Validation of diabetes medication self-efficacy scale in Chinese with type 2 diabetes.
Greater diabetes medication self-efficacy has been shown to associate with better medication adherence, which is critical for disease control for people living with type 2 diabetes (T2D). The Diabetes Medication Self-efficacy Scale (DMSS) is a 19-item instrument to measure diabetes medication self-efficacy. The aim of the current study was to translate the DMSS into Chinese and validate the Chinese version of DMSS (CDMSS) among Chinese T2D patients. The CDMSS was translated using forward-backward method, and its validity and reliability were assessed among 257 Chinese T2D patients. Exploratory factor analysis, Cronbach's α and Spearman's rank correlation coefficients were used to evaluate the psychometric properties of CDMSS. Receiver operating characteristic analysis was used to assess the discrimination of CDMSS for medication adherence and glycemic control. Exploratory factor analysis has generated a one-factor structure of the 11-item version of CDMSS (CDMSS-11), which accounted for 63.1% of the variance. The Spearman's rank correlation coefficient between the original 19-item and 11-item scale was 0.96. The Cronbach's α for internal consistency was 0.94, and the test-retest reliability coefficient was 0.76. The CDMSS-11 score was significantly correlated with diabetes distress, medication adherence, as well as blood levels of fasting plasma glucose and hemoglobin A1c (both P<0.001). The area under receiver operating characteristic curve and its corresponding 95% CI was 0.79 (0.73-0.84) for medication adherence, and it was 0.65 (0.57-0.72) for better glycemic control. The CDMSS-11 is a valid and reliable measure to assess medication self-efficacy among Chinese T2D patients.


Association Between Self-Rated Medication Adherence and Adverse Cardiovascular Outcomes in Patients With Hypertension.
Background Medication nonadherence contributes to poor health outcomes but remains challenging to identify. This study assessed the association between self-rated adherence and systolic blood pressure, low-density lipoprotein cholesterol levels, cardiovascular events, and all-cause mortality in SPRINT (Systolic Blood Pressure Intervention Trial). Methods and Results A total of 9361 patients randomized to 2 systolic blood pressure target groups, <120 mm Hg (intensive) and <140 mm Hg (standard), self-rated their medication adherence at each visit by marking a scale, ranging from 0% to 100%. Lower and high adherence were defined as scores ≤80% and >80%, respectively. Linear mixed effect regression models and Cox proportional hazard models were used to evaluate the association between self-rated adherence and systolic blood pressure and low-density lipoprotein cholesterol and cardiovascular events and all-cause mortality, respectively. A total of 9278 participants (mean age 68±9.4 years, 35.6% female) had repeated self-rated adherence measurements available, with a mean of 15±4 measurements per participant over 3.8 years follow-up. Of these, 2694 participants (29.0%) had ≥1 adherence measurements ≤80%. Compared with high-adherent patients, patients with lower adherence had significantly higher estimated on-treatment systolic blood pressure at 2-year follow-up: 128.7 (95% CI, 127.6-129.9) versus 120.0 (95% CI, 119.7-120.2) mm Hg in the intensive arm; and 139.8 (95% CI 138.4-141.1) versus 135.0 (95% CI 134.7-135.2) in the standard arm. Moreover, lower adherence was associated with an estimated 11 mg/dL higher low-density lipoprotein cholesterol level, more cardiovascular events (hazard ratio [HR], 1.69 [95% CI, 1.20-2.39]), and higher all-cause mortality (HR, 1.63 [95% CI, 1.16-2.31]). Conclusions Self-rated adherence allows identification of lower medication adherence and correlates with blood pressure control, low-density lipoprotein cholesterol levels, and adverse outcomes.


Prevalence of tobacco use among power loom workers - a cross-sectional study.
Tobacco use is a major public health problem globally. According to the World Health Organization (WHO), tobacco is the second most important cause of death in the world. It is currently estimated to be responsible for about 5 million deaths each year worldwide. In India, it is responsible for over 8 lakh deaths every year. To estimate the prevalence of tobacco use among power loom workers in Mau Aima Town, District Allahabad, UP. Five hundred power loom workers were randomly chosen. Out of them 448 workers were interviewed through a questionnaire survey during May-June 2007. Data on demographics, education, and type of work were collected along with details regarding tobacco use and smoking status, duration of the habit, and daily consumption. Prevalence of tobacco chewing and/or bidi and cigarette smoking, and their sociodemographic correlates, were examined. The overall prevalence of tobacco use was 85.9%; the prevalence of smoking and tobacco chewing were 62.28% and 66.07%, respectively. Statistical analysis showed that smoking is more common in the elderly, while chewing gutka (a type of chewing tobacco) is popular among the younger age-groups. The prevalence of tobacco use among power loom workers is very high compared to that in general population. Immediate intervention programs are warranted to reduce the future burden of tobacco-related morbidity among these workers who are already exposed to the highly polluted environment in power loom factories.


Does exergaming drive future physical activity and sport intentions?
We studied how usability and playability of sport exergames affect future intentions of participation in physical activity or actual sport. We employed questionnaires to measure participants' enjoyment, usability, game-experience, and future intentions of physical activity and real sport. We compared the outcomes based on players' gender, previous real-swimming, and exergame experience. Psychological parameters were not different between groups but players without exergame experience enjoyed the game more. Physical activity intentions increased for all participants but not swimming intentions. The limitations of current gaming systems and their effects on players' gaming experience and intentions are discussed.


Peripheral blood mononuclear phagocyte subpopulations as cellular markers in hypercholesterolemia.
Mononuclear phagocytes play a major role in the development of vascular lesions in atherogenesis. The goal of our study was to characterize circulating blood monocyte subpopulations as potential cellular markers of systemic immunological abnormalities in hypercholesterolemia. In normal subjects, three-parameter immunophenotyping of whole blood revealed that 61.3 +/- 6.0% of monocytes showed "bright" expression of the lipopolysaccharide receptor (LPSR: CD14) and Fc gamma receptor I (RI: CD64) without expression of Fc gamma-RIII (CD16). Other monocyte subsets (populations 2, 3, 4, and 5) were characterized by the simultaneous expression of both Fc gamma-R's (25.6 +/- 5.0%), isolated expression of Fc gamma-RIII (9.4 +/- 1.7%), or high expression of CD33 (3.7 +/- 1.1%) with only dim expression of CD14, respectively. The smallest subset of monocytes (population 5: 2.1 +/- 0.8%) differed from the predominant population of CD14brightCD64+CD16- monocytes by additional expression of neural cell adhesion molecule (N-CAM: CD56). In a group of hypercholesterolemic patients (n = 19), high density lipoprotein cholesterol levels were negatively correlated to the population size of CD64-CD16+ monocytes. In both healthy subjects (n = 55) and hypercholesterolemic patients, the rare apolipoprotein E3/E4 and E4/E4 phenotypes were associated with a tendency toward a larger population of CD64-CD16+ monocytes. Expression of the variant activation antigen CD45RA by peripheral blood mononuclear phagocytes showed a positive correlation to plasma levels of the atherogenic lipoproteins low density lipoprotein and lipoprotein(a). These data suggest that systemic abnormalities in mononuclear phagocyte subpopulations may play a role in the pathogenesis of atherosclerosis.


[Monothematic catathymic delusions in slowly progressive schizophrenia].
With special reference to erothomania in the framework of slowly progressive schizophrenia as a model, the author considers problems of psychopathology, the clinical picture and pathogenesis of sluggish form of endogenous delusional psychoses. Clinico-psychopathological descriptions of such cases, their differentiation from paranoiac variants of erothomanic delusional psychoses are given. It is also demonstrated that the clinical expression in slowly progressive processes may be related to mechanisms of a catathymic interpretation, common in the pathogenesis of morbid signs during the whole period of illness. As one of the leading major clinico-pathogenetic factors to which the slowly progressive development of delusional psychoses may be related is the clinical similarity of erothomanic delusional symptomatology with the constitutional traits of the patients.


Self-derogation and adjustment in the community: a longitudinal study of psychiatric patients.
The authors assessed the symptoms and role performance of a group of psychiatric inpatients 1 year after their discharge to determine their level of adjustment in the community. Level of self-derogation at the time of discharge was consistently found to predict the level of adjustment. The occurrence of stressful life events was also predictive of symptoms but was not found to be significantly related to role performance. The chronicity of the disease was unrelated to adjustment. The change in self-derogation level and its ability to predict community adjustment is interpreted in terms of reestablishing the patient's belief in his or her own worth and efficacy.


Rumen-protected glucose supplementation alters fecal microbiota and its metabolic profiles in early lactation dairy cows.
Negative energy balance (NEB) is the pathological basis of metabolic disorders in early lactation dairy cows. Rumen-protected glucose (RPG) is a feed additive to relieve NEB of cows in early lactation. The aims of the current study were to evaluate the impact of different doses of RPG supply on fecal microbiota and metabolome in early lactation dairy cows, and their correlation with each other. A total of 24 multiparous Holstein dairy cows in early lactation were randomly assigned to one of four treatments for the first 35 days of the early lactation period, as follows: control group, a basal diet without RPG (CON); low RPG, a basal diet plus 200 g/d RPG (LRPG); medium RPG, a basal diet plus 350 g/d RPG (MRPG); or HRPG, high RPG, a basal diet plus 500 g/d RPG (HRPG). After 35 days, fecal samples were obtained from cows in all groups individually and using 16S rRNA gene sequencing to evaluate their microbiotas, while their metabolites were evaluated through metabolomics. As expected, Firmicutes and Bacteroidetes were the core bacteria phyla. After RPG supplementation, there were an increase in Firmicutes and a decrease in Bacteroidetes. MRPG increased the relative abundance of cellulolytic bacteria, including Ruminococcaceae_UCG-005, Lachnospiraceae_UCG-008, Lachnospiraceae_FCS020_group, and Ruminiclostridium_9, while it decreased the relative abundance of Alistipes, Prevotellaceae_UCG-003, and Dorea. RPG supplementation could regulate the carbohydrate metabolism and amino acid metabolism pathway significantly and relieve lipolysis in dairy cows. Correlation analysis of fecal microbiome and metabolome showed that some major differential bacteria were the crucial contributors to differential metabolites. In conclusion, RPG supplementation can affect the fecal microbial components and microbial metabolism, and 350 g RPG might be the ideal dose as a daily supplement.


