Health care utilization among older adults with arthritis.
To evaluate the effect of arthritis on subsequent 2-year use of health care services and out-of-pocket costs among older adults and determine if comorbidities or economic resources mitigate that effect. Data were analyzed from 6230 participants interviewed in 1993 and 1995 in the Asset and Health Dynamic Survey Among the Oldest Old (AHEAD), a national probability sample of community-dwelling adults. Baseline arthritis status was ascertained from the report of an arthritis-related physician's visit or a joint replacement not associated with a hip fracture. The effect of baseline arthritis on the odds of subsequent 2-year health care utilization and high out-of-pocket expenses were estimated from multiple logistic regression controlling for demographic factors, comorbidity, and economic resources. Older adults with arthritis are significantly more likely to have a physician visit (odds ratio [OR] 3.0), hospital admission (OR 1.6), outpatient surgery (OR 1.3), receive home health care (OR 1.6), and have out-of-pocket cost >5000 US dollars (OR 1.6) compared with contemporaries having similar demographics (age, sex, racial/ethnic group, marital status), comorbid conditions, and economic resources (education, income, wealth, health insurance), but not reporting arthritis. Older adults with symptomatic arthritis reported greater medical utilization and cost compared with people not reporting arthritis. These disparities persisted after accounting for differences in demographics, comorbidities, and economic factors. These findings document greater economic burdens on a personal and societal level among people with arthritis. As individuals, older adults with arthritis spend more out-of-pocket dollars for health care than their contemporaries without arthritis. On a societal level, these findings of greater health care utilization among people with arthritis point to increasing future demands on the US health care system due to demographic increases in the numbers of older adults with arthritis and support policies aimed at improving arthritis prevention and treatment as well as reducing the economic disparities between those with and without arthritis.


The level of importance and level of confidence that midwives in the United States attach to using genetics in practice.
The clinical application of genetic advances has the potential to transform preconception and pregnancy care and improve pregnancy outcomes. The study aim was to evaluate the level of importance and level of confidence that midwives in the United States attach to using genetics in practice. The study was a descriptive, cross-sectional, online survey with a convenience sample of certified nurse-midwives who were active members of the American College of Nurse-Midwives (ACNM) and provided midwifery care in the United States. The survey contained genetic case studies and questions related to genetic activities that occur in clinical practice. Participants were asked to rate how important each genetic activity is to midwifery practice generally and their personal level of confidence in carrying out the stated activity at the present time; questions were rated on a Likert-type scale of 1 (not at all important, not at all confident) to 4 (essential, confident to teach). There were 612 survey responses from among the 4244 active members of ACNM (14.42%). Most midwives believed that genetics-related activities were very important or essential to their clinical practices, but they were only moderately confident in their abilities to perform these activities. The average importance survey score was 88%, and the average confidence survey score was 70%. Some midwives (17.5%) thought that taking a 3-generation family history was essential, and some midwives (20.9%) were extremely confident in their abilities to perform this activity. Almost all midwives (98.5%) indicated that they wanted to learn more about genetics and genomics. Genetics education programs need to be developed and made available to midwives to increase their confidence levels in using genetics in clinical practice.


The clinical significance of SWI/SNF complex in pancreatic cancer.
Chromatin remodeling factors have been the subject of great interest in oncology. However, little is known about their role in pancreatic cancer. The objective of this study was to clarify the clinical significance of the SWItch/sucrose non-fermentable (SWI/SNF) complex in patients with pancreatic cancer. A total of 68 patients with pancreatic cancer who underwent R0, 1 resection were enrolled. Cancer tissues were processed to tissue microarray, then stained immunohistochemically by using antibody of SWI/SNF components; BRM, BRG1, BAF250a, BAF180 and BAF47. The correlation of expression levels and clinicopathological outcomes were analyzed, followed by the multivariate analysis of prognostic factors for overall survival. The expression levels of the SWI/SNF components were categorized as low or high according to the median value of Histoscore. Statistical analysis revealed that BRM expression was related to tumor size, T factor, M factor, lymphatic invasion and stage BRG1 expression to histology and stage BAF180 expression to tumor size and BAF47 expression to lymphatic invasion, respectively. Multivariate Cox proportional hazard analysis showed that high BRM and low BAF180 expression levels were independent predictors of worse survival in patients with pancreatic cancer. High BRM, and low BAF180 were also independent prognostic factors for poor survival in the subgroup with adjuvant gemcitabine. These results suggest that the specific cofactors of SWI/SNF chromatin remodeling complex certainly have roles in pancreatic cancer. High BRM, and low BAF180 are useful biomarkers for poor prognosis in pancreatic cancer.


Using Convolutional Neural Networks to Derive Neighborhood Built Environments from Google Street View Images and Examine Their Associations with Health Outcomes.
Built environment neighborhood characteristics are difficult to measure and assess on a large scale. Consequently, there is a lack of sufficient data that can help us investigate neighborhood characteristics as structural determinants of health on a national level. The objective of this study is to utilize publicly available Google Street View images as a data source for characterizing built environments and to examine the influence of built environments on chronic diseases and health behaviors in the United States. Data were collected by processing 164 million Google Street View images from November 2019 across the United States. Convolutional Neural Networks, a class of multi-layer deep neural networks, were used to extract features of the built environment. Validation analyses found accuracies of 82% or higher across neighborhood characteristics. In regression analyses controlling for census tract sociodemographics, we find that single-lane roads (an indicator of lower urban development) were linked with chronic conditions and worse mental health. Walkability and urbanicity indicators such as crosswalks, sidewalks, and two or more cars were associated with better health, including reduction in depression, obesity, high blood pressure, and high cholesterol. Street signs and streetlights were also found to be associated with decreased chronic conditions. Chain link fence (physical disorder indicator) was generally associated with poorer mental health. Living in neighborhoods with a built environment that supports social interaction and physical activity can lead to positive health outcomes. Computer vision models using manually annotated Google Street View images as a training dataset were able to accurately identify neighborhood built environment characteristics. These methods increases the feasibility, scale, and efficiency of neighborhood studies on health.


James Drake (1667-1707): Anatomist and political activist.
James Drake (1667-1707) was a renowned physician, anatomist, and writer whose name was recognized throughout London. He was highly involved in the politics of his time and was a well-known pamphleteer. He also delved into comedies and plays. Drake became a fellow of the Royal Society and the College of Physicians before his early death at 40 years of age. He authored one of the most deservedly popular medical treatises of his time, Anthropologia Nova, which remained a valuable resource to physicians and anatomists alike for decades. The present article reviews the contributions of this little known name in the history of anatomy.


All-cause mortality of patients with dyslipidemia up to 19 years after a multidisciplinary lifestyle modification programme: a randomized trial.
Many studies have shown that individual lifestyle factors are associated with cardiovascular mortality and all-cause mortality. Observational studies of comprehensive programmes have reported risk reductions. The objectives were to assess the long-term all-cause mortality by diagnosis in patients referred to a lifestyle modification programme, aimed at combating coronary heart disease and stroke. A randomized trial with 325 patients referred to the centre between 1988 and 1989 for dyslipidemia, hypertension, type 2 diabetes and coronary heart disease; 239 patients were randomized to the programme, 86 randomized to usual care. Cases were admitted to the centre in groups of 30 for a 4-week residential comprehensive activity, in total 114 full-time hours, focusing on food preferences and selections, and physical exercise. The activities were repeated during a 4-day revisit to the centre 1 year and 5 years after the 4-week intervention. Controls were referred back to their doctors, mainly in primary care, for usual care. Main outcome measure was all-cause mortality during 11–12 and 18–19 years after intervention. At follow-up 11–12 years after referral, the relative risk reduction (RRR) was 76% with the intention-to-treat analysis among cases admitted for dyslipidemia (hazards ratio 0.24, confidence interval 0.06–0.89, P = 0.033). After 18–19 years, the RRR was 66% (hazards ratio 0.34, confidence interval 0.13–0.88, P = 0.026). No RRR was found for the other three diagnoses. Patients admitted for dyslipidemia reached a real long-term RRR of all-cause mortality. They had by definition a need for this programme.


Performance of forced expiratory manoeuvre in children.
The negative expiratory pressure (NEP) method has been previously used to assess the performance of forced vital capacity (FVC) manoeuvre in normal adults. The aim of the present study is to assess whether flow limitation is achieved during FVC manoeuvres in children aged 6-14 yrs. NEP (-10 cmH2O) was successfully applied in 177 normal children, the portion of FVC over which expiratory flow did or did not change with NEP being taken as effort-dependent and effort-independent, respectively. In all children peak expiratory flow (PEF) and forced expiratory volume in one second (FEV1) increased with NEP, indicating that PEF was in the effort-dependent portion of FVC. This portion decreased significantly with age (50-20% of FVC from 6-14 yrs). It is suggested that this mainly reflects the poorer coordination of specialized motor acts in younger children because of incomplete morphological and functional maturation of the relevant central nervous system (CNS) mechanisms. The results indicate that most unexperienced children aged 6-14 yrs can perform acceptable forced vital capacity manoeuvres, eventually achieving flow limitation over a portion of the forced vital capacity that increases with age. The negative expiratory pressure method can be used for online assessment of the performance of forced vital capacity manoeuvres and evaluation of treatment-related effects.


Confocal microscopy analysis of native, full length and B-domain deleted coagulation factor VIII trafficking in mammalian cells.
In mammalian cells, factor VIII (FVIII) secretion depends upon its interaction with chaperones of the endoplasmic reticulum (ER) and requires a unique ATP-dependent step to dissociate aggregates formed within the ER. To further elucidate mechanisms which might account for the inefficient secretion of recombinant FVIII (rFVIII), we have analyzed the pathways of recombinant full length (rFVIII-FL) and B-domain deleted (rFVIII Delta B) FVIII and compared these to the secretion route of native FVIII in primary hepatocytes. Using confocal laser scanning microscopy in combination with a pulse chase of a known secretion marker, we describe the trafficking route of FVIII, which upon release from the ER--where it colocalizes with calnexin--is transported to the Golgi complex in vesicular-tubular transport complexes (VTCs) which could be further identified as being COP I coated. However, a large portion of rFVIII is retained in the ER and additionally in structures which could not be assigned to the ER, Golgi complex or intermediate compartment. Moderate BiP transcription levels indicate that this observed retention of FVIII does not reflect cellular stress due to an overexpression of FVIII-protein in transduced cells. Moreover, a pulse of newly synthesized rFVIII protein is released within 4 hrs, indicating that once rFVIII is released from the ER there is no further limitation to its secretion. Our data provide new details about the secretory route of FVIII, which may ultimately help to identify factors currently limiting the efficient and physiological expression of FVIII in gene therapy and manufacture.


