Ibrutinib, lenalidomide and dexamethasone in patients with relapsed and/or refractory multiple myeloma: Phase I trial results.
Therapeutic strategies that target novel pathways are urgently needed for patients with relapsed/refractory multiple myeloma (RRMM). Ibrutinib is an oral covalent inhibitor of Bruton tyrosine kinase, which is overexpressed in MM cells. This phase 1 dose-escalation study examined various doses of ibrutinib in combination with standard doses of lenalidomide (25 mg) and dexamethasone (40 mg) using a standard 3 + 3 design in RRMM patients. The primary objective was to determine the maximum tolerated dose (MTD) of ibrutinib in combination with lenalidomide and dexamethasone. Patients (n = 15) had received a median of 4 prior regimens, 53% were triple-class exposed, 33% were penta-exposed, and 54% were lenalidomide-refractory. The MTD of ibrutinib was 840 mg (n = 6) and only 1 dose-limiting toxicity; a grade 3 rash possibly related to ibrutinib was noted. The most common ≥ grade 3 adverse events were rash in 2 (13%), lymphopenia in 2 (13%), leukopenia, neutropenia, thrombocytopenia, and anemia all occurring in 3 (20%) patients each. One patient achieved a partial response for an overall response rate of 7%. The clinical benefit rate was 80%. The median time to progression was 3.8 months. Ibrutinib, lenalidomide and dexamethasone appears to be a safe and well-tolerated regimen with reasonable efficacy in heavily pretreated RRMM patients.


School as a "protective factor" against drugs: perceptions of adolescents and teachers.
This study aims to discover and describe protective factors regarding the use of drugs, according to teachers and students, aged 14 to 15 years, from a Public Secondary School in Santiago de Querétaro, Mexico. This is a descriptive and exploratory study. Data collection was carried out through semi-structure interview and non-participative observation with ten students and five teachers. Three themes resulted from data analysis: school and school's environment: the school does not provide a healthy environment; use of drugs: perceived by both the students and teachers in the institution itself; prevention programs: there are health promotion and prevention programs available at the school. According to the students' and teachers' perceptions, the school represents a risk factor.


Effect of an educational intervention on requesting behaviour by a medical admission unit.
Previous studies have shown that of all the tests requested of hospital laboratories, 25-40% are thought to be unnecessary. Our hospital laboratory observed that a significant number of requests from the medical admissions unit (MAU) were probably inappropriate. In an attempt to improve requesting behaviour this observation was investigated and an educational intervention employed. We performed a survey of requesting behaviour by the MAU and a local protocol was designed as an audit standard. The influence of the educational intervention on requesting behaviour was audited. The generation of local guidelines and an educational intervention to promote them, significantly changed requesting behaviour. The main effect was the reduction in requesting of thyroid function tests, lipid profiles and coagulation screens. This process highlighted inappropriate requesting behaviour from the MAU which, following a process of investigation and education, resulted in a significant change with an associated cost benefit.


The path of microplastics through the rare biodiversity estuary region of the northern Bay of Bengal.
Due to its harmful effects on ecosystems and human health, microplastic (MP) pollution has become a significant environmental problem on a global scale. Although MPs' pollution path and toxic effects on marine habitats have been examined worldwide, the studies are limited to the rare biodiversity estuary region of Hatiya Island from the northern Bay of Bengal. This study aimed to investigate the MP pollution path and its influencing factors in estuarine sediments and water in rare biodiversity Hatiya Island in the northern Bay of Bengal. Sixty water and sediment samples were collected from 10 sampling sites on the Island and analyzed for MPs. The abundance of MPs in sediment ranged from 67 to 143 pieces/kg, while the abundance in water ranged from 24.34 to 59 pieces/m3. The average concentrations of MPs in sediment and water were 110.90 ± 20.62 pieces/kg and 38.77 ± 10.09 pieces/m3, respectively. Most identified MPs from sediment samples were transparent (51%), while about 54.1% of the identified MPs from water samples were colored. The fragment was the most common form of MP in both compartments, with a value of 64.6% in sediment samples and 60.6% in water samples. In sediment and water samples, almost 74% and 80% of MP were <0.5 mm, respectively. Polypropylene (PP) was the most abundant polymer type, accounting for 51% of all identified polymers. The contamination factor, pollution load index, polymer risk score, and pollution risk score values indicated that the study area was moderately polluted with MPs. The spatial distribution patterns and hotspots of MPs echoed profound human pathways. Based on the results, sustainable management strategies and intervention measures were proposed to reduce the pollution level in the ecologically diverse area. This study provides important insights into evaluating estuary ecosystem susceptibility and mitigation policies against persistent MP issues.


The impact of LSVT BIG therapy on postural control for individuals with Parkinson disease: A case series.
LSVT BIG therapy may improve motor function and gait in those with early Parkinson disease (PD), but its impact on postural control for those with moderate PD has not been investigated. The purpose of this case series is to describe the impact of LSVT BIG therapy on postural control and gait in three individuals with moderate PD. Three individuals with moderate PD, classified as stage 3 on the Hoehn and Yahr Scale, participated in the LSVT BIG therapy program. Intervention included 16-18 individual physical therapy sessions, provided within 4 weeks, focused on increasing amplitude of movement and a daily home exercise program. Outcomes, including balance, gait, dual-task performance, quality of life, and balance confidence, were examined after program completion, 1- and 4-months later. Clinically meaningful improvements in balance and gait, including performance under dual-task conditions, were achieved by all patients and many of these improvements were maintained up to 4 months later. Changes in quality of life were not observed during the length of the intervention. LSVT BIG therapy may improve postural control, gait, and dual-task performance, and therefore reduce fall risk for individuals with moderate PD.


Structural facets of disease-linked human prion protein mutants: a molecular dynamic study.
Prion propagation in transmissible spongiform encephalopathies involves the conversion of the cellular prion protein, PrPC, into the pathogenic conformer PrPSc. Human familial forms of the disease are linked to specific mutations in the PrP gene, PRNP, and include Gerstmann-Strussler-Scheinker syndrome (GSS), familial Creutzfeldt-Jakob disease (fCJD), and fatal familial insomnia. To gain insights into the molecular basis of these disorders, we performed 200 ns of classical molecular dynamic simulations in aqueous solution on wild type (WT) human PrP (HuPrP), and on three HuPrP variants located in the globular HuPrP domain: two pathological mutations, HuPrP(Q212P) and HuPrP(E200K), linked to GSS and to fCJD respectively, and one protective polymorphism, HuPrP(E219K) (total time-scale simulated 800 ns). A comparison between the predicted structural determinants of WT HuPrP and HuPrP(E200K) with their NMR structures established the accuracy of the methods used. Strikingly, the analyzed disease-linked variants produced their major effect on the α2-α3 region and the β2-α2 loop, regardless of the mutation position. The conformational change of the latter might affect the interactions with cellular partners in the fibrillation process. The protocol proposed here represents a powerful approach for reproducing the structural effects of genetic mutations located in the globular domain of HuPrP, such as the GSS-related HuPrP(Q212P) and the protective polymorphism HuPrP(E219K).


Desulfovirga adipica gen. nov., sp. nov., an adipate-degrading, gram-negative, sulfate-reducing bacterium.
A novel, mesophilic, Gram-negative bacterium was isolated from an anaerobic digestor for municipal wastewater. The bacterium degraded adipate in the presence of sulfate, sulfite, thiosulfate and elemental sulfur. (E)-2-Hexenedioate accumulated transiently in the degradation of adipate. (E)-2-Hexenedioate, (E)-3-hexenedioate, pyruvate, lactate, C1-C12 straight-chain fatty acids and C2-C10 straight-chain primary alcohols were also utilized as electron donors. 3-Phenylpropionate was oxidized to benzoate. The G + C content of the DNA was 60 mol%. 16S rDNA sequence analysis revealed that the new isolate clustered with species of the genus Syntrophobacter and Desulforhabdus amnigenus. Strain TsuAS1T resembles Desulforhabdus amnigenus DSM 10338T with respect to the ability to utilize acetate as an electron donor and the inability to utilize propionate without sulfate in co-culture with Methanospirillum hungatei DSM 864. Strains TsuAS1T and DSM 10338T form a 'non-syntrophic subcluster' within the genus Syntrophobacter. Desulfovirga adipica gen. nov., sp. nov. is proposed for the newly isolated bacterium, with strain TsuAS1T (= DSM 12016T) as the type strain.


The effectiveness of motivational interviewing delivered by youth workers in reducing drinking, cigarette and cannabis smoking among young people: quasi-experimental pilot study.
To test whether a single session of Motivational Interviewing (MI) focussing on drinking alcohol, and cigarette and cannabis smoking, would successfully lead to reductions in use or problems. Naturalistic quasi-experimental study, in 162 young people (mean age 17 years) who were daily cigarette smokers, weekly drinkers or weekly cannabis smokers, comparing 59 receiving MI with 103 non-intervention assessment-only controls. MI was delivered in a single session by youth workers or by the first author. Assessment was made of changes in self-reported cigarette, alcohol, cannabis use and related indicators of risk and problems between recruitment and after 3 months by self-completion questionnaire. 87% of subjects (141 of 162) were followed up. The most substantial evidence of benefit was achieved in relation to alcohol consumption, with those receiving MI drinking on average two days per month less than controls after 3 months. Weaker evidences of impact on cigarette smoking, and no evidence of impact on cannabis use, were obtained. Evidence of effectiveness for the delivery of MI by youth workers in routine conditions has been identified. However, the extent of benefit is much more modest than previously identified in efficacy studies.


Lifetime victimization and past year alcohol use in a U.S. population sample of men and women drinkers.
Research on alcohol use among victims of physical and sexual violence has focused mostly on women and alcohol use disorders. It is also limited by the relative lack of consideration of victimization over the lifetime and of population data on both men and women. We critically examined associations between lifetime victimization and diverse past year alcohol use patterns and problems and whether these associations differ for men and women. Population data from the 2005 U.S. National Alcohol Survey (NAS11, n=6919) are reported for 4256 adult men and women drinkers. Logistic regressions assessed associations between physical only or any sexual victimization experienced over the lifetime and past year heavy episodic drinking, drinking to intoxication, alcohol-related consequences and any alcohol use disorder. Models controlled for demographics and parental history of alcohol abuse and examined interactions of gender with victimization. Associations between victimization experienced over the lifetime and all past year alcohol measures were significant for both men and women. These associations did not differ by type of lifetime victimization (physical only vs any sexual). The association of physical only victimization with drinking to intoxication was stronger for victimized vs non-victimized women compared to victimized vs non-victimized men. This gender difference ceased to be significant when specific victimization characteristics were controlled for. Lifetime victimization is associated with increased risk for diverse alcohol use problems for both men and women. All prevention and treatment programs should screen men and women for lifetime victimization and diverse alcohol use problems.