Highly Efficient Spin-Orbit Torque and Switching of Layered Ferromagnet Fe3GeTe2.
Among van der Waals (vdW) layered ferromagnets, Fe3GeTe2 (FGT) is an excellent candidate material to form FGT/heavy metal heterostructures for studying the effect of spin-orbit torques (SOT). Its metallicity, strong perpendicular magnetic anisotropy built in the single atomic layers, relatively high Curie temperature (Tc ∼ 225 K), and electrostatic gate tunability offer a tantalizing possibility of achieving the ultimate high SOT limit in monolayer all-vdW nanodevices. In this study, we fabricate heterostructures of FGT/Pt with 5 nm of Pt sputtered onto the atomically flat surface of ∼15-23 nm exfoliated FGT flakes. The spin current generated in Pt exerts a damping-like SOT on FGT magnetization. At ∼2.5 × 1011 A/m2 current density, SOT causes the FGT magnetization to switch, which is detected by the anomalous Hall effect of FGT. To quantify the SOT effect, we measure the second harmonic Hall responses as the applied magnetic field rotates the FGT magnetization in the plane. Our analysis shows that the SOT efficiency is comparable with that of the best heterostructures containing three-dimensional (3D) ferromagnetic metals and much larger than that of heterostructures containing 3D ferrimagnetic insulators. Such large efficiency is attributed to the atomically flat FGT/Pt interface, which demonstrates the great potential of exploiting vdW heterostructures for highly efficient spintronic nanodevices.


The effects of early post-traumatic hyperthermia in female and ovariectomized rats.
Episodes of post-traumatic hyperthermia commonly occur in the head-injured patient population. Although post-traumatic hyperthermia has been shown to worsen outcome in experimental studies using male rats, the consequences of secondary hyperthermia following traumatic brain injury (TBI) have not been investigated in female animals. Thus, the purpose of this study was to examine the effects of post-traumatic hyperthermia after fluid-percussion (F-P) brain injury in intact and ovariectomized female rats. Thirty-eight female Sprague-Dawley rats were used in these experiments. Intact female rats underwent TBI followed 30 min later by a 4-h period of normothermia (37 degrees C) or brain hyperthermia (40 degrees C). Female rats that had been ovariectomized 10 days prior to TBI were also traumatized and followed by a period of normothermia or hyperthermia. At 72 h after TBI, rats were perfusion-fixed for quantitative histopathological and immunocytochemical evaluation. Following normothermic TBI, intact female rats demonstrated significantly smaller contusion volumes, decreased frequency of axonal beta-amyloid precursor protein (beta-APP) profiles, and greater numbers of NeuN-positive cortical neurons compared to traumatized ovariectomized females. Although post-traumatic hyperthermia increased contusion volume, cortical neuronal cell death and axonal damage in both intact and ovariectomized female groups, the effects of the induced hyperthermic period were more pronounced in ovariectomized animals. These findings demonstrate for the first time that post-traumatic hyperthermia worsens histopathological outcome in female rats, and that neural hormones, including estrogen and progesterone, may protect against secondary hyperthermic insults.


Social Outbreak in Chile, and Its Association with the Effects Biological, Psychological, Social, and Quality of Life.
The World Health Organization has defined collective violence as the instrumental use of violence by people who identify themselves as members of a group against other individuals and have political, economic, or social objectives. In Chile, the "Social Outbreak" was used to describe an episode of collective violence, which began on October 18, 2019, triggered by a multitude of socioeconomic and political factors, with protests and mobilizations in the country's large and small cities; in central, commercial, and residential areas, that lasted for several months, affecting a large part of the population. The objective of the present study was to associate the social outbreak in Chile with its biological, psychological, and social effects on people's health and quality of life, as well as its characteristics in terms of exposure, proximity, type, and frequency. This was a cross-sectional study with non-probabilistic national-level sampling, conducted from 28 November 2019, to 3 March 2020. The instrument had four sections. A total of 2651 participants answered the survey; 70.8% were female, and the mean age was 35.2. The main disturbances perceived were protests (70.9%), alarm sounds (68.1%), shooting sounds (59.0%), and tear gas bombs (56.9%). When quantifying the magnitude of these associations, people who had a medium exposure have a higher probability (OR: 1.99, CI: 1.58; 2.50) of suffering three or more biological effects than people that have a low exposure, while people with higher exposition have a 4.09 times higher probability (CI: 3.11; 5.38). A similar pattern was observed regarding psychological effects, although social effects were primarily experienced by those with high exposure. Social networks, TV, and radio were the most used media among people who perceived a greater effect. People who lived, worked, or shopped near the disturbance's areas show a higher proportion negative effect.


Modern approaches to vaccine development with special reference to the needs of developing countries.
Vaccination has proved to be one of the most effective public health measures to control infectious diseases. The eradication of smallpox by world-wide vaccination represents one of mankind's greatest achievements. Despite the availability of vaccines to control many diseases, they are generally under-used in many developing and some developed countries. However, there are many diseases for which current vaccines are inadequate or vaccines cannot be prepared using conventional approaches. This article describes the new approaches which are now available and are being used extensively to develop new vaccines against viral, bacterial and parasitic diseases. Success has already been achieved in a few cases and the prospect for others is encouraging. In addition, progress is being made to develop vaccines to control human fertility as this development is seen to complement the control of infectious diseases.


Cullin 5 regulates Dab1 protein levels and neuron positioning during cortical development.
Many laminated regions of the mammalian brain develop by the migration of neuronal precursor cells, whose final positions are coordinated by signals from the secreted molecule Reelin. Early events in Reelin signaling have been identified, but the mechanism of signal down-regulation has been unclear. A possible source of negative feedback is the Reelin-induced degradation of the critical intracellular signaling component, Disabled-1 (Dab1). Here we show that degradation of Dab1 depends on Dab1 phosphorylation at specific tyrosine residues and on the E3 ubiquitin ligase component Cullin 5 (Cul5). Cul5 forms complexes with SOCS (suppressors of cytokine signaling) proteins, which bind to phosphorylated Dab1 and target it for degradation in tissue culture cells. Ablation of Cul5 in migrating neurons causes an accumulation of active Dab1 protein and a unique cortical layering defect, characterized by excess migration and buildup of neurons at the top of the cortical plate. The results implicate Cul5 and SOCS proteins in down-regulation of Dab1 in vivo and show that Cul5 plays an essential role in regulating neuron migrations during cortical development, possibly by opposing a promigratory effect of Dab1.


Measuring and modelling cell-to-cell variation in uptake of gold nanoparticles.
The cell-to-cell variation of gold nanoparticle (GNP) uptake is important for therapeutic applications. We directly counted the GNPs in hundreds of individual cells, and showed that the large variation from cell-to-cell could be directly modelled by assuming log-normal distributions of both cell mass and GNP rate of uptake. This was true for GNPs non-specifically bound to fetal bovine serum or conjugated to a cell penetrating peptide. Within a population of cells, GNP content varied naturally by a factor greater than 10 between individual cells.


Prognostic relevance of viable circulating tumor cells detected by EPISPOT in metastatic breast cancer patients.
Detection of circulating tumor cells (CTC) in breast cancer patients is currently performed in many clinical trials, using different technologies, in particular the EpCAM-dependent CellSearch® system. The purpose of this study was to investigate the incidence and prognostic relevance of viable CTC in a large cohort of metastatic breast cancer (MBC) patients. A total of 254 MBC patients were enrolled in a prospective multicenter study at first diagnosis of metastatic disease or disease progression (before the start of a new treatment regimen). After EpCAM-independent enrichment, viable CTC releasing cytokeratin-19 as an epithelial cell marker were detected in the peripheral blood by an EPISPOT assay, and the Food and Drug Administration cleared CellSearch was used as the reference method. Using the EPISPOT assay, CTC were detected in 59% of MBC patients. The overall survival (OS) was linked with the CTC status measured by EPISPOT (P = 0.0191), which allowed stratification of MBC patients in low- and high-risk groups. This stratification could be improved by addition of the CTC status assessed by the CellSearch system. In multivariate Cox proportional-hazards regression analysis, the 3 methods used to determine the level of CTC (EPISPOT, CellSearch, and combination of EPISPOT/CellSearch) were compared by the Bayesian information criterion method. Interestingly, the combination of the EPISPOT and CellSearch assays was the strongest predictor of OS (hazard ratio, 22.6; 95% CI, 2.8-184.08). This is the first study in which CTC detection using the EPISPOT assay was evaluated on a large cohort of MBC patients, showing prognostic relevance of the presence of viable CTC.


A CBPR partnership increases HIV testing among men who have sex with men (MSM): outcome findings from a pilot test of the CyBER/testing internet intervention.
The Internet has emerged as an important tool for the delivery of health promotion and disease prevention interventions. Our community-based participatory research (CBPR) partnership developed and piloted CyBER/testing, a culturally congruent intervention designed to promote HIV testing among men who have sex with men (MSM) within existing Internet chat rooms. Using a quasi-experimental, single-group study design, cross-sectional data were collected from chat room participants, known as "chatters," at pretest (n = 346) and posttest (n = 315). Extant profile data also were collected to describe the demographics of the online population. The intervention significantly increased self-reported HIV testing among chatters overall, increasing rates from 44.5% at pretest to nearly 60% at posttest (p < .001). Furthermore, chatters who reported having both male and female sexual partners had nearly 6 times the odds of reporting HIV testing at posttest. Findings suggest that chat room-based HIV testing intervention may increase testing among MSM who may be difficult to reach in traditional physical spaces.


Pediatric transplantation, 1994-2003.
This article uses OPTN/SRTR data to review trends in pediatric transplantation over the last decade. In 2003, children younger than 18 made up 3% of the 82,885 candidates for organ transplantation and 7% of the 25,469 organ transplant recipients. Children accounted for 14% of the 6,455 deceased organ donors. Pediatric organ transplant recipients differ from their adult counterparts in several important aspects, including the underlying etiology of organ failure, the complexity of the surgical procedures, the pharmacokinetic properties of common immunosuppressants, the immune response following transplantation, the number and degree of comorbid conditions, and the susceptibility to post-transplant complications, especially infectious diseases. Specialized pediatric organ transplant programs have been developed to address these special problems. The transplant community has responded to the particular needs of children and has provided them special consideration in the allocation of deceased donor organs. As a result of these programs and protocols, children are now frequently the most successful recipients of organ transplantation; their outcomes following kidney, liver, and heart transplantation rank among the best. This article demonstrates that substantial improvement is needed in several areas: adolescent outcomes, outcomes following intestine transplants, and waiting list mortality among pediatric heart and lung candidates.