[Tritanopia and dominantly inherited optic atrophy (author's transl)].
The clinical picture of hereditary dominant optic atrophy is described and the particular importance of the concomitant tritan dyschromatopsia is stressed. Most cases of tritanopia are acquired, congenital ones are rare. Wright has studied 17 tritanopes - the greatest series ever reported. A full analysis of colour vision is given, but no detailed information about other visual functions and the condition of the fundi. As single members of families affected by cominantly inherited optic atrophy show typical tritanopia, a visual acuity of 6/8 and hardly any pallor of their disks, it is possible that such isolated cases are regarded wrongly as congenital tritanopes.


Thromboresistant and rapid-endothelialization effects of dopamine and staphylococcal protein A mediated anti-CD34 coating on 316L stainless steel for cardiovascular devices.
There is convincing evidence in vivo that the vascular homing of endothelial progenitor cells (EPCs) contributes to rapid endothelial regeneration, which could prevent thrombosis and restenosis of cardiovascular devices. To enhance the EPC homing on cardiovascular devices, immobilization of an EPC capture agent (e.g. an anti-CD34 antibody) on the surface of cardiovascular devices is critical. We describe a way of immobilizing anti-CD34 Ab on 316L Stainless Steel (316L SS). For this, surface modification of 316L SS was performed via self-polymerization of dopamine (DA) and covalent grafting of staphylococcal protein A (SPA). On this coating the anti-CD34 Abs were oriented immobilized through their Fc constant region with SPA. In this process, the results of quartz crystal microbalance, X-ray photoelectron spectroscopy and water contact angle studies indicate that DA, SPA and anti-CD34 Ab were successfully immobilized onto the surface step by step. In vitro blood-compatibility tests confirmed that the modified surface induced less pro-coagulant fibrinogen denaturation, less platelet adhesion and lower activation of the adherent platelets. The affinity of EPCs for the modified surface has been demonstrated under flow conditions. This study provides potential applications for cardiovascular implant materials.


Pharmacotherapy for the treatment of acute bipolar II depression: current evidence.
Bipolar II disorder is a common, recurrent, and disabling psychiatric illness, and yet little is known about how best to treat it. The pressing clinical need for evidence-based approaches to the treatment of bipolar II disorder, coupled with recent publication of pertinent studies, calls for an updated review of this literature. This review focuses on a critical examination of the evidence supporting the efficacy of treatments for acute depressive episodes in bipolar II disorder. A MEDLINE (via Ovid) search of journals, covering the period from January 1950 to January 2009, was performed to identify relevant studies. Keywords used were bipolar II disorder, bipolar disorder, bipolar depression, and pharmacotherapy. Studies were further limited to those that were in adult samples, published in peer-reviewed journals, and written in English. We examined all randomized trials evaluating the use of pharmacotherapy in the treatment of acute bipolar II depression. Studies with mixed samples of bipolar I and II or bipolar II and unipolar depression were examined as well. Twenty-one randomized trials were identified and reviewed. Therapeutic agents were rated according to the quality of evidence supporting their efficacy as treatments for bipolar II depression. Ninety percent of relevant trials were published after 2005. Quetiapine was judged as having compelling evidence supporting its efficacy. Lithium, antidepressants, and pramipexole were judged as having preliminary support for efficacy. Lamotrigine was considered to have mixed support. Although progress has been made, further research on bipolar II depression is warranted.


Pharmacotherapeutic management of asthma in pregnancy and the effect of sex hormones.
Asthma is a common medical condition that can frequently affect pregnancy, and thus optimal management of asthma in pregnancy is important for both mother and baby. This article reviews recent developments of asthma pharmacotherapy and provides emerging data on the safety of asthma controller medications and biological therapies in pregnancy. The authors highlight the clinical outcomes of asthma during pregnancy, and summarize emerging new data related to the influence of sex hormones and fetal sex on asthma severity. This review of asthma pharmacotherapy during pregnancy examines the recent guidelines and reports the most pertinent publications on safety data and asthma management. Asthma management during pregnancy follows the same principles as that of non-pregnant asthma. The available data for most asthma medications are reassuring, however there is a lack of adequate safety data available because pregnant women are generally excluded from clinical trials. More clarity is needed in guidelines regarding the management of asthma in pregnancy, and high-quality randomized control trials are required to strengthen the evidence base and inform future guidelines. In particular, safety studies examining biological therapies in pregnant women with severe asthma are needed.


Regioselective lithiation and functionalization of 3-(benzyloxy)isothiazole: application to the synthesis of thioibotenic acid.
Direct functionalization of the 3-oxygenated isothiazole heteroaromatic parental system has not yet been reported in the literature. Here, we report the first regioselective lithiation of the 5-position of 3-(benzyloxy)isothiazole (4) using LDA in diethyl ether. The versatility of the methodology was explored by quenching with a variety of electrophiles to give the desired products 7a,b,d-g in 54-68% yield. Only benzoylation aiming at the synthesis of 7c was unsuccessful. Furthermore, a highly convergent synthesis of thioibotenic acid (1), the sulfur analogue of the neurotoxic natural product ibotenic acid, was carried out.


Fingermark submission decision-making within a UK fingerprint laboratory: Do experts get the marks that they need?
Within UK policing it is routinely the responsibility of fingerprint laboratory practitioners to chemically develop areas of latent fingerprint ridge detail on evidential items and to determine which areas of ridge detail are of sufficient quality to be submitted to fingerprint experts for search or comparison against persons of interest. This study assessed the effectiveness of the fingermark submission process within the Evidence Recovery Unit Fingerprint Laboratory of the Metropolitan Police Service. Laboratory practitioners were presented with known source fingermark images previously deemed identifiable or insufficient by fingerprint experts, and were asked to state which of the marks they would forward to the Fingerprint Bureau. The results indicated that practitioners forwarded a higher percentage of insufficient fingermarks than is acceptable according to current laboratory guidelines, and discarded a number of marks that were of sufficient quality for analysis. Practitioners forwarded more insufficient fingermarks when considering fingermarks thought to be related to a murder and discarded more sufficient fingermarks when considering those thought to be related to a crime of 'theft from vehicle'. The results highlight the need for fingerprint laboratories to work alongside fingerprint experts to ensure that a consistent approach to decision-making is, as far as possible, achieved, and that appropriate thresholds are adopted so as to prevent the loss of valuable evidence and improve the efficiency of the fingerprint filtering process.


Sexual Activity is Associated with Greater Enjoyment of Life in Older Adults.
Relationships among sexual activity, problems and concerns, and well-being among older adults have not been fully explored. To investigate associations among sexual activity, problems and concerns, and experienced well-being in a representative sample of older adults. In this cross-sectional analysis from the English Longitudinal Study of Ageing, sexual behavior, problems, and concerns were assessed via a self-completed questionnaire. Covariates included age, partnership status, socioeconomic status, smoking status, alcohol intake, limiting long-standing illness, and depressive symptoms. Data were analyzed using 1-way independent analysis of variance. Enjoyment of life was assessed with the pleasure subscale of the CASP-19 (Control, Autonomy, Self-realization, and Pleasure), a validated measure of quality of life specific to older age. Data on sexual activity and enjoyment of life were available for a total of 3,045 men and 3,834 women (mean age 64.4 years in men and 65.3 years in women). Men and women who reported any sexual activity in the past year had significantly higher mean enjoyment of life scores compared with those who were not sexually active (men, 9.75 vs 9.44 [P < .001]; women, 9.86 vs 9.67 [P = .003]). Among sexually active men, frequent (≥2 times a month) sexual intercourse (P < .001) and frequent kissing, petting, or fondling (P < .001) were associated with greater enjoyment of life. Among sexually active women, frequent kissing, petting, or fondling was also associated with greater enjoyment of life (P < .001), but there was no significant association with frequent intercourse (P = .101). Concerns about one's sex life and problems with sexual function were strongly associated with lower levels of enjoyment of life in men and to a lesser extent in women. This is among the first studies to show that well-being is higher among older adults when they are sexually active. Preferences regarding the expression of sexual activity differed between the sexes. Further longitudinal research is needed to confirm a causal association between sexual activity and well-being. Smith L, Yang L, Veronese N, et al. Sexual Activity is Associated with Greater Enjoyment of Life in Older Adults. Sex Med 2019;7:11-18.


[Squamous cell carcinoma of the nasal vestibule].
The case of a 31-year-old man (smoker) with a progressively enlarging swelling and reddening in the region of the nasal vestibule is discussed. Before he was seen by us, he had been repeatedly treated with antibiotics, but to no avail. A deep excisional biopsy was obtained, and the histopathological work-up revealed a squamous cell carcinoma. Thereupon, complete surgical ablation in healthy tissue was carried out. This case shows that in chronic inflammation of the nasal vestibule that fails to respond to antibiotic treatment differential diagnostic consideration must be given to the possibility of a malignancy.


Supporting the minority physician pipeline: providing global health experiences to undergraduate students in the United States-Mexico border region.
The sizeable US Latino population calls for increasing the pipeline of minority and bilingual physicians who can provide culturally competent care. Currently, only 5.5% of US providers are Hispanic/Latino, compared with 16% of the US population (i.e., >50.5 million persons). By 2060, it is predicted that about one-third of all US residents will be of Latino ethnicity. This article describes the Health Frontiers in Tijuana Undergraduate Internship Program (HFiT-UIP), a new quarterly undergraduate internship program based at a US-Mexico binational student-run free clinic and sponsored by the University of California, San Diego School of Medicine and the Universidad Autónoma de Baja California in Tijuana, Mexico. The HFiT-UIP provides learning opportunities for students and underrepresented minorities interested in medical careers, specifically Latino health. The HFiT-UIP might serve as a model for other educational partnerships across the US-Mexico border region and may help minority and other undergraduates seeking academic and community-based enrichment experiences. The HFiT-UIP can also support students' desires to learn about Latino, border, and global health within resource-limited settings.


