Resistance-induced changes in triclabendazole transport in Fasciola hepatica: ivermectin reversal effect.
Triclabendazole (TCBZ) and albendazole (ABZ) are flukicidal benzimidazole compounds extensively used in veterinary medicine. Although TCBZ has excellent activity against mature and immature stages of the liver fluke, Fasciola hepatica, ABZ action is restricted to flukes older than 12 wk. The intensive use of TCBZ has resulted in the development of resistance. To gain insight into the mechanisms of resistance to TCBZ, the ex vivo diffusion of TCBZ, TCBZ sulfoxide (TCBZSO, the active metabolite of TCBZ), and ABZ into TCBZ-susceptible and -resistant adult flukes was compared. TCBZ-susceptible (Cullompton) and -resistant (Sligo) flukes were incubated in Krebs-Ringer Tris buffer with either TCBZ, TCBZSO, or ABZ (5 nmol/ ml) for 90 min. Drug/metabolite concentrations were quantified by high-performance liquid chromatography. All the assayed molecules penetrated through the tegument of both susceptible and resistant flukes. However, significantly lower concentrations of TCBZ and TCBZSO were recovered within the TCBZ-resistant flukes. In contrast, ABZ entrance into the susceptible and resistant flukes was equivalent. The influx/efflux balance for TCBZ, TCBZSO, and ABZ in susceptible and resistant flukes in the presence or absence of a substrate (ivermectin) of the drug transporter P-glycoprotein was assessed. The ivermectin-induced modulation of P-glycoprotein activity decreased TCBZ efflux from the resistant flukes. Higher concentrations of TCBZ and TCBZSO were recovered from the resistant liver flukes in the presence of ivermectin. Thus, an altered influx/efflux mechanism may account for the development of resistance to TCBZ in F. hepatica.


Microbial and potentially toxic elements risk assessment in high Andean river water based on Monte Carlo simulation, Peru.
The study evaluated microbial and Potentially Toxic Elements-PTEs risks in high Andean river water in Peru using Monte Carlo simulation. A total of 144 water samples were collected from four rivers and evaluated for physicochemical parameters, PTEs and bacterial pathogens. The microbial risk analysis for exposure to pathogens present in the water was based on the probability of occurrence of diseases associated with Escherichia coli, Pseudomonas aeruginosa and enterococci. PTEs risk analysis was performed using a Monte Carlo simulation approach. The results showed that the highest microbial risk due to exposure to water contaminated by E. coli, P. aeruginosa and enterococci was recorded in the Miraflores and Chia rivers. Meanwhile, the analysis of carcinogenic and non-carcinogenic risk by PTEs in adults and children revealed that the Chia river presents a high risk of contamination by PTEs, especially the carcinogenic risk for children. The Monte Carlo simulation indicated a 56.16% and 94.85% probability of exceeding the limit value of 0.0001 for carcinogenic risk in adults and children, respectively. It can be concluded that children consuming the waters of the Chia river are potentially at risk of As toxicity.


Can Results-Based Financing improve health outcomes in resource poor settings? Evidence from Zimbabwe.
Result Based Financing (RBF) has been implemented in health systems across low and middle-income countries (LMICs), with the objective of improving population health. Most evaluations of RBF schemes have focused on average programme effects for incentivised services. There is limited evidence on the potential effect of RBF on health outcomes, as well as on the heterogeneous effects across socio-economic groups and time periods. This study analyses the effect of Zimbabwe's national RBF scheme on neonatal, infant and under five mortality, using Demographic and Health Survey data from 2005, 2010 and 2015. We use a difference in differences design, which exploits the staggered roll-out of the scheme across 60 districts. We examine average programme effects and perform sub-group analyses to assess differences between socio-economic groups. We find that RBF reduced under-five mortality by two percentage points overall, but that this decrease was only significant for children of mothers with above median wealth (2.7 percentage points) and education (2.1 percentage points). RBF increased institutional delivery by seven percentage points - with a statistically significant effect for poorer socio-economic groups and least educated. We also find that RBF reduced c-section rates by three percentage points. We find no detectable effect of RBF on other incentivised services. When considering programme effects over time, we find that effects were only observed during the second phase of the programme (March 2012) with the exception of c-sections, which only reduced in the longer term. Further research is needed to examine whether these findings can be generalised to other settings.


