Attitudes and preferences towards screening for dementia: a systematic review of the literature.
Population screening might provide a mechanism to enable early detection of dementia. Yet the potential benefits, harms or acceptability of such a large-scale intervention are not well understood. This research aims to examine the attitudes and preferences of the general public, health care professionals, people with dementia and their carers towards population screening for dementia. A systematic review of the international literature was undertaken. A search of fifteen bibliographic databases was conducted (up to 12 July 2012; no language restriction) using terms related to dementia, screening, specific screening tools, case finding, and attitudes and preferences; genetic screening and biomarkers were excluded. All study designs were included except opinion-based papers. Included papers were doubly quality assessed and thematically analysed using NVivo. 29,910 papers were identified of which 29 met the inclusion criteria. We identified seventeen themes relating to the 3 phases of the screening process (pre-, in- and post-screen) - none emerged as more of a facilitator than a barrier to the acceptance of dementia screening. Seven themes emerged in relation to the patient, carer and general population: existing health state; lifestyle and life view; awareness of dementia; role of clinician; communication; benefit; and role of the family. Ten themes emerged in relation to the clinician and healthcare professional: patient's existing health and comorbidities; awareness of dementia; confidence; duration of patient contact; suitability of screening tool; cost; disclosure; time; treatment and prognosis; and stigma. As for all screening programmes, screening for dementia raises complex issues around preference and choice for clinicians and the public, and it is unclear what specific factors promote or reduce screening acceptance the most. Overall, the level of evidence is low, few large scale studies have been undertaken and none were conducted in representative samples, all affecting the generalizability of identified themes across healthcare contexts. Nevertheless, our findings suggest that population screening for dementia may not be acceptable to either the general public or health care professionals, and highlight where focused efforts are needed to gain insights into dementia specific issues.


Fork-tip needle biopsy versus fine-needle aspiration in endoscopic ultrasound-guided sampling of solid pancreatic masses: a randomized crossover study.
A novel fork-tip fine-needle biopsy (FNB) needle has recently been introduced for endoscopic ultrasound (EUS)-guided sampling. The aim of this study was to compare the performance of fork-tip FNB histology and standard fine-needle aspiration (FNA) cytology in the diagnosis of solid pancreatic masses. A randomized crossover study was performed in patients referred for EUS-guided sampling. Three passes were taken with each needle in a randomized order. Only samples reported as diagnostic of malignancy were considered positive. The primary end point was the sensitivity of diagnosis of malignancy. Secondary end points included the amount of sample obtained, ease of diagnosis, duration of tissue sampling, pathologist viewing time, and cost. 108 patients were recruited. Median age was 69 years (range 30 - 87) and 57 were male; 85.2 % had a final diagnosis of malignancy. There were statistically significant differences in sensitivity (82 % [95 % confidence interval (CI) 72 % to 89 %] vs. 71 % [95 %CI 60 % to 80 %]), accuracy (84 % [95 %CI 76 % to 91 %] vs. 75 % [95 %CI 66 % to 83 %]), proportion graded as a straightforward diagnosis (69 % [95 %CI 60 % to 78 %] vs. 51 % [95 %CI 41 % to 61 %]), and median pathology viewing time (188 vs. 332 seconds) (P < 0.001) between FNB and FNA needles, respectively. There was no significant difference in cost between an FNB or FNA strategy. The diagnostic performance of the fork-tip FNB needle was significantly better than that of FNA; it was associated with ease of diagnosis, shorter pathological viewing times, and was cost neutral.


Novel cell-cell interactions during vulva development in Pristionchus pacificus.
Vulva development differs between Caenorhabditis elegans and Pristionchus pacificus in several ways. Seven of 12 ventral epidermal cells in P. pacificus die of apoptosis, whereas homologous cells in C. elegans fuse with the hypodermal syncytium. Vulva induction is a one-step process in C. elegans, but requires a continuous interaction between the gonad and the epidermis in P. pacificus. Here we describe several novel cell-cell interactions in P. pacificus, focusing on the vulva precursor cell P8.p and the mesoblast M. P8.p in P. pacificus, unlike its homologous cell in C. elegans, is incompetent to respond to gonadal signaling in the absence of other vulva precursor cells, but can respond to lateral signaling from a neighboring vulval precursor. P8.p provides an inhibitory signal that determines the developmental competence of P(5,7).p. This lateral inhibition acts via the mesoblast M and is regulated by the homeotic gene Ppa-mab-5. In Ppa-mab-5 mutants, M is misspecified and provides inductive signaling to the vulval precursor cells, including P8.p. Taken together, vulva development in P. pacificus displays novel cell-cell interactions involving the mesoblast M and P8.p. In particular, P8.p represents a new ventral epidermal cell type, which is characterized by novel interactions and a specific response to gonadal signaling.


Plasma cholesteryl ester transfer protein is predominantly derived from Kupffer cells.
The role of Kupffer cells (KCs) in the pathophysiology of the liver has been firmly established. Nevertheless, KCs have been underexplored as a target for diagnosis and treatment of liver diseases owing to the lack of noninvasive diagnostic tests. We addressed the hypothesis that cholesteryl ester transfer protein (CETP) is mainly derived from KCs and may predict KC content. Microarray analysis of liver and adipose tissue biopsies, obtained from 93 obese subjects who underwent elective bariatric surgery, showed that expression of CETP is markedly higher in liver than adipose tissue. Hepatic expression of CETP correlated strongly with that of KC markers, and CETP messenger RNA and protein colocalized specifically with KCs in human liver sections. Hepatic KC content as well as hepatic CETP expression correlated strongly with plasma CETP concentration. Mechanistic and intervention studies on the role of KCs in determining the plasma CETP concentration were performed in a transgenic (Tg) mouse model expressing human CETP. Selective elimination of KCs from the liver in CETP Tg mice virtually abolished hepatic CETP expression and largely reduced plasma CETP concentration, consequently improving the lipoprotein profile. Conversely, augmentation of KCs after Bacille-Calemette-Guérin vaccination largely increased hepatic CETP expression and plasma CETP. Also, lipid-lowering drugs fenofibrate and niacin reduced liver KC content, accompanied by reduced plasma CETP concentration. Plasma CETP is predominantly derived from KCs, and plasma CETP level predicts hepatic KC content in humans.


THE EFFECTS OF ULTRAVIOLET-B RADIATION ON ANTARCTIC SEA-ICE ALGAE(1).
The impacts of ultraviolet-B radiation (UVB) on polar sea-ice algal communities have not yet been demonstrated. We assess the impacts of UV on these communities using both laboratory experiments on algal isolates and by modification of the in situ spectral distribution of the under-ice irradiance. In the latter experiment, filters were attached to the upper surface of the ice so that the algae were exposed in situ to treatments of ambient levels of PAR and UV radiation, ambient radiation minus UVB, and ambient radiation minus all UV. After 16 d, significant increases in chl a and cell numbers were recorded for all treatments, but there were no significant differences among the different treatments. Bottom-ice algae exposed in vitro were considerably less tolerant to UVB than those in situ, but this tolerance improved when algae were retained within a solid block of ice. In addition, algae extracted from brine channels in the upper meter of sea ice and exposed to PAR and UVB in the laboratory were much more tolerant of high UVB doses than were any bottom-ice isolates. This finding indicates that brine algae may be better adapted to high PAR and UVB than are bottom-ice algae. The data indicate that the impact of increased levels of UVB resulting from springtime ozone depletion on Antarctic bottom-ice communities is likely to be minimal. These algae are likely protected by strong UVB attenuation by the overlying ice and snow, by other inorganic and organic substances in the ice matrix, and by algal cells closer to the surface.


The child's right to an open future: is the principle applicable to non-therapeutic circumcision?
The principle of the child's right to an open future was first proposed by the legal philosopher Joel Feinberg and developed further by bioethicist Dena Davis. The principle holds that children possess a unique class of rights called rights in trust-rights that they cannot yet exercise, but which they will be able to exercise when they reach maturity. Parents should not, therefore, take actions that permanently foreclose on or pre-empt the future options of their children, but leave them the greatest possible scope for exercising personal life choices in adulthood. Davis particularly applies the principle to genetic counselling, arguing that parents should not take deliberate steps to create physically abnormal children, and to religion, arguing that while parents are entitled to bring their children up in accordance with their own values, they are not entitled to inflict physical or mental harm, neither by omission nor commission. In this paper, I aim to elucidate the open future principle, and consider whether it is applicable to non-therapeutic circumcision of boys, whether performed for cultural/religious or for prophylactic/health reasons. I argue that the principle is highly applicable to non-therapeutic circumcision, and conclude that non-therapeutic circumcision would be a violation of the child's right to an open future, and thus objectionable from both an ethical and a human rights perspective.


Demography can favour female-advantageous alleles.
When female fecundity is relatively independent of male abundance, while male reproduction is proportional to female abundance, females have a larger effect on population dynamics than males (i.e. female demographic dominance). This population dynamic phenomenon might not appear to influence evolution, because male and female genomes still contribute equally much to the next generation. However, here we examine two evolutionary scenarios to provide a proof of principle that spatial structure can make female demographic dominance matter. Our two simulation models combine dispersal evolution with local adaptation subjected to intralocus sexual conflict and environmentally driven sex ratio biases, respectively. Both models have equilibria where one environment (without being intrinsically poorer) has so few reproductive females that trait evolution becomes disproportionately determined by those environments where females survive better (intralocus sexual conflict model), or where daughters are overproduced (environmental sex determination model). Surprisingly, however, the two facts that selection favours alleles that benefit females, and population growth is improved when female fitness is high, together do not imply that all measures of population performance are improved. The sex-specificity of the source-sink dynamics predicts that populations can evolve to fail to persist in habitats where alleles do poorly when expressed in females.


