SRS for trigeminal neuralgia, suggesting that radiosurgery could be successful in relieving radiculopathic pain.


A Novel Environmental Justice Indicator for Managing Local Air Pollution.
Environmental justice efforts in the United States seek to provide equal protection from environmental hazards, such as air pollution, to all groups, particularly among traditionally disadvantaged populations. To accomplish this objective, the U.S. EPA has previously required states to use an environmental justice screening tool as part of air quality planning decision-making. The generally utilized approach to assess potential areas of environmental justice concern relies on static comparisons of environmental and demographic information to identify areas where minority and low income populations experience elevated environmental exposures, but does not include any additional information that may inform the trade-offs that sub-populations of varying socio-demographic groups make when choosing where to reside in cities. In order to address this limitation, job accessibility (measured by a mobility index defining the number of jobs available within a set commuting time) was developed as a novel environmental justice indicator of environmental justice priority areas at the local level. This approach is modeled using real-world data in Allegheny County, PA (USA), and identifies areas with relatively high levels of outdoor air pollution and low access to jobs. While traditional tools tend to flag the poorest neighborhoods for environmental justice concerns, this new method offers a more refined analysis, targeting populations suffering from the highest environmental burden without the associated benefits of urban living.


Computational modeling-based discovery of novel classes of anti-inflammatory drugs that target lanthionine synthetase C-like protein 2.
Lanthionine synthetase component C-like protein 2 (LANCL2) is a member of the eukaryotic lanthionine synthetase component C-Like protein family involved in signal transduction and insulin sensitization. Recently, LANCL2 is a target for the binding and signaling of abscisic acid (ABA), a plant hormone with anti-diabetic and anti-inflammatory effects. The goal of this study was to determine the role of LANCL2 as a potential therapeutic target for developing novel drugs and nutraceuticals against inflammatory diseases. Previously, we performed homology modeling to construct a three-dimensional structure of LANCL2 using the crystal structure of lanthionine synthetase component C-like protein 1 (LANCL1) as a template. Using this model, structure-based virtual screening was performed using compounds from NCI (National Cancer Institute) Diversity Set II, ChemBridge, ZINC natural products, and FDA-approved drugs databases. Several potential ligands were identified using molecular docking. In order to validate the anti-inflammatory efficacy of the top ranked compound (NSC61610) in the NCI Diversity Set II, a series of in vitro and pre-clinical efficacy studies were performed using a mouse model of dextran sodium sulfate (DSS)-induced colitis. Our findings showed that the lead compound, NSC61610, activated peroxisome proliferator-activated receptor gamma in a LANCL2- and adenylate cyclase/cAMP dependent manner in vitro and ameliorated experimental colitis by down-modulating colonic inflammatory gene expression and favoring regulatory T cell responses. LANCL2 is a novel therapeutic target for inflammatory diseases. High-throughput, structure-based virtual screening is an effective computational-based drug design method for discovering anti-inflammatory LANCL2-based drug candidates.


Evidence for an association between KIBRA and late-onset Alzheimer's disease.
We recently reported evidence for an association between the individual variation in normal human episodic memory and a common variant of the KIBRA gene, KIBRA rs17070145 (T-allele). Since memory impairment is a cardinal clinical feature of Alzheimer's disease (AD), we investigated the possibility of an association between the KIBRA gene and AD using data from neuronal gene expression, brain imaging studies, and genetic association tests. KIBRA was significantly over-expressed and three of its four known binding partners under-expressed in AD-affected hippocampal, posterior cingulate and temporal cortex regions (P<0.010, corrected) in a study of laser-capture microdissected neurons. Using positron emission tomography in a cohort of cognitively normal, late-middle-aged persons genotyped for KIBRA rs17070145, KIBRA T non-carriers exhibited lower glucose metabolism than did carriers in posterior cingulate and precuneus brain regions (P<0.001, uncorrected). Lastly, non-carriers of the KIBRA rs17070145 T-allele had increased risk of late-onset AD in an association study of 702 neuropathologically verified expired subjects (P=0.034; OR=1.29) and in a combined analysis of 1026 additional living and expired subjects (P=0.039; OR=1.26). Our findings suggest that KIBRA is associated with both individual variation in normal episodic memory and predisposition to AD.


Impact of manipulations of myogenesis in utero on the performance of adult skeletal muscle.
The possibility that early fetal programming affects health or disease status in adult life has been considered in relation to tissues such as the cardiovascular system but not with respect to skeletal muscle. Since muscle mass and function are important for life, it is pertinent to ask whether events during the development of muscle in utero can affect the performance of the tissue in later life. This review discusses the factors that influence muscle performance, outlines the current understanding of myogenesis and examines how manipulations alter myogenic outcome after birth. The performance of muscle is determined by the number, type and size of the muscle fibres, these in turn being affected by a number of factors, and the evidence indicates that the proportions of types of muscle fibre have a heritable component. The formation of muscle occurs early in embryogenesis and it appears that the major impacts on myogenesis are associated with extremes of treatment or embryo manipulations. The impact of extremes of treatment or embryo manipulations on myogenesis is seen in the secondary fibres whereas primary fibres appear to be insensitive or protected. Overall, the opportunities for manipulation of myogenesis in utero to improve adult performance are limited.


Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study.
The SMART study randomized 5,472 human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts >350 cells/microL to intermittent antiretroviral therapy (ART; the drug conservation [DC] group) versus continuous ART (the viral suppression [VS] group). In the DC group, participants started ART when the CD4+ cell count was <250 cells/microL. Clinical outcomes in participants not receiving ART at entry inform the early use of ART. Patients who were either ART naive (n=249) or who had not been receiving ART for >or= 6 months (n=228) were analyzed. The following clinical outcomes were assessed: (i) opportunistic disease (OD) or death from any cause (OD/death); (ii) OD (fatal or nonfatal); (iii) serious non-AIDS events (cardiovascular, renal, and hepatic disease plus non-AIDS-defining cancers) and non-OD deaths; and (iv) the composite of outcomes (ii) and (iii). A total of 477 participants (228 in the DC group and 249 in the VS group) were followed (mean, 18 months). For outcome (iv), 21 and 6 events occurred in the DC (7 in ART-naive participants and 14 in those who had not received ART for >or= 6 months) and VS (2 in ART-naive participants and 4 in those who had not received ART for 6 months) groups, respectively. Hazard ratios for DC vs. VS by outcome category were as follows: outcome (i), 3.47 (95% confidence interval [CI], 1.26-9.56; p=.02); outcome (ii), 3.26 (95% CI, 1.04-10.25; p=.04); outcome (iii), 7.02 (95% CI, 1.57-31.38; p=.01); and outcome (iv), 4.19 (95% CI, 1.69-10.39; p=.002 ). Initiation of ART at CD4+ cell counts >350 cells/microL compared with <250 cells/microL may reduce both OD and serious non-AIDS events. These findings require validation in a large, randomized clinical trial.


Early trends of socio-economic and health indicators influencing case fatality rate of COVID-19 pandemic.
Coronavirus disease 2019, i.e. COVID-19, started as an outbreak in a district of China and has engulfed the world in a matter of 3 months. It is posing a serious health and economic challenge worldwide. However, case fatality rates (CFRs) have varied amongst various countries ranging from 0 to 8.91%. We have evaluated the effect of selected socio-economic and health indicators to explain this variation in CFR. Countries reporting a minimum of 50 cases as on 14th March 2020, were selected for this analysis. Data about the socio-economic indicators of each country was accessed from the World bank database and data about the health indicators were accessed from the World Health Organisation (WHO) database. Various socioeconomic indicators and health indicators were selected for this analysis. After selecting from univariate analysis, the indicators with the maximum correlation were used to build a model using multiple variable linear regression with a forward selection of variables and using adjusted R-squared score as the metric. We found univariate regression results were significant for GDP (Gross Domestic Product) per capita, POD 30/70 (Probability Of Dying Between Age 30 And Exact Age 70 From Any of Cardiovascular Disease, Cancer, Diabetes or Chronic Respiratory Disease), HCI (Human Capital Index), GNI(Gross National Income) per capita, life expectancy, medical doctors per 10000 population, as these parameters negatively corelated with CFR (rho = -0.48 to -0.38 , p<0.05). Case fatality rate was regressed using ordinary least squares (OLS) against the socio-economic and health indicators. The indicators in the final model were GDP per capita, POD 30/70, HCI, life expectancy, medical doctors per 10,000, median age, current health expenditure per capita, number of confirmed cases and population in millions. The adjusted R-squared score was 0.306. Developing countries with a poor economy are especially vulnerable in terms of COVID-19 mortality and underscore the need to have a global policy to deal with this on-going pandemic. These trends largely confirm that the toll from COVID-19 will be worse in countries ill-equipped to deal with it. These analyses of epidemiological data are need of time as apart from increasing situational awareness, it guides us in taking informed interventions and helps policy-making to tackle this pandemic.


Subjective visual awareness emerges prior to P3.
Studies on the neural basis of visual awareness, the subjective experience of seeing, have found several potential neural correlates of visual awareness. Some of them may not directly correlate with awareness but with post-perceptual processes, such as reporting one's awareness of the stimulus. We dissociated potential electrophysiological correlates of visual awareness from those occurring during response selection and thus co-occurring with post-perceptual processing. The participants performed two GO-NOGO conditions. In the aware-GO condition they responded with a key press when they were aware of the stimulus and withheld responding when they were unaware of it. In the unaware-GO condition they withheld responding when they were aware and responded when they were not aware of the stimulus. Thus, event-related potentials could be measured to aware and unaware trials when responding was required and when not required. The results revealed that the N200 amplitude (180-280 ms) over the occipital and posterior temporal cortex was enhanced in aware trials as compared with trials without awareness. This effect (visual awareness negativity, VAN) did not depend on responding. The amplitude of P3 (350-450 ms) also was enhanced in aware trials as compared with unaware trials. In addition, the amplitudes in the P3 time window depended on responding: they were greater when awareness was mapped to GO-response than when not, suggesting that P3 reflects post-perceptual processing, that is, it occurs after awareness has emerged. These findings support theories of visual awareness that assume a relatively early onset of visual awareness before P3.