Evaluating the impact of the FDA's orphan drug designation on share prices of biotechnology companies.
This analysis explores the impact of the FDA's orphan drug designation (ODD) on biotechnology companies' share prices in the short and long term. Our analysis reveals that there is a significant immediate increase in share prices following an ODD announcement, which underscores its potential as a robust indicator of short-term investor returns. However, the long-term findings present a more complex picture, with a sustained impact within the biotech industry but a significant depreciation against the broader market over time. These findings elucidate the nuanced effects of regulatory milestones on the financial performance of pharmaceutical companies and highlight the need for more comprehensive studies to further unravel these complex dynamics.


NHE1 has a notable role in metastasis and drug resistance of T-cell acute lymphoblastic leukemia.
T-cell acute lymphoblastic leukemia (T-ALL) represents a spectrum of hematological malignancies that affect human health. Metastasis and chemotherapeutic drug resistance are the primary causes of mortality in patients with T-ALL. Sodium-hydrogen antiporter 1 (NHE1) is established to serve a role in metastasis and drug resistance in numerous types of cancer; however, the function of NHE1 in T-ALL remains to be elucidated. Previously, the C-C-motif chemokine ligand 25 (CCL25) was identified to be involved in metastasis and drug resistance in the MOLT4 T-ALL cell line, as was the ezrin protein. The present study investigated the role of NHE1 in the metastasis of T-ALL using a Transwell assay and scanning electron microscopy, using MOLT4 cells as a model. The association between NHE1 and ezrin was assessed using laser scanning confocal microscopy. The effect of NHE1 on resistance to the chemotherapy drug doxorubicin (DOX) was also investigated using a cell viability and cytotoxicity assay. Expression of NHE1 increased following treatment with CCL25, accompanied by morphological changes in MOLT4 cells and the co-localization of NHE1 with ezrin. In addition, wild-type MOLT4 cells exhibited an increased polarization ability compared with NHE1- or ezrin-silenced cells. NHE1- or ezrin-silenced cells exhibited higher sensitivity to DOX compared with wild-type MOLT4 cells. In conclusion, the increased expression or activity of NHE1 may potentially be a poor prognostic indicator for human T-ALL.


Patient and family physician preferences for care and communication in the eventuality of anthrax terrorism.
The threat of bioterrorism consequent to the September 11, 2001 attack in the USA generated suggestions for improved medical response mainly through hospital preparedness. The aim of the present study was to investigate the impact of this period of tension on patients' first choice for care and for receiving relevant information, and on primary care doctors' feelings of responsibility in the eventuality of an anthrax attack. During October 11-31, 2001, 500 patients from 30 clinics throughout Israel were asked to complete a questionnaire on their awareness of the anthrax threat, measures taken to prepare for it, and preferred sources of care and information. Their 30 physicians, and an additional 20, completed a questionnaire on knowledge about anthrax and anthrax-related patient behaviours and clinic visits. The outstanding finding was the low rate (30%) of patients who chose the hospital emergency department as their first choice for care or information if they were worried about an anthrax attack or the media communicated that an attack was in progress. The other two-thirds preferred their family doctor or the health authorities. Most of the physicians (89%) felt it was their responsibility to treat anthrax-infected patients and that they should therefore be supplied with appropriate guidelines. This study suggests that in Israel, a country with a high degree of awareness of civil defence aspects, both patients and primary care doctors believe that family physicians should have a major role in the case of bioterrorist attacks. This must be seriously considered during formulation of relevant health services programmes.


A novel, time-effective approach for capturing bacteria from contaminated urine samples.
A fundamental step in the race to design a rapid diagnostic test for antimicrobial resistance is the separation of bacteria from their matrix. Many recent studies have been focused on the development of systems capable of separating and capturing bacteria from liquid environments. Herein, we introduce a new approach to this issue by using the natural bacteria tendency to accumulate at naturally-occurring interfaces, such as liquid-gas and liquid-solid interfaces, where also organic molecules like lipids, proteins, and polysaccharides accumulate. This bacterial behavior leads to the formation of a superficial layer close to the interface rich in bacteria, from which it is possible to capture a consistent amount of bacteria by means of surfaces with high chemical affinity to the outer bacteria surface. This paper demonstrates how to capture bacteria from contaminated urine samples, by means of commercial microscope slides coated with positively charged biomolecules, without the utilization of the bacterial culture step for multiplying the bacteria. This approach is an easy, quick and economical method to concentrate living bacteria in a well-defined position onto a microscope slide, thus making them easily available for further diagnostic investigations.