Fibrinogen Niigata with impaired fibrin assembly: an inherited dysfibrinogen with a Bbeta Asn-160 to Ser substitution associated with extra glycosylation at Bbeta Asn-158.
A novel BbetaAsn-160 (TAA) to Ser (TGA) substitution has been identified in fibrinogen Niigata derived from a 64-year-old asymptomatic woman, who is heterozygotic for this abnormality. The mutation creates an Asn-X-Ser-type glycosylation sequence, and a partially sialylated biantennary oligosaccharide was linked to the BbetaAsn-158 residue. The functional abnormality was attributed to delayed lateral association of normally formed double-stranded protofibrils based on normal cross-linking of fibrin gamma-chains and tissue-type plasminogen activator-catalyzed plasmin generation by polymerizing fibrin monomers. Enzymatic removal of all the N-linked oligosaccharides from fibrinogen Niigata accelerated fibrin monomer polymerization that reached the level of untreated normal fibrin monomers, but the thrombin time was prolonged from 18.2 seconds to 113 seconds (normal: 11.2 seconds to 8.9 seconds). By scanning electron micrographic analysis, Niigata fibrin fibers were found to be more curvilinear than normal fibrin fibers. After deglycosylation, Niigata fibers became straight being similar to untreated normal fibrin fibers, whereas normal deglycosylated fibrin appeared to be less-branched than untreated normal or deglycosylated Niigata fibrin. Although normal and Niigata fibrins were similar to each other in permeation and compaction studies, deglycosylated normal and Niigata fibrins had much higher permeability and compaction values, indicating that deglycosylation had brought about the formation of more porous networks. The enzymatic deglycosylation necessitates an Asn to Asp change at position Bbeta-158 that is responsible for reducing the fiber thickness because of either local repulsive forces or steric hindrance in the coiled-coil region.


Uncorrected and corrected refractive error experiences of Nepalese adults: a qualitative study.
The aim of this study was to explore the impact of corrected and uncorrected refractive error (URE) on Nepalese people's quality of life (QoL), and to compare the QoL status between refractive error subgroups. Participants were recruited from Tilganga Institute of Ophthalmology and Dhulikhel Hospital, Nepal. Semi-structured in-depth interviews were conducted with 101 people with refractive error. Thematic analysis was used with matrices produced to compare the occurrence of themes and categories across participants. Themes were identified using an inductive approach. Seven major themes emerged that determined refractive error-specific QoL: activity limitation, inconvenience, health concerns, psycho-social impact, economic impact, general and ocular comfort symptoms, and visual symptoms. Activity limitation, economic impact, and symptoms were the most important themes for the participants with URE, whereas inconvenience associated with wearing glasses was the most important issue in glasses wearers. Similarly, possibilities of having side effects or complications were the major concerns for participants wearing contact lens. In general, refractive surgery addressed socio-emotional impact of wearing glasses or contact lens. However, the surgery participants had concerns such as possibility of having to wear glasses again due to relapse of refractive error. Impact of refractive error on people's QoL is multifaceted. Significance of the identified themes varies by refractive error subgroups. Refractive correction may not always address QoL impact of URE but often add unique QoL issues. This study findings also provide content for developing an item-bank for quantitatively measuring refractive error-specific QoL in developing country setting.


Brain atrophy over time in genetic and sporadic frontotemporal dementia: a study of 198 serial magnetic resonance images.
The aim of our study was to determine the utility of longitudinal magnetic resonance imaging (MRI) measurements as potential biomarkers in the main genetic variants of frontotemporal dementia (FTD), including microtubule-associated protein tau (MAPT) and progranulin (GRN) mutations and C9ORF72 repeat expansions, as well as sporadic FTD. In this longitudinal study, 58 subjects were identified who had at least two MRI and MAPT mutations (n = 21), GRN mutations (n = 11), C9ORF72 repeat expansions (n = 11) or sporadic FTD (n = 15). A total of 198 serial MRI measurements were analyzed. Rates of whole brain atrophy were calculated using the boundary shift integral. Regional rates of atrophy were calculated using tensor-based morphometry. Sample size estimates were calculated. Progressive brain atrophy was observed in all groups, with fastest rates of whole brain atrophy in GRN, followed by sporadic FTD, C9ORF72 and MAPT. All variants showed greatest rates in the frontal and temporal lobes, with parietal lobes also strikingly affected in GRN. Regional rates of atrophy across all lobes were greater in GRN compared to the other groups. C9ORF72 showed greater rates of atrophy in the left cerebellum and right occipital lobe than MAPT, and sporadic FTD showed greater rates in the anterior cingulate than C9ORF72 and MAPT. Sample size estimates were lowest using temporal lobe rates in GRN, ventricular rates in MAPT and C9ORF72, and whole brain rates in sporadic FTD. These data support the utility of using rates of atrophy as outcome measures in future drug trials in FTD and show that different imaging biomarkers may offer advantages in the different variants of FTD.


Attenders of a university hospital psychiatric emergency service in Belgium - general characteristics and gender differences.
The aim of this study was to provide a clinical and epidemiological profile of patients consulting the psychiatric emergency team (PET) of an emergency service of a Belgian university hospital. Of all PET patients (N = 1050), demographic characteristics, axis I diagnosis, any axis II diagnosis, presenting problems, psychiatric antecedents, and patterns of referral were assessed. Male patients presented more with hostility or violence towards others (10%) and substance abuse (23%); female patients presented more with suicidality (31%) and depressed mood (24%). Male patients had more psychoactive substance use disorders (21%); female patients had more mood (21%) and adjustment disorders (19%). About 50% of the patients were unemployed and had sought psychiatric help in the past. Female patients were more often referred by the emergency physician (35%) and health care professionals (29 %); male patients were more often self-referred (23%) and referred by the police (9%). A PET could overcome the discrepancy between the need of treatment and the effective use of mental health services. Male and female PET patients presented different complaints and were given different axis I diagnoses; they also had different pathways to care.


Methanol poisoning and formate oxidation in nitrous oxide-treated rats.
Formic acid does not accumulate in the rat after the administration of methanol as it does in methanol-poisoned humans and monkeys. In addition, rats do not manifest the metabolic acidosis and ocular toxicity characteristic of methanol intoxication in primates. Nitrous oxide treatment was used to inhibit 5-methyltetrahydrofolate homocysteine methyltransferase (methionine synthetase, EC 22.214.171.124) in order to delineate the role of this enzyme in regulating the metabolism of formate in rats and in determining the sensitivity of this species to methanol intoxication. Nitrous oxide treatment resulted in a decrease in hepatic levels of nonmethylated tetrahydrofolate forms and an increase in 5-methyltetrahydrofolate. Rats treated with nitrous oxide exhibited a marked decrease in the rate of oxidation of formate to carbon dioxide. The rate of disappearance of formate from the blood in these animals was decreased to half the control rate. Rats treated with nitrous oxide and administered methanol accumulated formate in blood and developed metabolic acidosis. These studies support the concept of a key role of methionine synthetase in supplying the tetrahydrofolate required for the folate-dependent oxidation of formate to carbon dioxide as well as the importance of this pathway in determining the sensitivity of a species to methanol poisoning.


Semiautomated image processing method for identification and quantification of geographic atrophy in age-related macular degeneration.
To determine intraobserver and interobserver longitudinal measurement variability of novel semiautomated software for quantification of age-related macular degeneration-associated geographic atrophy (GA) based on confocal scanning laser ophthalmoscopy fundus autofluorescence (FAF) imaging. Three-field FAF (excitation 488 nm, emission 500-700 nm), near-infrared reflectance (820 nm), and blue reflectance (488 nm) images of 30 GA subjects were recorded according to a standardized protocol at baseline after 6 and 12 months. At all visits, the GA area was analyzed on central FAF images by seven independent readers using semiautomated software. The software allows direct export of FAF images from the database and semiautomated detection of atrophic areas by shadow correction, vessel detection, and selection of seed points. The mean size of atrophy at baseline and the mean progression rate were 5.96 mm² (range, 1.80-15.87) and 1.25 mm²/year (0.42-2.93), respectively. Mean difference of interobserver agreement (Bland-Altman statistics) ranged from -0.25 to 0.30 mm² for the baseline visit and from -0.14 to 0.11 mm²/year for the atrophy progression rate. Corresponding reflectance images were helpful for lesion boundary discrimination, particularly for evaluation of foveal GA involvement and when image quality was poor. The new image processing software offers an accurate, reproducible, and time-efficient identification and quantification of outer retinal atrophy and its progression over time. It facilitates measurements both in natural history studies and in interventional trials to evaluate new pharmacologic agents designed to limit GA enlargement.


Transcatheter interventions for multiple lesions in adults with congenital heart disease.
Recent advances in diagnosis, surgery and interventional management have significantly changed the quality of life of patients with congenital heart disease. Historically, congenital heart disease patients with multiple cardiac lesions have been referred for surgery; however, with the advent of newer technologies and expertise, transcatheter treatment has evolved as an alternative option. A series of patients who underwent interventional procedures for multiple congenital heart disease lesions with excellent procedural and medium-term outcomes is reported.