A sensor system for monitoring the simple gases hydrogen, carbon monoxide, hydrogen sulfide, ammonia and ethanol in exhaled breath.
A sensor array system was constructed incorporating electrochemical sensors for hydrogen, carbon monoxide, hydrogen sulfide and ethanol, a ceramic sensor for total volatiles and a dye-based optical ammonia sensor. The system was calibrated using standard gases balanced with dry air. Limit of detection and % relative standard deviation values (n = 10) for the sensors in the array are hydrogen (0.1 ppm, 2.6%), carbon monoxide (0.4 ppm, 2.1%), ethanol (0.5 ppm, 1.5%), hydrogen sulfide (0.1 ppm, 1.5%) and ammonia (0.6 ppm, 10.7%). Humidity effects were assessed by calibrating with humidified standard gases (hydrogen, carbon monoxide) or spiked breath samples in Tedlar bags (hydrogen sulfide, ethanol and ammonia). The calibration data were used to establish a cross-sensitivity matrix. The concentration of breath volatiles was found to be dependent on exhalation rate and exhalation volume. A test protocol based on these data required volunteers to exhale 1 litre of breath at a rate between 7.5 and 17.5 l min(-1). Sensor responses were measured for 40 s then purged at 7 l min(-1) (150 s). A longitudinal study was undertaken of ten asymptomatic volunteers over a five-day period. Volunteers ate an ad hoc diet, but fasted prior to giving the first breath sample and then gave samples every hour for 8 h. Breath hydrogen levels for volunteers showed large variations within a day and also from day to day. Fasting levels ranged between 0.3 and 34.1 ppm (mean 9.1 ppm). The carbon monoxide levels for non-smokers were between 0.6 and 4.9 ppm (mean 2.1 ppm), whilst for smokers they were between 8.3 and 18.7 ppm (mean 12.8 ppm). The measured levels of other gases on breath were as follows: hydrogen sulfide (0-1.3 ppm, mean 0.33 ppm), ethanol (0-3.9 ppm, mean 0.62 ppm) and ammonia (0-1.3 ppm mean 0.42 ppm). The system was capable of direct quantitative measurements of low concentrations of a range of volatiles on exhaled breath. The measured values for compounds on the breath of asymptomatic volunteers were in broad agreement with quoted literature ranges. The system will now be assessed in a clinical setting.


Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence.
We reported that Notch-1, a potent breast oncogene, is activated in response to trastuzumab and contributes to trastuzumab resistance in vitro. We sought to determine the preclinical benefit of combining a Notch inhibitor (γ-secretase inhibitor (GSI)) and trastuzumab in both trastuzumab-sensitive and trastuzumab-resistant, ErbB-2-positive, BT474 breast tumours in vivo. We also studied if the combination therapy of lapatinib plus GSI can induce tumour regression of ErbB-2-positive breast cancer. We generated orthotopic breast tumour xenografts from trastuzumab- or lapatinib-sensitive and trastuzumab-resistant BT474 cells. We investigated the antitumour activities of two distinct GSIs, LY 411 575 and MRK-003, in vivo. Our findings showed that combining trastuzumab plus a GSI completely prevented (MRK-003 GSI) or significantly reduced (LY 411 575 GSI) breast tumour recurrence post-trastuzumab treatment in sensitive tumours. Moreover, combining lapatinib plus MRK-003 GSI showed significant reduction of tumour growth. Furthermore, a GSI partially reversed trastuzumab resistance in resistant tumours. Our data suggest that a combined inhibition of Notch and ErbB-2 signalling pathways could decrease recurrence rates for ErbB-2-positive breast tumours and may be beneficial in the treatment of recurrent trastuzumab-resistant disease.


Genetic Responses of Metabolically Active Limnospira indica Strain PCC 8005 Exposed to γ-Radiation during Its Lifecycle.
Two morphotypes of the cyanobacterial Limnospira indica (formerly Arthrospira sp.) strain PCC 8005, denoted as P2 (straight trichomes) and P6 (helical trichomes), were subjected to chronic gamma radiation from spent nuclear fuel (SNF) rods at a dose rate of ca. 80 Gy·h-1 for one mass doubling period (approximately 3 days) under continuous light with photoautotrophic metabolism fully active. Samples were taken for post-irradiation growth recovery and RNA-Seq transcriptional analysis at time intervals of 15, 40, and 71.5 h corresponding to cumulative doses of ca. 1450, 3200, and 5700 Gy, respectively. Both morphotypes, which were previously reported by us to display different antioxidant capacities and differ at the genomic level in 168 SNPs, 48 indels and 4 large insertions, recovered equally well from 1450 and 3200 Gy. However, while the P2 straight type recovered from 5700 Gy by regaining normal growth within 6 days, the P6 helical type took about 13 days to recover from this dose, indicating differences in their radiation tolerance and response. To investigate these differences, P2 and P6 cells exposed to the intermediate dose of gamma radiation (3200 Gy) were analyzed for differential gene expression by RNA-Seq analysis. Prior to batch normalization, a total of 1553 genes (887 and 666 of P2 and P6, respectively, with 352 genes in common) were selected based on a two-fold change in expression and a false discovery rate FDR smaller or equal to 0.05. About 85% of these 1553 genes encoded products of yet unknown function. Of the 229 remaining genes, 171 had a defined function while 58 genes were transcribed into non-coding RNA including 21 tRNAs (all downregulated). Batch normalization resulted in 660 differentially expressed genes with 98 having a function and 32 encoding RNA. From PCC 8005-P2 and PCC 8005-P6 expression patterns, it emerges that although the cellular routes used by the two substrains to cope with ionizing radiation do overlap to a large extent, both strains displayed a distinct preference of priorities.


PUF-8 negatively regulates RAS/MAPK signalling to promote differentiation of C. elegans germ cells.
Signals that promote germ cell self-renewal by preventing premature meiotic entry are well understood. However, signals that control mitotic proliferation to promote meiotic differentiation have not been well characterized. In Caenorhabditis elegans, GLP-1 Notch signalling promotes the proliferative fate by preventing premature meiotic entry. The germline niche cell, which is the source of the ligand for GLP-1, spatially restricts GLP-1 signalling and thus enables the germ cells that have moved away from the niche to enter meiosis. Here, we show that the suppression of RAS/MAP kinase signalling in the mitotic and meiotic-entry regions is essential for the regulation of the mitosis-meiosis switch by niche signalling. We provide evidence that the conserved PUF family RNA-binding protein PUF-8 and the RAS GAP protein GAP-3 function redundantly to suppress the LET-60 RAS in the mitotic and meiotic entry regions. Germ cells missing both PUF-8 and GAP-3 proliferate in an uncontrolled fashion and fail to undergo meiotic development. MPK-1, the MAP kinase downstream of the LET-60 RAS, is prematurely activated in these cells; downregulation of MPK-1 activation eliminates tumours and restores differentiation. Our results further reveal that PUF-8 negatively regulates LET-60 expression at a post-transcriptional step. LET-60 is misexpressed in the puf-8(-) mutant germlines and PUF-8 physically interacts with the let-60 3' UTR. Furthermore, PUF-8 suppresses let-60 3' UTR-mediated expression in the germ cells that are transitioning from the mitotic to meiotic fate. These results reveal that PUF-8-mediated inhibition of the RAS/MAPK pathway is essential for mitotic-to-meiotic fate transition.


Inhibition of protein synthesis in vitro by crotins and ricin. Effect on the steps of peptide chain elongation.
The effects of crotin I and crotin II on the partial reactions of polypeptide chain elongation were investigated and compared with the known effects of ricin. Crotin II was a more powerful inhibitor than crotin I, but no qualitative differences between the two crotins were found. Rat liver ribosomes, preincubated with crotins and washed through sucrose gradients, remained inactive in protein synthesis. Among the individual steps of elongation, the peptidyltransferase reaction was unaffected by crotins, but some of the reactions that involve the interaction of elongation factors 1 and 2 with ribosomes were modified. A strong inhibition of the binding of elongation factor 2 to ribosomes and a stimulation of the elongation factor2-dependent GTP hydrolysis were observed; this indicates the formation of a very unstable elongation factor 2--GDP--ribosome complex, which, however, allows a single round of translocation to take place in the presence ofelongation factor 2 and added GTP. The elongation factor 1-dependent GTP hydrolysis was inhibited by crotins, whereas the enzymic binding of aminoacyl-tRNA, to both rat liver and Artemia salina ribosomes, was scarcely affected. In a protein-synthesizing system the inhibition by crotins and by ricin leads to a block of the nascent peptides on the ribosomal aminoacyl-tRNA site, an effect consistent with inhibition at the level of translocation. The mechanism of action of crotins appears to be very similar to that of ricin.


Reduced genetic influence on childhood obesity in small for gestational age children.
Children born small-for-gestational-age (SGA) are at increased risk of developing obesity and metabolic diseases later in life, a risk which is magnified if followed by accelerated postnatal growth. We investigated whether common gene variants associated with adult obesity were associated with increased postnatal growth, as measured by BMI z-score, in children born SGA and appropriate for gestational age (AGA) in the Auckland Birthweight Collaborative. A total of 37 candidate SNPs were genotyped on 547 European children (228 SGA and 319 AGA). Repeated measures of BMI (z-score) were used for assessing obesity status, and results were corrected for multiple testing using the false discovery rate. SGA children had a lower BMI z-score than non-SGA children at assessment age 3.5, 7 and 11 years. We confirmed 27 variants within 14 obesity risk genes to be individually associated with increasing early childhood BMI, predominantly in those born AGA. Genetic risk variants are less important in influencing early childhood BMI in those born SGA than in those born AGA, suggesting that non-genetic or environmental factors may be more important in influencing childhood BMI in those born SGA.


Agreement between Breast Percentage Density Estimations from Standard-Dose versus Synthetic Digital Mammograms: Results from a Large Screening Cohort Using Automated Measures.
Purpose To evaluate agreement between automated estimates of breast density made from standard-dose versus synthetic digital mammograms in a large cohort of women undergoing screening. Materials and Methods This study received institutional review board approval with waiver of consent. A total of 3668 negative (Breast Imaging Reporting and Data System category 1 or 2) digital breast tomosynthesis (DBT) screening examinations consecutively performed over a 4-month period at one institution for which both standard-dose and synthetic mammograms were available for analysis were retrospectively analyzed. All mammograms were acquired with a Selenia Dimensions system (Hologic, Bedford, Mass), and synthetic mammograms were generated by using the U.S. Food and Drug Administration-approved "C-View" software module. The "For Presentation" standard-dose mammograms and synthetic images were analyzed by using a fully automated algorithm. Agreement between density estimates was assessed by using Pearson correlation, linear regression, and Bland-Altman analysis. Differences were evaluated by using the paired Student t test. Results Breast percentage density (PD) estimates from synthetic and standard-dose mammograms were highly correlated (r = 0.92, P < .001), and the 95% Bland-Altman limits of agreement between PD estimates were -6.4% to 9.9%. Synthetic mammograms had PD estimates by an average of 1.7% higher than standard-dose mammograms (P < .001), with a larger disagreement by 1.56% in women with highly dense breast tissue (P < .0001). Conclusion Fully automated estimates of breast density made from synthetic mammograms are generally comparable to those made from standard-dose mammograms. This may be important, as standard two-dimensional mammographic images are increasingly being replaced by synthetic mammograms in DBT screening in an attempt to reduce radiation dose. © RSNA, 2017 Online supplemental material is available for this article.