Health-related quality of life, mental health and psychotherapeutic considerations for women diagnosed with a disorder of sexual development: congenital adrenal hyperplasia.
Little is known about the long-term health-related quality of life (HRQL) and mental health outcomes for women diagnosed with congenital adrenal hyperplasia (CAH), a disorder of sex development. Though recommendations for therapists exist, no research has empirically investigated women's experiences in therapy or their recommendations for therapy. Thus the purpose of the study was to investigate HRQL, mental health concerns of women with CAH, and patients' recommendations for therapists. A qualitative methodology, consensual qualitative research, was used to answer these questions. Eight women with CAH participated in the study. Results from their interviews revealed six domains: physical functioning, psychological functioning, interpersonal processes and relationships, healthcare experiences of women with CAH, recommendations for health care professionals, and systemic considerations. Domains were further broken down into categories with results yielding implications for both medical and mental health professionals and shedding light on issues related to normalcy, concerns both related and unrelated to CAH, sex, and gender, and highlighting effective supports and therapeutic interventions.


MCG10, a novel p53 target gene that encodes a KH domain RNA-binding protein, is capable of inducing apoptosis and cell cycle arrest in G(2)-M.
p53, a tumor suppressor, inhibits cell proliferation by inducing cellular genes involved in the regulation of the cell cycle. MCG10, a novel cellular p53 target gene, was identified in a cDNA subtraction assay with mRNA isolated from a p53-producing cell line. MCG10 can be induced by wild-type but not mutant p53 and by DNA damage via two potential p53-responsive elements in the promoter of the MCG10 gene. The MCG10 gene contains 10 exons and is located at chromosome 3p21, a region highly susceptible to aberrant chromosomal rearrangements and deletions in human neoplasia. The MCG10 gene locus encodes at least two alternatively spliced transcripts, MCG10 and MCG10as. The MCG10 and MCG10as proteins contain two domains homologous to the heterogeneous nuclear ribonucleoprotein K homology (KH) domain. By generating cell lines that inducibly express either wild-type or mutated forms of MCG10 and MCG10as, we found that MCG10 and MCG10as can suppress cell proliferation by inducing apoptosis and cell cycle arrest in G(2)-M. In addition, we found that MCG10 and MCG10as, through their KH domains, can bind poly(C) and that their RNA-binding activity is necessary for inducing apoptosis and cell cycle arrest. Furthermore, we found that the level of the poly(C) binding MCG10 protein is increased in cells treated with the DNA-damaging agent camptothecin in a p53-dependent manner. These results suggest that the MCG10 RNA-binding protein is a potential mediator of p53 tumor suppression.


Comparative analysis of paw pad structure in the clouded leopard (Neofelis nebulosa) and domestic cat (Felis catus).
The Clouded leopard (Neofelis nebulosa) is a medium-sized highly arboreal cat. This study compares the structure of the digital, metacarpal and metatarsal pads of the manus and pes in N. nebulosa to that of the domestic cat (Felis catus). Covered by a stratified squamous cornified epithelium, the pads have a supple deposit of subepidermal fat that is partitioned by collagen fibers and extensively anchored to the muscle tendon sheaths. In both animals, a pes metatarsal pad suspensory ligament originates from the Mm. flexores digitorum profundi tendon and forms 3-4 small branches that project through the dermal fat layer and attach to the pad epidermis. In the cat manus, four tendons of equal size extend from the M. flexor digitorum superficialis (FDS) to form the manica flexoria in digits 2-4 from which extends a metacarpal pad suspensory ligament (MPSL) on digits 2 and 5 that extends into the tela subcutanea and epidermis. On digits 3 and 4 MPSL extends directly from the FDS tendon itself. In contrast, manus FDS tendons 1 and 5 in N. nebulosa were thin and either project directly to the tela subcutanea (tendon 1) or connect with the manica flexoria forming a metacarpal pad suspensory ligament (tendon 5). Tendons 2-4 connect with the manica flexoria from which MPSL project into the tela subcutanea and epidermis. In both species, the suspensory ligaments may serve to contract the pad to conform to the under lying substrate, thus enhancing the animal's ability to grip branches while climbing.