The effect of vascular reconstruction device-assisted coiling on packing density, effective neck coverage, and angiographic outcome: an in vitro study.
The objective of this study was to assess the variations in packing density, effective neck coverage, and angiographic outcome between aneurysm coiling alone and with the support of the Enterprise Vascular Reconstruction Device (VRD; Cordis Neurovascular, Inc., Miami Lakes, FL). Although the use of VRD-assisted coiling is growing due to the availability of better devices, little is known about the impact of the VRDs on the aforesaid variables. Ten groups of two silicone aneurysm models each were embolized with detachable coils, one with VRD support and one without. Coil embolization ceased once the microcatheter backed out of the aneurysm or there was a risk that further packing would lead to coil herniation. Angiograms were assessed using the Raymond classification scale. Gross macroscopic images of the aneurysm neck were taken to quantify the coil neck coverage, defined as the surface area fraction of coils at the neck divided by the total neck area. Packing density was calculated. Packing density significantly increased with VRD assistance (absolute increase, 10.5%; relative increase, 31%; P < 0.0001, paired t test). Effective neck coverage significantly increased by 9% with VRD deployment (P < 0.05, t test). Angiographically, aneurysms coiled without VRD support were more likely to have a dome remnant (P < 0.05, Fisher's exact test) and coil prolapse into the parent vessel. VRD deployment improves coil neck coverage and increases packing density. These results support the hypothesis that VRD deployment to reinforce coil embolization of cerebral aneurysms may lead to more durable aneurysm obliteration.


Sunitinib-associated hyperammonemic encephalopathy.
Sunitinib-associated hyperammonemic encephalopathy has not been previously reported in the emergency medicine literature. As newer treatments for cancer become more widespread and patients live longer, the emergence of previously unreported or rare adverse effects is expected to increase. Here we report the case of a 71-year-old woman with infiltrating ductal carcinoma of the breast with metastasis to the liver who developed hyperammonemic encephalopathy after taking sunitinib for 12 days. She presented to the emergency department (ED) with confusion and the initial workup revealed an elevated ammonia level (202 μmol/L; reference range, 11-51 μmol/L) without evidence of cirrhosis or portal hypertension. The patient was started on lactulose and admitted to the hospital, where her ammonia levels and mental status waxed and waned throughout her 12-day hospitalization. Further workup with magnetic resonance imaging and an electroencephalogram were negative. After 12 days, her ammonia level normalized and she was discharged without re-initiating Sunitinib. The patient was followed for three months post hospitalization without recurrence of symptoms. Patients on sunitinib should have their ammonia levels checked when presenting to the ED with altered mentation for early identification of hyperammonemic encephalopathy and its potential complications, such as seizures, brain edema, and death. Emergent management in the ED should include initiation of lactulose and consultation with the gastroenterology team.


Advances in endodontic surgery: Part 1.
It is generally accepted that non-surgical endodontic therapy eliminates periapical inflammation or infection and allows teeth to be restored that previously might have been extracted. However, failure does occur in a small percentage of cases. When confronted with such cases the clinician should be prepared to initiate alternative procedures, including surgery, to enhance the rate of success. This, the first of two articles, describes refinements in endodontic surgical techniques and introduces the research that has been used to develop new materials and devices.


Holmium laser ablation and enucleation of the prostate: a pilot study of the hybrid technique.
To report the initial clinical experience using a hybrid technique combining holmium laser ablation of the prostate (HoLAP) and holmium laser enucleation of the prostate (HoLEP) for the treatment of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). A total of 18 patients with documented moderate to severe LUTS underwent the hybrid technique. Baseline characteristics were documented for all patients. Operative and resection times, as well as intra and perioperative complications, were recorded. Additionally, changes in American Urological Association symptom index (AUA-SI) and quality of life (QoL) scores and serum prostate-specific antigen (PSA) values were recorded both pre and postoperatively. All patients experienced significant improvements in their AUA-SI and QoL scores, with a mean decrease in PSA of 74.6% postoperatively. There were no reported complications with this technique and the average resection time (48.2 min) was decreased in comparison to those reported for HoLAP or HoLEP monotherapies. This is the first report of surgical therapy for BPH involving two different holmium laser therapies. This hybrid technique offers tissue for pathologic analysis in comparison to HoLAP, and an improved learning curve and decreased complication rate in comparison to HoLEP. Additional studies are warranted to validate this data.


Functional domains of the yeast regulatory protein GAL4.
In the yeast Saccharomyces cerevisiae regulation of the galactose/melibiose regulon rests on a dosage-dependent functional interplay between the positive regulator of transcription, the GAL4 protein, and the negative regulator, GAL80 protein. We have used this interplay to select in vitro generated fusions between the yeast ADH1 promoter and GAL4 coding sequence that overproduce GAL4 protein, allowing the identification of GAL4 protein in crude extracts from yeast. One type of these constructions produces a GAL4 protein that lacks its normal NH2 terminus. This protein is unable to complement a gal4 lesion but still retains a domain that functionally antagonizes the negative regulatory protein. One defect in this truncated protein is its inability to be concentrated in the nucleus. However, the nuclear localization defect is complemented by full-length GAL4 protein. The truncated protein also appears to effect changes in the relative transcriptional levels of the structural genes. These observations imply that GAL4 protein consists of several domains, including ones for nuclear localization, interaction with the negative regulatory protein, and, possibly, separable transcriptional activation domains for the structural genes.


Genome-wide association study of circulating levels of glucagon during an oral glucose tolerance test.
In order to explore the pathophysiology underlying type 2 diabetes we examined the impact of gene variants associated with type 2 diabetes on circulating levels of glucagon during an oral glucose tolerance test (OGTT). Furthermore, we performed a genome-wide association study (GWAS) aiming to identify novel genomic loci affecting plasma glucagon levels. Plasma levels of glucagon were examined in samples obtained at three time points during an OGTT; 0, 30 and 120 min, in two separate cohorts with a total of up to 1899 individuals. Cross-sectional analyses were performed separately in the two cohorts and the results were combined in a meta-analysis. A known type 2 diabetes variant in EYA2 was significantly associated with higher plasma glucagon level at 30 min during the OGTT (Beta 0.145, SE 0.038, P = 1.2 × 10-4) corresponding to a 7.4% increase in plasma glucagon level per effect allele. In the GWAS, we identified a marker in the MARCH1 locus, which was genome-wide significantly associated with reduced suppression of glucagon during the first 30 min of the OGTT (Beta - 0.210, SE 0.037, P = 1.9 × 10-8), equivalent to 8.2% less suppression per effect allele. Nine additional independent markers, not previously associated with type 2 diabetes, showed suggestive associations with reduced glucagon suppression during the first 30 min of the OGTT (P < 1.0 × 10-5). A type 2 diabetes risk variant in the EYA2 locus was associated with higher plasma glucagon levels at 30 min. Ten additional variants were suggestively associated with reduced glucagon suppression without conferring increased type 2 diabetes risk.


Welfare state regime life courses: the development of western European welfare state regimes and age-related patterns of educational inequalities in self-reported health.
This article uses data from three waves of the European Social Survey (2002, 2004, 2006) to compare educational inequalities in self-reported health (good vs. bad) and limiting longstanding illness in six age groups based on decade of birth (1930s-1980s) in 17 countries, categorized into four welfare state regimes (Anglo-Saxon, Bismarckian, Scandinavian, Southern). The authors hypothesized that health inequalities in these age groups would vary because of their different welfare state experiences-welfare state regime life courses-both temporally, in terms of different phases of welfare state development (inequalities smaller among older people), and spatially, in terms of welfare state regime type (inequalities smaller among older Scandinavians). The findings are that inequalities in health tended to increase, not decrease, with age. Similarly, inequalities in health were not smallest in the Scandinavian regime or among the older Scandinavian cohorts. In keeping with the rest of the literature, the Bismarckian and Southern regimes had smaller educational inequalities in health. Longitudinal analysis that integrates wider public health factors or makes smaller comparisons may be a more productive way of analyzing cross-national variations in health inequalities and their relationship to welfare state life courses.


Assembly of the Trypanosoma brucei 60S ribosomal subunit nuclear export complex requires trypanosome-specific proteins P34 and P37.
We previously identified two Trypanosoma brucei RNA binding proteins, P34 and P37, and determined that they are essential for proper ribosomal assembly in this organism. Loss of these proteins via RNA interference is lethal and causes a decrease in both 5S rRNA levels and formation of 80S ribosomes, concomitant with a decrease in total cellular protein synthesis. These data suggest that these proteins are involved at some point in the ribosomal biogenesis pathway. In the current study, we have performed subcellular fractionation in conjunction with immune capture experiments specific for 60S ribosomal proteins and accessory factors in order to determine when and where P34 and P37 are involved in the ribosomal biogenesis pathway. These studies demonstrate that P34 and P37 associate with the 60S ribosomal subunit at the stage of the nucleolar 90S particle and remain associated subsequent to nuclear export. In addition, P34 and P37 associate with conserved 60S ribosomal subunit nuclear export factors exportin 1 and Nmd3, suggesting that they are components of the 60S ribosomal subunit nuclear export complex in T. brucei. Most significantly, the pre-60S complex does not associate with exportin 1 or Nmd3 in the absence of P34 and P37. These results demonstrate that, although T. brucei 60S ribosomal subunits utilize a nuclear export complex similar to that described for other organisms, trypanosome-specific factors are essential to the process.