Hemophilia B: molecular pathogenesis and mutation analysis.
Hemophilia B is an X-chromosome-linked inherited bleeding disorder primarily affecting males, but those carrier females with reduced factor IX activity (FIX:C) levels may also experience some bleeding. Genetic analysis has been undertaken for hemophilia B since the mid-1980s, through linkage analysis to track inheritance of an affected allele, and to enable determination of the familial mutation. Mutation analysis using PCR and Sanger sequencing along with dosage analysis for detection of large deletions/duplications enables mutation detection in > 97% of patients with hemophilia B. The risk of the development of inhibitory antibodies, which are reported in ~ 2% of patients with hemophilia B, can be predicted, especially in patients with large deletions, and these individuals are also at risk of anaphylaxis, and nephrotic syndrome if they receive immune tolerance induction. Inhibitors also occur in patients with nonsense mutations, occasionally in patients with small insertions/deletions or splice mutations, and rarely in patients with missense mutations (p.Gln237Lys and p.Gln241His). Hemophilia B results from several different mechanisms, and those associated with hemophilia B Leyden, ribosome readthrough of nonsense mutations and apparently 'silent' changes that do not alter amino acid coding are explored. Large databases of genetic variants in healthy individuals and patients with a range of disorders, including hemophilia B, are yielding useful information on sequence variant frequency to help establish possible variant pathogenicity, and a growing range of algorithms are available to help predict pathogenicity for previously unreported variants.


Correlates of employees' perceptions of a healthy work environment.
This study analyzed correlates of workers' perceptions of the extent to which their work environment is healthy and how these perceptions influence job satisfaction, employee commitment, workplace morale, absenteeism, and intent to quit. One-time cross-sectional telephone survey. Canadian employees in 2000. A randomly chosen, nationally representative sample of 2500 employed respondents, using a household sampling frame. The response rate was 39.2%. Self-employed individuals were excluded, leaving a subsample of 2112 respondents. The dependent variable was the response to the item, "The work environment is healthy" (5-point strongly agree-strongly disagree Likert scale). Independent variables used in bivariate and ordinary least-squares regression analyses included sociodemographic characteristics, employment status, organizational characteristics, and scales that measured job demands, intrinsic rewards, extrinsic rewards, communication/social support, employee influence, and job resources. Perceptions of a healthy work environment were related to job satisfaction, commitment, morale (measured on a 5-point scale), number of self-reported absenteeism days in the past 12 months, and whether or not the respondent had looked for a job with another employer in the past 12 months. The strongest correlate of a healthy work environment was a scale of good communication and social support (beta = .27). The next strongest was a job demands scale (beta = -.15.) Employees in self-rated healthier work environments had significantly (p < 0.01) higher job satisfaction, commitment and morale, and lower absenteeism and intent to quit. The study supports a comprehensive model of workplace health that targets working conditions, work relationships, and workplace organization for health promotion interventions.


"La Familia" HIV prevention program: a focus on disclosure and family acceptance for Latino immigrant MSM to the USA.
The objective of this study was to pilot test and evaluate a HIV prevention program that used a Freirean approach to engage Latino immigrant MSM (men who have sex with men) on issues of sexual orientation, family acceptance, stigma as well as HIV prevention and sexual risk behaviors. Participants were evaluated using a survey before and after participation in the program and compared to a control group. Focus groups where participants discussed their experiences in the program as well as perceptions of the program were held and analyzed. Survey results indicate that after their participation in the program, participants increased their safer sex behaviors, comfort disclosing their sexual orientation and support from friends. HIV prevention needs to incorporate cultural, social and structural factors.


Advances and Unmet Needs in the Therapeutics of Bone Fragility.
The prevalence of fragility fractures increases as longevity increases the proportion of the elderly in the community. Until recently, the majority of studies have targeted women with osteoporosis defined as a bone mineral density (BMD) T score of < -2.5 SD, despite evidence that the population burden of fractures arises from women with osteopenia. Antiresorptive agents reduce vertebral and hip fracture risk by ~50 percent during 3 years but efficacy against non-vertebral fractures, 80% of all fractures in the community, is reported in few studies, and of those, the risk reduction is only 20-30%. Recent advances in the use of antiresorptives and anabolic agents has addressed some of these unmet needs. Zoledronic acid is now reported to reduce vertebral and non-vertebral fractures rates in women with osteopenia. Studies using teriparatide demonstrate better vertebral and clinical (symptomatic vertebral and non-vertebral) antifracture efficacy than risedronate. Abaloparatide, a peptide sharing amino acid sequences with teriparatide, reduces vertebral and non-vertebral fractures. Romosozumab, a monoclonal antibody suppressing sclerostin, reduces vertebral and non-vertebral fractures within a year of starting treatment, and does so more greatly than alendronate. Some recent studies signal undesirable effects of therapy but provide essential cautionary insights into long term management. Cessation of denosumab is associated with a rapid increase in bone remodeling and the uncommon but clinically important observation of increased multiple vertebral fractures suggesting the need to start alternative anti-resorptive therapy around the time of stopping denosumab. Antiresorptives like bisphosphonates and denosumab suppress remodeling but not completely. Antifracture efficacy may be limited, in part, as a consequence of continued unsuppressed remodeling, particularly in cortical bone. Bisphosphonates may not distribute in deeper cortical bone, so unbalanced intracortical remodeling continues to cause microstructural deterioration. In addition, suppressed remodeling may compromise the material composition by increasing matrix mineral density and glycosylation of collagen. As antiresorptive agents do not restore microstructural deterioration existing at the time of starting treatment, under some circumstances, anabolic therapy may be more appropriate first line treatment. Combining antiresorptive and anabolic therapy is an alternative but whether anti-fracture efficacy is greater than that achieved by either treatment alone is not known.


Effect of holding time, temperature and different parenteral solutions on viability and functionality of adult bone marrow-derived mesenchymal stem cells before transplantation.
Mesenchymal stem cells (MSCs) have the ability to proliferate and differentiate into various lineages, given the appropriate microenvironment, thus making MSCs promising candidates for cell transplantation. For clinical applications, MSCs need to be stored in optimal conditions so that they may be transported and made available as an off-the-shelf product for companies to market. Freshly harvested and cultured or frozen-thawed bone marrow-derived MSCs were prepared for cell transplantation. Both freshly cultured or frozen-thawed MSCs were washed and resuspended in parenteral solutions, either 0.9% saline, Dulbecco's phosphate-buffered saline (DPBS), plasmalyte A or 5%dextrose and held for 2, 4, 6 and 8 h at 4 degrees C, 37 degrees C and RT (22 degrees C). The viability of the cells, differentiation capability and expression of cell surface markers were analysed. MSCs harvested from fresh cultures, resuspended in the parenteral solutions and maintained at 4 degrees C for 6 h showed more than 90% viability, and the viability was appreciably better when suspended in 5% dextrose at 4 degrees C for 8 h. In contrast, frozen-thawed cells can be held for a maximum of 2 h after thawing before losing their viability significantly below permissible limits for transplantation. We are reporting for the first time the effect of various parenteral solutions, holding times and temperatures on the viability and functionality of bone marrow-derived freshly cultured or frozen-thawed MSCs for transplantation. Our results suggested that freshly harvested MSCs can be held for 8 h at 4 degrees C in 5% dextrose or for up to 6 h at 4 degrees C in saline, DPBS or plasmalyte A. Freeze-thawed MSCs can be held for a maximum of 2 h in plasmalyte A before transplantation without affecting their viability and ability to differentiate.


Role of ACAT1-positive late endosomes in macrophages: cholesterol metabolism and therapeutic applications for Niemann-Pick disease type C.
Macrophages in hyperlipidemic conditions accumulate cholesterol esters and develop into foamy transformed macrophages. During this transformation, macrophages demonstrate endoplasmic reticulum fragmentation and consequently produce acyl coenzyme A: cholesterol acyltransferase 1 (ACAT1)-positive late endosomes (ACAT1-LE). ACAT1-LE-positive macrophages effectively esterify modified or native low-density lipoprotein-derived free cholesterol, which results in efficient cholesterol esterification as well as atherosclerotic plaque formation. These macrophages show significant cholesterol ester formation even when free cholesterol egress from late endosomes is impaired, which indicates that free cholesterol is esterified at ACAT1-LE. Genetic blockade of cholesterol egress from late endosomes causes Niemann-Pick disease type C (NPC), an inherited lysosomal storage disease with progressive neurodegeneration. Induction of ACAT1-LE in macrophages with the NPC phenotype led to significant recovery of cholesterol esterification. In addition, in vivo ACAT1-LE induction significantly extended the lifespan of mice with the NPC phenotype. Thus, ACAT1-LE not only regulates intracellular cholesterol metabolism but also ameliorates NPC pathophysiology.


Commodifying the polyvalent good of health care.
This essay serves as an introduction to this issue of the Journal of Medicine and Philosophy on commodification and health care. The essay attempts to sharpen the articulation of generally expressed worries about the commodification of health care. It does so by defining commodification, analyzing three components of the good of health care, and attempting to assess how commodification might distort the shape of each of those components. Next, it explores how the good of health care might be distorted by the market-based principle of distributive justice, "to each according to ability to pay." Finally, it identifies two basic questions about the relationship of medicine and the market that merit further exploration. (1) How does the market-based language of "incentives" so pervasive in the world of managed care distort the complex patterns of virtue and vice that motivate actors in the health care arena? (2) If we recognize that we cannot eliminate the influence of money from the health care system, how can we insure that the good of health care remains, in Radin's terms, "incompletely commodified"?