The genetic basis of cancer of the kidney.
The types of epithelial renal tumors are clear cell, types I and II papillary, chromophobe and oncocytoma. We identified the genetic basis of these different types of kidney cancer to provide better methods for early diagnosis of this disease as well as provide the foundation for the development of molecular therapeutic approaches. To identify the genetic basis of kidney cancer we studied families with an inherited predisposition to kidney cancer. Families in which 2 or more individuals had kidney cancer underwent a comprehensive evaluation to determine whether they were affected with a hereditary form of renal carcinoma. Genetic linkage analysis was performed to identify the gene for inherited forms of renal carcinoma. The gene for the inherited form of clear cell renal carcinoma associated with von Hippel-Lindau gene was identified. This gene has been found to be a tumor suppressor gene. A new form of inherited renal carcinoma, hereditary papillary renal carcinoma, was identified. The gene for this condition was identified and found to be the proto-oncogene c-Met. A previously unidentified form of familial renal oncocytoma was found. A familial form of chromophobe renal carcinoma and oncocytoma associated with Birt Hogg Dubé syndrome was found. The gene for this condition was localized on the short arm of chromosome 17 and it has been identified. We studied families with cutaneous leiomyomas, uterine leiomyomas and papillary renal carcinoma. We identified mutations in the fumarate hydratase gene in patients affected with this disorder, namely hereditary leiomyoma renal cell carcinoma. Kidney cancer used to be considered a single disease. It is now known that there are a number of different types of cancers of the kidney with different histological patterns and different clinical courses that appear to respond differently to therapy. These different types of kidney cancer are caused by different genes, ie they each have a distinct genetic basis. Understanding the molecular pathways of these cancer genes should provide insight into their varying clinical courses and responses to treatment as well as provide the foundation for the development of disease specific molecular therapeutic strategies.


Differential effects of Parkinson's disease and dopamine replacement on memory encoding and retrieval.
Increasingly memory deficits are recognized in Parkinson's disease (PD). In PD, the dopamine-producing cells of the substantia nigra (SN) are significantly degenerated whereas those in the ventral tegmental area (VTA) are relatively spared. Dopamine-replacement medication improves cognitive processes that implicate the SN-innervated dorsal striatum but is thought to impair those that depend upon the VTA-supplied ventral striatum, limbic and prefrontal cortices. Our aim was to examine memory encoding and retrieval in PD and how they are affected by dopamine replacement. Twenty-nine PD patients performed the Rey Auditory Verbal Learning Test (RAVLT) and a non-verbal analogue, the Aggie Figures Learning Test (AFLT), both on and off dopaminergic medications. Twenty-seven, age-matched controls also performed these memory tests twice and their data were analyzed to correspond to the ON-OFF order of the PD patients to whom they were matched. We contrasted measures that emphasized with those that accentuated retrieval and investigated the effect of PD and dopamine-replacement on these processes separately. For PD patients relative to controls, encoding performance was normal in the off state and was impaired on dopaminergic medication. Retrieval was impaired off medication and improved by dopamine repletion. This pattern of findings suggests that VTA-innervated brain regions such as ventral striatum, limbic and prefrontal cortices are implicated in encoding, whereas the SN-supplied dorsal striatum mediates retrieval. Understanding this pattern of spared functions and deficits in PD, and the effect of dopamine replacement on these distinct memory processes, should prompt closer scrutiny of patients' cognitive complaints to inform titration of dopamine replacement dosages along with motor symptoms.


Electrostatic effects and the dynamics of enzyme reactions at the surface of plant cells. 2. The role of pectin methyl esterase in the modulation of electrostatic effects in soybean cell walls.
The pectin methyl esterase from soybean cell walls has been isolated and purified to homogeneity. It is a protein with a relative molecular mass close to 33 000. The enzyme is maximally active at a pH close to 8 and its pH dependence may be explained by a classical Dixon model, where the two interconvertible enzyme ionization states coexist. The outflux of protons from cell walls, upon raising the ionic strength, may be taken as an indirect estimate of the fixed charge density. If the cell-wall fragments are pre-incubated at pH values between 5 and 9, the outflux of protons rises with the pH of pre-incubation. This implies, as postulated from the theory developed in the preceding paper, that alkaline pH favours the activity of pectin methyl esterase and that this enzyme effectively generates the fixed negative charges of the cell wall. Therefore the pectin methyl esterase reaction builds up the Donnan potential, delta psi, at the cell surface. The cell-wall charge density, estimated from the proton outflux, as well as from the titration of methyl groups on the cell wall, reaches a maximum between the third and the fourth day of growth. While the cell-wall volume increases and reaches a plateau, the fixed charge density increases at first and then declines. This is understandable if one assumes that the building up of a high charge density is a co-operative phenomenon and that the local pH inside the wall rises during cell growth. When both the cell-wall volume and the charge density increase together, this suggests that the local pH inside the wall lies within the critical pH range associated with the steep response of the system. When the cell-wall volume increases together with a decrease of the fixed charge density, the local pH should have dropped below this critical pH range. Under these conditions the pectin methyl esterase remains inactive, or poorly active. As the number of fixed negative charges increases, calcium becomes tightly bound to cell walls. This binding is so tight that the net charge density is minimum when the calcium concentration is maximum. The experimental results, presented above, offer experimental support to two important ideas discussed in the preceding paper, namely that pectin methyl esterase reaction builds up the Donnan potential at the cell surface, and that this response may be co-operative with respect to pH.


Transcriptional and histological analyses of the thymic developmental process in the fetal pig.
The humanized pig model, in which human cells or tissues can be functionally maintained in pigs, can be an invaluable tool for human medical research. Although the recent development of immunodeficient pigs has opened the door for the development of such a model, the efficient engraftment and differentiation of human cells may be difficult to achieve. The transplantation of human cells into fetal pigs, whose immune system is immature, will ameliorate this problem. Therefore, we examined the development of porcine fetal thymus, which is critical for the establishment of the immune system. We first analyzed the levels of mRNA expression of genes that are relevant to the function of thymic epithelial cells or thymocytes in whole thymi from 35 to 85 days of gestation (DG) and at 2 days postpartum (DP) by quantitative RT-PCR. In addition, immunohistochemical analyses of thymic epithelial cells from DG35 to DG55 and DP2 were performed. These analyses showed that the thymic cortex was formed as early as DG35, and thymic medulla gradually developed from DG45 to DG55. These findings suggested that, at least before DG45, the thymus do not differentiate to form fully functional T cells.


Functional heterogeneity of the transport iron compartment II. In vivo differences between transferrin iron binding sites, and in vitro interbinding site iron exchange.
First, an 80% 59Fe-saturated transferrin solution was exposed to reticulocytes to reduce its iron content. Iron-donating activity of the supernatant was subsequently compared to that of a fresh preparation equal in iron and transferrin concentration; it was found significantly reduced, but gradually improving in presence of 10(-3)M citrate. Second, two transferrin solutions saturated with 59FeCl3 or 56FeCl3 were exposed to reticulocytes and resaturated adding the opposite iron species. These preparations were injected into rats and the 59Fe plasma disappearance rate was followed; the 59Fe added after reticulocyte exposure was cleared more rapidly. It is concluded that citrate ions mediate interbinding site iron exchange. Further, iron distribution among binding sites is important for tissue iron delivery.


Examining the Role of National Context: Do Country Conditions During Childhood Impact Perpetration of Dating Violence in Emerging Adulthood?
The link between individual experiences in early childhood or adolescence years and future dating violence (DV) perpetration has been well established and explored across various populations. However, little is known on a worldwide scale, about the association between national conditions during childhood, like overall well-being or status of women in that nation, and perpetration of DV in emerging adulthood. Applying life-course theory and a socioecological framework to data from the International Dating Violence Study and country index scores, this study examines whether the overall well-being of a country during childhood affects the perpetration of DV in emerging adulthood. We also examine if the national status of women during childhood moderates the association between overall well-being of a country during childhood and DV perpetration in emerging adulthood, all while controlling for the individual effects of gender, violence approval, criminal history, neglect history, and anger management. The study's sample size included 4,280 people from 19 countries. Men reported less likelihood of perpetrating DV compared to women. Cross national comparative analysis revealed a significant interaction effect between country well-being and women status on DV perpetration (β = 0.69, p < .05) at the national level. When women's status was low or moderate, the well-being status showed an inverse effect on the probability of DV perpetration, but this direction switched in the face of high women's status. Contrary to previous research, higher women status may contribute to increased intimate partner violence (IPV) perpetration. Our findings underscore the existence of context-specific social conditions in relationship to IPV. Broad implications of the findings, potential explanations and directions for future research are discussed.


Miniaturized auto-focusing VCM actuator with zero holding current.
In keeping with consumers' preferences for electronic products of ever smaller size and enhanced functionality, it is necessary to reduce the profile of the auto-focusing actuators used in camera phones without sacrificing their performance. Accordingly, this study modifies the Voice Coil Motor (VCM) actuator proposed by the current group in a previous study (C. S. Liu and P. D. Lin, Opt. Express, 16, 2533-2540, 2008) to accomplish a miniaturized auto-focusing actuator for cell phone camera modules with minimal power consumption. The proposed device comprises a VCM, a closed-loop position control system, a magnetoconductive plate, and a lens support structure to drive the lens to the optimal focusing position. The experimental results show that the actuator has a zero holding current when maintaining the lens in the specified focusing position. Overall, it is shown that compared to existing VCM actuators, the proposed actuator has bo a higher power efficiency and an improved positioning repeatability.


Corticosteroids or ACTH for acute exacerbations in multiple sclerosis.
Corticosteroids are often used to improve the rate of recovery from acute exacerbation in multiple sclerosis (MS) patients. However, it is still unclear just how relatively effective these agents are and the type of drug, optimal dose, frequency, duration of treatment and route of administration are unknown. The object of this review was to determine the efficacy and safety of corticosteroids or ACTH in reducing the short and long term morbidity from MS. Moreover, we wished to examine from indirect comparisons if the effect of corticosteroids is different according to different doses and drugs, routes of administration, length of treatment. A search strategy developed for the Cochrane MS Group (last searched: June 1999) completed with handsearching and personal contacts with trialists and pharmaceutical companies was used. All randomised, double-blind, unconfounded trials comparing corticosteroids or ACTH to placebo in patients with MS, treated for acute exacerbations, without any age or severity restrictions, were evaluated. Two reviewers independently selected articles for inclusion, assessed trials' quality and extracted the data. A third reviewer cross-checked them and disagreements were resolved by a joint discussion. Six trials contributed to this review; a total of 377 participants (199 treatment, 178 placebo) were randomised. The drugs analysed were methylprednisolone (MP) (four trials, 140 patients) and ACTH (two trials, 237 patients). Overall, MP or ACTH showed a protective effect against the disease getting worse or stable within the first five weeks of treatment (odds ratio[OR]=0.37, 95% confidence interval [CI] 0.24-0.57) with some but non significant greater effect for MP and intravenous administration. Short (five days) or long (15 days) duration of treatment with MP did not show any significant difference. Only one study (with 51 patients) reported data after one year of follow-up: no difference between oral MP and placebo in the prevention of new exacerbations or improvement in long term disability was detected. No data are available beyond one year of follow-up to indicate whether steroids or ACTH have any effect on long-term progression. One study reported that a short term treatment with high dose intravenous MP was not attended by adverse events. On the contrary, gastrointestinal symptoms and psychic disorders were significantly more common in the oral, high-dose MP than in the placebo group. Weight gain and edema were significantly more frequent in the ACTH group than in controls. We found evidence favouring the corticosteroid MP for acute exacerbation in MS patients. Data are insufficient to reliably estimate effect of corticosteroids on prevention of new exacerbations and reduction of long-term disability. Studies assessing long term risk/benefit and adverse effects of corticosteroids in MS patients are urgently needed.