Competition of organic anions for furosemide and p-aminohippurate secretion in the rabbit.
The excretion of [14C]- or [35S]furosemide and [3H]-p-aminohippurate (PAH) injected within 4 min into the left renal artery of rabbits was measured under brisk mannitol diuresis. The estimated rate of furosemide secretion during the first pass through the left kidney was lower than that of PAH when neither of the two transport processes were saturated: 7.9 and 12.9% of the total amounts injected were secreted per minute, respectively. Different competitive inhibitors were injected i.v. Probenecid (50 mg/kg) inhibited furosemide and PAH secretion by 95 and 80%, respectively. Pyrazinoate at plasma concentrations of 3 to 5 mM had no effect on either anion. Indomethacin (10 mg/kg) depressed furosemide secretion by 24% but had no effect on PAH secretion. PAH at a concentration of 9 to 17 mM in plasma depressed furosemide secretion by only 44 to 66%. Furosemide did not inhibit PAH secretion when infused into the left renal artery at a rate 5000 times higher than PAH. It was concluded that furosemide is secreted partly by the transport system secreting PAH, for which it had only a low affinity, and partly by a transport system for which indomethacin had some affinity. This latter transport system, in turn, differs from that secreting pyrazinoate. The furosemide-induced natriuresis, in both kidneys, was proportional to the urinary excretion rate of furosemide until the fractional excretion of Na+ reached an apparent maximum of 20 to 30%.


A phase II Hoosier Oncology Group study of vinorelbine and estramustine phosphate in hormone-refractory prostate cancer.
The purpose was to evaluate the combined anti-microtubular regimen of vinorelbine and estramustine phosphate (EMP) in hormone refractory prostate cancer. Weekly vinorelbine 20 mg/m2 (or 15 mg/m2 if a history of prior pelvic radiotherapy) was combined with EMP at 280 mg orally tds for 3 days (the day before, the day of and the day after vinorelbine infusion). After 8 weeks of therapy the combination was given every other week. From February 1998 to February 1999, 23 men were enrolled with a median age of 69 years (range 50-83 years). The median prostate-specific antigen (PSA) at entry was 160 ng/ml (range 0-802 ng/ml). A median of 13 weeks of therapy was administered and the median follow-up was 14.8 months. Eleven patients (48%) had lower extremity edema requiring diuretic therapy, two (9%) had grade 2 granulocytopenia and four patients [17%; 95% confidence interval (CI) 5% to 39%] had a thromboembolic episode. There was no treatment-related mortality. Fifteen of 21 patients (71%; 95% CI 49% to 89%) had at least a 50% decrease in the PSA for at least 2 months with a median time to serologic progression of 3.5 months (range 0.75-10.5 months). One of eight patients (12.5%; 95% CI 0% to 53%) with measurable disease had a confirmed partial response. The estimated median survival was 15.1 months and the actual one year overall survival was 71% (95% CI 51% to 88%). Weekly vinorelbine with short course oral EMP is an active regimen as evaluated by rate of PSA response, time to progression and median survival. However, the toxicities of EMP, even when given as a short course, are still problematic.


Oxygen concentration determines regiospecificity in soybean lipoxygenase-1 reaction via a branched kinetic scheme.
The effect of oxygen concentration on the regiospecificity of the soybean lipoxygenase-1 dioxygenation reaction was studied. At low oxygen concentrations (<5 microM), a dramatic change in the regiospecificity of the enzyme was observed with the hydroperoxy-octadecadienoic acid (HPOD) 13:9 ratio closer to 50:50 instead of the generally reported 95:5. This alteration of regiospecificity is not an isolated phenomenon, since it occurs during a reaction carried out under "classical" conditions, i.e. in a buffer saturated with air before the reaction. beta-carotene bleaching and electronic paramagnetic resonance findings provided evidence that substrate-derived free radical species are released from the enzyme. The kinetic scheme proposed by Schilstra et al. (Schilstra, M. J., Veldink, G. A. & Vliegenthart, J. F. G. (1994) Biochemistry 33, 3974-3979) was thus expanded to account for the observed variations in specificity. The equations describing the branched scheme show two different kinetic pathways: a fully enzymatic one leading to a regio-isomeric composition of 13-HPOD:9-HPOD = 95:5, and a semienzymatic one leading to a regio-isomeric composition of 13-HPOD:9-HPOD = 50:50. The ratio between the two different pathways depends on oxygen concentration, which thus determines the overall specificity of the reaction.