Ultrasensitive serum prostate specific antigen nadir accurately predicts the risk of early relapse after radical prostatectomy.
Ultrasensitive prostate specific antigen (PSA) assays allow a lower limit of detection (less than 0.01 ng/ml) than standard PSA assays. In this study we examined the ability of ultrasensitive PSA nadir to predict relapse after radical prostatectomy (RP). A total of 906 men treated with RP were followed with PSA measurements at 3, 6 and 12 months, and yearly thereafter. Of the 906 men 545 (60%) with a PSA nadir of less than 0.01 ng/ml or at least 3 followup ultrasensitive PSA measurements underwent analysis and stratification by PSA nadir. Biochemical relapse was defined as 2 consecutive increasing post-nadir PSA measurements of 0.1 ng/ml or greater. The ability of ultrasensitive PSA nadir to predict relapse was assessed by univariate and multivariate analysis. At a mean followup of 3.1 years 54 of 545 men (9.9%) experienced biochemical relapse with a mean time to relapse of 25.2 months. Relapse rates in men with a PSA nadir of less than 0.01 (423), 0.01 (75), 0.02 (19) and 0.04 or greater ng/ml (28) were 4%, 12%, 16% and 89%, respectively. Men with a nadir of less than 0.01 ng/ml had a significantly lower relapse rate than men with a nadir of 0.01 (p <0.01), 0.02 (p <0.025) or 0.04 or greater ng/ml (p <0.01). Multivariate logistic regression analysis showed that a nadir of 0.01 (p <0.05), 0.02 (p <0.05) and 0.04 or greater ng/ml (p <0.01) independently predicted an increased risk of biochemical relapse compared to a nadir of less than 0.01 ng/ml. Ultrasensitive PSA nadir accurately predicts the risk of early biochemical relapse following RP. Men who achieve a nadir of less than 0.01 ng/ml have a low likelihood of early relapse. Higher nadir points may identify candidates for early adjuvant or salvage therapies.


Asymmetric Contrarians in Opinion Dynamics.
Asymmetry in contrarian behavior is investigated within the Galam model of opinion dynamics using update groups of size 3 with two competing opinions A and B. Denoting x and y the respective proportions of A and B contrarians, four schemes of implementations are studied. The first scheme activates contrarians after each series of updates with probabilities x and y for agents holding respectively opinion A and B. Second scheme activates contrarians within the update groups only against global majority with probability x when A is the majority and y when B is the majority. The third scheme considers in-group contrarians acting prior to the local majority update against both local majority and minority opinions. The last scheme activates in-group contrarians prior to the local majority update but only against the local majority. The main result is the loss of the fifty-fifty attractor produced by symmetric contrarians. Producing a bit less contrarians on its own side than the other side becomes the key to win a public debate, which in turn can guarantee an election victory. The associated phase diagram of opinion dynamics is found to exhibit a rich variety of counterintuitive results.


Efficacy, safety and feasibility of intravenous iloprost in the domiciliary treatment of patients with ischemic disease of the lower limbs.
Intravenous iloprost is an important option in the treatment of ischemic disease of the lower limbs; however, the administration of therapy is frequently compromised because of the need for long cycles of infusion in a hospital setting. The aim of the study is to evaluate the efficacy, safety, feasibility, and the economic impact of infusion therapy in the outpatient setting. Twenty-four consecutive patients were treated with iloprost at their homes where they were administered a slow rate of infusion for 24 hours a day, during 9.9 ± 2.3 days, with a portable syringe pump (Infonde®). The clinical condition of patients evaluated with the modified SVS/ISCVS scale significantly improved after treatment (+1.29 ± 1.04 points vs. baseline, p<0.001). The drug was well tolerated; neither significant adverse events associated with medication nor problems related to venous access were recorded at home. Ninety-six percent of patients successfully completed the entire treatment cycle, and the evaluation questionnaire showed a high acceptance of the therapy. From the perspective of the hospital authority, lower direct medical costs were estimated for the domiciliary infusion process compared with the inpatient infusion setting. Treatment with iloprost in the outpatient setting is effective, safe, feasible, and more acceptable to patients than infusion at the hospital. In addition, it has a favorable economic and organizational impact on the medical ward.


Effect of losartan, a type 1 angiotensin II receptor antagonist, on bronchial hyperresponsiveness to methacholine in patients with bronchial asthma.
It is unclear whether angiotensin II receptors are involved in bronchial hyperresponsiveness in asthmatic patients. We examined the effect of losartan, a specific angiotensin II type 1 (AT1) receptor antagonist, on bronchial responsiveness to inhaled methacholine in eight patients with stable asthma. Bronchial responsiveness to methacholine, assessed as the concentration of methacholine producing a 20% fall in FEV(1) (PC(20)-FEV(1)) and a 35% fall in standardized partial expiratory flow at 40% of FVC (PC(35)-PEF(40)), was measured on two occasions 2 wk apart. Losartan (50 mg once a day) or a placebo was orally administered for 1 wk before methacholine provocation test in a double-blind, randomized, crossover fashion. Although the PC(20)-FEV(1) values after placebo (2.037 [geometric standard error of the mean, GSEM = 0.210] mg/ml) and losartan (2.098 [GSEM, 0.239] mg/ml) were identical (p = 0.840), the geometric mean PC(35)-PEF(40) values significantly (p = 0.034) increased from 0.258 (GSEM, 0.156) mg/ml with placebo to 0.456 (GSEM, 0.186) mg/ml with losartan. We conclude that AT1 receptors are involved in bronchial hyperresponsiveness in asthmatic patients. This is the first report demonstrating the involvement of AT1 receptors in bronchial asthma.


Contrast material-induced nephrotoxicity and intravenous low-osmolality iodinated contrast material.
To determine whether intravenous low-osmolality iodinated contrast material is associated with post-computed tomography (CT) acute kidney injury (AKI). Institutional review board approval was obtained and patient consent waived for this HIPAA-compliant retrospective study. CT examinations performed over a 10-year period in adult inpatients with sufficient serum creatinine (SCr) data were identified. A one-to-one propensity-matched matched cohort analysis with multivariate analysis of effects was performed with post-CT AKI as the primary outcome measure (10,121 unenhanced and 10,121 intravenous contrast-enhanced CT examinations in 20,242 patients). Propensity matching was performed with respect to likelihood of patient receiving intravenous contrast material (36 tested covariates). The primary endpoint was post-CT AKI by using Acute Kidney Injury Network SCr criteria; the secondary endpoint was post-CT AKI by using traditional SCr criteria for contrast material-induced nephrotoxicity (CIN; SCr increase ≥0.5 mg/dL [44.20 μmol/L] or ≥25%). Multivariate subgroup threshold analysis was performed (SCr <1.5 [<132.60 μmol/L]; ≥1.5 to ≥2.0 mg/dL [≥132.60 to ≥176.80 μmol/L]) and adjusted for assigned propensity scores. Intravenous low-osmolality iodinated contrast material had a significant effect on the development of post-CT AKI for patients with pre-CT SCr levels of 1.6 mg/dL (141.44 μmol/L) or greater (odds ratio, 1.45; 95% confidence interval [CI]: 1.11, 1.89;P = .007). This effect strengthened as pre-CT SCr increased. Patients with stable SCr less than 1.5 mg/dL (132.60 μmol/L) were not at risk for developing CIN (P = .25, power > 95%). Both endpoints demonstrated similar results (eg, SCr ≥1.6 mg/dL [141.44 μmol/L] by using traditional CIN criteria: odds ratio, 1.64; 95% CI: 1.18, 2.28; P = .003). Post-CT AKI was prevalent in both the unenhanced and contrast-enhanced CT subgroups, and it increased with increases in pre-CT SCr. Many risk factors contributed to development of post-CT AKI, regardless of iodinated contrast material. Intravenous low-osmolality iodinated contrast material is a nephrotoxic risk factor, but not in patients with a stable SCr level less than 1.5 mg/dL. Many factors other than contrast material can affect post-CT AKI rates.


Longitudinal associations between maternal disrupted representations, maternal interactive behavior and infant attachment: a comparison between full-term and preterm dyads.
This prospective study examined whether or not a mother's representations of her infant were more often disrupted after premature childbirth. Furthermore, the study examined if different components of maternal interactive behavior mediated the relation between maternal disrupted representations and infant attachment. The participants were mothers of full-term (n = 75), moderately preterm (n = 68) and very preterm infants (n = 67). Maternal representations were assessed by the Working Model of the Child Interview at 6 months post-partum. Maternal interactive behavior was evaluated at 6 and 24 months post-partum, using the National Institute of Child Health and Human Development Early Care Research Network mother-infant observation scales. Infant attachment was observed at 24 months post-partum and was coded by the Attachment Q-Set. The results reveal that a premature childbirth does not necessarily generate disrupted maternal representations of the infant. Furthermore, maternal interactive behavior appears to be an important mechanism through which maternal representations influence the development of infant attachment in full-term and preterm infants. Early assessment of maternal representations can identify mother-infant dyads at risk, in full-term and preterm samples.


"By slapping their laps, the patient will know that you truly care for her": A qualitative study on social norms and acceptability of the mistreatment of women during childbirth in Abuja, Nigeria.
Many women experience mistreatment during childbirth in health facilities across the world. However, limited evidence exists on how social norms and attitudes of both women and providers influence mistreatment during childbirth. Contextually-specific evidence is needed to understand how normative factors affect how women are treated. This paper explores the acceptability of four scenarios of mistreatment during childbirth. Two facilities were identified in Abuja, Nigeria. Qualitative methods (in-depth interviews (IDIs) and focus group discussions (FGDs)) were used with a purposive sample of women, midwives, doctors and administrators. Participants were presented with four scenarios of mistreatment during childbirth: slapping, verbal abuse, refusing to help the woman and physical restraint. Thematic analysis was used to synthesize findings, which were interpreted within the study context and an existing typology of mistreatment during childbirth. Eighty-four IDIs and 4 FGDs are included in this analysis. Participants reported witnessing and experiencing mistreatment during childbirth, including slapping, physical restraint to a delivery bed, shouting, intimidation, and threats of physical abuse or poor health outcomes. Some women and providers considered each of the four scenarios as mistreatment. Others viewed these scenarios as appropriate and acceptable measures to gain compliance from the woman and ensure a good outcome for the baby. Women and providers blamed a woman's "disobedience" and "uncooperativeness" during labor for her experience of mistreatment. Blaming women for mistreatment parallels the intimate partner violence literature, demonstrating how traditional practices and low status of women potentiate gender inequality. These findings can be used to facilitate dialogue in Nigeria by engaging stakeholders to discuss how to challenge these norms and hold providers accountable for their actions. Until women and their families are able to freely condemn poor quality care in facilities and providers are held accountable for their actions, there will be little incentive to foster change.