Emerging role of the host microbiome in neuropsychiatric disorders: overview and future directions.
The human body harbors a diverse ecosystem of microorganisms, including bacteria, viruses, and fungi, collectively known as the microbiota. Current research is increasingly focusing on the potential association between the microbiota and various neuropsychiatric disorders. The microbiota resides in various parts of the body, such as the oral cavity, nasal passages, lungs, gut, skin, bladder, and vagina. The gut microbiota in the gastrointestinal tract has received particular attention due to its high abundance and its potential role in psychiatric and neurodegenerative disorders. However, the microbiota presents in other body tissues, though less abundant, also plays crucial role in immune system and human homeostasis, thus influencing the development and progression of neuropsychiatric disorders. For example, oral microbiota imbalance and associated periodontitis might increase the risk for neuropsychiatric disorders. Additionally, studies using the postmortem brain samples have detected the widespread presence of oral bacteria in the brains of patients with Alzheimer's disease. This article provides an overview of the emerging role of the host microbiota in neuropsychiatric disorders and discusses future directions, such as underlying biological mechanisms, reliable biomarkers associated with the host microbiota, and microbiota-targeted interventions, for research in this field.


Apical hypertrophic cardiomyopathy: evaluation by noninvasive and invasive techniques in 23 patients.
Over a 3 year period we evaluated 23 patients (16 men, seven women) with apical hypertrophic cardiomyopathy by noninvasive and invasive methods. Sixteen patients had chest pain. In 17, results of cardiovascular examination were normal. The electrocardiogram showed precordial inverted T waves in all patients and these were of mild-to-moderate amplitude (less than 10 mm) in 18 and giant (greater than 10 mm) in five. M mode echocardiography revealed a typical pattern of contraction and relaxation in the apical region of the left ventricle that was associated with significant hypertrophy. These findings were confirmed by two-dimensional echocardiography. Systolic anterior motion of the mitral valve was not observed nor was there any evidence of obstruction of the left ventricular outflow tract. Results of Doppler echocardiographic study of the mitral and aortic flow were normal in all patients but one who had mild mitral insufficiency. Radionuclide studies of 14 patients revealed a mean left ventricular ejection fraction of 66 +/- 6% (range 55% to 79%), with normal left ventricular contraction in all patients but two with apical hypokinesis. In all six patients who underwent catheterization a characteristic appearance of the left ventricle at end-systole as well as abnormal end-diastolic contour were noted on the left ventricular angiogram, but the "ace of spades" configuration was seen in only one. We conclude that the 23 patients studied form a homogeneous group of individuals with nonobstructive apical hypertrophic cardiomyopathy, which differs in many respects from cardiomyopathies reported by other investigators.


Method to reduce undesired multiple fundus scattering effects in double-pass systems.
Double-pass systems rely on backscattering of light by the human ocular fundus to assess the optical quality of the eye. In this work, we present a method to reduce double-pass image degradation caused by undesired multiple scattering effects in the eye fundus. The reduction is based on combined data processing of simultaneous measurements using two different configurations: one symmetric with equal entrance and exit pupils and another asymmetric with unequal entrance and exit pupils. Under certain conditions, such scattering effects may be effectively suppressed. Measurements of human eyes show that, although multiple fundus scattering imposes a shift on the estimations, double-pass systems can be used to predict the optical quality of the eye within a population.


Leukotriene B4 and 8-isoprostane in exhaled breath condensate of children with episodic and persistent asthma.
Leukotrienes and isoprostanes are biomarkers of airway inflammation and oxidative stress that can be detected in exhaled breath condensate (EBC). The aim of this study was to evaluate leukotriene B4 (LTB4) and 8-isoprostane levels in EBC of healthy and asthmatic children with episodic and moderate persistent asthma. EBC was collected from 62 children aged 6 to 14 years: 22 healthy children, 30 patients with episodic asthma, and 10 patients with moderate persistent asthma, without preventive treatment at the time of enrolment. LTB concentrations were higher in children with asthma than in healthy controls (50.7 pg/mL vs. 13.68 pg/mL, P < .011). The same was true for children with moderate persistent asthma compared to children with episodic asthma (146.9 pg/mL vs. 18.85 pg/mL, P < .0001), children with moderate persistent asthma compared to healthy controls (146.9 pg/mL vs. 13.68 pg/mL, P < .0001), and children with episodic asthma compared to healthy controls (P, nonsignificant). EBC concentrations of 8-isoprostane were higher in asthmatic than in healthy children (18.3 pg/mL vs. 6.59 pg/mL, P < .026). They were also increased in children with moderate persistent asthma compared to those with episodic asthma (36.25 pg/mL and 12.28 pg/mL, P < .012), and in children with moderate persistent asthma and episodic asthma compared to healthy controls (36.25 pg/mL vs. 6.59 pg/mL [P < .0001] and 12.28 pg/mL versus 6.59 pg/mL [P < .0001], respectively). LTB4 and 8-isoprostane concentrations were increased in asthmatic children compared to healthy individuals, with differences detected for 2 degrees of asthma severity. Our findings suggest that EBC is a noninvasive method for airway inflammation and oxidative stress assessment.


[Interrelationship between functional interhemispheric asymmetry and photic stimulus contrast in the visual system of cats and rats].
Transformation of stimuli contrast in animal visual system was revealed in experiments on cats and rats anaesthetized with Nembutal. With zero contrast, there was an initial functional interhemispheric asymmetry (FIAs) of evoked potentials (EPs) in the fields 17 and 18. Dependence of the initial FIAs on stimulation intensity was defined. The sign of the initial EPs asymmetry was stable in cats (right hemisphere) and unstable in rats. Differences in interdependence between FIAs and contrast were found in both animals. In cats, in a wide range of stimuli contrasts, the sign and value of the interhemispheric asymmetry were stable and close to the initial FIAs; while in rats FIAs value directly depended on stimuli contrast and its sign corresponded to that of the contrast. The role of transcallosal influences in the formation of certain EPs FIAs properties was traced down. The discovered characteristics of contrasts transformation seem to contribute to a more reliable functioning of the visual system.


Positional vertigo afterwards maxillary dental implant surgery with bone regeneration.
Benign paroxysmal positional vertigo (BPPV) is the most common form of vertigo. It is caused by loose otoconia from the utricle which, in certain positions, displaced the cupula of the posterior semicircular canal. BPPV most often is a result of aging. It also can occur after a blow to the head. Less common causes include a prolonged positioning on the back (supine) during some surgical procedures. Additionally one can include in this ethiopathogenesis the positioning required during the maxillary dental implant surgery with bone regeneration related to a forced head positioning and inner ear trauma induced by dental turbine noise working in the maxillary bone. Two cases of patients who suffered BPPV after undergoing maxillary dental implant with bone regeneration procedures are reported. Diagnosis and treatment are also described.


Carbon-based catalysts for Fischer-Tropsch synthesis.
Fischer-Tropsch synthesis (FTS) is an essential approach to convert coal, biomass, and shale gas into fuels and chemicals, such as lower olefins, gasoline, diesel, and so on. In recent years, there has been increasing motivation to deploy FTS at commercial scales which has been boosting the discovery of high performance catalysts. In particular, the importance of support in modulating the activity of metals has been recognized and carbonaceous materials have attracted attention as supports for FTS. In this review, we summarised the substantial progress in the preparation of carbon-based catalysts for FTS by applying activated carbon (AC), carbon nanotubes (CNTs), carbon nanofibers (CNFs), carbon spheres (CSs), and metal-organic frameworks (MOFs) derived carbonaceous materials as supports. A general assessment of carbon-based catalysts for FTS, concerning the support and metal properties, activity and products selectivity, and their interactions is systematically discussed. Finally, current challenges and future trends in the development of carbon-based catalysts for commercial utilization in FTS are proposed.


miR-181b-1-3p affects the proliferation and differentiation of chondrocytes in TD broilers through the WIF1/Wnt/β-catenin pathway.
Thiram is a plant fungicide, its excessive use has exceeded the required environmental standards. It causes tibial dyschondroplasia (TD) in broilers which is a common metabolic disease that affects the growth plate of tibia bone. It has been studied that many microRNAs (miRNAs) are involved in the differentiation of chondrocytes however, their specific roles and mechanisms have not been fully investigated. The selected features of tibial chondrocytes of broilers were studied in this experiment which included the expression of miR-181b-1-3p and the genes related to WIF1/Wnt/β-catenin pathway in chondrocytes through qRT-PCR, western blot and immunofluorescence. The correlation between miR-181b-1-3p and WIF1 was determined by dual luciferase reporter gene assay whereas, the role of miR-181b-1-3p and WIF1/Wnt/β-catenin in chondrocyte differentiation was determined by mimics and inhibitor transfection experiments. Results revealed that thiram exposure resulted in decreased expression of miR-181b-1-3p and increased expression of WIF1 in chondrocytes. A negative correlation was also observed between miR-181b-1-3p and WIF1. After overexpression of miR-181b-1-3p, the expression of ACAN, β-catenin and Col2a1 increased but the expression of GSK-3β decreased. It was observed that inhibition of WIF1 increased the expression of ALP, β-catenin, Col2a1 and ACAN but decreased the expression of GSK-3β. It is concluded that miR-181b-1-3p can reverse the inhibitory effect of thiram on cartilage proliferation and differentiation by inhibiting WIF1 expression and activating Wnt/β-catenin signaling pathway. This study provides a new molecular target for the early diagnosis and possible treatment of TD in broilers.