Cancer and orofacial pain.
Cancer pain is a devastating condition. Pain in the orofacial region, may be present as the single symptom of cancer or as a symptom of cancer in its later stages. This manuscript revises in a comprehensive manner the content of the conference entitled "Orofacial Pain and Cancer" (Dolor Orofacial y Cancer) given at the VI Simposio International "Advances in Oral Cancer" on the 22 July, 2016 in San Sebastioan-Donostia, Spain. We have reviewed (pubmed-medline) from the most relevant literature including reviews, systematic reviews and clinical cases, the significant and evidence-based mechanisms and mediators of cancer-associated facial pain, the diverse types of cancers that can be present in the craniofacial region locally or from distant sites that can refer to the orofacial region, cancer therapy that may induce pain in the orofacial region as well as discussed some of the new advancements in cancer pain therapy. There is still a lack of understanding of cancer pain pathophysiology since depends of the intrinsic heterogeneity, type and anatomic location that the cancer may present, making more challenging the creation of better therapeutic options. Orofacial pain can arise from regional or distant tumor effects or as a consequence of cancer therapy. The clinician needs to be aware that the pain may present the characteristics of any other orofacial pain disorder so a careful differential diagnosis needs to be given. Cancer pain diagnosis is made by exclusion and only can be reached after a thorough medical history, and all the common etiologies have been carefully investigated and ruled out. The current management tools are not optimal but there is hope for new, safer and effective therapies coming in the next years.


Regulation of mitochondrial morphology and function by stearoylation of TFR1.
Mitochondria are involved in a variety of cellular functions, including ATP production, amino acid and lipid biogenesis and breakdown, signalling and apoptosis. Mitochondrial dysfunction has been linked to neurodegenerative diseases, cancer and ageing. Although transcriptional mechanisms that regulate mitochondrial abundance are known, comparatively little is known about how mitochondrial function is regulated. Here we identify the metabolite stearic acid (C18:0) and human transferrin receptor 1 (TFR1; also known as TFRC) as mitochondrial regulators. We elucidate a signalling pathway whereby C18:0 stearoylates TFR1, thereby inhibiting its activation of JNK signalling. This leads to reduced ubiquitination of mitofusin via HUWE1, thereby promoting mitochondrial fusion and function. We find that animal cells are poised to respond to both increases and decreases in C18:0 levels, with increased C18:0 dietary intake boosting mitochondrial fusion in vivo. Intriguingly, dietary C18:0 supplementation can counteract the mitochondrial dysfunction caused by genetic defects such as loss of the Parkinson's disease genes Pink or Parkin in Drosophila. This work identifies the metabolite C18:0 as a signalling molecule regulating mitochondrial function in response to diet.


Performance evaluation of paediatric propofol pharmacokinetic models in healthy young children.
The performance of eight currently available paediatric propofol pharmacokinetic models in target-controlled infusions (TCIs) was assessed, in healthy children from 3 to 26 months of age. Forty-one, ASA I-II children, aged 3-26 months were studied. After the induction of general anaesthesia with sevoflurane and remifentanil, a propofol bolus dose of 2.5 mg kg(-1) followed by an infusion of 8 mg kg(-1) h(-1) was given. Arterial blood samples were collected at 1, 2, 3, 5, 10, 20, 40, and 60 min post-bolus, at the end of surgery, and at 1, 3, 5, 30, 60, and 120 min after stopping the infusion. Model performance was visually inspected with measured/predicted plots. Median performance error (MDPE) and the median absolute performance error (MDAPE) were calculated to measure bias and accuracy of each model. Performance of the eight models tested differed markedly during the different stages of propofol administration. Most models underestimated propofol concentration 1 min after the bolus dose, suggesting an overestimation of the initial volume of distribution. Six of the eight models tested were within the accepted limits of performance (MDPE<20% and MDAPE<30%). The model derived by Short and colleagues performed best. Our results suggest that six of the eight models tested perform well in young children. Since most models overestimate the initial volume of distribution, the use for TCI might result in the administration of larger bolus doses than necessary.


The effect of Integrated Management of Childhood Illness on observed quality of care of under-fives in rural Tanzania.
Integrated Management of Childhood Illness (IMCI) has been adopted by over 80 countries as a strategy for reducing child mortality and improving child health and development. It includes complementary interventions designed to address the major causes of child mortality at community, health facility, and health system levels. The Multi-Country Evaluation of IMCI Effectiveness, Cost and Impact (IMCI-MCE) is a global evaluation to determine the impact of IMCI on health outcomes and its cost-effectiveness. The MCE is coordinated by the Department of Child and Adolescent Health and Development of the World Health Organization. MCE studies are under way in Bangladesh, Brazil, Peru, Tanzania and Uganda. In Tanzania, the IMCI-MCE study uses a non-randomized observational design comparing four neighbouring districts, two of which have been implementing IMCI in conjunction with evidence-based planning and expenditure mapping at district level since 1997, and two of which began IMCI implementation in 2002. In these four districts, child health and child survival are documented at household level through cross-sectional, before-and-after surveys and through longitudinal demographic surveillance respectively. Here we present results of a survey conducted in August 2000 in stratified random samples of government health facilities to compare the quality of case-management and health systems support in IMCI and comparison districts. The results indicate that children in IMCI districts received better care than children in comparison districts: their health problems were more thoroughly assessed, they were more likely to be diagnosed and treated correctly as determined through a gold-standard re-examination, and the caretakers of the children were more likely to receive appropriate counselling and reported higher levels of knowledge about how to care for their sick children. There were few differences between IMCI and comparison districts in the level of health system support for child health services at facility level. This study suggests that IMCI, in the presence of a decentralized health system with practical health system planning tools, is feasible for implementation in resource-poor countries and can lead to rapid gains in the quality of case-management. IMCI is therefore likely to lead to rapid gains in child survival, health and development if adequate coverage levels can be achieved and maintained.


Periodontal infection and cardiorespiratory fitness in younger adults: results from continuous national health and nutrition examination survey 1999-2004.
Previous studies report associations between periodontal infection and cardiorespiratory fitness but no study has examined the association among younger adults. Our objective was to study the association between clinical measures of periodontal infection and cardiorespiratory fitness levels among a population-based sample of younger adults. The Continuous National Health and Nutrition Examination Survey 1999-2004 enrolled 2,863 participants (46% women) who received a partial-mouth periodontal examination and completed a submaximal treadmill test for the assessment of estimated VO2 max(eVO2 max ). Participants were mean±SD age 33±9 years (range = 20-49 years), 30% Hispanic, 48% White, 19% Black, and 3% other. Mean eVO2 max (mL/kg/minute) as well as eVO2 max≤32 mL/kg/minute (20th percentile) were regressed across quartiles of mean probing depth and mean attachment loss in multivariable linear and logistic regression models. After multivariable adjustment, mean eVO2 max levels±SE across quartiles of attachment loss were 39.72±0.37, 39.64±0.34, 39.59±0.36, and 39.85±0.39 (P = 0.99). Mean eVO2 max±SE across quartiles of probing depth were 39.57±0.32, 39.78±0.38, 39.19±0.25, and 40.37±0.53 (P = 0.28). Similarly, multivariable adjusted mean eVO2 max values were similar between healthy participants vs. those with moderate/severe periodontitis: 39.70±0.21 vs. 39.70±0.90 (P = 1.00). The odds ratio (OR) for low eVO2 max comparing highest vs. lowest quartile of attachment loss = 0.89[95% CI 0.64-1.24]. The OR for comparing highest vs. lowest probing depth quartile = 0.77[95% CI 0.51-1.15]. Clinical measures of periodontal infection were not related to cardiorespiratory fitness in a sample of generally healthy younger adults.


The cerebellum and motor dysfunction in neuropsychiatric disorders.
The cerebellum is densely interconnected with sensory-motor areas of the cerebral cortex, and in man, the great expansion of the association areas of cerebral cortex is also paralleled by an expansion of the lateral cerebellar hemispheres. It is therefore likely that these circuits contribute to non-motor cognitive functions, but this is still a controversial issue. One approach is to examine evidence from neuropsychiatric disorders of cerebellar involvement. In this review, we narrow this search to test whether there is evidence of motor dysfunction associated with neuropsychiatric disorders consistent with disruption of cerebellar motor function. While we do find such evidence, especially in autism, schizophrenia and dyslexia, we caution that the restricted set of motor symptoms does not suggest global cerebellar dysfunction. Moreover, these symptoms may also reflect involvement of other, extra-cerebellar circuits and detailed examination of specific sub groups of individuals within each disorder may help to relate such motor symptoms to cerebellar morphology.