Promising Natural Products in New Drug Design, Development, and Therapy for Skin Disorders: An Overview of Scientific Evidence and Understanding Their Mechanism of Action.
The skin is the largest organ in the human body, composed of the epidermis and the dermis. It provides protection and acts as a barrier against external menaces like allergens, chemicals, systemic toxicity, and infectious organisms. Skin disorders like cancer, dermatitis, psoriasis, wounds, skin aging, acne, and skin infection occur frequently and can impact human life. According to a growing body of evidence, several studies have reported that natural products have the potential for treating skin disorders. Building on this information, this review provides brief information about the action of the most important in vitro and in vivo research on the use of ten selected natural products in inflammatory, neoplastic, and infectious skin disorders and their mechanisms that have been reported to date. The related studies and articles were searched from several databases, including PubMed, Google, Google Scholar, and ScienceDirect. Ten natural products that have been reported widely on skin disorders were reviewed in this study, with most showing anti-inflammatory, antioxidant, anti-microbial, and anti-cancer effects as the main therapeutic actions. Overall, most of the natural products reported in this review can reduce and suppress inflammatory markers, like tumor necrosis factor-alpha (TNF-α), scavenge reactive oxygen species (ROS), induce cancer cell death through apoptosis, and prevent bacteria, fungal, and virus infections indicating their potentials. This review also highlighted the challenges and opportunities of natural products in transdermal/topical delivery systems and their safety considerations for skin disorders. Our findings indicated that natural products might be a low-cost, well-tolerated, and safe treatment for skin diseases. However, a larger number of clinical trials are required to validate these findings. Natural products in combination with modern drugs, as well as the development of novel delivery mechanisms, represent a very promising area for future drug discovery of these natural leads against skin disorders.


Automation in drug inventory management saves personnel time and budget.
Automation in the drug distribution processes is helpful to pharmacists in creating new clinical services. We have ameliorated the drug inventory control system seamlessly connected with the physician order-entry system. This control system application, named Artima, allows inventory functions to be faster and more efficient in real time. The medicines used in our hospital are automatically fixed and arranged to sold-packages, and are ordered from each wholesaler by a fax-modem every day. Artima can search the lot number and expiration date of drug in the purchase and delivery records. These functions are powerful and useful in patient's safety and cost containment. We surveyed the inventory amount stored in the computer database, and evaluated time required for inventory management by tabulating working records of employees during past decades. Inventory decreased by 70% along with the continuous improvement of the system during the past decade. The workload in the inventory management in each section of the Pharmacy Department as well as in clinical units was dramatically reduced after the implementation of this system. The automation system in the drug inventory management allows creating new clinical positions for pharmacists. This system also could pay for itself in time.


[How to judge a good anaesthesia from a bad one - a critical review of recovery scores and other techniques to assess the result quality of anaesthesia procedures].
Patients, general public and health insurance funds focus more and more on the quality of medical performance. Anaesthesia related severe morbidity and mortality are unsuitable to judge the quality of an anaesthesia procedure. Other aspects like rapid and comfortable postoperative recovery or satisfaction of the patients with the anaesthesia procedure experience therefore rising attention. With this critical review we aim to give support for appraisal of already published studies and for design and realization of future trials.


Effects of Aegilops longissima chromosome 1Sl on wheat bread-making quality in two types of translocation lines.
Two wheat-Ae. longissima translocation chromosomes (1BS·1SlL and 1SlS·1BL) were transferred into three commercial wheat varieties, and the new advanced lines showed improved bread-making quality compared to their recurrent parents. Aegilops longissima chromosome 1Sl encodes specific types of gluten subunits that may positively affect wheat bread-making quality. The most effective method of introducing 1Sl chromosomal fragments containing the target genes into wheat is chromosome translocation. Here, a wheat-Ae. longissima 1BS·1SlL translocation line was developed using molecular marker-assisted chromosome engineering. Two types of translocation chromosomes developed in a previous study, 1BS·1SlL and 1SlS·1BL, were introduced into three commercial wheat varieties (Ningchun4, Ningchun50, and Westonia) via backcrossing with marker-assisted selection. Advanced translocation lines were confirmed through chromosome in situ hybridization and genotyping by target sequencing using the wheat 40 K system. Bread-making quality was found to be improved in the two types of advanced translocation lines compared to the corresponding recurrent parents. Furthermore, 1SlS·1BL translocation lines displayed better bread-making quality than 1BS·1SlL translocation lines in each genetic background. Further analysis revealed that high molecular weight glutenin subunit (HMW-GS) contents and expression levels of genes encoding low molecular weight glutenin subunits (LMW-GSs) were increased in 1SlS·1BL translocation lines. Gliadin and gluten-related transcription factors were also upregulated in the grains of the two types of advanced translocation lines compared to the recurrent parents. This study clarifies the impacts of specific glutenin subunits on bread-making quality and provides novel germplasm resources for further improvement of wheat quality through molecular breeding.


Medical treatment of peripheral arterial disease.
The evolution of interventional treatments of peripheral arterial disease is progressing at a dizzying pace. However, optimized medical therapy of these patients may be neglected. Recent advances in our understanding of atherosclerosis and the epidemiology of vascular disease reemphasize the importance of a consistent and complete medical regimen. They have also opened new avenues for potential therapy. A diagnosis of peripheral arterial disease confers an increased risk of morbidity and mortality that can be at least partially mitigated with a properly designed medical regimen. New evidence supports the importance of risk factor modification including controlling hypertension, lowering lipid levels, and the routine use of antiplatelet agents. For claudication symptoms, several newer drugs and the use of immune-modifying therapy are showing some improvement in symptoms. The use of gene therapy and other means to achieve improved collateral formation in ischemic tissues are showing some promise in the early stages of study. Peripheral arterial disease is a marker of cardiovascular morbidity and mortality risk. An individualized plan should be devised to include smoking cessation, exercise, lowering serum lipids, lowering high blood pressure, and daily antiplatelet therapy. Supervised exercise programs and cilostazol remain the first-line medical therapies for claudication symptoms, and anticoagulants are added to patients who have bypasses at high risk for thrombosis. The utilities of immune-modifying, antibiotic, and angiogenic therapies remain to be proven.


A developmental characterization of mesolimbocortical serotonergic gene expression changes following early immune challenge.
An immunogenic challenge during early postnatal development leads to long-term changes in behavioural and physiological measures reflecting enhanced emotionality and anxiety. Altered CNS serotonin (5-HT) signalling during the third postnatal week is thought to modify the developing neurocircuitry governing anxiety-like behaviour. Changes in 5-HT signalling during this time window may underlie increased emotionality reported in early immune challenge rodents. Here we examine both the spatial and temporal profile of 5-HT related gene expression, including 5HT1A, 2A, 2C receptors, the 5-HT transporter (5HTT), and tryptophan hydroxylase 2 (TPH2) during early development (postnatal day [P]14, P17, P21, P28) in mice challenged with lipopolysaccharide (LPS) during the first postnatal week. Expression levels were measured using in situ hybridization in regions associated with mediating emotive behaviours: the dorsal raphe (DR), hippocampus, amygdala, and prefrontal cortex (PFC). Increased TPH2 and 5HTT expression in the ventrolateral region of the DR of LPS-mice accompanied decreased expression of ventral DR 5HT1A and dorsal DR 5HTT. In the forebrain, 5HT1A and 2A receptors were increased, whereas 5HT2C receptors were decreased in the hippocampus. Decreased mRNA expression of 5HT2C was detected in the amygdala and PFC of LPS-treated pups; 5HT1A was increased in the PFC. The majority of these changes were restricted to P14-21. These transient changes in 5-HT expression coincide with the critical time window in which 5-HT disturbance leads to permanent modification of anxiety-related behaviours. This suggests that alterations in CNS 5-HT during development may underlie the enhanced emotionality associated with an early immune challenge.


Tele-otology: planning, design, development and implementation.
The view of the tympanic membrane of the ear provides the specialist with important information for the assessment of ear disease and for treatment planning. In rural and remote areas, the incidence of ear disease is high but access to ear specialists is limited. As part of a project to deliver tele-otoscopy services to remote Western Australia, we have investigated various aspects of a tele-otoscopy system. We found that the MedRX video-otoscope is relatively safe to use and produces images of very good quality. A confident diagnosis could be made from still images compressed to 20 kByte. Video sequences could be compressed to a ratio of 1:300. Furthermore, a software package has been developed, and we are developing a training course for health-care workers in remote areas.


The factor structure of schizotypal symptoms in a clinical population.
There is some support for the hypothesis that the factor structure of schizophrenia symptoms is similar to the factor structure of schizotypal symptoms in nonschizophrenia populations. However, no studies to date have examined schizotypal symptoms in patients with personality disorders. In this study, confirmatory factor analyses were conducted to test the relative fit of several models of the factorial structure of schizotypal symptoms in patients diagnosed with personality disorders. The EQS: Structural Equations Program was used to analyze DSM-III symptoms of schizotypal personality disorder (SPD) based on structured clinical interviews with 213 patients meeting a diagnosis for at least one personality disorder. A subgroup of the total sample was also evaluated for DSM-III-R criteria (n = 143) to test competing models of the DSM-III-R symptoms of SPD. A three-factor model consisting of a cognitive-perceptual, interpersonal, and paranoid factor yielded the best fit to the data relative to the other models tested. These results suggest that the three-factor model of schizophrenia symptoms may not entirely correspond to the factors underlying milder schizotypal symptoms expressed in a clinical population. It is suggested that future research focus on both the similarities and the differences between SPD and schizophrenia.


The amino acid sequence of the PKR-eIF2alpha phosphorylation homology domain of hepatitis C virus envelope 2 protein and response to interferon-alpha.
A region of the hepatitis C virus (HCV) envelope 2 protein, the protein kinase, PKR and early initiation factor 2alpha phosphorylation homology domain (PePHD), may be important in interferon (IFN)-alpha resistance. The PePHD was amplified by polymerase chain reaction and sequenced, and the amino acid sequence derived from pretreatment serum of 14 genotype 3-infected patients with a range of responses to IFN-alpha therapy. Only 1 patient had a PePHD variant. IFN-resistant PePHD variants present at low titers in pretreatment serum should be selected by therapy; therefore, the PePHD amino acid sequence was also obtained from serum collected during or after treatment in 5 patients with breakthrough or relapse of HCV RNA positivity. No difference was found between the pre- and posttreatment PePHD sequences. Thus, it appears that pretreatment sequencing of the PePHD would not enable clinicians to predict the treatment response. There was no evidence that IFN therapy exerts selection pressure in this region.