Accuracy of self-reported diagnosis of hip replacement.
To examine the accuracy and validity of self-report of hip replacement for osteoarthritis (OA). We compared self-reported hip replacement and the reason for surgery in elderly, white women age > or =65 years from the Study for Osteoporotic Fractures cohort with medical records and pelvis radiographs. Women, followed for an average of 8 years at the fifth clinic visit, were asked about any hip replacements since baseline. Among 7,421 women attending the fifth clinic visit, 347 reported 387 hip replacements. Radiographs and/or medical records were available for 316 self-reported hip replacements. Participants accurately reported that hip replacements were for arthritis or fracture, with 94.5% and 97.2% of these self-reported diagnoses, respectively, confirmed from medical records. However, 1 in 8 self-reported hip replacements were not attributed by participants to either arthritis or a fracture; of these, medical records indicated that 88% were for OA. Overall, 302 self-reported hip replacements (95.6%) were confirmed as hip replacements (for agreement with self-report, kappa = 0.95 [95% confidence interval 0.92-0.96]). Under-reporting of hip replacements compared with hip replacements seen on radiographs was minimal (0.28%). Elderly women accurately reported hip replacements and whether the surgery was for arthritis or a hip fracture, although a small number of hip replacements for arthritis were not attributed to this diagnosis by the women. Because hip OA and hip fracture have very different determinants, epidemiologic studies that use self-reported hip replacement as an indicator for the presence of hip OA or as an outcome of hip OA should verify the underlying cause by asking about the reason for surgery.


Intracellular Crosslinking of Filoviral Nucleoproteins with Xintrabodies Restricts Viral Packaging.
Viruses assemble large macromolecular repeat structures that become part of the infectious particles or virions. Ribonucleocapsids (RNCs) of negative strand RNA viruses are a prime example where repetition of nucleoprotein (NP) along the genome creates a core polymeric helical scaffold that accommodates other nucleocapsid proteins including viral polymerase. The RNCs are transported through the cytosol for packaging into virions through association with viral matrix proteins at cell membranes. We hypothesized that RNC would be ideal targets for crosslinkers engineered to promote aberrant protein-protein interactions, thereby blocking their orderly transport and packaging. Previously, we had generated single-domain antibodies (sdAbs) against Filoviruses that have all targeted highly conserved C-terminal regions of NP known to be repetitively exposed along the length of the RNCs of Marburgvirus (MARV) and Ebolavirus (EBOV). Our crosslinker design consisted of dimeric sdAb expressed intracellularly, which we call Xintrabodies (X- for crosslinking). Electron microscopy of purified NP polymers incubated with purified sdAb constructs showed NP aggregation occurred in a genus-specific manner with dimeric and not monomeric sdAb. A virus-like particle (VLP) assay was used for initial evaluation where we found that dimeric sdAb inhibited NP incorporation into VP40-based VLPs whereas monomeric sdAb did not. Inhibition of NP packaging was genus specific. Confocal microscopy revealed dimeric sdAb was diffuse when expressed alone but focused on pools of NP when the two were coexpressed, while monomeric sdAb showed ambivalent partition. Infection of stable Vero cell lines expressing dimeric sdAb specific for either MARV or EBOV NP resulted in smaller plaques and reduced progeny of cognate virus relative to wild-type Vero cells. Though the impact was marginal at later time-points, the collective data suggest that viral replication can be reduced by crosslinking intracellular NP using relatively small amounts of dimeric sdAb to restrict NP packaging. The stoichiometry and ease of application of the approach would likely benefit from transitioning away from intracellular expression of crosslinking sdAb to exogenous delivery of antibody. By retuning sdAb specificity, the approach of crosslinking highly conserved regions of assembly critical proteins may well be applicable to inhibiting replication processes of a broad spectrum of viruses.


The inhibition of Staphylococcus epidermidis biofilm formation by vancomycin-modified titanium alloy and implications for the treatment of periprosthetic infection.
Peri-prosthetic infections are notoriously difficult to treat as the biomaterial implant is ideal for bacterial adhesion and biofilm formation, resulting in decreased antibiotic sensitivity. Previously, we reported that vancomycin covalently attached to a Ti alloy surface (Vanc-Ti) could prevent bacterial colonization. Herein we examine the effect of this Vanc-Ti surface on Staphylococci epidermidis, a Gram-positive organism prevalent in orthopaedic infections. By direct colony counting and fluorescent visualization of live bacteria, S. epidermidis colonization was significantly inhibited on Vanc-Ti implants. In contrast, the gram-negative organism Escherichia coli readily colonized the Vanc-Ti rod, suggesting retention of antibiotic specificity. By histochemical and SEM analysis, Vanc-Ti prevented S. epidermidis biofilm formation, even in the presence of serum. Furthermore, when challenged multiple times with S. epidermidis, Vanc-Ti rods resisted bacterial colonization. Finally, when S. epidermidis was continuously cultured in the presence of Vanc-Ti, the bacteria maintained a Vanc sensitivity equivalent to the parent strain. These findings indicate that antibiotic derivatization of implants can result in a surface that can resist bacterial colonization. This technology holds great promise for the prevention and treatment of periprosthetic infections.


Bilateral psoas abscesses and vertebral osteomyelitis in a patient with sickle cell disease.
The authors present a case of a patient with sickle-β thalassaemia (Sβ(0) Thal) who had bilateral psoas abscesses on a background of splenectomy in early childhood. The patient also turned out to have vertebral osteomyelitis and hydronephrosis on the side of the larger abscess. The only organism recovered from the patient was a Bacteroides species. The patient was managed with percutaneous drainage and intravenous antibiotics and made a full recovery.


Direct induction of interferon-gamma- and interferon-alpha/beta-inducible genes by double-stranded RNA.
Using Northern analysis, we here show that the inducibility by double-stranded (ds) RNA of interferon-alpha/beta-inducible genes is not restricted to a few genes but extends to all the genes known to be stimulated by IFN type I in fibroblasts. Moreover, we show that some genes, preferentially regulated by IFN-gamma, are also activated by dsRNA. We present a series of arguments demonstrating that the induction by dsRNA is not mediated by IFN. In addition to the fact that this induction occurs in the presence of cycloheximide and/or anti-IFN-alpha/beta antibodies in fibroblasts, we observed that, in IFN-resistant Daudi cells, ISG15 and IP-10 genes which are not induced by IFN-beta, are still inducible by dsRNA. dsRNA is also still active on 2-5 AS and ISG15 genes in cells carrying homozygous deletions of IFN alpha/beta genes. Actinomycin D experiments and nuclear in vitro elongation assays reveal that the induction by dsRNA involves, as its early step, a transcriptional event. This induction was found not to require protein synthesis, suggesting that activation of preexisting cellular factors is involved. The opposite inducibility by dsRNA of IFN-beta and 2',5'-oligoadenylate (2-5A) synthetase genes in serum-deprived fibroblasts indicates that pathways of induction by dsRNA of these two genes are not identical. Inhibition by 2-aminopurine of the induction of IFN-inducible mRNAs by IFN-beta or dsRNA suggests the participation of a protein kinase in their mechanism of action.


Enablers and barriers to referral and delivery of multidisciplinary prehabilitation in the autologous stem cell transplant population: a theory-based interview study.
Health care professionals (HCP) play a vital role in effectiveness of prehabilitation programs, but information is limited about what assists HCP deliver an effective service. This study evaluated HCP perceptions of enablers and barriers to two behaviours: referral for, and delivery of, multidisciplinary prehabilitation prior to autologous stem cell transplant. Based on the Theoretical Domains Framework (TDF) of behaviour change, we conducted semi-structured interviews, purposively sampling 14 participants (from various healthcare disciplines) at a tertiary cancer centre. Discipline-specific topic guides were created based on the TDF and the behaviours appropriate to each discipline. Interviews were audio-recorded, transcribed verbatim, anonymised, content analysed (grouping, then labelling, thematically similar responses), and classified into theoretical domains. Structured decision rules were used to classify themes as high, medium, or low priority. Fifty enablers and 31 barriers were identified; of these 26 enablers and 16 barriers classified as high priority. Four domains had the most frequent high-priority enablers: Social professional role and identity (e.g. multidisciplinary teamwork); Beliefs about consequences (e.g. patient benefit); Memory, attention, and decision processes (e.g. refer as early as possible); and Environmental context and resources (e.g. electronic medical records are beneficial). High-priority barriers were most frequent in four domains: Memory, attention, and decision processes (e.g. conflicting views about who should be referred); Environmental context and resources (e.g. lack of time); Social influences (e.g. families); and Emotions (e.g. patient distress). Participants reported more enablers than barriers. Findings can support delivery of prehabilitation programs in hospital settings where uptake remains low.


Energy expended by adults with and without intellectual disabilities during activities of daily living.
The aims of this study were to (1) determine the energy expenditure of adults with and without intellectual disabilities during common activities of daily living (ADL), (2) use these values to evaluate the accuracy of equivalent activity values reported in the Compendium of Physical Activities (CPA), and (3) identify ADL that may confer a health benefit for adults with intellectual disabilities when undertaken regularly. Energy expenditure was measured for adults with intellectual disabilities (N=31; 29.0±8.6 yr) and adults without intellectual disabilities (N=15; 30.4±9.6 yr) while undertaking each of seven ADL: sitting quietly (SitQ); sitting watching television (SitTV); sitting and standing while completing an assembly task (SitAT, StaAT); and walking at a slow (WalkS, 3.0 km h(-1)), quick (WalkQ, 6.0 km h(-1)) and fast (WalkF, 9.0 km h(-1)) speed, under laboratory conditions. Adults with intellectual disabilities were found to expend significantly more energy than adults without intellectual disabilities for SitQ, WalkS, WalkQ and WalkF (p<0.05). Energy expended by both populations was significantly more than CPA values for SitQ, SitTV, SitAT, WalkS, and WalkQ (p<0.02) and significantly less for WalkF (p<0.01). Walking at the speed of 3.0 km h(-1) (50 m min(-1)) was found to be sufficient to achieve moderate-intensity energy expenditure, surpassing the intensity threshold for conferring a health benefit. Energy expenditure inaccuracies of the CPA have important consequences when estimating prevalence of engagement in health enhancing physical activities among population sub-groups. The identification of slow walking as a moderate-intensity physical activity offers significant health promotion opportunities for adults with intellectual disabilities through active transport and leisure.