Pigmented eccrine poroma: dermoscopic and confocal features.
Eccrine poroma is a rare benign adnexal tumor of epithelial cells originating from the terminal ductal portion of the sweat glands that is typically located on palms and soles, although other cutaneous sites can be affected [1]. It is usually nonpigmented even if there is a pigmented variant that corresponds to 17% of cases and it is usually underdiagnosed, since it is mistakenly confused with other pigmented tumors [2,3]. Dermoscopy and reflectance confocal microscopy (RCM) may assist in the correct diagnosis of this tumor. Herein, we report one case of pigmented eccrine poroma (PEP) that simulated clinically a cutaneous melanoma or a basal cell carcinoma. Dermoscopy and RCM excluded the possibilities of those two diagnoses; the overall confocal findings were suggestive for a benign epithelial tumor. Histology was fundamental to diagnose this lesion as a pigmented eccrine poroma. Even if the diagnosis of eccrine poroma remains histopathological still, as in this case report, noninvasive tools such as dermoscopy and RCM examinations can be of help to rule out the diagnosis of melanoma. Larger studies on this rare pigmented variant of eccrine poroma could shed new light on the identification of specific diagnostic dermoscopic and confocal features.


The impact of clinical pharmacist services on patient health outcomes in Pakistan: a systematic review.
The pharmacist's role shifts from dispensing to bedside care, resulting in better patient health outcomes. Pharmacists in developed countries ensure rational drug use, improve clinical outcomes, and promote health status by working as part of a multidisciplinary team of healthcare professionals. However, clinical pharmacist services on healthcare utilization in low-and middle-income countries (LMICs) like Pakistan are unclear. As a result, we aim to systematically review pharmacists' clinical roles in improving Pakistani patients' therapeutic, safety, humanistic, and economic outcomes. We searched PubMed, Scopus, EMBASE, CINAHL, and Cochrane Library for relevant articles published from inception to 28th February 2021. All authors were involved in the screening and selection of studies. Original studies investigating the therapeutic, humanistic, safety, and economic impact of clinical pharmacists in Pakistani patients (hospitalised or outpatients) were selected. Two reviewers independently assessed the risk of bias in studies, and discrepancies were resolved through mutual consensus. All of the included studies were descriptively synthesised, and PRISMA reporting guidelines were followed. The literature search found 751 articles from which nine studies were included; seven were randomized controlled trials (RCTs), and two were observational studies. Three RCTs included were having a low risk of bias (ROB), two RCTs were having an unclear ROB, while two RCTs were having a high ROB. The nature of clinical pharmacist interventions included one or more components such as disease-related education, lifestyle changes, medication adherence counselling, medication therapy management, and discussions with physicians about prescription modification if necessary. Clinical pharmacist interventions reduce medication-related errors, improve therapeutic outcomes such as blood pressure, glycemic control, lipid control, CD4 T lymphocytes, and renal functions, and improve humanistic outcomes such as patient knowledge, adherence, and health-related quality of life. However, no study reported the economic outcomes of interventions. The findings of the studies included in this systematic review suggest that clinical pharmacists play important roles in improving patients' health outcomes in Pakistan; however, it should be noted that the majority of the studies have a high risk of bias, and more research with appropriate study designs is needed.


The effectiveness of joint crisis plans for people with borderline personality disorder: protocol for an exploratory randomised controlled trial.
Borderline personality disorder (BPD) is a common mental disorder associated with raised mortality, morbidity and substantial economic costs. Although complex psychological interventions have been shown to be useful in the treatment of BPD, such treatments are expensive to deliver and therefore have limited availability and questionable cost-effectiveness. Less complex interventions are required for the management of BPD. A joint crisis plan (JCP) is a record containing a service user's treatment preferences for the management of future crises and is created by the service user with the help of their treating mental health team. These plans have been shown to to be an effective way of reducing compulsory treatment in people with psychosis. However, to date they have not been used with individuals with BPD. This exploratory trial will examine whether use of a JCP is an effective and cost-effective intervention for people with BPD for reducing self-harm. In this single blind exploratory randomized controlled trial, a total of 120 participants (age >18 years with a primary diagnosis of DSM-IV borderline personality disorder) will be recruited from community mental health teams and, after completing a baseline assessment, will be assigned to one of two conditions: (1) a joint crisis plan, or (2) treatment as usual. Those allocated to the JCP condition will take part in a facilitated meeting, the purpose of which will be to agree the contents of the plan. Following the meeting, a typed version of the JCP will be sent to the patient and to any other individuals specified by the participant. All participants will be followed-up at 6 months. The primary outcome measures are: any self-harm event, time to first episode of self-harm and number of self-harm events over the follow-up period. Secondary outcome measures are length of time from contemplation to act of self-harm, help-seeking behaviour after self-harm, cost, working alliance, engagement with services and perceived coercion. Other outcome variables are quality of life, social impairment and satisfaction with treatment. Results of this trial will help to clarify the potential beneficial effects of JCPs for people with BPD and provide information to design a definitive trial. Current Controlled Trials ISRCTN12440268.


A design and implementation of multi-character classification scheme based on motor imagery EEG signals.
In the field of brain-to-text communication, it is difficult to finish highly dexterous behaviors of writing multi-character by motor-imagery-based brain-computer interface (MI-BCI), setting a barrier to restore communication in people who have lost the ability to move and speak. In this paper, we design and implement a multi-character classification scheme based on 29 characters of motor imagery (MI) electroencephalogram (EEG) signals, which contains 26 English letters and 3 punctuation marks. Firstly, we design a novel experimental paradigm to increase the variety of BCI inputs by asking subjects to imagine the movement of writing 29 characters instead of gross motor skills such as reaching or grasping. Secondly, because of the high dimension of EEG signals, we adopt power spectral density (PSD), principal components analysis (PCA), kernel principal components analysis (KPCA) respectively to decompose EEG signals and extract feature, and then test the results with pearson product-moment correlation coefficient (PCCs). Thirdly, we respectively employ k-nearest neighbor (kNN), support vector machine (SVM), extreme learning machine (ELM) and light gradient boosting machine (LightGBM) to classify 29 characters and compare the results. We have implemented a complete scheme, including paradigm design, signal acquisition, feature extraction and classification, which can effectively classify 29 characters. The experimental results show that the KPCA has the best feature extraction effect and the kNN has the highest classification accuracy, with the final classification accuracy reaching 96.2%, which is better than other studies.


[Morphofunctional changes in the midgut of ticks of the genus Ixodes (Acarina: Ixodidae) during life cycle].
Morphofunctional investigations of five Ixodes species (Ixodes pacificus, I. pavlovsky, I. persulcatus, I. ricinus and I. scapularis) were carried out. It was established, that the change of midgut epithelium lags at the each next developmental stage, and it is not synchronized with general processes of metamorphosis and organogenesis during molts. The midgut epithelium of a previous phase of the life cycle persists and functions during the feeding stage at the next phase.


Female smokers beyond the perimenopausal period are at increased risk of chronic obstructive pulmonary disease: a systematic review and meta-analysis.
Recent reports indicate that over the next decade rates of chronic obstructive pulmonary disease (COPD) in women will exceed those in men in the western world, though in most jurisdictions, women continue to smoke less compared with men. Whether female adult smokers are biologically more susceptible to COPD is unknown. This study reviewed the available evidence to determine whether female adult smokers have a faster decline in forced expiratory volume in one second (FEV1) compared with male adult smokers and whether age modifies the relationship between cigarette smoke and lung function decline. A systematic review and a meta-analysis was performed of population-based cohort studies that had a follow-up period of at least 3 years, measured FEV1 on at least two different time points, and presented FEV1 data stratified by gender and smoking status in adults. Of the 646 potentially relevant articles, 11 studies met these criteria and were included in the analyses (N = 55,709 participants). There was heterogeneity in gender-related results across the studies. However, on average current smokers had a faster annual decline rate in FEV1% predicted compared with never and former smokers. Female current smokers had with increasing age a significantly faster annual decline in FEV1% predicted than male current smokers (linear regression analysis, R2 = 0.56; p = 0.008). Age did not materially affect the rate of decline in FEV1% predicted in male and female former and never smokers (p = 0.775 and p = 0.326, respectively). As female smokers age, they appear to experience an accelerated decline in FEV1% predicted compared with male smokers. Future research powered specifically on gender-related changes in lung function is needed to confirm these early findings.


Electrochemical Characteristics of a Polymer/Garnet Trilayer Composite Electrolyte for Solid-State Lithium-Metal Batteries.
Although solid-state Li-metal batteries (LMBs) featuring polymer-based solid electrolytes might one day replace conventional Li-ion batteries, the poor Li-ion conductivity of solid polymer electrolytes at low temperatures has hindered their practical applications. Herein, we describe the first example of using a co-precipitation method in a Taylor flow reactor to produce the metal hydroxides of both the Ga/F dual-doped Li7La3Zr2O12 (Ga/F-LLZO) ceramic electrolyte precursors and the Li2MoO4-modified Ni0.8Co0.1Mn0.1O2 (LMO@T-LNCM 811) cathode materials for LMBs. The Li/Nafion (LiNf)-coated Ga/F-LLZO (LiNf@Ga/F-LLZO) ceramic filler was finely dispersed in the poly(vinylidene fluoride)/polyacrylonitrile/lithium bis(trifluoromethanesulfonimide)/succinonitrile matrix to give a trilayer composite polymer electrolyte (denoted "Tri-CPE") through a simple solution-casting. The bulk ionic conductivity of the Tri-CPE at room temperature was approximately 4.50 × 10-4 S cm-1 and exhibited a high Li+ ion transference number (0.84). It also exhibits a broader electrochemical window of 1-5.04 V versus Li/Li+. A full cell based on a CR2032 coin cell containing the LMO@T-LNCM811-based composite cathode, when cycled under 1 C/1 C at room temperature for 300 cycles, achieved an average Columbic efficiency of 99.4% and a capacity retention of 89.8%. This novel fabrication strategy for Tri-CPE structures has potential applications in the preparation of highly safe high-voltage cathodes for solid-state LMBs.