Analytical insights on theta-gamma coupled neural oscillators.
In this paper, we study the dynamics of a quadratic integrate-and-fire neuron, spiking in the gamma (30-100 Hz) range, coupled to a delta/theta frequency (1-8 Hz) neural oscillator. Using analytical and semianalytical methods, we were able to derive characteristic spiking times for the system in two distinct regimes (depending on parameter values): one regime where the gamma neuron is intrinsically oscillating in the absence of theta input, and a second one in which gamma spiking is directly gated by theta input, i.e., windows of gamma activity alternate with silence periods depending on the underlying theta phase. In the former case, we transform the equations such that the system becomes analogous to the Mathieu differential equation. By solving this equation, we can compute numerically the time to the first gamma spike, and then use singular perturbation theory to find successive spike times. On the other hand, in the excitable condition, we make direct use of singular perturbation theory to obtain an approximation of the time to first gamma spike, and then extend the result to calculate ensuing gamma spikes in a recursive fashion. We thereby give explicit formulas for the onset and offset of gamma spike burst during a theta cycle, and provide an estimation of the total number of spikes per theta cycle both for excitable and oscillator regimes.


Clarifying confusion: the confusion assessment method. A new method for detection of delirium.
To develop and validate a new standardized confusion assessment method (CAM) that enables nonpsychiatric clinicians to detect delirium quickly in high-risk settings. Prospective validation study. Conducted in general medicine wards and in an outpatient geriatric assessment center at Yale University (site 1) and in general medicine wards at the University of Chicago (site 2). The study included 56 subjects, ranging in age from 65 to 98 years. At site 1, 10 patients with and 20 without delirium participated; at site 2, 16 patients with and 10 without delirium participated. An expert panel developed the CAM through a consensus building process. The CAM instrument, which can be completed in less than 5 minutes, consists of nine operationalized criteria from the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R). An a priori hypothesis was established for the diagnostic value of four criteria: acute onset and fluctuating course, inattention, disorganized thinking, and altered level of consciousness. The CAM algorithm for diagnosis of delirium required the presence of both the first and the second criteria and of either the third or the fourth criterion. At both sites, the diagnoses made by the CAM were concurrently validated against the diagnoses made by psychiatrists. At sites 1 and 2 values for sensitivity were 100% and 94%, respectively; values for specificity were 95% and 90%; values for positive predictive accuracy were 91% and 94%; and values for negative predictive accuracy were 100% and 90%. The CAM algorithm had the highest predictive accuracy for all possible combinations of the nine features of delirium. The CAM was shown to have convergent agreement with four other mental status tests, including the Mini-Mental State Examination. The interobserver reliability of the CAM was high (kappa = 0.81 - 1.0). The CAM is sensitive, specific, reliable, and easy to use for identification of delirium.


Age- and Sex-Related Differences in Recovery From High-Intensity and Endurance Exercise: A Brief Review.
Postexercise recovery is a fundamental component for continuous performance enhancement. Due to physiological and morphological changes in aging and alterations in performance capacity, athletes of different ages may recover at different rates from physical exercise. Differences in body composition, physiological function, and exercise performance between men and women may also have a direct influence on restoration processes. This brief review examines current research to indicate possible differences in recovery processes between male and female athletes of different age groups. The paper focuses on postexercise recovery following sprint and endurance tests and tries to identify determinants that modulate possible differences in recovery between male and female subjects of different age groups. The literature analysis indicates age- and sex-dependent differences in short- and long-term recovery. Short-term recovery differs among children, adults, and masters. Children have shorter lactate half-life and a faster cardiac and respiratory recovery compared to adults. Additionally, children and masters require shorter recovery periods during interval bouts than trained adults. Trained women show a slower cardiac and respiratory recovery compared to trained men. Long-term recovery is strongly determined by the extent of muscle damage. Trained adults tend to have more extensive muscle damage compared to masters and children. The influence of age and sex on the recovery process varies among the different functional systems and depends on the time of the recovery processes. Irrespective of age and sex, the performance capacity of the individual determines the recovery process after high-intensity and endurance exercise.


Rapid and high yield production of phospholipids enriched in CLA via acidolysis: The critical role of the enzyme immobilization protocol.
Phospholipids (PL) rich in conjugated linolenic acid (CLA) have important health effects. Yields of phosphatidylcholine (PC) acidolysis with CLA use to be limited to <30%, due to competitive side-hydrolysis. Duolite A658-Lecitase is a very suitable biocatalyst for this reaction. In this study, PC hydrolysis has been practically eliminated using extremely dried lyophilized PC (279 ± 4 mg water/Kg PC), obtaining close to 100% molar yield of modified PC (72.3% CLA) with Duolite-Lecitase in 24 h, the highest yield reported in the literature for this reaction. It has been better improved by changing the immobilization support, using three food grade hydrophobic supports (Styrene, and two Octadecyl methacrylates (OM and OMC)). In only 2 h, with a 1/12 PC/CLA molar ratio at 50 °C, similar almost quantitative yields of PC with 74.4% CLA content has been obtained using OM-Lecitase. The fatty acid composition of modified PCs is not affected by the enzyme immobilization protocol.


Core Professionalism Education in Surgery: A Systematic Review.
Professionalism education is one of the major elements of surgical residency education. To evaluate the studies on core professionalism education programs in surgical professionalism education. Systematic review. This systematic literature review was performed to analyze core professionalism programs for surgical residency education published in English with at least three of the following features: program developmental model/instructional design method, aims and competencies, methods of teaching, methods of assessment, and program evaluation model or method. A total of 27083 articles were retrieved using EBSCOHOST, PubMed, Science Direct, Web of Science, and manual search. Eight articles met the selection criteria. The instructional design method was presented in only one article, which described the Analysis, Design, Development, Implementation, and Evaluation model. Six articles were based on the Accreditation Council for Graduate Medical Education criterion, although there was significant variability in content. The most common teaching method was role modeling with scenario- and case-based learning. A wide range of assessment methods for evaluating professionalism education were reported. The Kirkpatrick model was reported in one article as a method for program evaluation. It is suggested that for a core surgical professionalism education program, developmental/instructional design model, aims and competencies, content, teaching methods, assessment methods, and program evaluation methods/models should be well defined, and the content should be comparable.


Diagnosis of scrub typhus by immunohistochemical staining of Orientia tsutsugamushi in cutaneous lesions.
We assessed the clinical usefulness of immunohistochemical staining on skin biopsy specimens for the diagnosis of scrub typhus compared with indirect immunofluorescent antibody assay (IFA), the definitive diagnostic method for scrub typhus, in a prospective study of 125 patients with possible scrub typhus in 2005 and 2006. Skin biopsy specimens were obtained from 63 patients. To minimize the effects caused by antibiotics on immunohistochemical results, 46 patients were assessed before antibiotic administration (4 patients received antibiotic therapy before admission; 13 underwent skin biopsy after antibiotic administration at our hospital). Compared with IFA results, immunohistochemical results on maculopapular skin lesions demonstrated a sensitivity of 0.65 and a specificity of 1. Immunohistochemical results on eschars demonstrated a sensitivity of 1 and a specificity of 1. For immunohistochemical staining performed on skin lesions within 3 or 4 days of administration of antibiotics that are effective for Rickettsia, the antibiotics did not greatly influence diagnostic sensitivity. Immunohistochemical staining of skin biopsy specimens, particularly that of eschars, is sensitive and specific, and this technique can be reliable for confirming the diagnosis of scrub typhus.


Targeting aldehyde dehydrogenase activity in head and neck squamous cell carcinoma with a novel small molecule inhibitor.
Chemoresistant cancer cells express high levels of aldehyde dehydrogenases (ALDHs), particularly in head and neck squamous cell carcinoma (HNSCC). The ALDH family of enzymes detoxify both exogenous and endogenous aldehydes. Since many chemotherapeutic agents, such as cisplatin, result in the generation of cytotoxic aldehydes and oxidative stress, we hypothesized that cells expressing high levels of ALDH may be more chemoresistant due to their increased detoxifying capacity and that inhibitors of ALDHs may sensitize them to these drugs. Here, we show that overall ALDH activity is increased with cisplatin treatment of HNSCC and that ALDH3A1 protein expression is particularly enriched in cells treated with cisplatin. Activation of ALDH3A1 by a small molecule activator (Alda-89) increased survival of HNSCC cells treated with cisplatin. Conversely, treatment with a novel small molecule ALDH inhibitor (Aldi-6) resulted in a marked decrease in cell viability, and the combination of Aldi-6 and cisplatin resulted in a more pronounced reduction of cell viability and a greater reduction in tumor burden in vivo than what was observed with cisplatin alone. These data indicate that ALDH3A1 contributes to cisplatin resistance in HNSCC and that the targeting of ALDH, specifically, ALDH3A1, appears to be a promising strategy in this disease.


Cystic fibrosis in the United Kingdom 1977-85: an improving picture. British Paediatric Association Working Party on Cystic Fibrosis.
A national survey was conducted of patients with cystic fibrosis who were known to paediatricians, chest physicians, and others or whose deaths were reported through the death certification authorities in the United Kingdom during 1977 to 1985. From this population based study a revised incidence figure of one affected baby in 2500 live births was produced. Mortality was very high in the first year of life (7.6%) and was substantially greater for females than for males under age 20 years. A temporal improvement in mortality was found during the period under study, with about 100 more births than deaths occurring each year. This improvement was notable in the first five years of life. Meconium ileus, which used to be a primary cause of early mortality, is becoming increasingly rare as a cause of death. The total prevalence of cystic fibrosis in the UK in mid-1985 was estimated to be about 5000.