Circulating endothelial cells, endothelial apoptosis and soluble markers of endothelial dysfunction in patients with systemic lupus erythematosus-related vasculitis.
Evidence is accumulating for endothelial cell dysfunction as one of the main factors initiating vessel wall damage in SLE. Enhanced expression of endothelial adhesion molecules is suggested to play a crucial role in the pathogenesis of vasculitis, while the number of circulating endothelial cells (CECs) is believed to be a reliable marker of endothelial damage. It therefore seems relevant to investigate CECs counts and soluble markers of endothelial dysfunction in SLE patients with inflammatory microangiopathy. The aim of this study was to assess the number of CECs, including apoptotic CECs, as well as to determine serum levels of sVCAM-1, sICAM-1 and sE-selectin in patients with SLE-related vasculitis. The study included 51 women with SLE, divided into 2 subgroups: I patients with severe disease activity according to SLEDAI score, developing vascular complications, such as central nervous system affection and/or vasculitis and/or glomerulonephritis, II patients with mild or moderate disease activity, without vascular complications. The control group consisted of 16 healthy female volunteers. CECs, including apoptotic CECs, were isolated using anti-CD146-coated immunomagnetic Dynabeads. Serum levels of sVCAM-1, sICAM-1 and sE-selectin levels were determined with ELISA. In patients with SLE, CEC counts were significantly higher than in healthy controls, and strongly correlated with disease activity assessed by SLEDAI score. The number of apoptotic CECs, as compared with healthy subjects, increased considerably only in subgroup I. Serum sVCAM-1 levels were notably increased in subgroup I in relation to subgroup II and in subgroup II in relation to the control group, while serum sICAM-1 and sE-selectin levels in both subgroups were comparable and significantly higher than those of healthy subjects. The study showed that the number of CECs increases in SLE and strongly correlates with disease activity, reaching maximum values at the stage of inflammatory microangiopathy-related complications. Severe SLE flares are characterized by enhanced endothelial cell apoptosis. Progressive increase in serum sVCAM-1 levels is connected with disease activity aggravation and development of lupus microangiopathy.


Validation of somatic cell score-associated SNPs from Holstein cattle in Sudanese Butana and Butana × Holstein crossbred cattle.
The Bos indicus zebu cattle Butana is the most commonly used indigenous dairy cattle breed in Sudan. In the last years, high-yielding Holstein dairy cattle were introgressed into Butana cattle to improve their milk yield and simultaneously keep their good adaption to extreme environmental conditions. With the focus on the improvement of milk production, other problems arose such as an increased susceptibility to mastitis. Thus, genetic selection for mastitis resistance should be considered to maintain healthy and productive cows. In this study, we tested 10 single nucleotide polymorphisms (SNPs) which had been associated with somatic cell score (SCS) in Holstein cattle for association with SCS in 37 purebred Butana and 203 Butana × Holstein crossbred cattle from Sudan. Animals were genotyped by competitive allele-specific PCR assays and association analysis was performed using a linear mixed model. All 10 SNPs were segregating in the crossbred Butana × Holstein populations, but only 8 SNPs in Sudanese purebred Butana cattle. The SNP on chromosome 13 was suggestively associated with SCS in the Butana × Holstein crossbred population (rs109441194, 13:79,365,467, PBF = 0.054) and the SNP on chromosome 19 was significantly associated with SCS in both populations (rs41257403, 19:50,027,458, Butana: PBF = 0.003, Butana × Holstein: PBF = 6.2 × 10-16). The minor allele of both SNPs showed an increase in SCS. Therefore, selection against the disadvantageous minor allele could be used for genetic improvement of mastitis resistance in the studied populations. However, investigations in a bigger population and across the whole genome are needed to identify additional genomic loci.


[Should medical doctors contribute to reducing social inequality in health?].
Which role the health care system has and should have in reducing social inequality in health is unclear. The study objective is to gain knowledge about what Norwegian medical doctors believe their role should be. A questionnaire on how doctors take socioeconomic factors into account when treating patients was sent to a representative sample of 1,650 Norwegian doctors in 2008. 1,153 (70 %) doctors responded. 55 % believed doctors should contribute to reducing social inequality by offering patients with a low socioeconomic status extra help. However, the majority reported that they seldom/never take the patients' socioeconomic situation (such as bad private economy [81 %], little education [80 %], or unemployment [85 %]) into account in their clinical work. Some would consider lack of a social network (33 %), or heavy caring responsibilities (43 %) to be relevant. When responding to the question about how medical doctors take socioeconomic factors into account, 71 % said they give advice, 69 % spend more time, and 58 % offer an extra consultation. More regular GPs than other doctors reported they would take bad private economy (31 % vs. 15 %), unemployment (25 % vs. 12 %), or heavy caring responsibilities (54 % vs 39 %) into account. To treat all patients equally is a fundamental value among doctors. Practical implications of equal treatment to all are not clear. Apparently inconsistent answers reveal a need for a professional and political clarification of which principles of equality that should guide doctors' practice.