A nomogram for single-stage cluster-sample surveys in a community for estimation of a prevalence rate.
Proper assessment of the magnitude of the problem is essential for devising adequate allocation of available resources and for developing future strategies to combat a disease. The cluster random sampling (CRS) technique is commonly used for rapid assessment of public health problems in developing countries. Our objective is to devise a nomogram that can instantly provide the number of clusters of specified size needed to estimate the prevalence rate of a disease in a community with given precision, ratio of design-effect to cluster size and confidence level. This would be applicable only to single-stage CRS. We use a logarithmic transformation to linearize the relation between the number of clusters (C) on one side and design-effect (D), cluster size (B), precision (L), anticipated prevalence rate (P) and confidence level (alpha) on the other. By using this relation, we construct a nomogram using established methods. A nomogram is obtained that can be used to determine the number of clusters needed in a survey with the help of only a ruler when other parameters are known. This is a 6-in-1 figure as it gives the number of clusters C corresponding to any combination of alpha from among the popularly used 0.05, 0.10 and 0.20, and precision 10% of P or 20% of P. Using a very simple calculation, the number of clusters for the other values of alpha and L can also be obtained. This nomogram can be a useful aid in instantly providing the number of clusters required to rapidly estimate the prevalence rate of a disease in a community when the ratio of design-effect to cluster size, confidence level, and precision are specified. However, it is not applicable to intervention studies where interest mainly focuses on testing a hypothesis rather than estimation.


Functional interaction of nuclear domain 10 and its components with cytomegalovirus after infections: cross-species host cells versus native cells.
Species-specificity is one of the major characteristics of cytomegaloviruses (CMVs) and is the primary reason for the lack of a mouse model for the direct infection of human CMV (HCMV). It has been determined that CMV cross-species infections are blocked at the post-entry level by intrinsic cellular defense mechanisms, but few details are known. It is important to explore how CMVs interact with the subnuclear structure of the cross-species host cell. In our present study, we discovered that nuclear domain 10 (ND10) of human cells was not disrupted by murine CMV (MCMV) and that the ND10 of mouse cells was not disrupted by HCMV, although the ND10-disrupting protein, immediate-early protein 1 (IE1), also colocalized with ND10 in cross-species infections. In addition, we found that the UL131-repaired HCMV strain AD169 (vDW215-BADrUL131) can infect mouse cells to produce immediate-early (IE) and early (E) proteins but that neither DNA replication nor viral particles were detectable in mouse cells. Unrepaired AD169 can express IE1 only in mouse cells. In both HCMV-infected mouse cells and MCMV-infected human cells, the knocking-down of ND10 components (PML, Daxx, and SP100) resulted in significantly increased viral-protein production. Our observations provide evidence to support our hypothesis that ND10 and ND10 components might be important defensive factors against the CMV cross-species infection.


Legal barriers to second-trimester abortion provision and public health consequences.
Many women need access to abortion care in the second trimester. Most of this care is provided by a small number of specialty clinics, which are increasingly targeted by regulations including bans on so-called partial birth abortion and requirements that the clinic qualify as an ambulatory surgical center. These regulations cause physicians to change their clinical practices or reduce the maximum gestational age at which they perform abortions to avoid legal risks. Ambulatory surgical center requirements significantly increase abortion costs and reduce the availability of abortion services despite the lack of any evidence that using those facilities positively affects health outcomes. Both types of laws threaten to further reduce access to and quality of second-trimester abortion care.


Specialty hospitals: focused factories or cream skimmers?
Hospitals specializing in cardiovascular and orthopedic procedures are developing rapidly throughout the country, raising challenging questions for communities and policy makers. Proponents argue that specialty hospitals could improve quality and reduce costs, yet skeptics note that specialty hospitals might reduce quality, increase costs and decrease access to basic services. The Center for Studying Health System Change (HSC) site visit findings suggest that the relatively high profit margins of these select procedures and specialists' desire to increase control over the care environment and increase their income are among the key reasons for this specialty hospital building boom. Policy makers are exploring a range of responses with the goal of allowing specialty hospitals to compete and innovate while minimizing the potential for quality, cost and access problems.


Genome-Wide Identification, Characterization and Expression Analyses of Heat Shock Protein-Related Genes in a Highly Invasive Ascidian Ciona savignyi.
Biological response to rapid changing environments is an outstanding research question in ecology and evolution. Biological invasions provide excellent "natural" experiments to study such a complex response process, as invaders often encounter rapidly changing environments during biological invasions. The regulation of heat shock proteins (Hsp) is a common pathway responsible for various environmental stresses; however, the comprehensive study on Hsp system across the whole genome and potential roles in determining invasion success are still largely unexplored. Here, we used a marine invasive model ascidian, Ciona savignyi, to investigate transcriptional response of Hsp-related genes to harsh environments. We identified 32 genes, including three Hsp20, six Hsp40, ten Hsp60, eight Hsp70, three Hsp90, one Hsp100, and one heat shock transcription factor (Hsf), across the whole genome of C. savignyi. We further characterized gene structure and protein motifs, and identified potential heat shock elements (HSEs) in promoters of Hsp genes. The expression analysis showed that most Hsp genes, but not all, were involved in transcriptional response to temperature and salinity challenges in a duration- and stress-specific pattern, and the maximum amplitude of induction occurred in Hsp70-4 after 1-h of high temperature treatment. However, the Hsf gene was scarcely induced and limited interactions were predicted between Hsp and Hsf genes. Our study provide the first systematic genome-wide analysis of Hsp and Hsf family in the marine invasive model ascidian, and our results are expected to dissect Hsp-based molecular mechanisms responsible for extreme environmental adaptation using Ciona as a model system.


In vivo detection of choline in ovarian tumors using 3D magnetic resonance spectroscopy.
To assess the clinical feasibility of 3-dimensional (3D) proton magnetic resonance spectroscopy (MRS) of ovarian masses at 1.5 T. We prospectively evaluated 16 patients with 23 ovarian masses using contrast-enhanced magnetic resonance imaging and 3D chemical shift imaging MRS (time of reception/time of echo = 700/135 ms, number of excitations = 6, interpolated voxel = 5 × 5 × 5 mm(3), water and fat suppression). Spectral editing consisted of water reference, filtering, zero-filling, Fourier transformation, frequency shift, automatic baseline and phase correction, and curve fitting. The volume of interest was placed to encompass both solid and cystic tumor components as well as apparently healthy pelvic tissues. The presence of a choline peak at 3.14 to 3.34 ppm was considered as a marker of malignancy. All patients underwent surgery and histopathological evaluation. Of 23 masses, 19 were malignant and the remaining 4 benign lesions were a fibrothecoma, an endometriosis, a cyst, and a cystadenofibroma. A choline peak was detected in 17/19 malignant tumors (sensitivity 89%), absent in 2 G1 tumors. It was visible in 16 solid components of 19 malignant tumors (in one of them, a choline peak was detected only in the cystic component, in 6 in both solid and cystic components). The choline peak was absent in 20/21 apparently healthy pelvic tissues, with a very low choline peak being detected in one intraperitoneal fluid collection with malignant cells at cytologic analysis; 3/4 benign tumors showed a choline peak (overall specificity 21/25 = 84%). A significant difference between the mean choline peak integral detected within the solid component and that within the cystic component was observed (P = 0.002). No correlation between the choline peak integral and the tumor size was found (r = 0.120, P = 0.615). 3D MRS of ovarian masses is clinically feasible at 1.5 T. This opens new research strategies for early diagnosis of ovarian cancer.


SRF binding to SRE 6.9 in the Arc promoter is essential for LTD in cultured Purkinje cells.
It has been suggested that gene expression and protein synthesis are required for both long-term memory consolidation and late phases of long-term potentiation and long-term depression (LTD). The necessary genes and the specific transcription factor binding sites in their promoters remain unknown. We found that inhibition of the transcription factor SRF or its cofactor MAL blocked the late phase of LTD in mouse cultured cerebellar Purkinje cells, as did deletion of the immediate early gene Arc. Using neuronal bacterial artificial chromosome (BAC) transfection, we found that, in Arc-/- cells transfected with a wild-type Arc BAC, late-phase LTD was rescued. However, mutation of one SRF-binding site in the Arc promoter (SRE 6.9) blocked this rescue. Co-transfection of wild-type Arc and SRF engineered to bind mutated SRE 6.9 restored late-phase LTD in Arc-/-, SRE 6.9 mutant BAC cells. Thus, SRF binding to SRE 6.9 in the Arc promoter is required for the late phase of cerebellar LTD.


Cytoskeletal Components Define Protein Location to Membrane Microdomains.
The plasma membrane is an important compartment that undergoes dynamic changes in composition upon external or internal stimuli. The dynamic subcompartmentation of proteins in ordered low-density (DRM) and disordered high-density (DSM) membrane phases is hypothesized to require interactions with cytoskeletal components. Here, we systematically analyzed the effects of actin or tubulin disruption on the distribution of proteins between membrane density phases. We used a proteomic screen to identify candidate proteins with altered submembrane location, followed by biochemical or cell biological characterization in Arabidopsis thaliana. We found that several proteins, such as plasma membrane ATPases, receptor kinases, or remorins resulted in a differential distribution between membrane density phases upon cytoskeletal disruption. Moreover, in most cases, contrasting effects were observed: Disruption of actin filaments largely led to a redistribution of proteins from DRM to DSM membrane fractions while disruption of tubulins resulted in general depletion of proteins from the membranes. We conclude that actin filaments are necessary for dynamic movement of proteins between different membrane phases and that microtubules are not necessarily important for formation of microdomains as such, but rather they may control the protein amount present in the membrane phases.


Impact of socioeconomic factors on prostate cancer outcomes in black patients treated with surgery.
The role of socioeconomic factors in the worse outcome of black men with prostate cancer remains unclear. To determine whether socioeconomic factors affect prostate cancer outcomes, we studied a cohort of only black patients to minimize known confounding factors. We studied black men treated with radical prostatectomy at New York Veterans Administration Medical Center and Memorial Sloan-Kettering Cancer Center between 1990 and 2005. A centralized pathology review process determined the Gleason score of all cases. Prostate-specific antigen (PSA) recurrence at both sites was defined as PSA of 0.2 or greater with a confirmatory rise. By matching patients' home zip codes to the U.S. Census Bureau database, we obtained corresponding socioeconomic data regarding median household income (income) and percentage of population with a high school (degree). We analyzed income, education, and clinical and pathological parameters for the whole cohort. We studied 430 black patients. They resided in neighborhoods where median household income was $41,498.10 and mean percentage of high school graduates was 73.4%. A total of 88 patients (20.9%) had PSA recurrence. Median follow-up for survivors was 37 months. Neither income nor education evaluated as continuous or categorical variables were predictors of PSA recurrence. When evaluated as composite categorical variable, the combination of greater income and education did not predict disease-free survival. Data suggest that socioeconomic factors have limited impact on PSA recurrence in black men treated with radical prostatectomy. Thus, biologic factors might have a role in the poor outcomes in this population.