High Magnetic Field Detunes Vibronic Resonances in Photosynthetic Light Harvesting.
The origin and role of oscillatory features detected in recent femtosecond spectroscopy experiments of photosynthetic complexes remain elusive. A key hypothesis underneath of these observations relies on electronic-vibrational resonance, where vibrational levels of an acceptor chromophore match the donor-acceptor electronic gap, accelerating the downhill energy transfer. Here we identify and detune such vibronic resonances using a high magnetic field that exclusively shifts molecular exciton states. We implemented ultrafast pump-probe spectroscopy into a specialized 25 T magnetic field facility and studied the light-harvesting complex PC645 from a cryptophyte algae where strongly coupled chromophores form molecular exciton states. We detected a change in high-frequency coherent oscillations when the field was engaged. Quantum chemical calculations coupled with a vibronic model explain the experiment as a magnetic field-induced shift of the exciton states, which in turn affects the electronic-vibrational resonance between pigments within the protein. Our results demonstrate the delicate sensitivity of interpigment coherent oscillations of vibronic origin to electronic-vibrational resonance interactions in light-harvesting complexes.


A new multicompartmental reaction-diffusion modeling method links transient membrane attachment of E. coli MinE to E-ring formation.
Many important cellular processes are regulated by reaction-diffusion (RD) of molecules that takes place both in the cytoplasm and on the membrane. To model and analyze such multicompartmental processes, we developed a lattice-based Monte Carlo method, Spatiocyte that supports RD in volume and surface compartments at single molecule resolution. Stochasticity in RD and the excluded volume effect brought by intracellular molecular crowding, both of which can significantly affect RD and thus, cellular processes, are also supported. We verified the method by comparing simulation results of diffusion, irreversible and reversible reactions with the predicted analytical and best available numerical solutions. Moreover, to directly compare the localization patterns of molecules in fluorescence microscopy images with simulation, we devised a visualization method that mimics the microphotography process by showing the trajectory of simulated molecules averaged according to the camera exposure time. In the rod-shaped bacterium Escherichia coli, the division site is suppressed at the cell poles by periodic pole-to-pole oscillations of the Min proteins (MinC, MinD and MinE) arising from carefully orchestrated RD in both cytoplasm and membrane compartments. Using Spatiocyte we could model and reproduce the in vivo MinDE localization dynamics by accounting for the previously reported properties of MinE. Our results suggest that the MinE ring, which is essential in preventing polar septation, is largely composed of MinE that is transiently attached to the membrane independently after recruited by MinD. Overall, Spatiocyte allows simulation and visualization of complex spatial and reaction-diffusion mediated cellular processes in volumes and surfaces. As we showed, it can potentially provide mechanistic insights otherwise difficult to obtain experimentally. The online version of this article (doi:10.1007/s11693-009-9047-2) contains supplementary material, which is available to authorized users.


Gas-Phase Infrared Spectroscopy of Neutral Peptides: Insights from the Far-IR and THz Domain.
Gas-phase, double resonance IR spectroscopy has proven to be an excellent approach to obtain structural information on peptides ranging from single amino acids to large peptides and peptide clusters. In this review, we discuss the state-of-the-art of infrared action spectroscopy of peptides in the far-IR and THz regime. An introduction to the field of far-IR spectroscopy is given, thereby highlighting the opportunities that are provided for gas-phase research on neutral peptides. Current experimental methods, including spectroscopic schemes, have been reviewed. Structural information from the experimental far-IR spectra can be obtained with the help of suitable theoretical approaches such as dynamical DFT techniques and the recently developed Graph Theory. The aim of this review is to underline how the synergy between far-IR spectroscopy and theory can provide an unprecedented picture of the structure of neutral biomolecules in the gas phase. The far-IR signatures of the discussed studies are summarized in a far-IR map, in order to gain insight into the origin of the far-IR localized and delocalized motions present in peptides and where they can be found in the electromagnetic spectrum.


Could the eventual results of the NSABP* 39/RTOG** 0413 trial for partial breast irradiation (PBI) be improved by combining spherical applicators and whole breast irradiation? Radiobiology suggests it may.
There may be unacceptable risks associated with the relatively large single doses of irradiation prescribed over five days instead of over six weeks for three of the four trial arms of the NSABP39/RTOG 0413 clinical trial seeking to enlist 4,300 patients. The first arm prescribes 60 Gray (Gy) in two Gy fractions over six weeks, which is the present standard. The dose implications of the other three arms with reference to this standard were examined using the ID2 formalism. Particularly poor (non-homogeneous) dose distributions characterise spherical applicators like "MammoSite" used as a sole device for accelerated partial breast irradiation (APBI). The alternative treatment, APBI done by 3-D conformal radiation, may also have a drawback, namely a sudden sharp cut-off in dose which may cause cosmetic problems due to circumscribed fibrosis and edema. Some recently published results from this trial reveal an alarming level of complications. The possible causes of these complications and poor cosmetic outcomes and how to avoid them are examined. An obstacle to the more widespread use of the "MammoSite type of device is that the device is not allowed closer than 5-7 mm from the skin or ribs; a possible remedy for this restriction is offered. It is also intended to make the relevant radiobiological principles usable for surgical oncologists.


Gamma-amino butyric acid (GABA) prevents the induction of nicotinic receptor-regulated signaling by chronic ethanol in pancreatic cancer cells and normal duct epithelia.
Pancreatic cancer has a high mortality rate and alcoholism is a risk factor independent of smoking. We have shown that nicotinic acetylcholine receptors (nAChR) regulate pancreatic ductal epithelia and pancreatic ductal adenocarcinoma (PDAC) cells in an autocrine fashion by stimulating their production of the stress neurotransmitters noradrenaline and adrenaline that signal through β-adrenergic receptors (β-AR). Our current study has investigated the modulation of this autocrine regulatory loop by chronic ethanol and explored the potential prevention of these effects by γ-amino butyric acid (GABA). Using MTT assays, cell migration assays, Western blotting, immunoassays, and gene knockdown of individual nAChRs in two PDAC cell lines and in immortalized human pancreatic duct epithelial cells, our data show that treatment for seven days with ethanol induced the protein expression and sensitivity of nAChRs α3, α5, and α7 resulting in increased production of noradrenaline and adrenaline, which drive proliferation and migration via cyclic AMP (cAMP)-dependent signaling downstream of β-ARs. Treatment with GABA prevented all of these responses to chronic ethanol, reducing cell proliferation and migration below base levels in untreated cells. Our findings suggest that alcoholism induces multiple cAMP-dependent PDAC stimulating signaling pathways by upregulating the protein expression and sensitivity of nAChRs that regulate stress neurotransmitter production. Moreover, our data identify GABA as a promising agent for the prevention of PDAC in individuals at risk due to chronic alcohol consumption.


Inhibition of capsaicin-induced cough by the gamma-aminobutyric acid agonist baclofen.
Gamma-aminobutyric acid (GABA) is a central inhibitory neurotransmitter that also exists in the lungs. The GABA-agonist baclofen has been shown to have antitussive activity via a central mechanism in animals. Recently it was demonstrated that a 14-day course of baclofen given three times daily significantly inhibits the cough reflex in healthy volunteers. Because of the prolonged antitussive effect of baclofen that has been previously observed, the present study was conducted to evaluate the antitussive effect of low-dose, oral baclofen given once daily. Forty-one healthy volunteers were randomly assigned in a double-blind manner to receive a 28-day course of baclofen, either 10 mg or 20 mg once daily, or placebo. Subjects underwent cough challenge testing with inhaled capsaicin to establish baseline cough reflex sensitivity, and subsequently after 14 and 28 days of therapy. Subjects receiving baclofen 20 mg daily demonstrated significant inhibition of cough sensitivity after 14 days and after 28 days of therapy compared with baseline. Neither placebo nor baclofen 10 mg daily had a significant effect on cough sensitivity. No serious side effects were experienced by any study participant. These results confirm the recent observation that baclofen has significant antitussive activity in humans. Further, once-daily administration of a relatively low dose of baclofen is sufficient to achieve significant cough inhibition, although at least 14 to 28 days of therapy may be required to attain maximal antitussive effect. These results support further investigation of baclofen or other GABA-agonists as potential therapeutic agents for chronic, nonproductive cough.


Isolation of a high-affinity functional protein complex between OmcA and MtrC: Two outer membrane decaheme c-type cytochromes of Shewanella oneidensis MR-1.
Shewanella oneidensis MR-1 is a facultatively anaerobic bacterium capable of using soluble and insoluble forms of manganese [Mn(III/IV)] and iron [Fe(III)] as terminal electron acceptors during anaerobic respiration. To assess the structural association of two outer membrane-associated c-type decaheme cytochromes (i.e., OmcA [SO1779] and MtrC [SO1778]) and their ability to reduce soluble Fe(III)-nitrilotriacetic acid (NTA), we expressed these proteins with a C-terminal tag in wild-type S. oneidensis and a mutant deficient in these genes (i.e., Delta omcA mtrC). Endogenous MtrC copurified with tagged OmcA in wild-type Shewanella, suggesting a direct association. To further evaluate their possible interaction, both proteins were purified to near homogeneity following the independent expression of OmcA and MtrC in the Delta omcA mtrC mutant. Each purified cytochrome was confirmed to contain 10 hemes and exhibited Fe(III)-NTA reductase activity. To measure binding, MtrC was labeled with the multiuse affinity probe 4',5'-bis(1,3,2-dithioarsolan-2-yl)fluorescein (1,2-ethanedithiol)2, which specifically associates with a tetracysteine motif engineered at the C terminus of MtrC. Upon titration with OmcA, there was a marked increase in fluorescence polarization indicating the formation of a high-affinity protein complex (Kd < 500 nM) between MtrC and OmcA whose binding was sensitive to changes in ionic strength. Following association, the OmcA-MtrC complex was observed to have enhanced Fe(III)-NTA reductase specific activity relative to either protein alone, demonstrating that OmcA and MtrC can interact directly with each other to form a stable complex that is consistent with their role in the electron transport pathway of S. oneidensis MR-1.