Refractoriness to migration inhibitory factor of macrophages of LPS nonresponder mouse strains.
The responsiveness to macrophage migration inhibitory factor (MIF) of peritoneal exudate cells (PEC) from the LPS unresponsive C3H/HeJ and C57BL/10ScCR mice was assessed by the indirect agarose microdroplet macrophage migration inhibition assay. No migration inhibition with PEC from C3H/HeJ nor C57BL/10ScCR mice was detected, whereas PEC from both C3H/HeN and C57BL/10Sn mice were significantly inhibited by even a 1/32 dilution of MIF-containing supernatants. Responsiveness to MIF of C3H/HeJ PEC could, however, be induced. In vivo inoculations of Mycobacterium bovis, strain BCG, 7 days before in vitro assay rendered C3H/HeJ PEC responsive to MIF. The lack of responsiveness to MIF by C3H/HeJ PEC appeared related to some form of suppression, since a mixture of PEC from C3H/HeN mice with 10 to 15% PEC from C3H/HeJ mice resulted in undetectable migration inhibition at any MIF dilution. In contrast to the usual lack of responsiveness of their macrophage to MIF, C3H/HeJ mice were able to produce MIK in response to PPD as well as their counterpart C3H/HeN mice after BCG sensitization. These results demonstrate that macrophages from C3H/HeJ and C57BL/10ScCR mice are unable to be inhibited in their in vitro migration of MIF (possibly being directly or indirectly influenced by a suppressor cell), whereas lymphoid cells from at least one of these strains, the C3H/HeJ mice, can produce MIF in response to antigenic stimulation.


Stat3 mediates LIF-induced protection of astrocytes against toxic ROS by upregulating the UPC2 mRNA pool.
Reactive oxygen species (ROS) have been implicated in various types of CNS damage, including stroke. We used a cultured astrocyte model to explore mechanisms of survival of CNS cells following ROS damage. We found that pretreatment with leukemia inhibitory factor (LIF) preserves astrocytes exposed to toxic levels of t-BHP by inhibiting an increase in intracellular ROS following t-BHP treatment. Astrocytes lacking functional Stat3 did not benefit from the pro-survival or antioxidant effects of LIF. Inhibition of mitochondrial uncoupling protein 2 (UCP2) using a chemical inhibitor or siRNA abrogates the prosurvival effects of LIF, indicating a critical role for UCP2 in modulation of mitochondrial ROS production in survival following ROS exposure. LIF treatment of astrocytes results in increased UCP2 mRNA that is accompanied by an increase in Stat3 binding to the UCP2 promoter region. Although treatment with LIF alone did not increase UCP2 protein, a combination of LIF treatment and ROS stress led to increased UCP2 protein levels. We conclude that LIF protects astrocytes from ROS-induced death by increasing UCP2 mRNA, allowing cells to respond to ROS stress by rapidly producing UCP2 protein that ultimately decreases endogenous mitochondrial ROS production.


Real-Time Assessment of the Size Changes of Individual Sub-Visible Protein Particles under Buffer Variations: A Microfluidic Study.
Protein particles in biological drugs can significantly impact drug efficacy and carry the risk of adverse effects. Despite advancements, the understanding and control of particle formation in biopharmaceutical manufacturing remain incomplete. Therefore, further investigation into protein particles is warranted, especially considering that novel formats of biological drugs may be more susceptible to aggregation and particle formation than conventional monoclonal antibodies. In this study, we introduce a microfluidic approach for the real-time analysis of individual sub-visible protein particles during buffer exchange. We find that the modulation of intermolecular forces, achieved by changing the buffer pH or urea concentration, leads to the reversible swelling and shrinkage of particles by up to 50%, which is a consequence of altered intermolecular distances. Additionally, we identify a discrepancy in the biophysical behavior of protein particles compared to monomeric protein. This finding highlights the limited predictive power of commonly applied biophysical characterization methods for particle formation in early formulation development. Moreover, the observed particle swelling may be associated with manufacturing deviations, such as filter clogging. These results highlight the importance of studying individual particles to gain a comprehensive insight into particle behavior and the impact of formulation variations in the biopharmaceutical industry.


Generation of glucose-responsive, insulin-producing cells from human umbilical cord blood-derived mesenchymal stem cells.
We sought to assess the potential of human cord blood-derived mesenchymal stem cells (CB-MSCs) to derive insulin-producing, glucose-responsive cells. We show here that differentiation protocols based on stepwise culture conditions initially described for human embryonic stem cells (hESCs) lead to differentiation of cord blood-derived precursors towards a pancreatic endocrine phenotype, as assessed by marker expression and in vitro glucose-regulated insulin secretion. Transplantation of these cells in immune-deficient animals shows human C-peptide production in response to a glucose challenge. These data suggest that human cord blood may be a promising source for regenerative medicine approaches for the treatment of diabetes mellitus.


Excellent long-term results of the Müller acetabular reinforcement ring in primary cup revision.
Background and purpose - The original Müller acetabular reinforcement ring (ARR) was developed to be used for acetabular revisions with small cavitary and/or segmental defects or poor acetabular bone quality. Long-term data for this device are scarce. We therefore investigated long-term survival and radiographic outcome for revision total hip arthroplasty using the ARR. Patients and methods - Between October 1984 and December 2005, 259 primary acetabular revisions using an ARR were performed in 245 patients (259 hips). The mean follow-up time was 10 (0-27) years; 8 hips were lost to follow-up. The cumulative incidence for revision was calculated using a competing risk model. Radiographic assessment was performed for 90 hips with minimum 10 years' follow-up. It included evaluation of osteolysis, migration and loosening. Results - 16 ARRs were re-revised: 8 for aseptic loosening, 6 for infection, 1 for suspected infection, and 1 due to malpositioning of the cup. The cumulative re-revision rate for aseptic loosening of the ARR at 20 years was 3.7% (95% CI 1.7-6.8%). Assuming all patients lost to follow-up were revised for aseptic loosening, the re-revision rate at 20 years was 6.9% (95% CI 4.1-11%). The overall re-revision rate of the ARR for any reason at 20 years was 7.0% (95% CI 4.1-11%). 21 (23%) of the 90 radiographically examined ARR had radiographic changes: 12 showed isolated signs of osteolysis but were not loose; 9 were determined loose on follow-up, of which 5 were revised. Interpretation - Our data suggest that the long-term survival and radiographic results of the ARR in primary acetabular revision are excellent.


Dietary Intake and Health Status of Elderly Patients With Type 2 Diabetes Mellitus: Cross-sectional Study Using a Mobile App in Primary Care.
Healthy dietary intake reduces the risk of complications of diabetes mellitus. Using assessment methods helps to understand these circumstances, and an electronic application may optimize this practice. In this study, we aimed to (1) assess the dietary intake and health status of elderly patients with type 2 diabetes mellitus (T2DM) in primary care, (2) use a mobile app as a tool for data collection and analysis in the context of primary care, and (3) verify the perceptions of multidisciplinary health professionals regarding app use. First, we developed a mobile app comprised of the questions of the Food and Nutrition Surveillance System (SISVAN) of Brazil, which includes a food frequency questionnaire of food categories with a recall of the previous 7 days. Thereafter, we used the app to collect data on the health status and dietary intake of 154 participants, aged 60-96 years, diagnosed with T2DM, and under treatment in primary care centers in the northern region of Rio Grande do Sul, Brazil. We also collected participants' demographic, anthropometric, biochemical, and lifestyle variables. The associations between dietary intake and other variables were tested using chi-square tests with a 5% significance level. Regarding the app, we assessed usability and acceptance with 20 health professionals. Between August 2018 and December 2018, participants had an intake in line with recommended guidelines for raw salads (57.1%), fruits (76.6%), milk products (68.2%), fried foods (72.7%), savory biscuits (60.4%), cookies or sweets (72.1%), and sugary drinks (92.9%) Meanwhile, the consumption of beans (59.7%), pulses and cooked vegetables (73.4%), and processed meat products (59.7%) was not in line with the guidelines. There were statistically significant differences in meeting the recommended guidelines among participants of different genders (P=.006 and P=.035 for the intake of fried foods and sugary drinks, respectively), place of residence (P=.034 for the intake of cookies and sweets), family history of diabetes (P<.001 for the intake of beans), physical activity engagement (P=.003 for the intake fresh fruits), history of smoking (P=.001 for the intake of raw salads), and presence of coronary disease (P=.050 for the intake of pulses and cooked vegetables). The assessment of usability resulted in a mean score of 71.75 points. Similarly, the assessment of the 15 acceptance questions revealed high scores, and the qualitative questions revealed positive perceptions. We identified that most participants complied with recommended intake guidelines for 7 of 10 categories in the SISVAN guidelines. However, most participants were overweight and had nutritional and clinical disorders, which justifies further investigations in this population. The app was well-rated by health professionals and considered a useful and promising tool for collecting and analyzing data in primary care settings.


8-Diethylamino-octyl-3,4,5-trimethoxybenzoate, a calcium store blocker, increases calcium influx, inhibits alpha-1 adrenergic receptor calcium mobilization, and alters iodide transport in FRTL-5 rat thyroid cells.
8-Diethylamino-octyl-3,4,5-trimethoxybenzoate (TMB-8) is known to inhibit mobilization of calcium from intracellular stores but, more recently, other cellular effects have been described. In the present study, the effects of TMB-8 on cytosolic free calcium [Ca2+]i levels in FRTL-5 rat thyroid cells were determined using the fluorescent dye, Indo-1. TMB-8 increased [Ca2+]i in a dose-dependent manner, with a maximum rise from 120 +/- 7 nM to 229 +/- 16 nM (90 +/- 5% increase) at 5 x 10(-4) M. This effect was considerably reduced in Ca2+ free buffer, demonstrating a dependency upon extracellular calcium influx but not upon membrane potential and which did not involve the Na+/Ca2+ exchanger. In Ca2+ free buffer TMB-8, at a dose which did not affect [Ca2+]i, completely prevented norepinephrine (10(-5) M) from mobilizing intracellular Ca2+. To determine whether TMB-8 affected differentiated functions, iodide uptake and efflux studies were performed with 125I. TMB-8 (10(-4) M) inhibited iodide uptake by approximately 40% without affecting efflux. At 10(-3) M TMB-8, efflux was also enhanced. These studies demonstrate that TMB-8 has at least two effects on [Ca2+]i, promoting calcium influx and preventing alpha-1 adrenergic mobilization from intracellular stores. TMB-8 also has multiple effects on 125I transport, both inhibiting influx and increasing efflux. The results emphasize the importance of characterizing the behavior of this compound in any cell system before using it as a biological probe.