The therapeutic and prophylactic role of oral zinc sulfate in management of recurrent aphthous stomatitis (ras) in comparison with dapsone.
To evaluate the therapeutic and prophylactic effectiveness of oral zinc sulfate in recurrent aphthous stomatitis (RAS) in comparison with dapsone. A double-blind placebo controlled study, conducted in the Department of Dermatology, Baghdad Teaching Hospitals, Baghdad, Iraq between May 2005 and October 2006, in which 45 patients with RAS were recruited and divided into 3 equal groups: group A (on zinc sulfate 150 mg twice daily), group B (on dapsone 50 mg twice daily), and group C (on glucose 250 mg as placebo). The drugs were prepared in identical capsules, and the patients were instructed to take the capsules twice daily after meals (in a double-blind manner). Assessment of each patient was carried out by the Oral Clinical Manifestation Index (OCMI) and the diameter of the ulcers at day 0, day 4, and at the second, fourth, sixth, eighth, tenth, and twelfth weeks of therapy. Forty-five patients were included in the study (25 males and 20 females), and their ages ranged between 16-45 years (mean+/-SD 31.24+/-8.14). In group A, the mean of OCMI and diameter of ulcers improved, with a p=0.0001 for OCMI, and 0.0001 for the diameter for ulcers at the end of the twelfth week of therapy, which was statistically significant. Group B, also showed significant improvement, however, the action was lower and slower (p=0.0001 for OCMI, and 0.001 for the diameter for ulcers). Group C revealed slight non-significant improvement (p=0.028 for OCMI, and 0.034 for the diameter of ulcers). In the sixth week of therapy, zinc sulfate was more effective than dapsone in reducing the OCMI of the ulcers (p=0.007). The present study showed that both zinc sulfate and dapsone had significant therapeutic and prophylactic effects in controlling RAS, however, zinc sulfate had much more rapid and sustained action.


Efficacy of Glutathione Biomolecule in Reducing the Tooth Discoloration Associated with Silver Diamine Fluoride: A Split-mouth In vivo Study.
The necessity to modify silver diamine fluoride (SDF) to make it esthetically acceptable without affecting its beneficial properties keeps the research in this field pertinent. This study aims to comparatively evaluate the efficacy of Glutathione (GSH) in reducing tooth discoloration associated with SDF. This split-mouth in vivo study was conducted on 20 children aged 3-8 years having a minimum of 3 active carious primary teeth. The three teeth in each patient were randomly divided into Group I - 38% SDF; Group II - 38% SDF followed by application of potassium iodide; and Group III - 38% SDF mixed with 20% GSH. Standardized photographs were taken immediately after application and after 6 months, which were analyzed using Image J software. The carious lesions were clinically classified as active or arrested after 6 months. When mean gray values of three groups were compared postoperative, the highest value (lighter shade) was observed for group II and least (darker shade) for group I, whereas, during the 6-month follow-up, the highest value was seen for group III and least for group I. The color change from preoperative to 6 months' follow-up was compared, and a statistically significant difference was observed between groups I and II (P = 0.003) and groups I and III (P = 0.001). When caries arresting effectiveness was analyzed, there was no significant difference found between any of the groups (P = 1). Mixing 20% GSH with 38% SDF was an effective measure in reducing the tooth discoloration associated with SDF, without affecting caries arresting the efficiency of the latter.


Is late seroma a phenomenon related to textured implants? A report of rare complications and a literature review.
Late seroma is an infrequent complication that manifests as fluid collection in the periprosthetic space at least 1 year after breast enlargement surgery. Interest in late seroma has grown with the potential connection between breast implants and anaplastic large cell lymphoma (ALCL), which presents with clinical symptoms similar to those of late seroma. This report presents a case of late seroma experienced by a patient with a history of multiple implant ruptures and a review of the relevant literature. Details are reported for a patient who presented with sudden swelling of an augmented breast that was initially suspected to be symptomatic of ALCL. A literature search of PubMed regarding this phenomenon also was conducted. The literature review identified 14 articles on late seroma involving 60 patients, including the reported case. Analyses included epidemiology, etiology, and management strategy. Although a detailed statistical analysis was not performed, 55 cases (92 %) of late seroma occurred that involved patients with textured implants. No evidence-based guideline for the management of late seroma has been established, although the patients were managed successfully in all cases using various strategies. The reported case and data from the literature provide evidence of a relationship between textured implant use and late seroma. Based on their review, the authors offer "sequential treatment steps," from conservative treatment to surgical management, which will be helpful for successful management of future late seroma cases. However, further study is needed to clarify the relationship, if any, between a particular type of textured implant and the development of late seroma. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


The Effects of Contextual Factors on Hospital Chaplains: A Qualitative Study.
Critical questions arise about how contextual factors affect hospital chaplains. We interviewed 23 chaplains in-depth. Hospitals' religious or other institutional affiliation, geography, and leadership can influence chaplains both explicitly/directly and implicitly/indirectly-for example, in types/amounts of support chaplains receive, scope of chaplains' roles/activities, amounts/types of chaplains' interactions, chaplains' views of their roles and freedom to innovate, and patients', families' and other providers' perceptions/expectations regarding spiritual care. These data have critical implications for research, practice, and education.


[Foot-and-mouth disease of cattle is not a zoonosis].
In 1997 there was an outbreak of foot-and-mouth disease (FMD) among cattle in Turkey. People visiting that country were warned against importing animal products into the Netherlands. This had nothing to do with hazards to human health, as FMD virus is not a zoonotic virus, but with the risk of spread of the disease to livestock in the Netherlands, notably to cattle and pigs. A disease with similar clinical symptoms in pigs is swine vesicular disease (SVD), which is not a zoonosis either. FMD virus is an aphtovirus, SVD virus is an enterovirus. Hand-foot-and-mouth disease in humans is caused by other enteroviruses, i.e. Coxsackie virus and enterovirus 71.


Chiral Systems Made from DNA.
The very chemical structure of DNA that enables biological heredity and evolution has non-trivial implications for the self-organization of DNA molecules into larger assemblies and provides limitless opportunities for building functional nanostructures. This progress report discusses the natural organization of DNA into chiral structures and recent advances in creating synthetic chiral systems using DNA as a building material. How nucleic acid chirality naturally comes into play in a diverse array of situations is considered first, at length scales ranging from an individual nucleotide to entire chromosomes. Thereafter, chiral liquid crystal phases formed by dense DNA mixtures are discussed, including the ongoing efforts to understand their origins. The report then summarizes recent efforts directed toward building chiral structures, and other structures of complex topology, using the principle of DNA self-assembly. Discussed last are existing and proposed functional man-made nanostructures designed to either probe or harness DNA's chirality, from plasmonics and spintronics to biosensing.


Recoupling Industrial Dairy Feedlots and Industrial Farmlands Mitigates the Environmental Impacts of Milk Production in China.
Dairy production is becoming more industrialized globally, especially in developing countries. The large amount of animal wastes from industrial feedlots cannot be fully used on nearby farmlands, leading to severe environmental problems. Using China as a case study, we found that most dairy feedlots employ a semicoupled mode that only recycles solid manure to farmlands, and only a few dairy feedlots employ a fully coupled mode that recycles both solid and liquid animal manure. To produce 1 ton of milk, the fully coupled mode could reduce greenhouse gas (including carbon dioxide, methane, and nitrous oxide in this paper) emissions by 24%, ammonia emissions by 14%, and N discharge into water by 29%, compared with the semicoupled systems. Coupling feedlots with constructed wetlands can further result in greater mitigation of N leaching into groundwater. However, the fully coupled system has not been widely used due to the low benefit to farmers and the institutional barrier that the feedlot owners have no right to use adjacent farmlands. Since a fully coupled system improves net ecosystem services that favor the public, a policy that supports removing the economic and institutional barriers is necessary. Our approach provides a template for mitigating environmental impacts from livestock production without sacrificing milk production.


Lung toxicity associated with cyclophosphamide use. Two distinct patterns.
Cyclophosphamide-induced lung toxicity may be difficult to recognize because of the presence of confounding variables such as concomitant use of other cytotoxic drugs, opportunistic infections, diffuse pulmonary malignancy, radiation pneumonitis, and oxygen toxicity. The purpose of this retrospective analysis was to identify the clinical spectrum of pulmonary toxicity of cyclophosphamide. In our review of case records, we sought to identify patients in whom cyclophosphamide was the only identifiable etiologic factor for lung toxicity. In a 20-yr period six patients were identified with cyclophosphamide-induced lung disease, including five men and one woman ranging in age from 42 to 78 yr. Clinical features of toxicity include dyspnea, fever, cough, new parenchymal infiltrates, gas exchange abnormalities on pulmonary function tests, and pleural thickening on chest roentgenogram. Two patterns of cyclophosphamide-induced lung toxicity were identified. A single patient presented with early-onset pneumonitis and responded to discontinuation of the drug. Five patients with late-onset pneumonitis developed progressive pulmonary fibrosis associated with bilateral pleural thickening. Patients with late-onset pneumonitis showed no response to cessation of cyclophosphamide and institution of corticosteroid therapy. Three of these patients died of respiratory failure. Careful review of the individual cases reported in the literature as cyclophosphamide lung toxicity revealed only 12 cases in whom none of the additional confounding factors could be identified. These could easily be divided in the same two categories. Early-onset pneumonitis is reversible and may respond to corticosteroid therapy. Late-onset pneumonitis, frequently associated with pleural thickening, is clinically distinct from idiopathic pulmonary fibrosis but has a chronically progressive course. It appears unresponsive to corticosteroid therapy.


Psychosis in Dementia With Lewy Bodies.
Prominent psychotic symptoms, particularly hallucinations and delusions, have been estimated to occur in approximately 60% of patients with dementia with Lewy bodies (DLB). Many of these individuals experience psychotic symptoms before the onset of other features characteristic of DLB. To facilitate consistent diagnosis of DLB, an international consortium recently created consensus guidelines for the clinical and pathological diagnosis of this disease. Accurate diagnosis of DLB is particularly important as these patients may have greater neuroleptic sensitivity than other elderly patients. Currently there is no verified treatment specifically for psychotic symptoms in DLB. However, if neuroleptic treatment cannot be avoided, low doses of atypical antipsychotics may prove beneficial, while minimizing anticholinergic and extrapyramidal side effects.