Postsurgical management strategies in patients with skull base chondrosarcomas.
Chondrosarcomas of the skull base are rare, slow-growing tumors that are often lethal and remain a management quandary. A systematic review was performed to understand postsurgical management options for patients with these tumors. The current standard of care includes surgical resection followed by either adjuvant radiation therapy and/or early radiosurgery. The role of chemotherapy has been limited, but remains under investigation. Overall survival and progression-free survival range between 70 and 100% at 5 years when multimodality approaches are used. Overall survival may be greater for patients who have a shorter interval (<6 months) between diagnosis and radiosurgery, an older age, and either a single or no prior resection. Progression-free survival may be increased for patients older than 40 years of age, who have not had prior radiation therapy, and for those with smaller tumors that do not compress the brainstem.


Effects of antiepileptic drugs on mitochondrial functions, morphology, kinetics, biogenesis, and survival.
Antiepileptic drugs (AEDs) exhibit adverse and beneficial effects on mitochondria, which have a strong impact on the treatment of patients with a mitochondrial disorder (MID) with epilepsy (mitochondrial epilepsy). This review aims at summarizing and discussing recent findings concerning the effect of AEDs on mitochondrial functions and the clinical consequences with regard to therapy of mitochondrial epilepsy and of MIDs in general. Literature review. AEDs may interfere with the respiratory chain, with non-respiratory chain enzymes, carrier proteins, or mitochondrial biogenesis, with carrier proteins, membrane-bound channels or receptors and the membrane potential, with anti-oxidative defense mechanisms, with morphology, dynamics and survival of mitochondria, and with the mtDNA. There are AEDs of which adverse effects outweigh beneficial effects, such as valproic acid, carbamazepine, phenytoin, or phenobarbital and there are AEDs in which beneficial effects dominate over mitochondrial toxic effects, such as lamotrigine, levetiracetam, gabapentin, or zonisamide. However, from most AEDs only little is known about their interference with mitochondria. Mitochondrial epilepsy might be initially treated with AEDs with low mitochondrial toxic potential. Only in case mitochondrial epilepsy is refractory to these AEDs, AEDs with higher mitochondrial toxic potential might be tried. In patients carrying POLG1 mutations AEDs with high mitochondrial toxic potential are contraindicated.


Determining call-to-entry rate and recruitment barriers in clinical studies for community clinics serving low-income populations: a cohort study.
Recruitment for clinical studies is challenging. To overcome barriers, investigators have previously established call-to-entry rates to assist in planning. However, rates specific to low-income minority populations are needed to account for additional barriers to enrolment these individuals face. To obtain a call-to-entry rate in a low-income uninsured Hispanic population with chronic disease. We used data from four of our randomised clinical studies to determine the call-to-entry rate for individuals (n=1075) with or at risk for type 2 diabetes: participants needed/potential participants contacted=recruitment rate (yield). Research staff contacted potential participants to enrol in a study that evaluated 6 month diabetes programmes at community clinics from 2015 to 2020. We recorded call-to-entry rates, reasons for declining the study, show rates, and attrition. The call-to-entry rate was 14.5%. Forty per cent of potential participants could not be contacted, and 30.6%, 19.1%, and 5.4% responded yes, no, and maybe, respectively. No show percentages were 54% for yes and 91.4% for maybe responders. The majority (61.6%) declined due to inability to attend; reasons to decline included work (43%), eligibility (18%), transportation (10%), out of town (9%), did not think they needed the programme (7%) and other/unknown (14%). Being a physician predicted inability to reach participants (adjusted OR 2.91, 95% CI 1.73 to 4.90). Attrition was 6.8%. We described a call-to-entry rate and detailed recruitment data, including reasons to decline the study. This valuable information can assist investigators in study planning and overcoming enrolment barriers in low-income populations. Telehealth-based or strategies that limit transportation needs may increase participant involvement. NCT03394456.