Intrinsic sensitivity of Kir1.1 (ROMK) to glibenclamide in the absence of SUR2B. Implications for the identity of the renal ATP-regulated secretory K+ channel.
The precise molecular identity of the renal ATP-regulated secretory K+ channel is still a matter of some controversy. The inwardly rectifying K+ channel, Kir1.1 (ROMK) appears to form the pore of the channel, and mutations in Kir1.1 are responsible for Bartter syndrome. The native channel is sensitive to inhibition by the sulfonylurea glibenclamide, and it has been proposed that an accessory protein is required to confer glibenclamide sensitivity to Kir1.1. Several recent studies have suggested that the native channel is composed of the splice variant Kir1.1b (ROMK2) and the sulfonylurea receptor isoform SUR2B and that there is a direct physical interaction between these subunits. In this study, we have monitored the interaction between Kir1.1b and SUR2B. We find that SUR2B reaches the plasma membrane when coexpressed with Kir6.1 or Kir6.2 but not when coexpressed with Kir1.1b. Furthermore, we find that Kir1.1b exhibits an intrinsic sensitivity to inhibition by glibenclamide with an affinity similar to the native channel. These results demonstrate that SUR2B does not traffic to the membrane in the presence of Kir1.1b and is not required to confer glibenclamide sensitivity to Kir1.1b. This has important implications for the presumed structure of the renal ATP-regulated secretory K+ channel.


Harmful postures and musculoskeletal symptoms among sanitation workers of a fish processing factory in ghana: a preliminary investigation.
This study investigated musculoskeletal symptoms among sanitation workers of a fish-processing factory. The methods used included administration of a questionnaire, walk through observation, interview, task analysis and future workshop. All 27 male participants answered and submitted their questionnaires. Of the 11 operations identified, all except one was considered safe. Bent back, bent legs, and heavy manual handling were observed to impose intolerable health risk on participants. This corresponds with questionnaire results in which musculoskeletal symptoms were mostly prevalent in the neck, the shoulder, the low back, the wrists/hands and the upper back regions. Poor psychosocial complaints were also made on the job. There was no significant correlation (p < .05) between musculoskeletal symptoms and age, working hours and length of service. Neither was any significant correlation observed (p < .05) between psychosocial work factors and musculoskeletal symptoms. Recommendations such as task redesign to eliminate high-risk elements in operations, workplace changes and worker training were suggested.


Michael addition reactions between chiral Ni(II) complex of glycine and 3-(trans-enoyl)oxazolidin-2-ones. A case of electron donor-acceptor attractive interaction-controlled face diastereoselectivity.
This study has demonstrated that the readily available and inexpensive 3-(trans-3'-alkyl/arylpropenoyl)oxazolidin-2-ones, featuring high electrophilicity and conformational homogeneity, are synthetically superior Michael acceptors over the conventionally used alkyl enoylates, allowing for a remarkable improvement in reactivity and, in most cases, diastereoselectivity of the addition reactions with a Ni(II) complex of the chiral Schiff base of glycine with (S)-o-[N-(N-benzylprolyl)amino]benzophenone. Kinetically controlled diastereoselectivity in the corresponding Michael addition reactions between the Ni(II) complex of glycine and the oxazolidin-2-ones was systematically studied as a function of steric, electronic, and position effects of the substituents on the starting Michael acceptor. In both aliphatic and aromatic series the simple diastereoselectivity was found to be virtually complete, affording the products via the corresponding TSs with the approach geometry like. The face diastereoselectivity of the reactions between the Ni(II) complex of glycine and the 3-(trans-3'-alkylpropenoyl)oxazolidin-2-ones was found to depend exclusively on the steric bulk of the alkyl group on the starting Michael acceptor. In contrast, the face diastereoselectivity in the reactions of aromatic oxazolidin-2-ones with the Ni(II) complex of glycine was shown to be controlled predominantly by the electronic properties of the aryl ring. In particular, the additions of the Ni(II) complex of glycine with 3-(trans-3'-arylpropenoyl)oxazolidin-2-ones, bearing electron-withdrawing substituents on the phenyl ring, afforded the (2S,3R)-configured products with synthetically useful diastereoselectivity and in quantitative chemical yields, thus allowing for an efficient access to the sterically constrained beta-aryl-substituted pyroglutamic and glutamic acids.


Sink- and vascular-associated sucrose synthase functions are encoded by different gene classes in potato.
Two differentially regulated classes of sucrose synthase genes, Sus3 and Sus4, were identified in potato. They cannot be classified as Sus1 and Sus2 types based on sequence homology and appear to have evolved after the divergence of the major families of dicotyledonous plants but before the divergence of tomato and potato. The potato sucrose synthase clones Sus3-65 and Sus4-16 share an 87% nucleotide identity in the coding regions, and both are interrupted by 13 introns, including a long leader intron. Potato Sus3 genes are expressed at the highest levels in stems and roots and appear to provide the vascular function of sucrose synthase. In contrast, Sus4 genes are expressed primarily in the storage and vascular tissue of tubers and appear to facilitate sink function. The genes are differentially regulated in root tips, with Sus3 expressed at high levels in the cell division zone and Sus4 expressed at high levels in the meristem and cap.


Biomechanical Modeling of Cesarean Section Scars and Scar Defects.
Uterine rupture is an intrinsically biomechanical process associated with high maternal and fetal mortality. A previous Cesarean section (C-section) is the main risk factor for uterine rupture in a subsequent pregnancy due to tissue failure at the scar region. Finite element modeling of the uterus and scar tissue presents a promising method to further understand and predict uterine ruptures. Using patient dimensions of an at-term uterus, a C-section scar was modeled with an applied intrauterine pressure to study how scars affect uterine stress. The scar positioning and uterine thickness were varied, and a thickness defect was incorporated into the scar region. The modeled stress distributions confirmed clinical observations as the increased regions of stress due to scar positioning, thinning of the uterine walls, and the presence of a defect are consistent with clinical observations of features that increase the risk of uterine rupture.


Bacopasides I and II Act in Synergy to Inhibit the Growth, Migration and Invasion of Breast Cancer Cell Lines.
Bacopaside (bac) I and II are triterpene saponins purified from the medicinal herb Bacopa monnieri. Previously, we showed that bac II reduced endothelial cell migration and tube formation and induced apoptosis in colorectal cancer cell lines. The aim of the current study was to examine the effects of treatment with combined doses of bac I and bac II using four cell lines representative of the breast cancer subtypes: triple negative (MDA-MB-231), estrogen receptor positive (T47D and MCF7) and human epidermal growth factor receptor 2 (HER2) positive (BT-474). Drug treatment outcome measures included cell viability, proliferation, cell cycle, apoptosis, migration, and invasion assays. Relationships were analysed by one- and two-way analysis of variance with Bonferroni post-hoc analysis. Combined doses of bac I and bac II, each below their half maximal inhibitory concentration (IC50), were synergistic and reduced the viability and proliferation of the four breast cancer cell lines. Cell loss occurred at the highest dose combinations and was associated with G2/M arrest and apoptosis. Migration in the scratch wound assay was significantly reduced at apoptosis-inducing combinations, but also at non-cytotoxic combinations, for MDA-MB-231 and T47D (p < 0.0001) and BT-474 (p = 0.0003). Non-cytotoxic combinations also significantly reduced spheroid invasion of MDA-MB-231 cells by up to 97% (p < 0.0001). Combining bac I and II below their IC50 reduced the viability, proliferation, and migration and invasiveness of breast cancer cell lines, suggesting synergy between bac I and II.


Characterizing the Exercise Behaviour, Preferences, Barriers, and Facilitators of Cancer Survivors in a Rural Canadian Community: A Cross-Sectional Survey.
Barriers, facilitators, and motivators to exercise for cancer survivors living in urban settings are well described in the literature. However, there is a lack of comparable information for cancer survivors living in rural communities. We describe the exercise behaviours, barriers, facilitators, and motivators to exercise participation of cancer survivors living in a rural Canadian community. Adult cancer survivors with a primary address in a rural region of Ontario, Canada, who had visited a community hospital in the previous five years were mailed a cross-sectional survey assessing current exercise volume (minutes of moderate-to-vigorous aerobic and resistance exercise), as well as exercise preferences, barriers, and facilitators. Seventy-two survivors (mean age 65 years) completed the survey (16% response rate). A majority of respondents were diagnosed with breast cancer (49%) in the last 5 years (61%). Aerobic- and resistance-training guidelines for cancer survivors were met by 38% and 10% of respondents, respectively. Physical side effects were the most common barrier to exercise during treatment (65%) and post-treatment (35%). Being unaware of available exercise programs, time for exercise, distance to exercise services, and cost were commonly reported barriers during and post-treatment (reported by 10-22%). Respondents reported needing information from a qualified exercise professional (46%), access to a gym (33%) and exercise equipment (26%), and social support (25%) to facilitate exercise participation. Consistent with urban-based cancer survivors, most rural survivors surveyed in this study were not meeting the physical-activity guidelines and reported numerous exercise barriers. These findings can serve as a resource for this and similar rural communities when developing community-based exercise-support services for cancer survivors.


Revealing Latent Value of Clinically Acquired CTs of Traumatic Brain Injury Through Multi-Atlas Segmentation in a Retrospective Study of 1,003 with External Cross-Validation.
Medical imaging plays a key role in guiding treatment of traumatic brain injury (TBI) and for diagnosing intracranial hemorrhage; most commonly rapid computed tomography (CT) imaging is performed. Outcomes for patients with TBI are variable and difficult to predict upon hospital admission. Quantitative outcome scales (e.g., the Marshall classification) have been proposed to grade TBI severity on CT, but such measures have had relatively low value in staging patients by prognosis. Herein, we examine a cohort of 1,003 subjects admitted for TBI and imaged clinically to identify potential prognostic metrics using a "big data" paradigm. For all patients, a brain scan was segmented with multi-atlas labeling, and intensity/volume/texture features were computed in a localized manner. In a 10-fold cross-validation approach, the explanatory value of the image-derived features is assessed for length of hospital stay (days), discharge disposition (five point scale from death to return home), and the Rancho Los Amigos functional outcome score (Rancho Score). Image-derived features increased the predictive R2 to 0.38 (from 0.18) for length of stay, to 0.51 (from 0.4) for discharge disposition, and to 0.31 (from 0.16) for Rancho Score (over models consisting only of non-imaging admission metrics, but including positive/negative radiological CT findings). This study demonstrates that high volume retrospective analysis of clinical imaging data can reveal imaging signatures with prognostic value. These targets are suited for follow-up validation and represent targets for future feature selection efforts. Moreover, the increase in prognostic value would improve staging for intervention assessment and provide more reliable guidance for patients.