Fasting, lipid metabolism, and triiodothyronine in rat gastrocnemius muscle: interrelated roles of uncoupling protein 3, mitochondrial thioesterase, and coenzyme Q.
We investigated the role of uncoupling protein 3 (UCP3) during fasting and examined the effect of triiodothyronine (T3) administration in such a condition. The possible involvement of mitochondrial thioesterase (MTE I) and the role of putative cofactors, such as coenzyme Q (CoQ), was also examined. Here, we report that fasting induced a more than twofold elevation in the expression and activity of MTE I, and an increase in UCP3 expression, without any associated uncoupling activity. Administration of T3 to fasting rats further up-regulated UCP3 as well as MTE I expression, markedly enhanced MTE I enzyme activity and prevented the impairment of the uncoupling activity of UCP3 normally seen during fasting. Indeed, T3-treatment induced an UCP3-dependent decrease in mitochondrial membrane potential, which was abolished by the addition of either GDP or superoxide dismutase (SOD). T3 administration also prevented the marked decrease of CoQ levels observed in fasting rats and this provides evidence that also, in vivo, CoQ represents an essential cofactor for the UCP3-mediated uncoupling. The data also show that MTE I and UCP3 are likely involved in the same biochemical mechanism and that UCP3 postulated functions, such as lipid handling and uncoupling, are not mutually exclusive but may coexist in vivo.


Bacterial expression, purification and preliminary X-ray crystallographic characterization of the invertase inhibitor Nt-CIF from tobacco.
Acid invertases catalyzing the breakdown of sucrose are regulated at the post-translational level by extracellular inhibitory proteins of 16-20 kDa molecular weight in a pH-dependent manner. Little is known about the characteristics of the underlying protein-protein interaction. Here, the expression, purification, characterization, crystallization and initial X-ray analysis of a biologically active invertase inhibitor Nt-CIF from tobacco is reported. Four crystal forms covering a wide pH range have been obtained and data sets at resolutions higher than 2.5 A have been collected.


PdMo bimetallene nanozymes for photothermally enhanced antibacterial therapy and accelerated wound healing.
Although antibacterial platforms involving nanozymes have been extensively investigated, there are still problems of poor reactive oxygen species generation efficiency and obstinate bacterial biofilms. Developing a nanozyme-photothermal therapy nanoplatform with superior sterilization effects and minimal side effects would be a good alternative for completely eliminating bacteria and biofilms. Herein, an ultrathin PdMo bimetallene nanozyme with a planar topology and boosted metal utilization, exhibiting excellent photothermal and peroxidase-like activity, is designed for synergistic nanozyme-photothermal sterilization applications and accelerated wound healing. The superior catalytic activity of PdMo bimetallene nanozymes could convert a biosafe concentration of hydrogen peroxide (H2O2) into large quantities of toxic hydroxyl radicals (•OH) under laser irradiation, enhancing bacterial membrane permeability and thermal sensitivity for efficient removal of bacteria and biofilms. In addition, PdMo bimetallene presents a good wound-healing ability according to the results of fibroblast proliferation and collagen deposition with minor side effects. This work would provide an innovative avenue for developing metallene-based nanozymes for biomedical applications.


Modulation by eicosanoid biosynthesis inhibitors of immune responses by the insect Manduca sexta to the pathogenic fungus Metarhizium anisopliae.
Metarhizium anisopliae conidia (spores) reduced weight gain and caused death when injected into Manduca sexta larvae. When the fungus was co-injected with the eicosanoid biosynthesis inhibitor dexamethasone, larval weight gain was further reduced and mortality increased. These effects were reversed when dexamethasone was given together with the eicosanoid precursor arachidonic acid (AA). Similarly, treatment with other eicosanoid biosynthesis inhibitors (esculetin, phenidone, ibuprofen, and indomethacin) with differing modes of action enhanced the reduction in weight gain caused by mycosis. Injection of M. anisopliae conidia induced nodule formation in vivo; nodule numbers were reduced by dexamethasone, and restored by AA. Incubation of hemocytes with conidia caused microaggregation of hemocytes (indicative of nodule formation) in vitro and this was inhibited by dexamethasone, suggesting that dexamethasone acts directly on hemocytes, although inhibition was only partially reversed by AA. We suggest that the M. sexta immune response to fungal pathogens is normally modulated by physiological systems that include eicosanoid biosynthesis. This is the first demonstration that the virulence of a fungal entomopathogen can be enhanced by compromising the insect host's immune system.


Detection of Babesia odocoilei in Ixodes scapularis Ticks Collected from Songbirds in Ontario and Quebec, Canada.
Songbirds widely disperse ticks that carry a diversity of pathogens, some of which are pathogenic to humans. Among ticks commonly removed from songbirds, the blacklegged tick, Ixodes scapularis, can harbor any combination of nine zoonotic pathogens, including Babesia species. From May through September 2019, a total 157 ticks were collected from 93 songbirds of 29 species in the Canadian provinces of Ontario and Québec. PCR testing for the 18S gene of Babesia species detected Babesia odocoilei in 12.63% of I. scapularis nymphs parasitizing songbirds in Ontario and Québec; none of the relatively small numbers of Ixodes muris, Ixodes brunneus, or Haemaphysalis leporispalustris were PCR-positive. For ticks at each site, the prevalence of B. odocoilei was 16.67% in Ontario and 8.89% and 5.26% in Québec. Of 31 live, engorged I. scapularis larvae and nymphs held to molt, 25 ticks completed the molt; five of these molted ticks were positive for B. odocoilei. PCR-positive ticks were collected from six bird species-namely, Common Yellowthroat, Swainson's Thrush, Veery, House Wren, Baltimore Oriole, and American Robin. Phylogenetic analysis documented the close relationship of B. odocoilei to Babesia canis canis and Babesia divergens, the latter a known pathogen to humans. For the first time in Canada, we confirm the transstadial passage of B. odocoilei in I. scapularis molting from larvae to nymphs. A novel host record reveals I. scapularis on a Palm Warbler. Our findings show that B. odocoilei is present in all mobile life stages of I. scapularis, and it is widely dispersed by songbirds in Ontario and Québec.


Matrine induced G0/G1 arrest and apoptosis in human acute T-cell lymphoblastic leukemia (T-ALL) cells.
Matrine, a natural product extracted from the root of Sophora flavescens, is a promising alternative drug in different types of cancer. Here, we aimed to investigate the therapeutic effects and underlying molecular mechanisms of matrine on human acute lymphoblastic leukemia (ALL) cell line, CCRF-CEM. Cell viability and IC50 values were determined by WST-1 cell cytotoxicity assay. Cell cycle distribution and apoptosis rates were analyzed by flow cytometry. Expression patterns of 44 selected miRNAs and 44 RNAs were analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) using the Applied Biosystems 7500 Fast Real-Time PCR System. Matrine inhibited cell viability and induced apoptosis of CCRF-CEM cells in a dose-dependent manner. Cell cycle analysis demonstrated that matrine-treated CCRF-CEM cells significantly accumulated in the G0/G1 phase compared with the untreated control cells. hsa-miR-376b-3p (-37.09 fold, p = 0.008) and hsa-miR-106b-3p (-16.67 fold, p = 0.028) expressions were decreased, whereas IL6 (95.47 fold, p = 0.000011) and CDKN1A (140.03 fold, p = 0.000159) expressions were increased after matrine treatment. Our results suggest that the downregulation of hsa-miR-106b-3p leads to the upregulation of target p21 gene, CDKN1A, and plays a critical role in the cell cycle progression by arresting matrine-treated cells in the G0/G1 phase.


Changing perspectives on aging and energy requirements: aging and digestive function in humans, dogs and cats.
When considering the question of energy balance, it is important to take into account energy provision and the ability of aging animals to digest macronutrients and thus obtain their maintenance energy requirement. A large number of studies have been conducted in humans in an effort to establish whether aging of the gastrointestinal tract has a significant effect on availability of dietary energy. The results of these studies have been conflicting, with indications that some aspects of gut functionality do decline with age, but little evidence overall to suggest that aging humans are at risk of energy deficit due to compromised digestive efficiency. A number of digestibility studies carried out with dogs confirm that there is no evidence of an age-related decline in digestive efficiency. This knowledge makes the determination of energy provision to senior dogs relatively straightforward to calculate. Many senior cats appear to exhibit quite a marked reduction in their ability to digest macronutrients, particularly fat, efficiently. Because this reduces the overall capacity to obtain energy from the diet, it is recommended that old cats should not routinely be offered reduced energy diets. For senior cats, the feeding regimen in later life should be to offer highly digestible diets that provide as much energy as adult maintenance rations.


Strategies for the Identification of Bioactive Neuropeptides in Vertebrates.
Neuropeptides exert essential functions in animal physiology by controlling e.g., reproduction, development, growth, energy homeostasis, cardiovascular activity and stress response. Thus, identification of neuropeptides has been a very active field of research over the last decades. This review article presents the various methods used to discover novel bioactive peptides in vertebrates. Initially identified on the basis of their biological activity, some neuropeptides have also been discovered for their ability to bind/activate a specific receptor or based on their biochemical characteristics such as C-terminal amidation which concerns half of the known neuropeptides. More recently, sequencing of the genome of many representative species has facilitated peptidomic approaches using mass spectrometry and in silico screening of genomic libraries. Through these different approaches, more than a hundred of bioactive neuropeptides have already been identified in vertebrates. Nevertheless, researchers continue to find new neuropeptides or to identify novel functions of neuropeptides that had not been detected previously, as it was recently the case for nociceptin.


Antifungal susceptibilities and genetic relatedness of serial Trichophyton rubrum isolates from patients with onychomycosis of the toenail.
Onychomycosis is a common fungal disease infecting up to 20% of the population over age 40. The major causative agent of onychomycosis is Trichophyton rubrum. Uncontrolled infection may eventually lead to penetration of the newly forming nail plate. In spite of the encouraging cure rate with recent antifungal agents such as the allylamines (terbinafine) and azoles (itraconazole and fluconazole) some patients inevitably fail therapy. In this investigation, a group of patients from a multi-center study designed to assess the efficacy of terbinafine with known cases of onychomycosis were selected for evaluation. Nail samples from this patient group were colonized with T. rubrum throughout the terbinafine therapy. Antifungal susceptibility testing was performed on these T. rubrum isolates to detect change in MIC values. Strain relatedness was examined using random amplified polymorphic DNA (RAPD) technique. Our results revealed failure of patients to clear T. rubrum is not related to the development of resistance to the drug. While species determination was possible, we were not able to identify differences that would indicate reinfection with a new strain. Analysis of patient demographic data revealed that 70% of patients were over 45 years old, 56.6% were previously treated with antifungals, 60% came from family history with onychomycosis and 13 % were diabetic. In conclusion, our data indicate that patients' failure to clear onychomycosis was not associated with resistant development. Failure of terbinafine therapy may be dependent on host-related factors.