Feeding protein supplements in alfalfa hay-based lactation diets improves nutrient utilization, lactational performance, and feed efficiency of dairy cows.
Due to the increasing cost of soybean meal and concerns of excess N being excreted into the environment, new protein supplements have been developed. Two products that have shown potential in increasing N utilization efficiency are slow-release urea (SRU; Optigen; Alltech Inc., Nicholasville, KY) and ruminal-escape protein derived from yeast (YMP; DEMP; Alltech Inc.). The objective of this study was to assess the effects of feeding these 2 supplements in alfalfa hay-based [45.7% of forage dietary dry matter (DM)] dairy diets on nutrient utilization, feed efficiency, and lactational performance of dairy cows. Twelve multiparous dairy cows were used in a triple 4 × 4 Latin square design with one square consisting of ruminally cannulated cows. Treatments included (1) control, (2) SRU-supplemented total mixed ration (SRUT), (3) YMP-supplemented total mixed ration (YMPT), and (4) SRU- and YMP-supplemented total mixed ration (SYT). The control consisted only of a mixture of soybean meal and canola meal in a 50:50 ratio. The SRU and the YMP were supplemented at 0.49 and 1.15% DM, respectively. The experiment consisted of 4 periods lasting 28 d each (21 d of adaptation and 7 d of sampling). Cows fed YMPT and SYT had decreased intake of DM, and all supplemented treatments had lower crude protein intake compared with those fed the control. Milk yield tended to have the greatest increase in YMPT compared with the control (41.1 vs. 39.7 kg/d) as well as a tendency for increased milk fat and protein yields. Feed efficiencies based on yields of milk, 3.5% fat-corrected milk, and energy-corrected milk increased at 10 to 16% due to protein supplementation. Cows fed protein supplements partitioned less energy toward body weight gain, but tended to partition more energy toward milk production. Efficiency of use of feed N to milk N increased by feeding SRUT and YMPT, and milk N-to-manure N ratio increased with YMPT. Overall results from this experiment indicate that replacing the mixture of soybean meal and canola meal with SRU and YMP in alfalfa hay-based dairy diets can be a good approach to improve nutrient utilization efficiencies in lactating dairy cows.


[The role of boundary lipids in phase transitions of biological membranes].
In terms of the Landau thermodynamic expansion the model of lipid-protein interaction is considered for the case of relatively low protein concentrations. It is established that the proteins inserted into the lipid membrane can change its phase transition temperature. The expression determining the region size of the "boundary" lipids is obtained and the connection between the ordering extent of the "boundary" lipids and the sign and the value of the temperature shift of the phase transition is calculated.


Somatisation Disorder Detection via Speech: Introducing a Self-Supervised Learning Model.
With the depressive psychiatric disorders becoming more common, people are gradually starting to take it seriously. Somatisation disorders, as a general mental disorder, are rarely accurately identified in clinical diagnosis for its specific nature. In the previous work, speech recognition technology has been successfully applied to the task of identifying somatisation disorders on the Shenzhen Somatisation Speech Corpus. Nevertheless, there is still a scarcity of labels for somatisation disorder speech database. The current mainstream approaches in the speech recognition heavily rely on the well labelled data. Compared to supervised learning, self-supervised learning is able to achieve the same or even better recognition results while reducing the reliance on labelled samples. Moreover, self-supervised learning can generate general representations without the need for human hand-crafted features depending on the different recognition tasks. To this end, we apply self-supervised learning pre-trained models to solve few-labelled somatisation disorder speech recognition. In this study, we compare and analyse the results of three self-supervised learning models (contrastive predictive coding, wav2vec and wav2vec 2.0). The best result of wav2vec 2.0 model achieves 77.0 % unweighted average recall and is significantly better than CPC (p < .005), performing better than the benchmark of the supervised learning model.Clinical relevance- This work proposed a self-supervised learning model to resolve the few-labelled SD speech data, which can be well used for helping psychiatrists with clinical assistant to diagnosis. With this model, psychiatrists no longer need to spend a lot of time labelling SD speech data.


Doxorubicin metabolism and toxicity in human myocardium: role of cytoplasmic deglycosidation and carbonyl reduction.
The anthracycline doxorubicin (DOX) is an exceptionally good antineoplastic agent, but its use is limited by formation of metabolites which induce acute and chronic cardiac toxicities. Whereas the acute toxicity is mild, the chronic toxicity can produce a life-threatening cardiomyopathy. Studies in laboratory animals are of limited value in predicting the structure and reactivity of toxic metabolites in humans; therefore, we used an ethically acceptable system which is suitable for exploring DOX metabolism in human myocardium. The system involves cytosolic fractions from myocardial samples obtained during aorto-coronary bypass grafting. After reconstitution with NADPH and DOX, these fractions generate the alcohol metabolite doxorubicinol (DOXol) as well as DOX deoxyaglycone and DOXol hydroxyaglycone, reflecting reduction of the side chain carbonyl group, reductase-type deglycosidation of the anthracycline, and hydrolase-type deglycosidation followed by carbonyl reduction, respectively. The efficiency of each metabolic route has been evaluated at low and high DOX:protein ratios, reproducing acute, single-dose and chronic, multiple-dose regimens, respectively. Low DOX:protein ratios increase the efficiency of formation of DOX deoxyaglycone and DOXol hydroxyaglycone but decrease that of DOXol. Conversely, high DOX:protein ratios facilitate the formation of DOXol but impair reductase- or hydrolase-type deglycosidation and uncouple hydrolysis from carbonyl reduction, making DOXol accumulate at levels higher than those of DOX deoxyaglycone and DOXol hydroxyaglycone. Structure-activity considerations have suggested that aglycones and DOXol may inflict cardiac damage by inducing oxidative stress or by perturbing iron homeostasis, respectively. Having characterized the influence of DOX:protein ratios on deglycosidation or carbonyl reduction, we propose that the benign acute toxicity should be attributed to the oxidant activity of aglycones, whereas the life-threatening chronic toxicity should be attributed to alterations of iron homeostasis by DOXol. This picture rationalizes the limited protective efficacy of antioxidants against chronic cardiomyopathy vis-à-vis the better protection offered by iron chelators, and forms the basis for developing analogues which produce less DOXol.