Qualitative Hormonal Profiling of the Lacrimal Drainage System: Potential Insights into the Etiopathogenesis of Primary Acquired Nasolacrimal Duct Obstruction.
To investigate the presence and distribution patterns of hormone receptors in the lacrimal drainage system in normal and diseased states. The study was performed on cadaveric and clinical samples of the lacrimal drainage system. Immunohistochemical labeling was performed for assessing the presence and distribution of receptors of estrogen alpha, estrogen beta, aromatase (CYP19), testosterone, progesterone, oxytocin, prolactin, and somatostatins 1 to 5 (SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5). The immunohistochemistry stains were scored as positive or negative, and the distribution patterns in the canaliculus, lacrimal sac, and nasolacrimal duct were assessed. There was a strong expression of estrogen alpha, estrogen beta, and oxytocin, but this showed variations in distribution patterns. Testosterone and progesterone expressions were more localized to the basement membrane of the epithelium in postmenopausal females. While SSTR2 and SSTR4 expressed only on the villus surfaces of superficial epithelial cells; oxytocin, aromatase, and prolactin additionally expressed in the subepithelial lamina propria and submucosal glands. Diseased samples from primary acquired nasolacrimal duct obstruction showed dramatic reduction or absence of the receptor expression patterns of all the hormones with the exception of epithelial immunoreactivity with prolactin. This study provides a proof of principle for the presence of multiple hormone receptors and hypothesizes their possible links in the etiopathogenesis of primary acquired nasolacrimal duct obstructions.


Single-dose dexamethasone induces whole-body insulin resistance and alters both cardiac fatty acid and carbohydrate metabolism.
Glucocorticoids impair insulin sensitivity. Because insulin resistance is closely linked to increased incidence of cardiovascular diseases and given that metabolic abnormalities have been linked to initiation of heart failure, we examined the acute effects of dexamethasone (DEX) on rat cardiac metabolism. Although injection of DEX for 4 h was not associated with hyperinsulinemia, the euglycemic-hyperinsulinemic clamp showed a decrease in glucose infusion rate. Rates of cardiac glycolysis were unaffected, whereas the rate of glucose oxidation following DEX was significantly decreased and could be associated with augmented expression of PDK4 mRNA and protein. Myocardial glycogen content in DEX hearts increased compared with control. Similar to hypoinsulinemia induced by streptozotocin (STZ), hearts from insulin-resistant DEX animals also demonstrated enlargement of the coronary lipoprotein lipase (LPL) pool. However, unlike STZ, DEX hearts showed greater basal release of LPL and were able to maintain their high heparin-releasable LPL in vitro. This effect could be explained by the enhanced LPL mRNA expression following DEX. Our data provide evidence that in a setting of insulin resistance, an increase in LPL could facilitate increased delivery of fatty acid to the heart, leading to excessive triglyceride storage. It has not been determined whether these acute effects of DEX on cardiac metabolism can be translated into increased cardiovascular risk.


[Study of eugenol distribution in the body of warm-blooded animals after lethal poisoning].
This study was designed to investigate the distribution of eugenol (2-methoxy-4-allylhydroxybenzene) in different tissues of homoiothermal animals (rats) after the intragastric administration of this toxic agents. It was shown that 2-methoxy-4-allylhydroxybenzene was present in large quantities in blood and splanchnic organs of the poisoned animals. The largest amounts of eugenol were found in the stomach and small intestine, their contents, spleen, and heart.


Perceptions of Seasonal Influenza Vaccine Among U.S. Army Civilians and Dependents in the Kaiserslautern Military Community: A Mixed-Methods Survey.
Influenza is a globally occurring viral respiratory infection that can lead to hospitalizations and death. An influenza outbreak can interfere with combat readiness in a military setting, as the infection can incapacitate soldiers. Vaccination remains the most effective tool to prevent and mitigate seasonal influenza. Although influenza vaccinations for U.S. Army soldiers can be monitored through military health systems, those systems cannot capture DoD civilians and Army dependents who may not use military health services. This study aims to gauge flu vaccine uptake and perceptions in U.S. Army civilians and dependents. An online survey was e-mailed to civilian and dependent enrollees of Landstuhl Regional Medical Center. The survey contained 24 questions pertaining to demographics, vaccine history, history of the flu, and beliefs toward vaccines. Chi-square tests, t-tests, and logistic regressions were performed to investigate the association between demographic, behavior, and belief factors with vaccine uptake. Free-text answers were coded and categorized by themes. Over 70% of respondents were vaccinated for the flu. There were differences between vaccinated and unvaccinated respondents regarding their perceptions of barriers to vaccination, benefits of the flu vaccine, severity of flu symptoms, and personal risk of getting ill with the flu. After controlling for confounders, flu vaccination in the previous season and healthcare worker status were associated with increased vaccine uptake, while perceived barriers to influenza vaccination were associated with decreased vaccine uptake. Flu vaccine uptake may be increased by increasing access to vaccination, promoting vaccination and addressing concerns at the provider level, and engaging positively framed public messaging. Increasing flu vaccine uptake is of particular importance as the flu season approaches during the COVID-19 (Coronavirus disease 2019) pandemic.


Relationship between caffeine effects and calcium in canine cardiac Purkinje fibers.
The actions of caffeine (1-9 mM) on electrical and mechanical events were studied under conditions known to change the intracellular calcium in canine cardiac Purkinje fibers perfused in vitro. It was found that caffeine in a dose-dependent manner 1) shifts the early repolarization to more positive values, 2) shifts the plateau to more negative values, 3) prolongs the terminal phase 3 (induction of a "tail"), 4) transiently increases and then decreases the force of contraction with respect to control values, 5) causes a smaller tail in the presence of agents (local anesthetics, tetrodotoxin, high potassium) that have been shown to diminish the force of contraction, presumably by decreasing cellular calcium, 6) causes the oscillatory potentials in high calcium to peak sooner after the action potential and eventually to disappear as the tail develops, 7) induces a tail at lower concentrations when cellular calcium is enhanced by lowering the external sodium concentration or in the presence of veratridine, and 8) fails to induce a marked tail in the presence of metabolic inhibitors. It is concluded that in Purkinje fibers caffeine induces a marked delay in the final repolarization through a process modulated by calcium. This process may be related to an electrogenic sodium-calcium exchange.


Relative Abundance of [Formula: see text] Topological Order in Exfoliable Two-Dimensional Insulators.
Quantum spin Hall insulators make up a class of two-dimensional materials with a finite electronic band gap in the bulk and gapless helical edge states. In the presence of time-reversal symmetry, [Formula: see text] topological order distinguishes the topological phase from the ordinary insulating one. Some of the phenomena that can be hosted in these materials, from one-dimensional low-dissipation electronic transport to spin filtering, could be promising for many technological applications in the fields of electronics, spintronics, and topological quantum computing. Nevertheless, the rarity of two-dimensional materials that can exhibit nontrivial [Formula: see text] topological order at room temperature hinders development. Here, we screen a comprehensive database we recently identified of 1825 monolayers that can be exfoliated from experimentally known compounds to search for novel quantum spin Hall insulators. Using density-functional and many-body perturbation theory simulations, we identify 13 monolayers that are candidates for quantum spin Hall insulators including high-performing materials such as AsCuLi2 and (platinum) jacutingaite (Pt2HgSe3). We also identify monolayer Pd2HgSe3 (palladium jacutingaite) as a novel Kane-Mele quantum spin Hall insulator and compare it with platinum jacutingaite. A handful of promising materials are mechanically stable and exhibit [Formula: see text] topological order, either unperturbed or driven by small amounts of strain. Such screening highlights a relative abundance of [Formula: see text] topological order of around 1% and provides an optimal set of candidates for experimental efforts.


Correlations of inheritance and expression between a tumor gene and the cellular homolog of the Rous sarcoma virus-transforming gene in Xiphophorus.
Neoplastic transformation of pigment cells in the teleostean fish Xiphophorus is mediated by a cellular oncogene (Tu). Normally. Tu is suppressed by multiple regulating genes (R). Depending on impairment and loss of R genes, Tu is permitted to express itself phenotypically. In the pigment cell system, different degrees of Tu expression lead to small spots of transformed cells or to benign or malignant melanoma. All neoplastic and nonneoplastic cells of all Xiphophorus genotypes tested thus far appear to contain the cellular homolog (c-src) of the avian sarcoma virus oncogene (v-src). The evidence for this stems from the detectability of a Mr 60,000 phosphoprotein with associated kinase activity (pp60c-src) that reacts with antiserum against viral pp60src. We followed the inheritance of Tu (identified by spots and melanomas) compared to the expression of c-src identified by the pp60c-src-associated protein kinase). By quantitative determination of kinase activity in immunoprecipitated pp60c-src from fish showing different degrees of Tu expression, we have investigated whether there exists a correlation between the expression of c-src and Tu. In genotypes with the same genetic background, cells from Tu-containing fish express more pp60c-src than do cells from fish lacking Tu. In genotypes carrying a Tu gene and which show differences in the amount of gene expression due to a different extent of repression by regulating genes, analysis of kinase activity revealed that an increase of Tu expression is correlated with an elevated level of pp60c-src-associated kinase activity. Our findings may indicate that c-src activity in Xiphophorus is modulated by the Tu gene product or that Tu and c-src are regulated coordinately.


Update on active specific immunotherapy with melanoma vaccines.
Although a randomized clinical trial has yet to show a statistically significant improvement in the survival of patients receiving vaccine therapy for malignant melanoma, several studies have shown enhanced survival of patients developing an immune response to a melanoma vaccine. The knowledge and techniques of modern molecular biology and immunology suggest multiple strategies to augment this response. The challenge of immunotherapy research is to determine which combination of approaches leads to a favorable clinical response and how to monitor that response effectively. This review identifies components of a successful vaccine, discusses new ways to modulate and stimulate the immune system, and summarizes some of the more interesting clinical trials of melanoma vaccine immunotherapy.