Improving the ascertainment of families at high risk of colorectal cancer: a prospective GP register study.
Screening for colorectal cancer is effective in family members with a high risk of this condition, owing to single gene mutations. However, it is not known which is the most effective method of ascertaining these families at high risk. To investigate whether a case-finding approach using computerised general practitioner (GP) registers would improve the ascertainment of families at high risk of colorectal cancer due to family history. Prospective GP register study. General practices in Oxfordshire. Identification of patients with colorectal cancer using GP registers, followed by a family history questionnaire survey to identify those at high risk. Using GP registers, 758 patients with a diagnosis of colorectal cancer were identified; a prevalence of 172 cases per 100 000 (95% confidence interval = 159 to 184). Of these, 305 patients, diagnosed under the age of 65 years, were sent a family history questionnaire. Two hundred and one (66%) patients responded to the survey; 10 (5%) patients were assessed as having high-risk families and 47 (23%) patients were assessed as having families at moderate risk. Eight of the high-risk patients had 34 first degree relatives who would benefit from routine disease surveillance, and 37 moderate-risk patients had 153 first degree relatives. Only two high-risk and six moderate-risk patients identified were previously known to the local Clinical Genetics Department. A case-finding approach using GP records and a family history questionnaire is an effective way of identifying families at high risk of developing colorectal cancer, who can then be offered disease surveillance.


Further insights into the insulin-like growth factor-I system of bony fish pituitary with special emphasis on reproductive phases and social status.
Insulin-like growth factor (IGF)-I, which is crucially involved in fish growth, differentiation, and reproduction, occurs in tilapia pituitary. IGF-I peptide, which is probably produced in hypothalamic perikarya, is present in axons of the neurohypophysis, and IGF-I mRNA and peptide are present in the adenohypophysis in adrenocorticotrophic hormone cells, melanocyte-stimulating hormone cells, with interindividual differences in growth hormone cells, and, starting with puberty, in gonadotrophic hormone (GTH) cells. Subordinate males showed a high IGF-I but a lower beta-luteinizing hormone expression, while in dominant males the opposite was found. IGF-I from the GTH cells may act as auto/paracrine regulators of GTH cell proliferation and enhance GTH synthesis and release during puberty and reproduction, depending on the social status.


Neonatal atlas construction using sparse representation.
Atlas construction generally includes first an image registration step to normalize all images into a common space and then an atlas building step to fuse the information from all the aligned images. Although numerous atlas construction studies have been performed to improve the accuracy of the image registration step, unweighted or simply weighted average is often used in the atlas building step. In this article, we propose a novel patch-based sparse representation method for atlas construction after all images have been registered into the common space. By taking advantage of local sparse representation, more anatomical details can be recovered in the built atlas. To make the anatomical structures spatially smooth in the atlas, the anatomical feature constraints on group structure of representations and also the overlapping of neighboring patches are imposed to ensure the anatomical consistency between neighboring patches. The proposed method has been applied to 73 neonatal MR images with poor spatial resolution and low tissue contrast, for constructing a neonatal brain atlas with sharp anatomical details. Experimental results demonstrate that the proposed method can significantly enhance the quality of the constructed atlas by discovering more anatomical details especially in the highly convoluted cortical regions. The resulting atlas demonstrates superior performance of our atlas when applied to spatially normalizing three different neonatal datasets, compared with other start-of-the-art neonatal brain atlases.


Body size and premolar evolution in the early-middle eocene euprimates of Wyoming.
The earliest euprimates to arrive in North America were larger-bodied notharctids and smaller-bodied omomyids. Through the Eocene, notharctids generally continued to increase in body size, whereas omomyids generally radiated within small- and increasingly mid-sized niches in the middle Eocene. This study examines the influence of changing body size and diet on the evolution of the lower fourth premolar in Eocene euprimates. The P4 displays considerable morphological variability in these taxa. Despite the fact that most studies of primate dental morphology have focused on the molars, P4 can also provide important paleoecological insights. We analyzed the P4 from 177 euprimate specimens, representing 35 species (11 notharctids and 24 omomyids), in three time bins of approximately equal duration: early Wasatchian, late Wasatchian, and Bridgerian. Two-dimensional surface landmarks were collected from lingual photographs, capturing important variation in cusp position and tooth shape. Disparity metrics were calculated and compared for the three time bins. In the early Eocene, notharctids have a more molarized P4 than omomyids. During the Bridgerian, expanding body size range of omomyids was accompanied by a significant increase in P4 disparity and convergent evolution of the semimolariform condition in the largest omomyines. P4 morphology relates to diet in early euprimates, although patterns vary between families.


Management of patients with ≥4 brain metastases using stereotactic radiosurgery boost after whole brain irradiation.
Brain metastases are a prevalent consequence of systemic cancer, and patients suffering from brain metastases usually present with multiple metastatic lesions. An overwhelming majority of the available literature assessing the role of stereotactic radiosurgery in brain metastasis management includes patients with up to 4 metastases. Given the significant benefit of stereotactic radiosurgery for the treatment of 1 to 3 brain metastases, we evaluated the use of stereotactic radiosurgery boost after whole brain irradiation in the management of patients with ≥4 brain metastases. In this retrospective analysis, outcomes of 50 patients who underwent linear accelerator-based stereotactic radiosurgery boost within 4 to 6 weeks of whole brain irradiation for ≥4 brain metastases were assessed in terms of local control, overall survival, primary involved organ, recursive partitioning analysis class and Karnofsky performance status at the time of stereotactic radiosurgery, number of lesions, age, status of the primary cancer (controlled vs uncontrolled), presence of extracranial disease and toxicity. Fifty patients with ≥4 brain metastases were treated using linear accelerator-based stereotactic radiosurgery boost after whole brain irradiation between April 1998 and April 2013. Mean and median number of intracranial lesions was 6.02 and 6, respectively. Median lesion volume was 10.9 cc (range, 0.05-32.6). Median survival time after radiosurgery was 10.1 months (range, 1-25). Status of the primary cancer (controlled vs uncontrolled), recursive partitioning analysis class, Karnofsky performance status, and extracranial metastasis showed statistically significant correlations with overall survival (P <0.001). Treatment-related side effects after stereotactic radiosurgery included temporary edema (n = 14, 28%), hemiparesis (n = 1, 2%), seizure (n = 1, 2%), leukoencephalopathy (n = 2, 4%), and radiation necrosis (n = 6, 12%). Linear accelerator-based stereotactic radiosurgery boost within 4 to 6 weeks after whole brain irradiation proved to be an efficacious and well-tolerated treatment strategy for the management of patients with ≥4 brain metastases in our study.


Benchmark of ReaxFF force field for subcritical and supercritical water.
Water in the subcritical and supercritical states has remarkable properties that make it an excellent solvent for oxidation of hazardous chemicals, waste separation, and green synthesis. Molecular simulations are a valuable complement to experiments in order to understand and improve the relevant sub- and super-critical reaction mechanisms. Since water molecules under these conditions can act not only as a solvent but also as a reactant, dissociative force fields are especially interesting to investigate these processes. In this work, we evaluate the capacity of the ReaxFF force field to reproduce the microstructure, hydrogen bonding, dielectric constant, diffusion, and proton transfer of sub- and super-critical water. Our results indicate that ReaxFF is able to simulate water properties in these states in very good quantitative agreement with the existing experimental data, with the exception of the static dielectric constant that is reproduced only qualitatively.


Mass-like lesions as a rare form of neuro-Behçet's disease: A case report and review of the literature.
Cerebral mass-like lesion (MLL) is a rare form of Neuro-Behçet's (NB) disease. There is currently no detailed knowledge on this issue in the literature. Our aim was to describe a Behçet's disease (BD) patient with MLL, followed by a clinical analysis in light of the available literature regarding BD patients who suffered from an MLL or tumefactive lesion in the brain. We conducted a review of the English literature to analyse data on MLL in BD. The Pub-Med, Web of Science, Proquest and Ovid databases were searched for articles or abstracts using the term "Behçet's disease" combined with one of the following terms: mass-like lesion, tumour-like lesion and tumefactive lesion. We compared clinical and laboratory features of BD patients with MLL with NB patients. We found 12 cases plus our case (6 male, 7 female; mean age: 40 years) with BD who developed MLL alongside BD. Five out of 13 BD patients (38%) had a history of BD before the onset of neurological symptoms. In 8 patients (62%), BD was diagnosed after the onset of neurological involvement. Headache, hemiparesis, dizziness, aphasia, nausea and vomiting were the presenting manifestations of NB patients with MLL. Genital ulceration, eye involvement, skin lesion and arthritis/arthralgia were less commonly reported in NB patients with MLL compared to NB patients without MLL. NB disease should be considered in the differential diagnosis of cerebral MLL even when other cardinal manifestations of BD are absent. Mucocutaneous manifestations, eye and joint involvement may be seen less often in these patients.