Profile of patients presenting at a low vision clinic in a developing country.
Low vision is an important public health problem; however, very few low vision clinics are available to address the needs of low vision patients in most developing countries. The purpose of this study was to describe the characteristics of patients attending the low vision clinic of a Nigerian tertiary hospital. This was a prospective cross sectional study of all new patients seen at the low vision clinic over a 36 month period. Patients were administered with a structured questionnaire, and were examined and tested with low vision devices by the attending low vision specialist. Information on the demographic and clinical characteristics of the patients was recorded. A total of 193 new patients seen during the period were studied. The mean age was 41.4 years, and their ages ranged between 6 and 90 years with a male to female ratio of 1.9:1. Majority (58%) were aged below 50 years, 23.3% were children (≤ 15 years), while 21.8% were elderly patients (≥ 65 years). The commonest cause of low vision was retinitis pigmentosa (16.6%); 14.5% had age related macular degeneration (ARMD); 9.8% had albinism; while only 1% had diabetic retinopathy. ARMD (45.2%) was the commonest cause in the elderly patients, while albinism (24.4%) and optic atrophy (24.4%) were the commonest in children. The demographic and clinical characteristics of low vision patients seen in this clinic are similar to that of patients in other developing countries, but different from those in developed countries. Elderly patients and females may be under-utilising low vision services. There is a need for further research into the determinants of low vision service utilisation in developing countries. This would further aid the planning and delivery of services to low vision patients in these countries.


Dual blockade of the A1 and A2A adenosine receptor prevents amyloid beta toxicity in neuroblastoma cells exposed to aluminum chloride.
In a previous work we have shown that exposure to aluminum (Al) chloride (AlCl3) enhanced the neurotoxicity of the amyloid beta(25-35) fragment (Abeta(25-35)) in neuroblastoma cells and affected the expression of Alzheimer's disease (AD)-related genes. Caffein, a compound endowed with beneficial effects against AD, exerts neuroprotection primarily through its antagonist activity on A2A adenosine receptors (A2AR), although it also inhibits A1Rs with similar potency. Still, studies on the specific involvement of these receptors in neuroprotection in a model of combined neurotoxicity (Abeta(25-35)+AlCl3) are missing. To address this issue, cultured SH-SY5Y cells exposed to Abeta(25-35)+AlCl3 were assessed for cell viability, morphology, intracellular ROS activity and expression of apoptosis-, stress- and AD-related proteins. To define the role of A1R and A2ARs, pretreatment with caffein, specific receptor antagonists (DPCPX or SCH58261) or siRNA-mediated gene knockdown were delivered. Results indicate that AlCl3 treatment exacerbated Abeta(25-35) toxicity, increased ROS production, lipid peroxidation, β-secretase-1 (BACE1) and amyloid precursor protein (APP). Interestingly, SCH58261 successfully prevented toxicity associated to Abeta(25-35) only, whereas pretreatment with both DPCPX and SCH58261 was required to fully avert Abeta(25-35)+AlCl3-induced damage, suggesting that A1Rs might also be critically involved in protection during combined toxicity. The effects of caffein were mimicked by both N-acetyl cysteine, an antioxidant, and desferrioxamine, likely acting through distinct mechanisms. Altogether, our data establish a novel protective function associated with A1R inhibition in the setting of combined Abeta(25-35)+AlCl3 neurotoxicity, and expand our current knowledge on the potential beneficial role of caffein to prevent AD progression in subjects environmentally exposed to aluminum.


Disparities in underserved white populations: the case of cancer-related disparities in Appalachia.
There are meaningful cancer-related disparities in the Appalachian region of the U.S. To address these disparities, the Appalachia Community Cancer Network (ACCN), a collaboration of investigators and community partners in five states (Kentucky, Ohio, Pennsylvania, Virginia, and West Virginia), is involved in increasing cancer education and awareness, conducting community-based participatory research (CBPR), and creating mentorship and training opportunities. The primary objective of this paper is to describe cancer-related disparities in the Appalachian region of the U.S. as an example of the disparities experienced by underserved, predominantly white, rural populations, and to describe ACCN activities designed to intervene regarding these disparities. An ACCN overview/history and the diverse activities of ACCN-participating states are presented in an effort to suggest potential useful strategies for working to reduce health-related disparities in underserved white populations. Strengths that have emerged from the ACCN approach (e.g., innovative collaborations, long-standing established networks) and remaining challenges (e.g., difficulties with continually changing communities, scarce resources) are described. Important recommendations that have emerged from the ACCN are also presented, including the value of allowing communities to lead CBPR efforts. Characteristics of the community-based work of the ACCN provide a framework for reducing health-related disparities in Appalachia and in other underserved white and rural populations.


The effect of acute organophosphate intoxication on female rat hippocampus cornu ammonis region pyramidal neuron numbers, biochemistry and morphology.
The most commonly used insecticides and pesticides worldwide are organophosphate compounds, chemicals that irreversibly inhibit the cholinesterase enzyme. Acute intoxication with cholinesterase inhibitors is known to cause permanent effects on both the human and rat brains. To investigate the effect of acute organophosphate intoxication on hippocampus morphology, biochemistry, and pyramidal neuron numbers in female rats. Twenty-one rats were randomly divided into three groups. The control group received normal nutrition and underwent no procedures. The sham group received intraperitoneal physiological serum, while the experimental group received intraperitoneal 0.8 g/kg fenthion. Rats were sacrificed 24 h after these procedures. The brains were removed and divided in two halves medially, with one side being kept in 10% neutral formalin. After fixation procedures, tissues were embedded in blocks, sliced, and stained. A neuron count was then performed for the hippocampus. The other hippocampus was homogenized and used for biochemical procedures. Hippocampus sections from rats in the experimental group exhibited swelling and loss of shape in pyramidal cells, while no changes were observed in the control or sham groups. The number of neurons in the experimental group was lower than in the control and sham groups. Biochemical analysis revealed higher MDA and GSH values in the experimental group compared to the control and sham groups. Our results show increased apoptotic neurodegeneration of cells in the cornu ammonis region of the hippocampus and changes in biochemical values in rats with acute organophosphate exposure.


Simulations for parallel processing of ultrasound reflection-mode tomography with applications to two-phase flow measurement.
An evaluation of the application of a parallel-processing array to the measurement of two-phase flow, such as bubbly oil flow through a pipe, in real-time is described. Pulse-echo ultrasound tomography is used to generate a cross-sectional image of the flow that forms the basis for the deduction of flow parameters, such as the void fraction. The tomographic algorithm used is backprojection adapted for execution on an array of parallel-processing devices. It is shown that real-time reconstruction is feasible using the concepts of parallel processing. Different sensor arrangements were investigated by computer simulation. It is shown that a special multisegment sensor results in a significant improvement in signal-to-noise ratio and image quality and that the reconstructed image benefits from the concurrent activation of multiple receivers per transmitted pulse. The findings may also be useful for nondestructive testing and medical applications.


A call for greater conceptual clarity in the field of mental health and psychosocial support in humanitarian settings.
When the Interagency Standing Committee (IASC) adopted the composite term mental health and psychosocial support (MHPSS) and published its guidelines for MHPSS in emergency settings in 2007, it aimed to build consensus and strengthen coordination among relevant humanitarian actors. The term MHPSS offered an inclusive tent by welcoming the different terminologies, explanatory models and intervention methods of diverse actors across several humanitarian sectors (e.g., health, protection, education, nutrition). Since its introduction, the term has become well-established within the global humanitarian system. However, it has also been critiqued for papering over substantive differences in the intervention priorities and conceptual frameworks that inform the wide range of interventions described as MHPSS. Our aims are to clarify those conceptual frameworks, to argue for their essential complementarity and to illustrate the perils of failing to adequately consider the causal models and theories of change that underlie our interventions. We describe the historical backdrop against which the term MHPSS and the IASC guidelines were developed, as well as their impact on improving relations and coordination among different aid sectors. We consider the conceptual fuzziness in the field of MHPSS and the lack of clear articulation of the different conceptual frameworks that guide interventions. We describe the explanatory models and intervention approaches of two primary frameworks within MHPSS, which we label clinical and social-environmental. Using the examples of intimate partner violence and compromised parenting in humanitarian settings, we illustrate the complementarity of these two frameworks, as well as the challenges that can arise when either framework is inappropriately applied. Clinical interventions prioritise the role of intrapersonal variables, biological and/or psychological, as mediators of change in the treatment of distress. Social-environmental interventions emphasise the role of social determinants of distress and target factors in the social and material environments in order to lower distress and increase resilience in the face of adversity. Both approaches play a critical role in humanitarian settings; however, the rationale for adopting one or the other approach is commonly insufficiently articulated and should be based on a thorough assessment of causal processes at multiple levels of the social ecology. Greater attention to the 'why' of our intervention choices and more explicit articulation of the causal models and theories of change that underlie those decisions (i.e., the 'how'), may strengthen intervention effects and minimise the risk of applying the inappropriate framework and actions to a particular problem.


A case report of adrenocorticotropic hormone to treat recurrent focal segmental glomerular sclerosis post-transplantation and biomarker monitoring.
Recurrent focal segmental glomerular sclerosis (rFSGS) in renal transplant recipients (RTR) is difficult to predict and treat. Early rFSGS is likely from circulating factors and preformed antibodies. We present the case of a 23-year-old white man who presented with rFSGS and acute renal failure, requiring dialysis 9-months after a 1-haplotype matched living-related transplant. We retrospectively analyzed serum samples from various clinical stages for rFSGS biomarkers: serum glomerular albumin permeability (Palb), soluble urokinase-type plasminogen activator receptor (suPAR) serum level with suPAR-β3 integrin signaling on human podocytes, and angiotensin II type I receptor-antibody (AT1R-Ab) titer. All biomarkers were abnormal at 1-year pre-transplant prior to initiation of dialysis and at the time of transplant. After initiation of hemodialysis, β3 integrin activity on human podocytes, in response to patient serum, as well as AT1R-Ab were further elevated. At the time of biopsy-proven recurrence, all biomarkers were abnormally high. One week after therapy with aborted plasmapheresis (secondary to intolerance), and high dose steroids, the Palb and suPAR-β3 integrin activity remained significantly positive. After 12-weeks of treatment with high-dose steroids, rituximab, and galactose, the patient remained hemodialysis-dependent. Three-months after his initial presentation, we commenced adrenocorticotropic hormone (ACTH, Acthar(®) Gel), 80 units subcutaneously twice weekly. Four-weeks later, he was able to discontinue dialysis. After 8-months of maintenance ACTH therapy, his serum creatinine stabilized at 1.79 mg/dL with <1 g of proteinuria. ACTH therapy was associated with improvement in renal function within 4 weeks. The use of rFSGS biomarkers may aid in predicting development of rFSGS.