Role of stem-cell-derived microvesicles in the paracrine action of stem cells.
The paracrine theory has recently changed the view of the biological action of stem cells and of the subsequent potential application of stem cells in regenerative medicine. Indeed, most of the beneficial effects of stem-cell-based therapy have been attributed to soluble factors released from stem cells. In this context, MVs (microvesicles) released as exosomes from the endosomal compartment, or as shedding vesicles from the cell surface, may play a relevant role in the intercellular communication between stem and injured cells. By transferring proteins, bioactive lipids, mRNA and microRNA, MVs act as vehicles of information that may lead to alteration of the phenotype of recipient cells. The exchange of information between stem cells and tissue-injured cells is reciprocal. The MV-mediated transfer of tissue-specific information from the injured cells to stem cells may reprogramme the latter to gain phenotypic and functional characteristics of the cell of origin. On the other hand, MVs released from stem cells may confer a stem-cell-like phenotype to injured cells, with the consequent activation of self-regenerative programmes. In fact, MVs released from stem cells retain several biological activities that are able to reproduce the beneficial effects of stem cells in a variety of experimental models.


A one-step approach for the fabrication of polymer and metal nanowires.
The fabrication of one-dimensional (1D) polymer and metal nanowires were obtained in a one-step mechanical approach. This approach is based on a controlled chattering process at the cutting edge of an oscillating diamond knife to conduct wavy cutting. Consecutive shallow wavy cuttings at different phases yield uniform ultra-long nanowire products with controlled lateral dimensions in the range of sub-100 nanometers to micrometers. The morphologies and lateral dimensions of the nanowires can be tuned through phase alignment, cutting depth and cutting speed, as demonstrated in this paper through examples of its application to polymethyl methacrylate, aluminum and copper. This facile one-step 'cutting-edge' method is robust, clean, involves no chemicals, and can be readily scaled up with precision machining for long-range and large-area fabrications.


Real-World Comparative Evaluation of Add-On Glucagon-like Peptide 1 Receptor Agonist in Type 2 Diabetes Treated with or without Insulin.
Glucagon-like peptide 1 receptor agonist (GLP-1 RA) is a potent antidiabetic agent with cardiorenal and weight-losing benefits in patients with type 2 diabetes (T2D). The combination of GLP-1 RA with basal insulin has been suggested in several clinical studies as a useful treatment for intensifying insulin therapy in T2D. However, there has been no real-world evidence study comparing the glycemic effects of GLP-1 RAs add-on to background treatment with and without insulin. A retrospective study was performed in 358 patients with T2D who initiated liraglutide or dulaglutide. Among them, 147 patients were prior and concurrent insulin users, and 211 patients were non-insulin users. After 12 months of GLP-1 RA treatment, the changes in hemoglobin A1c (HbA1C) and body weight were evaluated. The effectiveness of GLP-1 RAs on HbA1C reduction was greater in insulin users than non-insulin users at 12 months (−1.17% vs. −0.76%; p = 0.018). There was no significant difference in body weight change between insulin users and non-insulin users at 12 months (−1.42 kg vs. −1.87 kg; p = 0.287). The proportion of responders (decrease of HbA1C > 1%) in insulin users was much higher than that in non-insulin users (48% vs. 37 %; p = 0.04). In insulin users, those who had increased insulin dosage at 12 months had significantly less HbA1C reduction than that of non-increased patients (−0.62% vs. −1.57%; p = 0.001). GLP-1 RAs provide superior glucose-lowering effects in insulin-treated patients compared with non-insulin-treated patients with T2D without significant differences in body weight decrease.


Strongly correlated superconductivity.
High-temperature superconductivity in doped Mott insulators such as the cuprates contradicts the conventional wisdom that electron repulsion is detrimental to superconductivity. Because doped fullerene conductors are also strongly correlated, the recent discovery of high-critical-temperature, presumably s-wave, superconductivity in C60 field effect devices is even more puzzling. We examine a dynamical mean-field solution of a model for electron-doped fullerenes that shows how strong correlations can indeed enhance superconductivity close to the Mott transition. We argue that the mechanism responsible for this enhancement could be common to a wider class of strongly correlated models, including those for cuprate superconductors.


Successful reinduction of patients with acute lymphoblastic leukemia who relapse following bone marrow transplantation.
At the present time, there is limited information on the outcome of patients with acute lymphoblastic leukemia (ALL) who relapse after bone marrow transplantation (BMT). Intuitively, it might be expected that leukemia recurring after BMT would be refractory to further treatment. In an attempt to improve survival in patients with ALL who relapse after BMT, we used standard chemotherapy for reinduction and maintenance. Of 65 patients who relapsed following allogeneic, autologous, or syngeneic BMT, 12 elected to receive no further chemotherapy, and their median survival from relapse was 36 days (range 13 to 167 days). The 53 patients who received therapy had a significantly longer median survival of 168 days (range 18 days to 4.7 years). With multidrug induction regimens there were 29 of 52 (56%) complete remissions. Six patients are currently alive, with two off therapy. In the patients who received therapy, the following factors were independent predictors of prolonged survival: longer time from BMT to relapse; younger age at diagnosis; and the use of a preparative regimen containing fractionated total body irradiation. In conclusion, leukemia recurring after BMT remains sensitive to standard therapy in many patients. We recommend that patients with ALL who relapse after BMT receive reinduction and maintenance therapy as additional good quality survival time is achieved in patients who attain a remission.


Rainbow beads: a color coding method to facilitate high-throughput screening and optimization of one-bead one-compound combinatorial libraries.
We have developed a new color-encoding method that facilitates high-throughput screening of one-bead one-compound (OBOC) combinatorial libraries. Polymer beads displaying chemical compounds or families of compounds are stained with oil-based organic dyes that are used as coding tags. The color dyes do not affect cell binding to the compounds displayed on the surface of the beads. We have applied such rainbow beads in a multiplex manner to discover and profile ligands against cell surface receptors. In the first application, a series of OBOC libraries with different scaffolds or motifs are each color-coded; small samples of each library are then combined and screened concurrently against live cells for cell attachment. Preferred libraries can be rapidly identified and selected for subsequent large-scale screenings for cell surface binding ligands. In a second application, beads with a series of peptide analogues (e.g., alanine scan) are color-coded, combined, and tested for binding against a specific cell line in a single-tissue culture well; the critical residues required for binding can be easily determined. In a third application, ligands reacting against a series of integrins are color-coded and used as a readily applied research tool to determine the integrin profile of any cell type. One major advantage of this straightforward and yet powerful method is that only an ordinary inverted microscope is needed for the analysis, instead of sophisticated (and expensive) fluorescent microscopes or flow cytometers.


Return to play and performance after shoulder instability in National Basketball Association athletes.
We hypothesized that players in the National Basketball Association (NBA) who sustained a shoulder destabilizing injury could return to play (RTP) successfully at a high rate regardless of treatment type. We used publicly available data to identify and evaluate 50 players who sustained an in-season shoulder instability event (subluxation/dislocation) while playing in the NBA. Demographic variables, return to NBA gameplay, incidence of surgery, time to RTP, recurrent instability events, and player efficiency rating (PER) were collected. Overall RTP was determined, and players were compared by type of injury and mode of treatment. All players (50/50) returned to game play after sustaining a shoulder instability event. In those treated nonoperatively, athletes who sustained shoulder subluxations returned after an average of 3.6 weeks, compared with 7.6 weeks in those who sustained a shoulder dislocation (P = .037). Players who underwent operative management returned after an average of 19 weeks. Athletes treated operatively were found to have a longer time interval between a recurrent instability event (70 weeks vs. 28.5 weeks, P = .001). We found 100% rate of RTP after a shoulder instability event in an NBA athlete. Players who experience shoulder dislocations were found to miss more time before RTP and were more likely to undergo surgical intervention compared with those who experienced a subluxation. Surgical repair maintained a longer interval between recurrent instability. Future investigations should aim to evaluate outcomes based on surgical procedures and identify possible risk factors predictive of recurrent instability or failure to RTP.


Suppression of meal size by intestinal nutrients is eliminated by celiac vagal deafferentation.
The arrival of nutrients in the gastrointestinal tract suppresses intake. To specify the neural pathways and receptor locations of this feedback, we examined the effects of intraduodenal infusions of 10 nutrients plus saline on short-term food intake of rats with selective deafferentations of vagal celiac branches. Three response profiles were observed: 1) isotonic saline, 5.6% glycerol, and 3% fructose did not inhibit intake of controls or selectively deafferented animals; 2) 3% glucose, 3% maltose, 3% L-phenylalanine, 12% Isocal, and 1.4% oleic acid suppressed intake of controls, but this inhibition was eliminated by vagal celiac deafferentation; and 3) 3% casein hydrolysate and 24% Isocal suppressed intake of controls and rats with selective vagotomies, although the latter exhibited significantly less suppression. In addition, elimination of celiac afferents chronically reduced meal size (i.e., first 30-min intake) without reducing daily food intake or body weight. Furthermore, D-phenylalanine infusions produced a delayed suppression of food intake in controls (possibly from intraluminal irritation); however, this reduction was eliminated with celiac deafferentation. Overall, this experiment indicates that vagal celiac afferents are critical for preabsorptive detection of some energy-yielding molecules or properties of nutrient solutions (as well as, perhaps, intraluminal inflammation), but not others, which are still detected, although only partially.