Evidence of a role for heterotrimeric GTP-binding proteins in endosome fusion.
Guanosine triphosphate (GTP)-binding proteins are required for intracellular vesicular transport. Mastoparan is a peptide component of wasp venom that increases nucleotide exchange in some classes of G alpha subunits of regulatory heterotrimeric GTP-binding proteins (G proteins). Mastoparan and other compounds that increase nucleotide exchange by G proteins inhibited endosome fusion in vitro and reversed the effects of guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S), a nonhydrolyzable GTP analog. Addition of beta gamma subunits of G proteins to the fusion assay antagonized the stimulatory effect of GTP-gamma-S, confirming the participation of G proteins. These results indicate that GTP-binding proteins are required for endosome fusion and in particular that a G protein is involved. Given the function of G proteins in signal transduction, these findings may provide insight into the mechanism by which endosomal vesicles become competent for fusion after their formation at the cell surface.


Post-traumatic stress disorder in the forensic psychiatric setting.
The objective was to assess the prevalence of post-traumatic stress disorder (PTSD) in offenders who undergo forensic psychiatric evaluation (FPE), compare differences with regard to the prevalence of PTSD between immigrants and Swedes, compare psychiatric comorbidity and offenses between PTSD and non-PTSD patients, and compare various instruments and questionnaires when assessing the level of PTSD symptoms. Twenty-five immigrants and 25 Swedes were studied consecutively. The Clinician-Administered PTSD Scale (CAPS), Impact of Event Scale-22 (IES), Post-traumatic Symptom Scale (PTSS-10), and Structured Clinical Interview for DSM-IV (SCID)-PTSD were administered. In the immigrant group, 60 percent had PTSD, compared with 12 percent of the Swedes. Subjects with PTSD scored higher on IES-22 and PTSS-10 than those without PTSD. Considering the number of sexual and violent offenses together, the proportion of these types of offenses was higher in the PTSD group than in the non-PTSD group.


Organosilica hybrid nanomaterials with a high organic content: syntheses and applications of silsesquioxanes.
Organic-inorganic hybrid materials garner properties from their organic and inorganic matrices as well as synergistic features, and therefore have recently attracted much attention at the nanoscale. Non-porous organosilica hybrid nanomaterials with a high organic content such as silsesquioxanes (R-SiO1.5, with R organic groups) and bridged silsesquioxanes (O1.5Si-R-SiO1.5) are especially attractive hybrids since they provide 20 to 80 weight percent of organic functional groups in addition to the known chemistry and stability of silica. In the organosilica family, silsesquioxanes (R-SiO1.5) stand between silicas (SiO2) and silicones (R2SiO), and are variously called organosilicas, ormosil (organically-modified silica), polysilsesquioxanes and silica hybrids. Herein, we comprehensively review non-porous silsesquioxane and bridged silsesquioxane nanomaterials and their applications in nanomedicine, electro-optics, and catalysis.


Responses to familiar and unfamiliar objects by belugas (Delphinapterus leucas), bottlenose dolphins (Tursiops truncatus), and Pacific white-sided dolphins (Lagenorhynchus obliquidens).
Previous research with bottlenose dolphins (Tursiops truncatus) demonstrated their ability to discriminate between familiar and unfamiliar stimuli. Dolphins gazed longer at unfamiliar stimuli. The current study attempted to extend this original research by examining the responses of three species of cetaceans to objects that differed in familiarity. Eleven belugas from two facilities, five bottlenose dolphins and five Pacific white-sided dolphins housed at one facility were presented different objects in a free-swim scenario. The results indicated that the animals gazed the longest at unfamiliar objects, but these gaze durations did not significantly differ from gaze durations when viewing familiar objects. Rather, the animals gazed longer at unfamiliar objects when compared to the apparatus alone. Species differences emerged with longer gaze durations exhibited by belugas and bottlenose dolphins and significantly shorter gaze durations for Pacific white-sided dolphins. It is likely that the animals categorized objects into familiar and unfamiliar categories, but the free-swim paradigm in naturalistic social groupings did not elicit clear responses. Rather this procedure emphasized the importance of attention and individual preferences when investigating familiar and unfamiliar objects, which has implications for cognitive research and enrichment use.


Time-Optimal Velocity Tracking Control for Consensus Formation of Multiple Nonholonomic Mobile Robots.
The problem of velocity tracking is considered essential in the consensus of multi-wheeled mobile robot systems to minimise the total operating time and enhance the system's energy efficiency. This study presents a novel switched-system approach, consisting of bang-bang control and consensus formation algorithms, to address the problem of time-optimal velocity tracking of multiple wheeled mobile robots with nonholonomic constraints. This effort aims to achieve the desired velocity formation in the least time for any initial velocity conditions in a multiple mobile robot system. The main findings of this study are as follows: (i) by deriving the equation of motion along the specified path, the motor's extremal conditions for a time-optimal trajectory are introduced; (ii) utilising a general consensus formation algorithm, the desired velocity formation is achieved; (iii) applying the Pontryagin Maximum Principle, the new switching formation matrix of weights is obtained. Using this new switching matrix of weights guarantees that at least one of the system's motors, of either the followers or the leader, reaches its maximum or minimum value by using extremals, which enables the multi-robot system to reach the velocity formation in the least time. The proposed approach is verified in a theoretical analysis along with the numerical simulation process. The simulation results demonstrated that using the proposed switched system, the time-optimal consensus algorithm behaved very well in the networks with different numbers of robots and different topology conditions. The required time for the consensus formation is dramatically reduced, which is very promising. The findings of this work could be extended to and beneficial for any multi-wheeled mobile robot system.


Identification of a novel deletion in the MMAA gene in two Iranian siblings with vitamin B12-responsive methylmalonic acidemia.
Adenosylcobalamin (vitamin B12) is a coenzyme required for the activity of methylmalonyl-CoA mutase. Defects in this enzyme are a cause of methylmalonic acidemia (MMA). Methylmalonic acidemia, cblA type, is an inborn error of vitamin B12 metabolism that occurs due to mutations in the MMAA gene. MMAA encodes the enzyme which is involved in translocation of cobalamin into the mitochondria. One family with two MMA-affected children, one unaffected child, and their parents were studied. The two affected children were diagnosed by urine organic acid analysis using gas chromatography-mass spectrometry. MMAA was analyzed by PCR and sequencing of its coding region. A homozygous deletion in exon 4 of MMAA, c.674delA, was found in both affected children. This deletion causes a nucleotide frame shift resulting in a change from asparagine to methionine at amino acid 225 (p.N225M) and a truncated protein which loses the ArgK conserved domain site. mRNA expression analysis of MMAA confirmed these results. We demonstrate that the deletion in exon 4 of the MMAA gene (c.674 delA) is a pathogenic allele via a nucleotide frame shift resulting in a stop codon and termination of protein synthesis 38 nucleotides (12 amino acids) downstream of the deletion.


Functional but not structural subgenual prefrontal cortex abnormalities in melancholia.
Major depression is a heterogeneous condition, and the search for neural correlates specific to clinically defined subtypes has been inconclusive. Theoretical considerations implicate frontostriatal, particularly subgenual prefrontal cortex (PFC), dysfunction in the pathophysiology of melancholia--a subtype of depression characterized by anhedonia--but no empirical evidence has been found yet for such a link. To test the hypothesis that melancholic, but not nonmelancholic depression, is associated with the subgenual PFC impairment, concurrent measurement of brain electrical (electroencephalogram, EEG) and metabolic (positron emission tomography, PET) activity were obtained in 38 unmedicated subjects with DSM-IV major depressive disorder (20 melancholic, 18 nonmelancholic subjects), and 18 comparison subjects. EEG data were analyzed with a tomographic source localization method that computed the cortical three-dimensional distribution of current density for standard frequency bands, allowing voxelwise correlations between the EEG and PET data. Voxel-based morphometry analyses of structural magnetic resonance imaging (MRI) data were performed to assess potential structural abnormalities in melancholia. Melancholia was associated with reduced activity in the subgenual PFC (Brodmann area 25), manifested by increased inhibitory delta activity (1.5-6.0 Hz) and decreased glucose metabolism, which themselves were inversely correlated. Following antidepressant treatment, depressed subjects with the largest reductions in depression severity showed the lowest post-treatment subgenual PFC delta activity. Analyses of structural MRI revealed no group differences in the subgenual PFC, but in melancholic subjects, a negative correlation between gray matter density and age emerged. Based on preclinical evidence, we suggest that subgenual PFC dysfunction in melancholia may be associated with blunted hedonic response and exaggerated stress responsiveness.


Scientific evidence of interventions using the Mediterranean diet: a systematic review.
The Mediterranean Diet has been associated with greater longevity and quality of life in epidemiological studies, the majority being observational. The application of evidence-based medicine to the area of public health nutrition involves the necessity of developing clinical trials and systematic reviews to develop sound recommendations. The purpose of this study was to analyze and review the experimental studies on Mediterranean diet and disease prevention. A systematic review was made and a total of 43 articles corresponding to 35 different experimental studies were selected. Results were analyzed for the effects of the Mediterranean diet on lipoproteins, endothelial resistance, diabetes and antioxidative capacity, cardiovascular diseases, arthritis, cancer, body composition, and psychological function. The Mediterranean diet showed favorable effects on lipoprotein levels, endothelium vasodilatation, insulin resistance, metabolic syndrome, antioxidant capacity, myocardial and cardiovascular mortality, and cancer incidence in obese patients and in those with previous myocardial infarction. Results disclose the mechanisms of the Mediterranean diet in disease prevention, particularly in cardiovascular disease secondary prevention, but also emphasize the need to undertake experimental research and systematic reviews in the areas of primary prevention of cardiovascular disease, hypertension, diabetes, obesity, infectious diseases, age-related cognitive impairment, and cancer, among others. Interventions should use food scores or patterns to ascertain adherence to the Mediterranean diet. Further experimental research is needed to corroborate the benefits of the Mediterranean diet and the underlying mechanisms, and in this sense the methodology of the ongoing PREDIMED study is explained.