An Evaluation of the Numbers and Locations of Coronary Artery Disease with Some of the Major Atherosclerotic Risk Factors in Patients with Coronary Artery Disease.
Despite definite recognition of major atherosclerotic risk factors, the relationship between the pattern of coronary artery disease and these risk factors is unknown. The aim of this study was to identify the relationship between some of the major atherosclerotic risk factors and the number and pattern of coronary artery disease in patients with coronary artery disease who presented to Farshchian Heart University Hospital, Hamadan, Iran. In this descriptive cross-sectional study, we investigated some of the major atherosclerotic risk factors and their relationships with the type of coronary artery disease in terms of number and location of disease. A total of 1100 patients were enrolled with coronary artery disease confirmed by selective coronary angiography from 2010-2014. A p-value<0.05 was considered statistically significant. A total of 1100 patients enrolled in this study. The patient population consisted of 743 (67.5%) males and 357 (32.5%) females. A meaningful relationship existed between ageing, diabetes mellitus, hypertension and 3-Vessel Disease (3VD, p<0.001) as well as between hyperlipidemia and Single Vessel Disease (SVD, p<0.001). Patients diagnosed with diabetes mellitus, hypertension, and hyperlipidemia showed greater potential to develop coronary artery disease at the proximal section of the coronary arteries. Based on the relationship between some of the major risk factors and the pattern of coronary artery disease in the current study, prospective studies should investigate other risk factors. We recommend that a plan should be developed to reduce adjustable risk factors such as diabetes mellitus, hypertension and hyperlipidemia in order to decrease coronary artery disease.


Aldose reductase inhibitor, fidarestat regulates mitochondrial biogenesis via Nrf2/HO-1/AMPK pathway in colon cancer cells.
Although we have shown earlier that aldose reductase (AR) inhibitors prevent colorectal cancer cell (CRC) growth in culture as well as in nude mice xenografts, the mechanism(s) is not well understood. In this study, we have investigated how AR inhibition prevents CRC growth by regulating the mitochondrial biogenesis via Nrf2/HO-1 pathway. Incubation of CRC cells such as SW-480, HT29, and HCT116 with AR inhibitor, fidarestat that non-covalently binds to the enzyme, increases the expression of Nrf2. Further, fidarestat augmented the EGF-induced expression of Nrf2 in CRC cells. Fidarestat also increased the Nrf2 -DNA binding activity as well as expression of HO-1 and NQO1 and activation of SOD and catalase in SW480 cells. Similarly, in nude mice xenograft tumor tissues, Nrf2 and HO-1 levels were significantly higher in fidarestat-treated mice compared to controls. Further, stimulation of CRC cells with EGF in the presence of fidarestat increased the mRNA levels of PGC-1α, Nrf1 and TFAM and protein levels of PGC-1α, TFAM and COX-IV and decreased the mitochondrial DNA damage as measured by 8-hydroxy-2'-deoxyguanosine levels. AR inhibitor also modulated the phosphorylations of AMPK and mTOR and expression of p53 in EGF-treated cells. Collectively, our results indicate that AR inhibitor prevents CRC growth by increasing mitochondrial biogenesis via increasing the expression of Nrf2/HO-1/AMPK/p53 and decreasing the mitochondrial DNA damage.


Lateropulsion After Hemispheric Stroke: A Form of Spatial Neglect Involving Graviception.
To test the hypothesis that lateropulsion is an entity expressing an impaired body orientation with respect to gravity in relation to a biased graviception and spatial neglect. Data from the DOBRAS cohort (ClinicalTrials.gov: NCT03203109) were collected 30 days after a first hemisphere stroke. Lateral body tilt, pushing, and resistance were assessed with the Scale for Contraversive Pushing. Among 220 individuals, 72% were upright and 28% showed lateropulsion (tilters [14%] less severe than pushers [14%]). The 3 signs had very high factor loadings (>0.90) on a same dimension, demonstrating that lateropulsion was effectively an entity comprising body tilt (cardinal sign), pushing, and resistance. The factorial analyses also showed that lateropulsion was inseparable from the visual vertical (VV), a criterion referring to vertical orientation (graviception). Contralesional VV biases were frequent (44%), with a magnitude related to lateropulsion severity: upright -0.6° (-2.9; 2.4), tilters -2.9° (-7; 0.8), and pushers -12.3° (-15.4; -8.5). Ipsilesional VV biases were less frequent and milder (p < 0.001). They did not deal with graviception, 84% being found in upright individuals. Multivariate, factorial, contingency, and prediction analyses congruently showed strong similarities between lateropulsion and spatial neglect, the latter encompassing the former. Lateropulsion (pusher syndrome) is a trinity constituted by body tilt, pushing, and resistance. It is a way to adjust the body orientation in the roll plane to a wrong reference of verticality. Referring to straight above, lateropulsion might correspond to a form of spatial neglect (referring to straight ahead), which would advocate for 3D maps in the human brain involving the internal model of verticality.


Key residues controlling phenacetin metabolism by human cytochrome P450 2A enzymes.
Cytochrome P450s (P450s) metabolize a large number of diverse substrates with specific regio- and stereospecificity. A number of compounds, including nicotine, cotinine, and aflatoxin B(1), are metabolites of the 94% identical CYP2A13 and CYP2A6 enzymes but at different rates. Phenacetin and 4-aminobiphenyl were identified as substrates of human cytochromes P450 1A2 and 2A13 but not of CYP2A6. The purpose of this study was to identify active site amino acids that are responsible for CYP2A substrate specificity using phenacetin as a structural probe. Ten amino acid residues that differ in the CYP2A13 and CYP2A6 active sites were exchanged between the two enzymes. Phenacetin binding revealed that the six substitution, CYP2A13 S208I, A213S, F300I, A301G, M365V, and G369S decreased phenacetin affinity. Although incorporation of individual CYP2A13 residues into CYP2A6 had little effect on this enzyme's very low levels of phenacetin metabolism, the combination of double, triple, and quadruple substitutions at positions 208, 300, 301, and 369 increasingly endowed CYP2A6 with the ability to metabolize phenacetin. Enzyme kinetics revealed that the CYP2A6 I208S/I300F/G301A/S369G mutant protein O-deethylated phenacetin with a K(m) of 10.3 muM and a k(cat) of 2.9 min(-1), which compare very favorably with those of CYP2A13 (K(m) of 10.7 muM and k(cat) of 3.8 min(-1)). A 2.15 A crystal structure of the mutant CYP2A6 I208S/I300F/G301A/S369G protein with phenacetin in the active site provided a structural rationale for the differences in phenacetin metabolism between CYP2A6 and CYP2A13.


Ginsenoside F1 promotes angiogenesis by activating the IGF-1/IGF1R pathway.
Ischemic stroke is one of the most lethal and highly disabling diseases that seriously affects the human health and quality of life. A therapeutic angiogenic strategy has been proposed to alleviate ischemia-induced injury by promoting angiogenesis and improving cerebrovascular function in the ischemic regions. The insulin-like growth factor 1 (IGF-1)/insulin-like growth factor 1 receptor (IGF1R) axis is crucial for cerebral angiogenesis and neurogenesis. However, effective drugs that prevent cerebral ischemic injury by inducing cerebral angiogenesis via activation of the IGF1R pathway are lacking. Here, we screened a pro-angiogenic agent ginsenoside F1 (GF1), a ginseng saponin isolated from a traditional Chinese medicine that was widely used in ischemic stroke treatment. It promoted the proliferation, mobility and tube formation of human umbilical vein endothelial cells and human brain microvascular endothelial cells, as well as pericytes recruitment to the endothelial tubes. GF1 stimulated vessel sprouting in the rat arterial ring and facilitated neovascularization in chicken embryo chorioallantoic membrane (CAM). In the in vivo experiments, GF1 rescued the axitinib-induced vascular defect in zebrafish. It also increased the microvessel density (MVD) and improved focal cerebral blood perfusion in the rat middle cerebral artery occlusion (MCAO) model. Mechanism studies revealed that GF1-induced angiogenesis depended on IGF1R activation mediated by the autocrine IGF-1 loop in endothelial cells. Based on our findings, GF1-induced activation of the IGF-1/IGF1R pathway to promote angiogenesis is an effective approach to alleviate cerebral ischemia, and GF1 is a potential agent that improves cerebrovascular function and promotes recovery from ischemic stroke.


Glioblastoma survival is associated with distinct proteomic alteration signatures post chemoirradiation in a large-scale proteomic panel.
Glioblastomas (GBM) are rapidly progressive, nearly uniformly fatal brain tumors. Proteomic analysis represents an opportunity for noninvasive GBM classification and biological understanding of treatment response. We analyzed differential proteomic expression pre vs. post completion of concurrent chemoirradiation (CRT) in patient serum samples to explore proteomic alterations and classify GBM by integrating clinical and proteomic parameters. 82 patients with GBM were clinically annotated and serum samples obtained pre- and post-CRT. Serum samples were then screened using the aptamer-based SOMAScan® proteomic assay. Significant traits from uni- and multivariate Cox models for overall survival (OS) were designated independent prognostic factors and principal component analysis (PCA) was carried out. Differential expression of protein signals was calculated using paired t-tests, with KOBAS used to identify associated KEGG pathways. GSEA pre-ranked analysis was employed on the overall list of differentially expressed proteins (DEPs) against the MSigDB Hallmark, GO Biological Process, and Reactome databases with weighted gene correlation network analysis (WGCNA) and Enrichr used to validate pathway hits internally. 3 clinical clusters of patients with differential survival were identified. 389 significantly DEPs pre vs. post-treatment were identified, including 284 upregulated and 105 downregulated, representing several pathways relevant to cancer metabolism and progression. The lowest survival group (median OS 13.2 months) was associated with DEPs affiliated with proliferative pathways and exhibiting distinct oppositional response including with respect to radiation therapy related pathways, as compared to better-performing groups (intermediate, median OS 22.4 months; highest, median OS 28.7 months). Opposite signaling patterns across multiple analyses in several pathways (notably fatty acid metabolism, NOTCH, TNFα via NF-κB, Myc target V1 signaling, UV response, unfolded protein response, peroxisome, and interferon response) were distinct between clinical survival groups and supported by WGCNA. 23 proteins were statistically signficant for OS with 5 (NETO2, CST7, SEMA6D, CBLN4, NPS) supported by KM. Distinct proteomic alterations with hallmarks of cancer, including progression, resistance, stemness, and invasion, were identified in serum samples obtained from GBM patients pre vs. post CRT and corresponded with clinical survival. The proteome can potentially be employed for glioma classification and biological interrogation of cancer pathways.