Differentiating hypochondriasis from panic disorder.
Hypochondriasis and panic disorder are both characterized by prevalent health anxieties and illness beliefs. Therefore, the question as to whether they represent distinct nosological entities has been raised. This study examines how clinical characteristics can be used to differentiate both disorders, taking the possibility of mixed symptomatologies (comorbidity) into account. We compared 46 patients with hypochondriasis, 45 with panic disorder, and 21 with comorbid hypochondriasis plus panic disorder. While panic patients had more comorbidity with agoraphobia, hypochondriasis was more closely associated with somatization. Patients with panic disorder were less pathological than hypochondriacal patients on all subscales of the Whiteley Index (WI) and the Illness Attitude Scales (IAS) except for illness behavior. These differences were independent of somatization. Patients with hypochondriasis plus panic had higher levels of anxiety, more somatization, more general psychopathology and a trend towards increased health care utilization. Clinicians were able to distinguish between patient groups based upon the tendency of hypochondriacal patients to demand unnecessary medical treatments. These results confirm that hypochondriasis and panic disorder are distinguishable clinical conditions, characterized by generally more psychopathology and distress in hypochondriasis.


Nanophotonic trapping: precise manipulation and measurement of biomolecular arrays.
Optical trapping is a powerful and widely used laboratory technique in the biological and materials sciences that enables rapid manipulation and measurement at the nanometer scale. However, expanding the analytical throughput of this technique beyond the serial capabilities of established single-trap microscope-based optical tweezers remains a current goal in the field. In recent years, advances in nanotechnology have been leveraged to create innovative optical trapping methods that increase the number of available optical traps and permit parallel manipulation and measurement of arrays of optically trapped targets. In particular, nanophotonic trapping holds significant promise for integration with other lab-on-a-chip technologies to yield compact, robust analytical devices. In this review, we highlight progress in nanophotonic manipulation and measurement, as well as the potential for implementing these on-chip functionalities in biological research and biomedical applications. WIREs Nanomed Nanobiotechnol 2018, 10:e1477. doi: 10.1002/wnan.1477 This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.


Methylprednisolone treatment delays remote cell death after focal brain lesion.
Glucocorticoids have a prominent role in the treatment of CNS injuries. However, the cellular consequences of glucocorticoid treatment on remote degenerative responses after focal brain lesions have been poorly investigated. Here we examine the effectiveness of a high dose (50 mg/kg) of methylprednisolone sodium succinate (MPSS) in reducing neuronal loss, glial response and glial-derived inflammatory mediators in inferior olive and pontine nuclei after lesion of the contralateral cerebellar hemisphere using immunohistochemistry and Western blot techniques. Quantitative analysis demonstrated that MPSS treatment significantly improved the survival of neurons in remote precerebellar stations. This survival was accompanied by reduction in the postlesional activation of microglia, astrocytes and interleukin-1 beta (IL-1beta). Cell death resumed after suspension of MPSS treatment and this delayed wave of cell loss was paralleled by reactivation of the inflammatory markers analyzed. The present study confirms the importance of inflammatory events in inducing remote cell death and that this type of degeneration can be delayed by MPSS treatment. Furthermore, the sustained effect of MPSS treatment, up to 28 days postlesion, and the reactivation of the degenerative phenomena after its suspension, support the hypothesis that glucocorticoid treatment, although capable of delaying cell death mechanisms, is not effective in blocking the cascade of remote degenerative events started by the primary lesion.


The neighborhood characteristics of malapropisms.
This study examined the phonological neighborhood characteristics (frequency, density, and neighborhood frequency) of 138 malapropisms. Malapropisms are whole word substitutions that are phonologically, but not semantically, related. A statistical analysis of a speech error corpus suggests that neighborhood density and word frequency differentially affected the number of malapropisms. Specifically, a greater number of malapropisms were found among high frequency words with dense neighborhoods than with sparse neighborhoods. Exactly the opposite pattern was found among low frequency words. That is, more errors were found among low frequency words with sparse neighborhoods than with dense neighborhoods. More malapropisms resided in low frequency neighborhoods than in high. The average word frequency, average neighborhood density, and average neighborhood frequency of the malapropisms were significantly lower than the same averages computed from randomly sampled control words. Finally, more target words were replaced by error words that had relatively higher frequency than by error words that had relatively lower frequency. The implications of these findings for models of lexical representation and processing are discussed.


Induction of IκBζ Augments Cytokine and Chemokine Production by IL-33 in Mast Cells.
IκBζ (encoded by the Nfkbiz) is a member of the nuclear IκB family, which is involved in the expression of secondary response genes based on signals from TLR or IL-1R. ST2L, an IL-33R, is a member of the IL-1R family and abundantly expressed in tissue-resident immune cells, such as mast cells and innate lymphoid cells; however, its downstream signaling pathway remains unelucidated. In this study, we examined the role of IκBζ in ST2L-mediated cytokine and chemokine production in mast cells. Murine bone marrow cells were differentiated ex vivo into bone marrow-derived mast cells (BMMCs). The treatment of BMMCs with IL-33 transiently induced robust IκBζ expression. Of the 40 cytokines and chemokines examined using a cytokine and chemokine array, the concentrations of IL-6, IL-13, CCL2, CCL3, and TNF-α in the supernatant were augmented by IL-33. The deletion of IκBζ in BMMCs resulted in a significant reduction of the production of these mediators and the expression of their mRNA. NF-κB p50 but not p65 translocated to the nucleus by IL-33 and was not affected by the deletion of IκBζ. However, induction of IκBζ and the resultant cytokine and chemokine productions were significantly inhibited by pretreatment with an NF-κB inhibitor. The deletion of IκBζ did not affect the phosphorylation of ERK, p38 MAPK, or JNK by IL-33, and the treatment with inhibitors of these mitogen-activated kinases failed to abolish the expression of Nfkbiz Our findings suggest that IκBζ augments IL-33-dependent cytokine and chemokine production in BMMCs through the action of NF-κB.


A systematic review of orofacial pain in patients receiving cancer therapy.
We present the findings of a structured systematic review of the literature assessing orofacial pain induced by malignant disease and/or its therapy (excluding mucositis). This evaluation of the literature published after the 1989 NIH Development Consensus conference on the oral complications of cancer therapies is an effort to assess the prevalence of pain, quality of life and economic impact, and management strategies for cancer therapy-induced orofacial pain. A systematic medical literature search was conducted with assistance from a research librarian in MEDLINE/PubMed and EMBASE databases for articles published between January 1, 1990 and December 31, 2008. Each study was independently assessed by two reviewers with expertise in the field of oral oncology. Thirty-nine studies assessed pain in the head and neck region. The measure was commonly embedded in quality of life studies. Most of these studies described pain in head and neck cancer (HNC) patients, which therefore became the focus of the report. Pain is common in patients with HNC and is reported by approximately half of patients prior to cancer therapy, 81% during therapy, 70% at the end of therapy, and by 36% at 6 months after treatment. Pain is experienced beyond the 6-month period by approximately one third of patients and is typically more severe than pre-treatment cancer-induced pain. This systematic review identified the presence of pain before cancer therapy, likely attributable to the cancer; an increase in pain during therapy and the common persistence of pain following cancer treatment. Continuing research should use validated tools to prospectively assess orofacial pain, its causes and pathophysiology, and its effect on quality of life and economic impact. Clinical trials of pain management in this setting are also warranted.


Exclusion of melanocortin-1 receptor (mc1r) and agouti as candidates for dominant black in dogs.
The domestic dog exhibits a variety of coat colors that encompass a wide range of variation among different breeds. Very little is known about the molecular biology of dog pigmentation; current understanding is based mostly on traditional breeding experiments, which in some cases have suggested genetic interactions that are different from those reported in other mammals. We have examined the molecular genetics of dominant black, a uniform coat color characteristic of black Labrador retrievers or Newfoundlands that has been proposed to be caused by either variation in the melanocortin-1 receptor gene (Mc1r) or by variation in the Agouti gene (A). We identified several coding polymorphisms within Mc1r and several simple sequence repeat polymorphisms closely linked to A, and examined their inheritance in a Labrador retriever x greyhound cross that segregates dominant black. No single Mc1r allele was found consistently in animals carrying dominant black, and neither Mc1r nor A cosegregated with dominant black. These results refine our understanding of mammalian coat color inheritance and suggest that dominant black coat color in dogs is caused by a gene not previously implicated in pigment type switching.


Misuse of analysis of covariance in aging research revisited.
Storandt and Hudson's treatment of the issue of which general linear model technique is preferable to use when age effects are confounded is misleading. Contrary to their position that hierarchical ANOVA or step-wise multiple regression is superior to ANCOVA, it is demonstrated, using hypothetical data, that identical amounts of variance can be explained by ANCOVA relative to hierarchical ANOVA and multiple regression. Multiple regression is recommended as the most appropriate technique for a variety of pragmatic reasons concerning calculation of significance tests, the distinction between gross and net effects, and the choice of the metric used in measurement.


[Phosphodiesterase type 5 inhibitors in the treatment of pulmonary arterial hypertension].
The pathology of pulmonary arterial hypertension (PAH) is characterized by vascular vasoconstriction, smooth muscle cell proliferation, and thrombosis. Experimental studies have shown the beneficial effect of phosphodiesterase type 5 (PDE-5) inhibitors on pulmonary vascular remodeling and vasodilatation. Randomized clinical trials in monotherapy or combination therapy have been conducted in PAH with sildenafil and tadalafil which significantly improve clinical status, exercise capacity and hemodynamics of PAH patients. Combination therapy of PDE-5 inhibitors with prostacyclin analogs and endothelin receptor antagonists may be helpful in management of PAH. The third PDE-5 inhibitor, vardenafil, is currently being investigated in PAH. Side effects are usually mild and transient and include headache, flushing, nasal congestion, digestive disorders, and myalgia.


Mono- and dihydroxyeicosatetraenoic acids alter calcium homeostasis in rabbit neutrophils.
Products of the lipoxygenation of arachidonic acid that express neutrophil chemotactic activity were examined in vitro for effects on the uptake of 45Ca by rabbit peritoneal neutrophils. At optimally chemotactic concentrations, 5- and 11-hydroperoxyeicosatetraenoic acid, 11- and 12L-hydroxyeicosatetraenoic acid, and leukotriene B4 enhanced 45Ca uptake within 1 min by a mean of 212-694% of the values for control neutrophils incubated in buffer alone, as compared with 75% for 5(S)-hydroxyeicosatetraenoic acid and no effect for 15-hydroperoxyeicosatetraenoic acid and 15-hydroxyeicosatetraenoic acid. The approximate rank of potency of the factors stimulating 45Ca uptake was similar to that observed for chemotaxis. Leukotriene B4, in addition to stimulating the rate of 45Ca uptake into rabbit neutrophils, also displaced intracellular calcium. The net result of the leukotriene B4-induced changes in calcium homeostasis ws to elevate transiently the intracellular level of exchangeable calcium. That neutrophil lipoxygenase metabolites of endogenous arachidonic acid rapidly enhance the influx of 45Ca supports a possible role for such metabolites in general, and leukotriene B4 in particular, in the regulation of the intracellular levels of free calcium in the neutrophils and possibly in other hormonally sensitive cells in which this cation is a second messenger.