Effects of peanut genotypes on meloidogyne species interactions.
A 3-year microplot study was conducted to characterize the interaction between Meloidogyne arenaria race 1 (MA1) and M. hapla (MH), as affected by the five peanut genotypes: Florigiant, NC 7, NC 6, NC Ac 18416, and NC Ac 18016. The interactive effects on infection (total parasitic forms per root unit) and reproduction potentials of each nematode species and crop damage were determined. As a single population, MA1 had greater infection capacity and caused more crop damage than did MH, but both species had similar reproduction potentials. In mixed infestations, MA1 was more competitive than MH, as reflected by incidence of infection. Infection and reproduction potentials, and crop-damage capabilities of the mixed populations were similar to those of MA1 alone. All peanut genotypes were susceptible to infection by both nematodes. NC 6 was less susceptible to damage by MA1 and the mixed populations than other genotypes. A nematode treatment x genotype interaction was detected for root infection and crop damage, but not for population density or reproduction. With high preplant nematode levels (Pi), the populations reached their peak by midseason, whereas those with low Pi peaked after midseason. Crop damage in the second and third years was correlated with Pi level.


Research methods for obtaining primary evidence.
The use of new therapeutic and diagnostic technologies has become commonplace in modern medical practice. To avoid both clinical disappointment and the waste of money, health, and lives, the introduction of these technologies will have to be based on evidence that these technologies will do more good than harm. The evidence supporting their use should be derived using research methods designed to deal with placebo effects, confounders, and biases. Some of these methods, and the rationale for their use, are discussed in this article. Although the value of evidence derived from randomized controlled trials is stressed, the importance of reviewing critically the methodological details of such trials and interpreting their results with caution is emphasized. The benefits and risks of relying on case-control and cohort studies are reviewed.


Nanoparticle Classification Using Frequency Domain Analysis on Resource-Limited Platforms.
A mobile system that can detect viruses in real time is urgently needed, due to the combination of virus emergence and evolution with increasing global travel and transport. A biosensor called PAMONO (for Plasmon Assisted Microscopy of Nano-sized Objects) represents a viable technology for mobile real-time detection of viruses and virus-like particles. It could be used for fast and reliable diagnoses in hospitals, airports, the open air, or other settings. For analysis of the images provided by the sensor, state-of-the-art methods based on convolutional neural networks (CNNs) can achieve high accuracy. However, such computationally intensive methods may not be suitable on most mobile systems. In this work, we propose nanoparticle classification approaches based on frequency domain analysis, which are less resource-intensive. We observe that on average the classification takes 29 μ s per image for the Fourier features and 17 μ s for the Haar wavelet features. Although the CNN-based method scores 1-2.5 percentage points higher in classification accuracy, it takes 3370 μ s per image on the same platform. With these results, we identify and explore the trade-off between resource efficiency and classification performance for nanoparticle classification of images provided by the PAMONO sensor.


Clinical similarities: an innovative approach for supporting medical decisions.
Taking decisions in the medical domain is a very complex task. The context is strongly affected by uncertainty and the possible undesired side effects of the treatments have to be carefully considered. Currently, these decisions are based on the physician's own experience and the evidences of the published literature, according, when available, with the philosophy of Evidence Based Medicine. The main issues of this approach are that the own experience can be different, and the results in the literature are sometimes contrasting. For helping physicians while taking medical decisions, we are proposing an innovative approach based on the idea of the clinical similarity. Given a set of clinical variables, the proposed approach selects patients that are similar, presenting to the physician the respective decisions taken and the corresponding clinical effects.


Interleukin 6 gene polymorphisms are not associated with aneurysmal subarachnoid haemorrhage in an Italian population.
Several lines of evidence indicate a role for inflammatory processes in the development of cerebral aneurysms. Recently, polymorphisms in the promoter region of the interleukin 6 (IL6) gene were shown to be associated with intracranial aneurysmal disease. The purpose of this study was to verify the association of two functionally active polymorphisms (-174 G>C and -572 G>C) in the promoter region of the IL6 gene with the risk and clinical features of aneurysmal subarachnoid haemorrhage (SAH) in an Italian population. A total of 179 consecutive aneurysmal SAH patients and 156 healthy controls were involved in the study. Cases and controls were genotyped for the -174 G<C and the -572 G<C biallelic polymorphisms of the IL6 gene. The frequencies of different promoter haplotypes were compared between cases and controls. Allelic and genotypic frequencies of the examined polymorphism were not significantly different between cases and controls. Inferred haplotypes were not significantly different in both groups. Finally, the different IL6 genotypes did not seem to significantly modify the main clinical features of the disease. Our study did not confirm the association between functionally active polymorphisms in the IL6 gene and the risk of aneurysmal SAH in an Italian population. Additional studies in different populations are warranted to clarify the role of the IL6 gene in the pathogenesis of aneurysmal SAH.


Metabolic activation and bronchiolar Clara cell necrosis from naphthalene in the isolated perfused mouse lung.
A method for isolation and maintenance of the mouse lung ex vivo suitable for the study of the relationship between metabolism and toxicity is described. Physical, biochemical and morphological evaluations revealed that the lung is viable for up to 5 hr. No significant alterations in the architecture of the bronchiolar epithelium were observed by light or electron microscopy, despite evidence of interstitial and peribronchial edema. Although increases in pulmonary arterial pressure were noted at 5 hr, lung wet/dry weight was elevated only minimally (11%). Glutathione levels remained stable for the first 3 hr but fell to 57 +/- 14% of control at 5 hr. Naphthalene monooxygenase activity was not altered significantly during 5 hr of perfusion. Perfusion of the lung with naphthalene resulted in swelling and vacuolation of Clara cells followed by concentration-dependent losses of this cell type from the bronchiolar epithelium. Clara cells comprised 63% of the epithelial cells in terminal airways of control mice; 10 mumol of naphthalene decreased this number to 30%. Perfusion with naphthalene resulted in concentration-dependent decreases in pulmonary glutathione. Reactive metabolites were bound covalently to protein in the lung and in the perfusate. This study is the first to provide unambiguous evidence that naphthalene-induced Clara cell necrosis can be mediated entirely by processes resident in the lung. In addition, this work validates the use of the isolated perfused mouse lung for studying the role of reactive metabolites produced in situ vs. those entering the lung via the circulation.


Dietary soy protein isolate attenuates metabolic syndrome in rats via effects on PPAR, LXR, and SREBP signaling.
To determine the effects of feeding soy or isoflavones on lipid homeostasis in early development, weanling rats were fed AIN-93G diets made with casein, soy protein isolate (SPI+), isoflavone-reduced SPI+ (SPI-), or casein supplemented with genistein or daidzein for 14 d. PPARalpha-regulated genes and proteins involved in fatty acid degradation were upregulated by SPI+ (P < 0.05) accompanied by increased promoter binding and expression of PPARalpha mRNA (P < 0.05). Feeding SPI- or pure isoflavones did not alter PPARalpha-regulated pathways. SPI+ feeding had similar effects on PPARgamma signaling. SPI+, SPI-, and casein plus isoflavones all increased liver X-receptor (LXR)alpha-regulated genes and enzymes involved in cholesterol homeostasis. Feeding SPI+ increased promoter binding of LXRalpha, expression of the transcription factor mRNA, and protein (P < 0.05). In a second experiment, male Sprague-Dawley rats were fed casein diets from postnatal d (PND) 24 to PND64 or were fed high-fat Western diets containing 5 g x kg(-1) cholesterol made with either casein or SPI+. Insulin resistance, steatosis, and hypercholesterolemia in the Western diet-fed rats were partially prevented by SPI+ (P < 0.05). Nuclear sterol receptor element binding protein (SREBP)-1c protein and mRNA and protein expression of enzymes involved in fatty acid synthesis were increased by feeding Western diets containing casein but not SPI+ (P < 0.05). These data suggest that activation of PPAR and LXR signaling and inhibition of SREBP-1c signaling may contribute to insulin sensitization and improved lipid homeostasis in SPI+-fed rats after consumption of diets high in fat and cholesterol.


Severe attacks by dogs: characteristics of the dogs, the victims, and the attack settings.
Sixteen incidents involving dog bites fitting the description "severe" were identified among 5,711 dog bite incidents reported to health departments in five South Carolina counties (population 750,912 in 1980) between July 1, 1979, and June 30, 1982. A "severe" attack was defined as one in which the dog "repeatedly bit or vigorously shook its victim, and the victim or the person intervening had extreme difficulty terminating the attack." Information from health department records was clarified by interviews with animal control officers, health and police officials, and persons with firsthand knowledge of the events. Investigation disclosed that the dogs involved in the 16 severe attacks were reproductively intact males. The median age of the dogs was 3 years. A majority of the attacks were by American Staffordshire terriers, St. Bernards, and cocker spaniels. Ten of the dogs had been aggressive toward people or other dogs before the incident that was investigated. Ten of the 16 victims of severe attacks were 10 years of age or younger; the median age of all 16 victims was 8 years. Twelve of the victims either were members of the family that owned the attacking dog or had had contact with the dog before the attack. Eleven of the victims were bitten on the head, neck, or shoulders. In 88 percent of the cases, the attacks took place in the owner's yard or home, or in the adjoining yard. In 10 of the 16 incidents, members of the victims' families witnessed the attacks. The characteristics of these attacks, only one of which proved fatal, were similar in many respects to those that have been reported for other dog bite incidents that resulted in fatalities. On the basis of this study, the author estimates that a risk of 2 fatalities per 1,000 reported dog bites may exist nationwide. Suggestions made for the prevention of severe attacks focus on changing the behavior of both potential canine attackers and potential victims.