In vitro canal and isthmus debris removal of the self-adjusting file, K3, and WaveOne files in the mesial root of human mandibular molars.
The purpose of this study was to compare the effectiveness of debris removal between the Self-Adjusting File (SAF), WaveOne, and K3 file systems in the mesial roots of mandibular molars. In addition, the SAF was tested as a potential adjunct after instrumentation with other systems. The mesial roots of 30 extracted mandibular molars were mounted in resin by using the K-Kube, sectioned at 2 and 4 mm from working length, and randomly placed into 3 groups: K3 group, sequential preparation with K3 files to an apical size of 35/.04; WaveOne group, preparation with WaveOne primary file; and SAF group, preparation with SAF. Images were taken before instrumentation, after instrumentation, after final irrigation, and after SAF adjunct irrigation. A cleanliness percentage was calculated by using interactive software. Comparisons between groups were analyzed with repeated-measures analysis of variance and post hoc tests (P < .05). There was no significant difference in canal cleanliness among the groups, but the WaveOne was significantly worse for isthmus cleanliness. Use of the SAF as an adjunct only significantly improved canal cleanliness in the K3 group at the 2-mm level by an average of 1.7%. There was no difference in canal cleanliness between the 3 file systems; however, the SAF and K3 files performed significantly better than the WaveOne with respect to isthmus cleanliness. When used as a final irrigation adjunct device after instrumentation, the SAF provided a significant improvement only in a subset of the K3 group.


[Does the transition to clinical training change students' perception of career choice, physician's character and preclinical studies?].
In Israel, the transition to clinical training in hospitals is the first direct encounter of the medical student with the reality of the profession. This is a significant socialization step for his upcoming professional decisions. This study aimed to identify how this encounter influences students' perceptions of career choice, physician's character and preclinical studies. Fourth year Israeli medical students at the Tel Aviv University voluntarily completed a questionnaire before and after their first clinical clerkship. The questionnaire was comprised of 30 5-point Likert scale statements and 3 multiple choice questions with the possibility to add remarks. The random response rate was 90% (81/90) before the clerkship and 82% (90/110) at its end. Results indicate that the students are satisfied with their medical studies at both junctures. However, after the clerkship, 23% of the students consider alternatives to clinical medicine compared with only 6% before, and 16% would rethink studying medicine. Physicians are perceived as professional, compassionate, respectful to colleagues and actively participating in students' education. Physicians' levels of workload and bitterness are evaluated as high and moderate, respectively, while their levels of reward and satisfaction with medicine are evaluated as low and moderate, respectively. Their evaluation of the contribution of preclinical studies as preparation for clinical studies had not changed after the clerkship and was moderate, and earlier exposure to patients and clinical relevancy of the learned subjects were preferred. The students enter the medical world highly satisfied, and this feeling shall be maintained until the stage of being independent physicians and choosing their specialties. The picture that evolved, in which a high proportion of the students consider alternatives to clinical medicine, is disappointing. Educators should be aware of their role model function not only in knowledge and skills, but also in behavior and communication with patients. The students pointed to necessary changes in the medical curriculum to make basic sciences more relevant to clinical medicine. A broader study at different stages of studies in the rest of the medical faculties in Israel may be needed.


Impact of hydrophobic chain composition on amphiphilic macromolecule antiatherogenic bioactivity.
Amphiphilic macromolecules (AMs) composed of sugar backbones modified with branched aliphatic chains and a poly(ethylene glycol) (PEG) tail can inhibit macrophage uptake of oxidized low-density lipoproteins (oxLDL), a major event underlying atherosclerosis development. Previous studies indicate that AM hydrophobic domains influence this bioactivity through interacting with macrophage scavenger receptors, which can contain basic and/or hydrophobic residues within their binding pockets. In this study, we compare two classes of AMs to investigate their ability to promote athero-protective potency via hydrogen-bonding or hydrophobic interactions with scavenger receptors. A series of ether-AMs, containing methoxy-terminated aliphatic arms capable of hydrogen-bonding, was synthesized. Compared to analogous AMs containing no ether moieties (alkyl-AMs), ether-AMs showed improved cytotoxicity profiles. Increasing AM hydrophobicity via incorporation of longer and/or alkyl-terminated hydrophobic chains yielded macromolecules with enhanced oxLDL uptake inhibition. These findings indicate that hydrophobic interactions and the length of AM aliphatic arms more significantly influence AM bioactivity than hydrogen-bonding.


Predicting transient particle transport in enclosed environments with the combined computational fluid dynamics and Markov chain method.
To quickly obtain information about airborne infectious disease transmission in enclosed environments is critical in reducing the infection risk to the occupants. This study developed a combined computational fluid dynamics (CFD) and Markov chain method for quickly predicting transient particle transport in enclosed environments. The method first calculated a transition probability matrix using CFD simulations. Next, the Markov chain technique was applied to calculate the transient particle concentration distributions. This investigation used three cases, particle transport in an isothermal clean room, an office with an underfloor air distribution system, and the first-class cabin of an MD-82 airliner, to validate the combined CFD and Markov chain method. The general trends of the particle concentrations vs. time predicted by the Markov chain method agreed with the CFD simulations for these cases. The proposed Markov chain method can provide faster-than-real-time information about particle transport in enclosed environments. Furthermore, for a fixed airflow field, when the source location is changed, the Markov chain method can be used to avoid recalculation of the particle transport equation and thus reduce computing costs.


[Autonomic neuropathy in diabetes mellitus].
We analyse the different studies conducted on the prevalence, aetiopathology, clinical symptoms and treatment of diabetic autonomic neuropathy (AN), together with its involvement in the mortality of patients. AN can affect any part of the nervous system to varying degrees and at different moments in time, and its prevalence is significant in any of the stages of diabetes. The aetiopathogenesis of AN results from a multifactorial process involving metabolic disorders triggered by the activation of the polyolic pathway, microangiopathy and alterations affecting the synthesis of essential fatty acids due to hyperglycemia, which is made worse by a deficient regeneration of nerve tissue. Any of the systems innervated by the autonomous nervous system can be affected; the initial symptoms are insidious and of little cause for concern until the more advanced stages of the disease. The chief dysfunctions affect the cardiovascular, digestive, genitourinary and thermoregulatory systems. How AN courses in time varies from patient to patient and depends on the glycemic control that is carried out. Its presence is a factor that increases the mortality rate in diabetic patients. The prevalence of AN is notable, and the symptoms of autonomic dysfunction are usually under-diagnosed owing to its variability, lack of specificity and the wide range of symptoms. It is important to recognise this entity because of its effects on increasing morbidity and mortality, although they can be reduced by means of a strict glycemic control and specific treatment.


Two novel members of the prolactin/growth hormone family are expressed in the mouse placenta.
Two novel members of the mouse PRL/GH family have been identified through a search of an expressed sequence tag database. The encoded proteins do not appear to be homologs of other known members of this hormone family. One of these proteins, designated PRL-like protein E (PLP-E), is predicted to be synthesized as a precursor of 265 amino acids, modified by N-linked glycosylation, and secreted as a mature glycoprotein of 236 residues. The second clone encodes a protein of 253 residues with consensus sites for N-linked glycosylation; the secreted form of the protein, designated PRL-like protein F (PLP-F), is predicted to be 223 amino acids in length. Both of these messenger RNAs are expressed specifically in the placenta, with peak levels of PLP-E on days 10-12 and of PLP-F on days 14-16. Expression of PLP-E is restricted to the trophoblast giant cells, whereas PLP-F is synthesized only in the spongiotrophoblasts. The genes for both of these proteins map to a 700-kilobase region of mouse chromosome 13 that includes other members of the PRL/GH family.


(+)- And (-)-borneol: efficacious positive modulators of GABA action at human recombinant alpha1beta2gamma2L GABA(A) receptors.
(+)-Borneol is a bicyclic monoterpene used for analgesia and anaesthesia in traditional Chinese and Japanese medicine and is found in the essential oils of medicinal herbs, such as valerian. (+)-Borneol was found to have a highly efficacious positive modulating action at GABA(A) receptors, as did its enantiomer (-)-borneol. The effects of these bicyclic monoterpenes alone and with GABA were evaluated at recombinant human alpha(1)beta(2)gamma(2L) GABA(A) receptors expressed in Xenopus laevis oocytes using two-electrode voltage-clamp electrophysiology. (+)-Borneol (EC(50) 248microM) and (-)-borneol (EC(50) 237microM) enhanced the action of low concentrations of GABA by more than 1000%. These enhancing effects were highly dependent on the relative concentrations of the borneol enantiomer and GABA, and were insensitive to flumazenil indicating that (+)- and (-)-borneol were not acting at classical benzodiazepine sites. The maximal responses to GABA were enhanced 19% by (+)-borneol and reduced 21% by (-)-borneol. The borneol analogues isoborneol, (-)-bornyl acetate and camphor, produced less marked effects. At high concentrations (>1.5mM) (+)- and (-)-borneol directly activated GABA(A) receptors producing 89% and 84%, respectively, of the maximal GABA response indicative of a weak partial agonist action. Although of lower potency, the highly efficacious positive modulatory actions of (+)- and (-)-borneol on GABA responses were at least equivalent to that of the anaesthetic etomidate and much greater than that of diazepam or 5alpha-pregnan-3alpha-ol-20-one. The relatively rigid cage structure of these bicyclic monoterpenes and their high efficacy may aid in a greater understanding of molecular aspects of positive modulation of the activation of GABA(A) receptors.


Lymphoedema and health-related quality of life by early treatment in long-term survivors of breast cancer. A comparative retrospective study up to 15 years after diagnosis.
The purpose was to compare progression/regression of arm lymphoedema, health-related quality of life and medical background data among women who discontinued their treatment (non-continued treatment group, NCTG) with these factors among women who continued treatment (continued treatment group, CTG). Seventy-two women were included in the NCTG and 58 women in the CTG. Women in the NCTG were invited to an examination and measurement of affected arm volume at the clinic in 2008. Medical background data and arm volume values, measured using the water displacement method, were collected from patient records and the Breast Cancer Quality Register of the Uppsala Örebro Region. The functional assessment of cancer therapy for breast cancer (FACT-B) was used to assess health-related quality of life in both groups. There were no differences with regard to progression/regression of arm lymphoedema or health-related quality of life. The CTG had experienced more advanced disease and received more extensive surgical and oncological treatment. The CTG had significantly larger arm volume due to lymphoedema at diagnosis (mean 422 ml) compared to the NCTG (mean 283 ml; p < 0.001), and at the last visit at the clinic (CTG mean 414 ml versus NCTG mean 239 ml; p < 0.001). The results indicate that there might be a spontaneous regression of lymphoedemas in the NCTG but there is a need for more research to make it possible to draw firm conclusions regarding this.