Evidence of sub-10 nm aluminum-oxygen precipitates in silicon.
In this research, ultraviolet laser-assisted atom-probe tomography (APT) was utilized to investigate precisely the behavior at the atomistic level of aluminum impurities in ultrathin epitaxial silicon layers. Aluminum atoms were incorporated in situ during the growth process. The measured average aluminum concentration in the grown layers exceeds by several orders of magnitude the equilibrium bulk solubility. Three-dimensional atom-by-atom mapping demonstrates that aluminum atoms precipitate in the silicon matrix and form nanoscopic precipitates with lateral dimensions in the 1.3 to 6.2 nm range. These precipitates were found to form only in the presence of oxygen impurity atoms, thus providing clear evidence of the longhypothesized role of oxygen and aluminum-oxygen complexes in facilitating the precipitation of aluminum in a silicon lattice. The measured average aluminum and oxygen concentrations in the precipitates are ∼10 ± 0.5 at.% and ∼4.4 ± 0.5 at.%, respectively. This synergistic interaction is supported by first-principles calculations of the binding energies of aluminum-oxygen dimers in silicon. The calculations demonstrate that there is a strong binding between aluminum and oxygen atoms, with Al-O-Al and O-Al-Al as the energetically favorable sequences corresponding to precipitates in which the concentration of aluminum is twice as large as the oxygen concentration in agreement with APT data.


Docetaxel-based therapy with and without antiangiogenic agents as first-line chemotherapy for castration-resistant prostate cancer: A meta-analysis of nine randomized controlled trials.
The aim of this study was to systematically assess the effectiveness and safety of the addition of antiangiogenic agents to docetaxel-based chemotherapy for the treatment of castration-resistant prostate cancer. Computerized electronic databases, including Embase, PubMed and The Cochrane Library were searched for randomized controlled trials (RCTs) on the comparison between docetaxel-based therapy with and without antiangiogenic agents for the treatment of prostate cancer. The search time limit was from the building of the database until July 18, 2013. Following extracting information and conducting a methodological quality evaluation for study inclusion based on inclusion and exclusion criteria, RevMan 5.2 and Stata 12.0 software were used to perform a meta-analysis and the Jadad scale was used for evaluation of study quality. A total of 9 RCTs and 4,681 patients were included in this meta-analysis. The comparison between docetaxel-based therapy with and without antiangiogenic agents revealed no statistically significant differences regarding prostate-specific antigen response rate [risk ratio (RR)=0.99, 95% confidence interval (CI): 0.87-1.12, P=0.84], overall survival (OS) [hazard ratio (HR)=0.97, 95%CI: 0.91-1.05)] and progression-free survival (PFS) (HR=0.99, 95%CI: 0.83-1.18); however, the incidence of treatment-related mortality was higher in the docetaxel-based therapy with antiangiogenic agents group (RR=1.95, 95%CI: 1.23-3.11, P=0.005), whereas the incidence of thrombus formation was higher in the docetaxel-based therapy without antiangiogenic agents group (RR=0.57, 95%CI: 0.41-0.80, P=0.001). In conclusion, our findings indicated that docetaxel combined with antiangiogenic agents did not increase the OS or the PFS of the patients with castration-resistant prostate cancer, whereas it may increase the risk of treatment-related mortality. However, further RCTs with larger, high-quality patient samples are required to verify these findings.


Towards Harmonized Biobanking for Biomonitoring: A Comparison of Human Biomonitoring-Related and Clinical Biorepositories.
Human biomonitoring (HBM) depends on high-quality human samples to identify status and trends in exposure and ensure comparability of results. In this context, much effort has been put into the development of standardized processes and quality assurance for sampling and chemical analysis, while effects of sample storage and shipment on sample quality have been less thoroughly addressed. To characterize the currently applied storage and shipment procedures within the consortium of the European Human Biomonitoring Initiative (HBM4EU), which aims at harmonization of HBM in Europe, a requirement analysis based on data from an online survey was conducted. In addition, the online survey was addressed to professionals in clinical biobanking represented by members of the European, Middle Eastern and African Society for Biopreservation and Biobanking (ESBB) to identify the current state-of-the-art in terms of sample storage and shipment. Results of this survey conducted in these two networks were compared to detect processes with potential for optimization and harmonization. In general, many similarities exist in sample storage and shipment procedures applied by ESBB members and HBM4EU partners and many requirements for ensuring sample quality are already met also by HBM4EU partners. Nevertheless, a need for improvement was identified for individual steps in sample storage, shipment, and related data management with potential impact on sample and data quality for HBM purposes. Based on these findings, recommendations for crucial first steps to further strengthen sample quality, and thus foster advancement in HBM on a pan-European level are given.


Sex chromosome anomalies, hormones, and aggressivity.
This double-blind, controlled study of XYY and XXY men found in a birth cohort of 4,591 tall men born in Copenhagen assessed evidence of delinquent and aggressive behavior and explored the role of hormonal determinants in the behavioral and psychological differences noted among groups. Information from social records, a structured psychological interview, and projective tests did not support the notion that men with sex chromosome anomalies are particularly violent or aggressive. Hormonally, XYY men had significantly higher concentrations of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) than matched control groups. In contrast, XXY men had higher levels of LH, FSH, and prolactin, but low concentrations of testosterone. There was a significantly positive relation among all subjects as well as XY controls alone between plasma testosterone level and evidence of criminal convictions. A proportionate increase in testosterone levels was noted when subjects were divided into nondelinquents, delinquents without violent convictions, and delinquents with violent convictions. The relation between testosterone level and criminal behavior was not reflected in measures of aggression derived from the psychological interview and projective tests. There was no specific evidence that testosterone is a mediating factor in the criminal behavior of XYY men.


Recovering a Targeted Mutation in Mice from Embryonic Stem Cell Chimeras or CRISPR-Cas Founders.
Following the production of chimeras from targeted embryonic stem (ES) cells or obtaining founders from CRISPR-Cas gene editing in preimplantation embryos, the desired targeted mutation must be recovered and established in the heterozygous state in a strain or stock of mice for further study. The breeding schemes for ES chimeras and CRISPR-Cas founders differ. For ES cell chimeras, we discuss the relative benefits of breeding from male or female chimeras. We discuss the importance of genetic background and provide practical advice for putting the mutation on inbred or outbred backgrounds or producing a coisogenic strain. For CRISPR-Cas founders, which will most likely be mosaic for different mutations, initial breeding strategies are discussed to maintain a desired genetic background at the same time as producing progeny to segregate different alleles. Strategies for testing the progeny to recognize indels, missense mutations, and knock-in mutations are discussed. In the event that ES cell chimeras or CRISPR-Cas founders produce no offspring or fail to transmit the mutant allele(s), there is a troubleshooting guide to pinpoint the problem. If heterozygous offspring from the chimeras or founders are normal, fertile, and of both sexes, the analysis of homozygous effects of the mutation can now begin; if not, possible dominant effects are considered.


Towards an understanding of the herpes simplex virus type 1 latency-reactivation cycle.
Infection by herpes simplex virus type 1 (HSV-1) can cause clinical symptoms in the peripheral and central nervous system. Recurrent ocular shedding can lead to corneal scarring and vision loss making HSV-1 a leading cause of corneal blindness due to an infectious agent. The primary site of HSV-1 latency is sensory neurons within trigeminal ganglia. Periodically, reactivation from latency occurs resulting in virus transmission and recurrent disease. During latency, the latency-associated transcript (LAT) is abundantly expressed. LAT expression is important for the latency-reactivation cycle in animal models, in part, because it inhibits apoptosis, viral gene expression, and productive infection. A novel transcript within LAT coding sequences (AL3) and small nonprotein coding RNAs are also expressed in trigeminal ganglia of latently infected mice. In this review, an update of viral factors that are expressed during latency and their potential roles in regulating the latency-reactivation cycle is discussed.


Microarray analysis reveals global modulation of endogenous retroelement transcription by microbes.
A substantial proportion of both the mouse and human genomes comprise of endogenous retroelements (REs), which include endogenous retroviruses. Over evolutionary time, REs accumulate inactivating mutations or deletions and thus lose the ability to replicate. Additionally, REs can be transcriptionally repressed by dedicated mechanisms of the host. Nevertheless, many of them still possess and express intact open reading frames, and their transcriptional activity has been associated with many physiological and pathological processes of the host. However, this association remains tenuous due to incomplete understanding of the mechanism by which RE transcription is regulated. Here, we use a bioinformatics tool to examine RE transcriptional activity, measured by microarrays, in murine and human immune cells responding to microbial stimulation. Immune cell activation by microbial signals in vitro caused extensive changes in the transcription not only of the host genes involved in the immune response, but also of numerous REs. Modulated REs were frequently found near or embedded within similarly-modulated host genes. Focusing on probes reporting single-integration, intergenic REs, revealed extensive transcriptional responsiveness of these elements to microbial signals. Microbial stimulation modulated RE expression in a cell-intrinsic manner. In line with these results, the transcriptional activity of numerous REs followed characteristics in different tissues according to exposure to environmental microbes and was further heavily altered during viral infection or imbalances with intestinal microbiota, both in mice and humans. Together, these results highlight the utility of improved methodologies in assessing RE transcription profiles in both archived and new microarray data sets. More importantly, application of this methodology suggests that immune activation, as a result of infection with pathogens or dysbiosis with commensal microbes, causes global modulation of RE transcription. RE responsiveness to external stimuli should, therefore, be considered in any association between RE transcription and disease.