Diffusion tensor imaging detects areas of abnormal white matter microstructure in patients with partial ornithine transcarbamylase deficiency.
OTCD, an X-linked disorder, is the most common of the UCDs. Neonatal onset is associated with uniformly poor outcome. Males with late-onset OTCD show deficits in executive function, motor planning, and working memory. A broad phenotype is observed in heterozygous females. A specific neurobehavioral phenotype with white matter dysfunction and impaired attention and working memory has been described. The extent to which the deficits involve specific pathways in the brain is unknown. We hypothesized that DTI would disclose white matter microstructure in OTCD correlating with cognitive deficits. Nineteen adults with partial OTCD and 18 adult control subjects ages 19-59 years participated. MR imaging was performed by using a 3T whole-body scanner. Anisotropy was calculated from the eigenvalues of the diffusion tensor by using the FA metric and was compared between the study and control groups. FA of the frontal white matter was significantly decreased in subjects, indicating changes in white matter microstructure. There was an inverse relationship between FA and disease severity, but not with age. Findings of MR imaging in OTCD are often normal in patients with late-onset disease, heterozygotes, or in those not in hyperammonemic crisis. DTI was more sensitive than FSE T2-weighted imaging for detecting abnormalities in normal-appearing white matter. The extent of abnormality correlated with cognitive deficits. The location of the deficits in the frontal white matter is important because this area connects fibers that are vital to executive function, attention, and working memory.


Cellular uptake and biological activity of peptide nucleic acids conjugated with peptides with and without cell-penetrating ability.
A 12-mer peptide nucleic acid (PNA) directed against the nociceptin/orphanin FQ receptor mRNA was disulfide bridged with various peptides without and with cell-penetrating features. The cellular uptake and the antisense activity of these conjugates were assessed in parallel. Quantitation of the internalized PNA was performed by using an approach based on capillary electrophoresis with laser-induced fluorescence detection (CE-LIF). This approach enabled a selective assessment of the PNA moiety liberated from the conjugate in the reducing intracellular environment, thus avoiding bias of the results by surface adsorption. The biological activity of the conjugates was studied by an assay based on the downregulation of the nociceptin/orphanin FQ receptor in neonatal rat cardiomyocytes (CM). Comparable cellular uptake was found for all conjugates and for the naked PNA, irrespective of the cell-penetrating properties of the peptide components. All conjugates exhibited a comparable biological activity in the 100 nM range. The naked PNA also exhibited extensive antisense activity, which, however, proved about five times lower than that of the conjugates. The found results suggest cellular uptake and the bioactivity of PNA-peptide conjugates to be not primarily related to the cell-penetrating ability of their peptide components. Likewise from these results it can be inferred that the superior bioactivity of the PNA-peptide conjugates in comparison with that of naked PNA rely on as yet unknown factors rather than on higher membrane permeability. Several hints point to the resistance against cellular export and the aggregation propensity combined with the endocytosis rate to be candidates for such factors.


Influence of Xiaoyaosan on depressive-like behaviors in chronic stress-depressed rats through regulating tryptophan metabolism in hippocampus.
Tryptophan metabolism has always been considered to play a vital role in mental disorder diseases, and how traditional Chinese formula Xiaoyaosan regulates the tryptophan metabolism is a complement to the pathogenesis of depression. This study established a depression rat model by the chronic immobilization stress (CIS) method and observed the change in tryptophan metabolism in hippocampus and the effects of Xiaoyaosan. Forty-eight male Sprague Dawley (SD) rats were randomly divided into the following four groups: control group, CIS group, Xiaoyaosan group, and fluoxetine group. The depression model was established by the 21-day CIS. The food intake and body weight were recorded, and the sucrose preference test (SPT), novelty suppressed feeding (NSF) test and open field test (OFT) were also used to evaluate the model. Then, the contents of tryptophan and 5-hydroxytryptamine (5-HT) in hippocampus were detected by the ELISA method, and the expression levels of tryptophan hydrogenase 2 (TPH2) and indoleamine 2,3-dioxygenase 1 (IDO1) in hippocampus were determined by quantitative reverse transcriptase polymerase chain reaction reaction (qRT-PCR) and Western blot methods. The behavioral data showed a significant difference between the model group and the normal group. The 5-HT content in the hippocampi of CIS rats was significantly reduced, whereas the tryptophan content in the hippocampi of model rats was significantly increased. The TPH2 level in hippocampus of the model group was significantly decreased, and the IDO1 level was significantly increased. Xiaoyaosan and fluoxetine could significantly reverse these changes and had obvious curative effects. The abnormal tryptophan metabolism existed in the hippocampi of chronic stress-depressed rats, which was closely related to the pathogenesis of depression. Xiaoyaosan could improve the tryptophan metabolism by regulating the expression levels of TPH2 and IDO1, thus exerting an antidepressant-like effect.


A real-time and self-calibrating algorithm based on triaxial accelerometer signals for the detection of human posture and activity.
Assessment of human activity and posture with triaxial accelerometers provides insightful information about the functional ability: classification of human activities in rehabilitation and elderly surveillance contexts has been already proposed in the literature. In the meanwhile, recent technological advances allow developing miniaturized wearable devices, integrated within garments, which may extend this assessment to novel tasks, such as real-time remote surveillance of workers and emergency operators intervening in harsh environments. We present an algorithm for human posture and activity-level detection, based on the real-time processing of the signals produced by one wearable triaxial accelerometer. The algorithm is independent of the sensor orientation with respect to the body. Furthermore, it associates to its outputs a "reliability" value, representing the classification quality, in order to launch reliable alarms only when effective dangerous conditions are detected. The system was tested on a customized device to estimate the computational resources needed for real-time functioning. Results exhibit an overall 96.2% accuracy when classifying both static and dynamic activities.


Melanoma: a model for testing new agents in combination therapies.
Treatment for both early and advanced melanoma has changed little since the introduction of interferon and IL-2 in the early 1990s. Recent data from trials testing targeted agents or immune modulators suggest the promise of new strategies to treat patients with advanced melanoma. These include a new generation of B-RAF inhibitors with greater selectivity for the mutant protein, c-Kit inhibitors, anti-angiogenesis agents, the immune modulators anti-CTLA4, anti-PD-1, and anti-CD40, and adoptive cellular therapies. The high success rate of mutant B-RAF and c-Kit inhibitors relies on the selection of patients with corresponding mutations. However, although response rates with small molecule inhibitors are high, most are not durable. Moreover, for a large subset of patients, reliable predictive biomarkers especially for immunologic modulators have not yet been identified. Progress may also depend on identifying additional molecular targets, which in turn depends upon a better understanding of the mechanisms leading to response or resistance. More challenging but equally important will be understanding how to optimize the treatment of individual patients using these active agents sequentially or in combination with each other, with other experimental treatment, or with traditional anticancer modalities such as chemotherapy, radiation, or surgery. Compared to the standard approach of developing new single agents for licensing in advanced disease, the identification and validation of patient specific and multi-modality treatments will require increased involvement by several stakeholders in designing trials aimed at identifying, even in early stages of drug development, the most effective way to use molecularly guided approaches to treat tumors as they evolve over time.


Natural genetic variation of Arabidopsis thaliana is geographically structured in the Iberian peninsula.
To understand the demographic history of Arabidopsis thaliana within its native geographical range, we have studied its genetic structure in the Iberian Peninsula region. We have analyzed the amount and spatial distribution of A. thaliana genetic variation by genotyping 268 individuals sampled in 100 natural populations from the Iberian Peninsula. Analyses of 175 individuals from 7 of these populations, with 20 chloroplast and nuclear microsatellite loci and 109 common single nucleotide polymorphisms, show significant population differentiation and isolation by distance. In addition, analyses of one genotype from 100 populations detected significant isolation by distance over the entire Iberian Peninsula, as well as among six Iberian subregions. Analyses of these 100 genotypes with different model-based clustering algorithms inferred four genetic clusters, which show a clear-cut geographical differentiation pattern. On the other hand, clustering analysis of a worldwide sample showed a west-east Eurasian longitudinal spatial gradient of the commonest Iberian genetic cluster. These results indicate that A. thaliana genetic variation displays significant regional structure and consistently support the hypothesis that Iberia has been a glacial refugium for A. thaliana. Furthermore, the Iberian geographical structure indicates a complex regional population dynamics, suggesting that this region contained multiple Pleistocene refugia with a different contribution to the postglacial colonization of Europe.


[Episodic memory in Alzheimer's disease: decline in recollection and familiarity?].
According to the dual-process recognition models, the retrieval of information from long-term memory is supported by recollection and familiarity. Alzheimer's disease is consistently found to affect recollection. As for familiarity, however, no consensus has been reached so far. Some studies are in favor of an early impairment of familiarity, while others are in favor of a preservation of familiarity in the mild and moderate stages of the disease. This lack of consensus can be partly explained by methodological differences between studies. We discuss three methodological dimensions: the type of recognition test, the type of paradigm for estimating familiarity and recollection, and the nature of the material used. These differences reveal the complex nature of familiarity which would be underlied by different mechanisms that may be -selectively altered or preserved in the disease.