Diagnostic value of troponin T in neonates of mild pre-eclamptic mothers.
The measurement of myocardial damage by newer, highly specific markers of myocardial damage is now possible, including cardiac structural proteins such as troponin T (TnT). In neonates of pre-eclamptic mothers, it identifies minor myocardial damage missed by other biochemical markers. The present study was designed to determine the diagnostic value of TnT concentrations in neonates of pre-eclamptic mothers. Fifteen neonates of pre-eclamptic mothers were studied (9 boys and 6 girls), and 17 healthy full-term neonates (9 boys and 8 girls) were selected as a control group. The serum TnT concentration in neonates of pre-eclamptic mothers (0.70 ng/ml) was significantly higher than that in the control group (0.10 ng/ml). In an echocardiographic study, the mean mitral peak velocity at an atrial contraction (A) value of 39 cm/s in neonates of pre-eclamptic mothers was significantly lower than that in the control group (53 cm/s), and the mean mitral peak velocity of early diastole to peak velocity of the atrial contraction (E/A) value (1.75) in neonates of pre-eclamptic mothers was significantly higher than that in the control subjects (1.23). In conclusion, our study demonstrated high levels of cardiac TnT, lower mitral A values and high mitral E/A values in neonates of pre-eclamptic mothers, presumably associated with mild myocardial damage in the neonates of pre-eclamptic mothers.


Development of a differential optical-fiber displacement sensor.
A novel optical-fiber displacement sensor is proposed and demonstrated. It consists of a laser diode light source, an optical-fiber probe, and two photodetectors. The bundling of the probe is sectioned into three parts: a centrally positioned fiber in the bundle for illumination, the first-neighbor fibers for receiving (part I), and the remaining fibers for receiving (part II). The ratio of the difference to the sum of the output signals from the part I and the part II receiving fibers can eliminate the variation in the sensitivity of the sensor to reflectivity of the target. The performance of the sensor is geometrically analyzed. The working distance is determined by the distance from the centered illuminating fiber to the boundary between the part I and the part II receiving fibers. The experimental measurements made with three different reflectivity targets confirm that the sensor performance is independent of the three reflectivities, as predicted by the analysis.


Tiered analysis of whole-exome sequencing for epilepsy diagnosis.
It is thought that despite highly variable phenotypic expression, 70-80% of all epileptic cases are caused by one or more genetic mutations. Next generation sequencing technologies, such as whole exome sequencing (WES), can be used in a diagnostic or research setting to identify genetic mutations which may have significant prognostic implications for patients and their families. In this study, 398 genes associated with epilepsy or recurrent seizures were stratified into tiers based on genotype-phenotype concordance, tissue gene expression, frequency of affected individuals with mutations and evidence from functional and family studies. WES was completed on 14 DNA samples (2 with known mutations in SCN1A and 12 with no known mutations) from individuals diagnosed with epilepsy using an Ion AmpliSeq approach. WES confirmed positive SCN1A mutations in two samples. In n = 5/12 samples (S-3 to -14) we identified potentially causative mutations across five different genes. S-5 was identified to have a novel missense mutation in CCM2; S-6 a novel frameshift mutation identified in ADGRV1; S-10 had a previously reported pathogenic mutation in PCDH19, whilst a novel missense mutation in PCDH19 was shown in S-12; and S-13 identified to have separate missense mutations in KCNA2 and NPRL3. The application of WES followed by a targeted variant prioritization approach allowed for the discovery of potentially causative mutations in our cohort of previously undiagnosed epilepsy patients.


Natural history of HIV infection in the era of combination antiretroviral therapy.
The use of protease inhibitor-containing (PI) combination antiretroviral therapy has led to a reduction in the incidence of opportunistic illness and mortality (events) in HIV infection. We wished to quantify the changing incidence of these events in our clinical practice and delineate the relationship between CD4, HIV-1 RNA, and development of events in patients receiving PI combination therapy. We assessed HIV-infected patients with CD4 counts < or =500 cells x10(6)/l. We calculated the incidence of events from 1994 through 1998 and analyzed the association of temporal changes in event incidence and use of antiretroviral therapy. In patients on PI combination therapy, we determined the probability of achieving and maintaining an undetectable HIV-1 RNA response and determined the association of CD4, HIV-1 RNA, and developing an event. The incidence of opportunistic illness declined from 23.7 events/100 person-years in 1994 to 14.0 events/100 person-years in 1998 (P<0.001). Mortality declined from 20.2 deaths/100 person-years in 1994 to 8.4 deaths/ 100 person-years in 1998 (P<0.001). Use of PI combination therapy was associated with a relative rate of opportunistic illness or death of 0.66 [95% confidence interval (CI), 0.51-0.85; P<0.001]. The relative incidence of each of 16 opportunistic illnesses was approximately the same in 1998 as in 1994 except for lymphoma, cervical cancer and wasting syndrome which do not appeared to have declined in incidence. Approximately 60% of patients who received PI therapy achieved an undetectable HIV-1 RNA, and 65% of these patients maintained durable suppression of HIV-1 RNA. Achieving an undetectable HIV-1 RNA was associated with a decreased risk of an event, and was the variable most strongly associated with an increase in CD4 level. By multivariate analysis, the concurrent CD4 level was most strongly associated with developing an event. We observed a significant decline in the incidence of opportunistic illness and death from 1994 through 1998 associated with combination antiretroviral therapy. Patients who develop events while being treated with PI combination therapy were not likely to have achieved an undetectable HIV-1 RNA and are likely to have a low concurrent CD4 level.


Role of glutathione, glutathione transferase, and glutaredoxin in regulation of redox-dependent processes.
Over the last decade fundamentally new features have been revealed for the participation of glutathione and glutathione-dependent enzymes (glutathione transferase and glutaredoxin) in cell proliferation, apoptosis, protein folding, and cell signaling. Reduced glutathione (GSH) plays an important role in maintaining cellular redox status by participating in thiol-disulfide exchange, which regulates a number of cell functions including gene expression and the activity of individual enzymes and enzyme systems. Maintaining optimum GSH/GSSG ratio is essential to cell viability. Decrease in the ratio can serve as an indicator of damage to the cell redox status and of changes in redox-dependent gene regulation. Disturbance of intracellular GSH balance is observed in a number of pathologies including cancer. Consequences of inappropriate GSH/GSSG ratio include significant changes in the mechanism of cellular redox-dependent signaling controlled both nonenzymatically and enzymatically with the participation of isoforms of glutathione transferase and glutaredoxin. This review summarizes recent data on the role of glutathione, glutathione transferase, and glutaredoxin in the regulation of cellular redox-dependent processes.


The construct validity of the Lees-Haley Fake Bad Scale. Does this scale measure somatic malingering and feigned emotional distress?
The Fake Bad Scale (FBS [Psychol. Rep. 68 (1991) 203]) was created from MMPI-2 items to assess faking of physical complaints among personal injury claimants. Little psychometric information is available on the measure. This study was conducted to investigate the psychometric characteristics of the FBS using MMPI-2 profiles from six settings: Psychiatric Inpatient (N=6731); Correctional Facility (N=2897); Chronic Pain Program (N=4408); General Medical (N=5080); Veteran's Administration Hospital Inpatient (N=901); and Personal Injury Litigation (N=157). Most correlations of the FBS and raw scores on the MMPI-2 were positive with correlations among the validity scales being lower than correlations among the clinical and content scales. The FBS was most strongly correlated with raw scores on Hs, D, Hy, HEA, and DEP. When the more conservative cutoff of 26 was used, the FBS classified 2.4-30.6% of individuals as malingerers. The highest malingering classification was for the women's personal injury sample (37.9%) while the lowest was among male prison inmates (2.3%). Compared to men, in most samples, almost twice as many women were classified as malingerers. The results indicate that the FBS is more likely to measure general maladjustment and somatic complaints rather than malingering. The rate of false positives produced by the scale is unacceptably high, especially in psychiatric settings. The scale is likely to classify an unacceptably large number of individuals who are experiencing genuine psychological distress as malingerers. It is recommended that the FBS not be used in clinical settings nor should it be used during disability evaluations to determine malingering.


Practical approach to the treatment of hypothyroidism.
Hypothyroidism most commonly is the result of primary thyroid failure due to autoimmune thyroiditis, but also may follow treated Graves' disease or may occur as transient hypothyroidism. Laboratory evaluation of thyroid function has been refined by the development of ultrasensitive thyroid-stimulating hormone determinations, allowing accurate diagnosis of primary hypothyroidism and assessment of treatment response. Determining whether therapy is appropriate for patients with subclinical hypothyroidism or euthyroid sick syndrome requires clinical judgment in addition to laboratory evaluation. Thyroid hormone replacement for hypothyroidism is best accomplished with levothyroxine. Factors that may affect serum thyroxine levels include thyroid binding globulin levels, drug interactions and variations in thyroxine absorption and clearance.