A randomized, placebo-controlled trial of the effect of antihistamine or corticosteroid treatment in acute otitis media.
To determine whether the adjunctive drugs antihistamine and corticosteroid improve immediate and long-term outcomes of acute otitis media (AOM). Children with AOM (3 mos-6 y) were enrolled in a randomized, double-blind, placebo-controlled trial. All 179 children received one dose of intramuscular ceftriaxone and were assigned to receive either chlorpheniramine maleate (0.35 mg/kg/d) and/or prednisolone (2 mg/kg/day) or placebo for 5 days. Main outcome measures were rate of treatment failure during the first 2 weeks, duration of middle ear effusion, and rate of recurrences of AOM to 6 months. Clinical outcomes and recurrence rates did not differ significantly with treatment. Children who received antihistamine alone had significantly longer duration of middle ear effusion (median, 73 days) than subjects in other treatment groups (median, 23 to 36 days, P=.04). Temporary normalization of tympanometric findings on day 5 occurred more frequently in the corticosteroid-treated group (P=.04). Five-day treatment with antihistamine or corticosteroid, in addition to antibiotic, did not improve AOM outcomes. Antihistamine use during an acute episode of OM should be avoided, since the drug may prolong the duration of middle ear effusion. The efficacy of 7- to 10-day treatment of AOM with corticosteroid, in addition to antibiotic, deserves further investigation.


Processes Linking Religious Involvement and Telomere Length.
Although numerous studies suggest that religious involvement is associated with better health and longer life expectancies, it is unclear whether these general patterns extend to cellular aging. The mechanisms linking indicators of religious involvement with indicators of cellular aging are also undefined. We employed longitudinal data from the 2004 and 2008 Health and Retirement Study, a national probability sample of Americans aged 50 and older, to test whether average telomere length varied according to level of religious attendance. We also tested several potential mechanisms. Our results showed that respondents who attended religious services more frequently in 2004 also exhibited fewer stressful events, lower rates of smoking, fewer symptoms of depression, and lower levels of C-reactive protein in 2008. Respondents who increased their level of attendance from 2004 to 2008 also exhibited lower rates of smoking in 2008. Although religious attendance was not directly associated with telomere length, our mediation analyses revealed significant indirect effects through depression and smoking, but not stressful events or C-reactive protein. We conclude that religious attendance may promote telomere length indirectly by reducing symptoms of depression and the risk of smoking. There was no evidence to support stressful events or C-reactive protein as mechanisms of religious attendance.


Catalytic regeneration of a Th-H bond from a Th-O bond through a mild and chemoselective carbonyl hydroboration.
Here we present an unprecedented chemoselective hydroboration for aldehydes and ketones catalysed by actinides. The reaction features a very low catalyst loading (0.1-0.004 mol%) and quantitative product formation in less than 15 minutes, at room temperature. Thermodynamic and kinetic studies including stoichiometric and labeling studies with deuterated pinacolborane allow us to propose a plausible mechanism for this remarkable catalytic regeneration of a Th-H bond via carbonyl hydroboration.


Identifying distinct sets of predictors of specific functions of autobiographical memory.
Grounded in the ecological approach, research has charted several adaptive functions of autobiographical remembering. Each represents a rather different psychosocial domain (i.e., self, social, directive). The goal of this research was to determine the contributions of each of a set of variables, controlling for all others, in predicting use of autobiographical memory to serve each specific function. In two studies, participants (N = 100; N = 195) rated frequency of functional use of specific event memories and completed a brief battery of memory-related measures. Most Study One results were replicated in Study Two. Self-relevance of memories was related to their functional use regardless of domain. Each function was also, however, predicted by a unique set of variables consistent with its use in a given psychosocial domain. Findings emphasise how a combination of factors come into play to allow humans to use autobiographical memory to serve various different functions in navigating daily life.


Gamma band pitch responses in human auditory cortex measured with magnetoencephalography.
We have previously used direct electrode recordings in two human subjects to identify neural correlates of the perception of pitch (Griffiths, Kumar, Sedley et al., Direct recordings of pitch responses from human auditory cortex, Curr. Biol. 22 (2010), pp. 1128-1132). The present study was carried out to assess virtual-electrode measures of pitch perception based on non-invasive magnetoencephalography (MEG). We recorded pitch responses in 13 healthy volunteers using a passive listening paradigm and the same pitch-evoking stimuli (regular interval noise; RIN) as in the previous study. Source activity was reconstructed using a beamformer approach, which was used to place virtual electrodes in auditory cortex. Time-frequency decomposition of these data revealed oscillatory responses to pitch in the gamma frequency band to occur, in Heschl's gyrus, from 60 Hz upwards. Direct comparison of these pitch responses to the previous depth electrode recordings shows a striking congruence in terms of spectrotemporal profile and anatomical distribution. These findings provide further support that auditory high gamma oscillations occur in association with RIN pitch stimuli, and validate the use of MEG to assess neural correlates of normal and abnormal pitch perception.


An in vitro study of the effects of lovastatin on human fetal brain cells.
We used various cultures of embryonic brain cells and a line of immortal astrocytes as in vitro model systems to study the direct effects of the hypolipidemic drug lovastatin on developing human CNS cells. Our data showed that pharmacological concentrations of the drug significantly affected growth and development of neuronal and astroglial cells in serum- and lipid-free media. Lovastatin at concentrations of 0.01-1000 ng/ml effectively inhibited intracellular cholesterol synthesis in primary and immortal astrocytes as well as in glial-neuronal reaggregated cultures. Primary astrocytes were more sensitive to minimal concentrations of the drug than their immortal counterparts and glial-neuronal aggregates. A concentration of 100 ng/ml of lovastatin significantly increased activity of LDL receptors both in primary and immortal astrocytes by about 100% and 50%, respectively (p < 0.001 and p < 0.01, respectively). Proliferation of immortal astrocytes in serum-free medium was entirely inhibited by 100 ng/ml of lovastatin. By contrast, a concentration of 5 ng/ml of lovastatin had no significant effect on cell proliferation. Long-term exposure of human brain explants to 100 ng/ml of lovastatin resulted in detrimental ultrastructural changes in neuronal and glial cells and led to cell death. Our data suggest that lovastatin is neurotoxic to developing brain cells and we propose that its in vivo adverse effects on the CNS may be attributed, at least in part, to its direct influence on human neurons and astrocytes as observed in vitro.


Neural stem cell differentiation is mediated by integrin beta4 in vitro.
Neural stem cells are capable of differentiating into three major neural cell types, but the underlying molecular mechanisms remain unclear. Here, we investigated the mechanism by which integrin beta4 modulates mouse neural stem cell differentiation in vitro. Inhibition of endogenous integrin beta4 by RNA interference inhibited the cell differentiation and the expression of fibroblast growth factor receptor 2 but not fibroblast growth factor receptor 1 or fibroblast growth factor receptor 3. Overexpression of integrin beta4 in neural stem cells promoted neural stem cell differentiation. Furthermore, integrin beta4-induced differentiation of neural stem cells was attenuated by SU5402, the inhibitor of fibroblast growth factor receptors. Finally, we investigated the role of integrin beta4 in neural stem cell survival: knockdown of integrin beta4 did not affect survival or apoptosis of neural stem cells. These data provide evidence that integrin beta4 promotes differentiation of mouse neural stem cells in vitro possibly through fibroblast growth factor receptor 2.


The myelodysplastic syndromes flow cytometric score: a three-parameter prognostic flow cytometric scoring system.
The prognosis of myelodysplastic syndromes (MDS) is currently estimated by using the revised International Prognostic Scoring System (IPSS-R). Several studies have shown that further refinement of prognostication for MDS can be achieved by adding flow cytometric parameters. However, widespread implementation of flow cytometry for the prognosis of MDS is hampered by complexity of the analysis. Therefore, the aim of this study was to construct a robust and practical flow cytometric score that could be implemented as a routine procedure. To achieve this, bone marrow aspirates of 109 MDS patients were analyzed by flow cytometry. A second cohort consisting of 103 MDS patients was used to validate the MDS flow cytometric score (MFS). The parameters forming the MFS were sideward light scatter and CD117 expression of myeloid progenitor cells and CD13 expression on monocytes. Three MFS risk categories were formed. Patients with MDS and intermediate MFS scores had significantly better overall survival (OS) compared with the patients with high MFS scores. The MFS further refined prognostication within the IPSS-R low-risk category, by identifying patients with worse OS in case of high MFS. In conclusion, a practical three parameter flow cytometric prognostic score was constructed enabling further refinement of prognostication of MDS.


Neural Mechanisms of Social Cognition in Primates.
Activity in a network of areas spanning the superior temporal sulcus, dorsomedial frontal cortex, and anterior cingulate cortex is concerned with how nonhuman primates negotiate the social worlds in which they live. Central aspects of these circuits are retained in humans. Activity in these areas codes for primates' interactions with one another, their attempts to find out about one another, and their attempts to prevent others from finding out too much about themselves. Moreover, important features of the social world, such as dominance status, cooperation, and competition, modulate activity in these areas. We consider the degree to which activity in these regions is simply encoding an individual's own actions and choices or whether this activity is especially and specifically concerned with social cognition. Recent advances in comparative anatomy and computational modeling may help us to gain deeper insights into the nature and boundaries of primate social cognition.