Metabolic alterations in mammary cancer prevention by withaferin A in a clinically relevant mouse model.
Efficacy of withaferin A (WA), an Ayurvedic medicine constituent, for prevention of mammary cancer and its associated mechanisms were investigated using mouse mammary tumor virus-neu (MMTV-neu) transgenic model. Incidence and burden of mammary cancer and pulmonary metastasis were scored in female MMTV-neu mice after 28 weeks of intraperitoneal administration with 100 µg WA (three times/week) (n = 32) or vehicle (n = 29). Mechanisms underlying mammary cancer prevention by WA were investigated by determination of tumor cell proliferation, apoptosis, metabolomics, and proteomics using plasma and/or tumor tissues. Spectrophotometric assays were performed to determine activities of complex III and complex IV. All statistical tests were two-sided. WA administration resulted in a statistically significant decrease in macroscopic mammary tumor size, microscopic mammary tumor area, and the incidence of pulmonary metastasis. For example, the mean area of invasive cancer was lower by 95.14% in the WA treatment group compared with the control group (mean = 3.10 vs 63.77 mm2, respectively; difference = -60.67 mm2; 95% confidence interval = -122.50 to 1.13 mm2; P = .0536). Mammary cancer prevention by WA treatment was associated with increased apoptosis, inhibition of complex III activity, and reduced levels of glycolysis intermediates. Proteomics confirmed downregulation of many glycolysis-related proteins in the tumor of WA-treated mice compared with control, including M2-type pyruvate kinase, phospho glycerate kinase, and fructose-bisphosphate aldolase A isoform 2. This study reveals suppression of glycolysis in WA-mediated mammary cancer prevention in a clinically relevant mouse model.


Treg-protected donor lymphocyte infusions: a new tool to address the graft-versus-leukemia effect in the absence of graft-versus-host disease in patients relapsed after HSCT.
In high-risk acute leukemia patients undergoing haploidentical hematopoietic stem cell transplantation (HSCT), adoptive immunotherapy with T regulatory cells (Tregs) and T conventional cells (Tcons) prevented acute and chronic graft-versus-host disease (GvHD), favored post-transplant immunological reconstitution and was associated with a powerful graft-versus-leukemia (GvL) effect. With a particularly innovative approach, we developed a treatment with a Treg-protected donor lymphocyte infusion (DLI) for patients with early relapse after HSCT and we report here the results obtained in the first patient with APL (M3v) relapsed after a second matched allogeneic HSCT (15% blasts and 75% of donor cells in bone marrow). The patient received a first infusion of 2.5 × 106/kg Tregs derived from matched donor followed 7 days later by 5 × 106/kg Tcons. GvL effect was strongly evident as the percentage of leukemic cells decreased to 5%. A second infusion of Tregs (2.5 × 106/kg) and Tcons (2 × 106/kg) was performed. No GvHD was observed. Disease evaluation showed the absence of blastic cells at flow-cytometry, a normal caryotype and full donor chimerism. We also observed NOTCH1 down-regulation in peripheral blood. This new immunotherapy approach showed that Treg-protected DLI is effective in preventing GvHD and is associated with a strong GvL effect.


Scotopic microperimetry: evolution, applications and future directions.
For many inherited and acquired retinal diseases, reduced night vision is a primary symptom. Despite this, the clinical testing options for spatially resolved scotopic vision have until recently been limited. Scotopic microperimetry is a relatively new visual function test that combines two-colour perimetry with fundus-controlled perimetry performed in scotopic luminance conditions. The technique enables spatially resolved mapping of central retinal sensitivity alongside the ability to distinguish between rod and cone photoreceptor sensitivities. Two companies produce commercially available scotopic microperimeters - Nidek (Nidek Technologies Srl, Padova, Italy) and CenterVue (CenterVue S.p.A., Padova, Italy). Scotopic microperimetry is a promising technology capable of detecting changes in retinal sensitivity before changes in other measures of visual function. Scotopic microperimetry is a promising functional biomarker that has the potential as a useful clinical trial outcome measure. This review summarises the evolution and applications of scotopic microperimetry, and discusses testing options, including testing grid selection, dark-adaptation time and threshold sensitivity analyses.


Ratiometric temperature sensing with semiconducting polymer dots.
This communication describes ultrabright single-nanoparticle ratiometric temperature sensors based on semiconducting polymer dots (Pdots). We attached the temperature sensitive dye-Rhodamine B (RhB), whose emission intensity decreases with increasing temperature-within the matrix of Pdots. The as-prepared Pdot-RhB nanoparticle showed excellent temperature sensitivity and high brightness because it took advantage of the light harvesting and amplified energy transfer capability of Pdots. More importantly, the Pdot-RhB nanoparticle showed ratiometric temperature sensing under a single wavelength excitation and has a linear temperature sensing range that matches well with the physiologically relevant temperatures. We employed Pdot-RhB for measuring intracellular temperatures in a live-cell imaging mode. The exceptional brightness of Pdot-RhB allows this nanoscale temperature sensor to be used also as a fluorescent probe for cellular imaging.


2-Color calcium pump reveals closure of the cytoplasmic headpiece with calcium binding.
The sarco(endo)plasmic reticulum calcium ATPase (SERCA) undergoes conformational changes while transporting calcium, but the details of the domain motions are still unclear. The objective of the present study was to measure distances between the cytoplasmic domains of SERCA2a in order to reveal the magnitude and direction of conformational changes. Using fluorescence microscopy of live cells, we measured intramolecular fluorescence resonance energy transfer (FRET) from a donor fluorescent protein fused to the SERCA N-terminus to an acceptor fluorescent protein fused to either the N-, P-, or transmembrane domain. The "2-color" SERCA constructs were catalytically active as indicated by ATPase activity in vitro and Ca uptake in live cells. All constructs exhibited dynamic FRET changes in response to the pump ligands calcium and thapsigargin (Tg). These FRET changes were quantified as an index of SERCA conformational changes. Intramolecular FRET decreased with Tg for the two N-domain fusion sites (at residue 509 or 576), while the P- (residue 661) and TM-domain (C-terminus) fusions showed increased FRET with Tg. The magnitude of the Tg-dependent conformational change was not decreased by coexpression of phospholamban (PLB), nor did PLB slow the kinetics of Tg binding. FRET in ionophore-permeabilized cells was lower in EGTA than in saturating calcium for all constructs, indicating a decrease in domain separation distance with the structural transition from E2 (Ca-free) to E1 (Ca-bound). The data suggest closure of the cytoplasmic headpiece with Ca-binding. The present results provide insight into the structural dynamics of the Ca-ATPase. In addition, the 2-color SERCA constructs developed for this study may be useful for evaluating candidate small molecule regulators of Ca uptake activity.


The public health impact of prion diseases.
Several prion disease-related human health risks from an exogenous source can be identified in the United States, including the iatrogenic transmission of Creutzfeldt-Jakob disease (CJD), the possible occurrence of variant CJD (vCJD), and potential zoonotic transmission of chronic wasting disease (CWD). Although cross-species transmission of prion diseases seems to be limited by an apparent "species barrier," the occurrence of bovine spongiform encephalopathy (BSE) and its transmission to humans indicate that animal prion diseases can pose a significant public health risk. Recent reports of secondary person-to-person spread of vCJD via blood products and detection of vCJD transmission in a patient heterozygous at codon 129 further illustrate the potential public health impacts of BSE.


Do adverse histopathologic findings in colorectal cancer patients explain disparate outcomes?
We have previously reported reduced overall and disease-free survival in black patients from a 10-year retrospective review of 668 patients from tumor registry data. This study of 213 patients reports the analysis of available archived tissue from a city hospital (n=44 patients, 53% black) and from a university medical center (n=169, 10.6% black). Two senior pathologists independently reviewed slides for predetermined histologic criteria reported to correlate with survival: tumor type, stage at diagnosis, character of invasion, vascular or perineural invasion, the presence of residual adenoma, the presence of a Crohn's-like reaction and number of nodes resected. Differences in discrete variables were compared using the Chi-squared test. Differences in continuous variables were analyzed using independent t tests. No statistically significant differences were identified in tumor stage or type by institution or race. In patients treated at the city hospital, there was a higher incidence of infiltrating tumors (85% vs. 61%, p<0.001), vascular invasion (70% vs. 36%, p<0.05) and residual adenoma (84% vs. 39%, p<0.05); however, no differences by race were identified. Blacks at both hospitals had significantly more perineural invasion (81% vs. 30%, p<0.05) and Crohn's-like reaction (64% vs. 30%, p<0.05) when compared to white patients, although there was no difference between hospitals. The total number of lymph nodes resected was higher at the university hospital (17.0 vs. 8.9, p<0.001). There were no differences in number of nodes resected at either institution by race. Histopathologic findings did not explain the apparent disparity in survival. The differences in number of nodes harvested may suggest inadequate resection or insufficient recovery of nodes by the pathologist.


Lifelong exposure to caffeine increases anxiety-like behavior in adult mice exposed to tobacco smoke during adolescence.
Caffeine and tobacco smoke are among the most frequently self-administered licit psychoactive drugs in the world. Both drugs affect anxiety levels, however, little is known on the impact of the dual exposure in the adolescent brain, the period during which smoking begins. Considering that anxiety is a relevant factor for smoking maintenance and relapse, we investigated the effects of lifelong exposure to caffeine on anxiety levels of Swiss mice exposed to tobacco smoke during adolescence. Caffeine was administrated during all prenatal and postnatal life (CAF, 0.1 g/l to drink). From postnatal day 30-45, animals were exposed to tobacco smoke (SMK, whole body exposure, 8 h/day) generated from research cigarettes type 3R4F (nicotine = 0.73 mg/per cigarette). Four groups were analyzed: (1) CAF + SMK exposure; (2) SMK exposure; (3) CAF exposure; (4) Control. Anxiety levels were assessed in the elevated plus maze at the end of smoke exposure (PN45), at short- (PN55) and long-term (PN75) withdrawal. Caffeine exposure reduced decision making time (time in center of maze) during adolescence (PN45 and PN55). In addition, caffeine increased anxiety-like behavior during long-term tobacco smoke withdrawal. The present study provides experimental evidence that caffeine and tobacco smoke during adolescence interact resulting in emotional dysregulation during tobacco smoke withdrawal. Particularly, increased anxiety-like behavior during long-term withdrawal in CAF + SMK animals demonstrates late-emergent effects. In this sense, our data suggest that lifelong caffeine exposure may be an important factor in tobacco relapse.