Travel Cost Savings and Practicality for Low-Vision Telerehabilitation.
Introduction: Veterans with low vision who live in rural communities have limited access to low-vision rehabilitation services, unless they are able to travel several miles to a specialty low-vision clinic. A low-vision optometry telerehabilitation evaluation is a thorough assessment of patient's functional vision. Following each low-vision optometry telerehabilitation evaluation is a low-vision telerehabilitation initial assessment with a blind rehabilitation therapist. Our objective was to estimate the acceptance and practicality of low-vision telerehabilitation and investigate the travel cost and time savings. Methods: Utilizing Google Maps™, round-trip travel mileage and travel time can be estimated between the veteran's home and the Buffalo Veterans Affairs (VA) and compared with the round-trip mileage and travel time between the veteran's home and local community-based outpatient center (CBOC) or local VA for low-vision telerehabilitation services. The difference is the savings in travel miles and time. Cost saving can be calculated by multiplying difference in travel miles by cost per mile. Results: Veterans who chose not to schedule face-to-face low-vision rehabilitation at the Buffalo VA due to an average round-trip travel distance of 151 miles scheduled a low-vision telerehabilitation at a local CBOC or local VA with an average round-trip travel distance of 29 miles. Adding low-vision telerehabilitation services from fiscal year (FY) 13 to FY 17 resulted in a 24% increase in low-vision patient care. The median saving of travel miles for rural veterans was 122 miles per veteran, and the median saving of travel time was 2.09 h per veteran. Overall, the median saving of the travel cost was $65.29 per veteran. Conclusions: This study shows and supports low-vision telerehabilitation as an accepted, practical, time-saving, and cost-saving alternative option to traditional face-to-face consultations with a low-vision optometrist and blind rehabilitation therapist.


Peptide-chain initiation in duodenal mucosa of rachitic chicks after 1 alpha-,25-dihydroxycholecalciferol administration.
The post-ribosomal fraction of chick duodenal mucosa contains Met-tRNAMetf-binding protein(s) that behaves like the eukaryotic initiation factor (eIF-2) in protein synthesis. The binding activity of cytosol protein can be measured by retention of the radioactive complex formed on a nitrocellulose membrane. Complex-formation requires Met-tRNAMetf and GTP or guanosine [beta, gamma-methylene] triphosphate, and is inhibited by aurintricarboxylic acid. The ternary initiation complex thus formed can bind to ribosomal particles from chick intestine. By sucrose-density-gradient centrifugation, [35S]Met-tRNAMetf was found to bind exclusively to 40S and not to 60S ribosomal subunit particles. In the duodenal mucosa of rachitic chicks the ability of the cytosol proteins to promote the binding of Met-tRNAMetf to ribosomal particles via ternary-complex formation is detectably increased by 3 h after injection of 1 alpha,25-dihydroxycholecalciferol, the active form of vitamin D. Cholecalciferol and ergocalciferol under the same experimental conditions failed to stimulate Met-tRNAMetf-binding activity.


The Arctic AβPP mutation leads to Alzheimer's disease pathology with highly variable topographic deposition of differentially truncated Aβ.
The Arctic mutation (p.E693G/p.E22G)fs within the β-amyloid (Aβ) region of the β-amyloid precursor protein gene causes an autosomal dominant disease with clinical picture of typical Alzheimer's disease. Here we report the special character of Arctic AD neuropathology in four deceased patients. Aβ deposition in the brains was wide-spread (Thal phase 5) and profuse. Virtually all parenchymal deposits were composed of non-fibrillar, Congo red negative Aβ aggregates. Congo red only stained angiopathic vessels. Mass spectrometric analyses showed that Aβ deposits contained variably truncated and modified wild type and mutated Aβ species. In three of four Arctic AD brains, most cerebral cortical plaques appeared targetoid with centres containing C-terminally (beyond aa 40) and variably N-terminally truncated Aβ surrounded by coronas immunopositive for Aβx-42. In the fourth patient plaque centres contained almost no Aβ making the plaques ring-shaped. The architectural pattern of plaques also varied between different anatomic regions. Tau pathology corresponded to Braak stage VI, and appeared mainly as delicate neuropil threads (NT) enriched within Aβ plaques. Dystrophic neurites were scarce, while neurofibrillary tangles were relatively common. Neuronal perikarya within the Aβ plaques appeared relatively intact. In Arctic AD brain differentially truncated abundant Aβ is deposited in plaques of variable numbers and shapes in different regions of the brain (including exceptional targetoid plaques in neocortex). The extracellular non-fibrillar Aβ does not seem to cause overt damage to adjacent neurons or to induce formation of neurofibrillary tangles, supporting the view that intracellular Aβ oligomers are more neurotoxic than extracellular Aβ deposits. However, the enrichment of NTs within plaques suggests some degree of intra-plaque axonal damage including accumulation of hp-tau, which may impair axoplasmic transport, and thereby contribute to synaptic loss. Finally, similarly as the cotton wool plaques in AD resulting from exon 9 deletion in the presenilin-1 gene, the Arctic plaques induced only modest glial and inflammatory tissue reaction.


One-pot, mix-and-read peptide-MHC tetramers.
Cytotoxic T Lymphocytes (CTL) recognize complexes of peptide ligands and Major Histocompatibility Complex (MHC) class I molecules presented at the surface of Antigen Presenting Cells (APC). Detection and isolation of CTL's are of importance for research on CTL immunity, and development of vaccines and adoptive immune therapy. Peptide-MHC tetramers have become important reagents for detection and enumeration of specific CTL's. Conventional peptide-MHC-tetramer production involves recombinant MHC production, in vitro refolding, biotinylation and tetramerization; each step followed by various biochemical steps such as chromatographic purification, concentration etc. Such cumbersome production protocols have limited dissemination and restricted availability of peptide-MHC tetramers effectively precluding large-scale screening strategies involving many different peptide-MHC tetramers. We have developed an approach whereby any given tetramer specificity can be produced within 2 days with very limited effort and hands-on time. The strategy is based on the isolation of correctly oxidized, in vivo biotinylated recombinant MHC I heavy chain (HC). Such biotinylated MHC I HC molecules can be refolded in vitro, tetramerized with streptavidin, and used for specific T cell staining-all in a one-pot reaction without any intervening purification steps. We have developed an efficient "one-pot, mix-and-read" strategy for peptide-MHC tetramer generation, and demonstrated specific T cell straining comparable to a commercially available MHC-tetramer. Here, seven peptide-MHC tetramers representing four different human MHC (HLA) class I proteins have been generated. The technique should be readily extendable to any binding peptide and pre-biotinylated MHC (at this time we have over 40 different pre-biotinylated HLA proteins). It is simple, robust, and versatile technique with a very broad application potential as it can be adapted both to small- and large-scale production of one or many different peptide-MHC tetramers for T cell isolation, or epitope screening.


Trace elements in the spinal cord and other tissues in motor neuron disease.
Trace elements were estimated in the spinal cord, liver and bone of five patients dying of motor neuron disease and five control subjects dying of non-neurological disease. The content of selenium in cord and liver and the cord manganese level were significantly increased in the motor neuron disease patients. These findings are discussed in terms of the possible aetiology of motor neuron disease.


Neofunctionalization of "Juvenile Hormone Esterase Duplication" in Drosophila as an odorant-degrading enzyme towards food odorants.
Odorant degrading enzymes (ODEs) are thought to be responsible, at least in part, for olfactory signal termination in the chemosensory system by rapid degradation of odorants in the vicinity of the receptors. A carboxylesterase, specifically expressed in Drosophila antennae, called "juvenile hormone esterase duplication (JHEdup)" has been previously reported to hydrolyse different fruit esters in vitro. Here we functionally characterize JHEdup in vivo. We show that the jhedup gene is highly expressed in large basiconic sensilla that have been reported to detect several food esters. An electrophysiological analysis demonstrates that ab1A olfactory neurons of jhedup mutant flies exhibit an increased response to certain food acetates. Furthermore, mutant flies show a higher sensitivity towards the same odorants in behavioural assays. A phylogenetic analysis reveals that jhedup arose as a duplication of the juvenile hormone esterase gene during the evolution of Diptera, most likely in the ancestor of Schizophora, and has been conserved in all the 12 sequenced Drosophila species. Jhedup exhibits also an olfactory-predominant expression pattern in other Drosophila species. Our results support the implication of JHEdup in the degradation of food odorants in D. melanogaster and propose a neofunctionalization of this enzyme as a bona fide ODE in Drosophilids.


Multiple autoclave cycle effects on cyclic fatigue of nickel-titanium rotary files produced by new manufacturing methods.
Novel nickel-titanium rotary files with proprietary manufacturing techniques have recently been marketed. The purpose of this study was to assess multiple autoclave cycle effects on cyclic fatigue of GT Series X files (Dentsply Tulsa Dental Specialties, Tulsa, OK) and Twisted Files (SybronEndo, Orange, CA) METHODS: A jig using a 5-mm radius curve with 90° of maximum file flexure was used to induce cyclic fatigue failure. Files (n = 10) representing each experimental group (GT Series X 20/.04 and 20/.06; Twisted Files 25/.04 and 25/.06) were first tested to establish baseline mean cycles to failure (MCF). Experimental groups (n = 20) were then cycled to 25% of the established baseline MCF and then autoclaved. Additional autoclaving was accomplished at 50% and 75% of MCF followed by continual testing until failure. Control groups (n = 20) underwent the same procedures except autoclaving was not accomplished. The GT Series X (20/.04 and 20/.06) files showed no significant difference (p = 0.918/p = 0.096) in MCF for experimental versus control files. Twisted Files (25/.04) showed no significant difference (p = 0.432) in MCF between experimental and control groups. However, the Twisted Files (25/.06) experimental group showed a significantly lower (p = 0.0175) MCF compared with the controls. Under the conditions of this evaluation, autoclave sterilization significantly decreased cyclic fatigue resistance of one of the four file groups tested. Repeated autoclaving significantly reduced the MCF of 25/.06 Twisted Files; however, 25/.04 Twisted Files and both GT Series X files tested were not significantly affected by the same conditions.


Porphyrin Binding and Irradiation Promote G-Quadruplex DNA Dimeric Structure.
Nucleic acid sequences rich in guanines can organize into noncanonical DNA G-quadruplexes (G4s) of variable size. The design of small molecules stabilizing the structure of G4s is a rapidly growing area for the development of novel anticancer therapeutic strategies and bottom-up nanotechnologies. Among a multitude of binders, porphyrins are very attractive due to their light activation that can make them valuable conformational regulators of G4s. Here, a structure-based strategy, integrating complementary probes, is employed to study the interaction between TMPyP4 porphyrin and a 22-base human telomeric sequence (Tel22) before and after irradiation with blue light. Porphyrin binding is discovered to promote Tel22 dimerization, while light irradiation of the Tel22-TMPyP4 complex controls dimer fraction. Such a change in quaternary structure is found to be strictly correlated with modifications at the secondary structure level, thus providing an unprecedented link between the degree of dimerization and the underlying conformational changes in G4s.