Role of interleukin 6 (IL-6) in protection from lethal irradiation and in endocrine responses to IL-1 and tumor necrosis factor.
Primary responsibility for the induction of various acute phase reactions has been ascribed to interleukin 1 (IL-1), tumor necrosis factor (TNF), or IL-6, suggesting that these cytokines may have many overlapping activities. Thus, it is difficult to identify the cytokine primarily responsible for a particular biologic effect, since IL-1 and TNF stimulate one another, and both IL-1 and TNF stimulate IL-6. In this work, the contribution of IL-6 in radioprotection, induction of adrenocorticotropic hormone (ACTH), and induction of hypoglycemia was assessed by blocking IL-6 activity. Administration of anti-IL-6 antibody to otherwise untreated mice greatly enhanced the incidence of radiation-induced mortality, indicating that like IL-1 and TNF, IL-6 also contributes to innate resistance to radiation. Anti-IL-6 antibody given to IL-1-treated or TNF-treated mice reduced survival from lethal irradiation, demonstrating that IL-6 is also an important mediator of both IL-1- and TNF-induced hemopoietic recovery. A similar IL-1/IL-6 interaction was observed in the case of ACTH induction. Anti-IL-6 antibody blocked the IL-1-induced increase in plasma ACTH, whereas recombinant IL-6 by itself did not induce such an increase. Anti-IL-6 antibody also mitigated TNF-induced hypoglycemia, but did not reverse IL-1-induced hypoglycemia. It is, therefore, likely that TNF and IL-1 differ in their mode of induction of hypoglycemia. Our results suggest that an interaction of IL-6 with IL-1 and TNF is a prerequisite for protection from radiation lethality, and its interaction with IL-1 for induction of ACTH.


The relationship between IL-28B polymorphisms and the response to peginterferon alfa-2a monotherapy in anti-HBe-positive patients with chronic HBV infection.
The impact of interleukin 28B (IL-28B) on the results of interferon (IFN)-based therapy in patients chronically infected with hepatitis B virus (HBV) is poorly understood. The aim of this study was to evaluate the relationship between IL-28B markers and the response to IFN monotherapy in Polish patients with anti-hepatitis B e (HBe)-positive chronic hepatitis B (CHB). We determined three single-nucleotide polymorphisms (SNPs) of IL-28B (rs12979860, rs12980275, and rs8099917) in 86 patients who were treated with pegylated interferon (PEG-IFN) for 48 weeks. The effectiveness of the therapy was evaluated based on the virological and biochemical response. The primary efficacy parameters were the HBV DNA viral load below 400 IU/ml and 2,000 IU/ml in combination with alanine aminotransferase (ALT) normalization (<40 IU/l), measured 24 weeks after the treatment. Viral load below 400 IU/ml or 2,000 IU/ml with ALT normalization was achieved by 37 % and 46 % of patients, respectively. It has been shown that the distribution of IL-28B genotypes in the dominant genetic model in patients with different therapeutic success differ significantly only for rs12979860. The IL-28B rs12979860 CC genotype was associated with lower treatment success [odds ratio (OR), 0.31; p = 0.025 and OR, 0.37; p = 0.044 for <400 IU/ml HBV DNA with <40 IU/l ALT, and <2,000 IU/ml HBV DNA with <40 IU/l ALT, respectively]. However, in the conditional logistic regression analysis adjusted by factors associated with combined response, rs12979860 was significantly associated only with <400 IU/ml HBV DNA with <40 IU/l ALT (OR, 0.24; p = 0.026). IL-28B polymorphisms have prognostic significance in assessing the treatment effectiveness based on the virological and biochemical response of patients with anti-HBe-positive CHB.


Evaluation of gravity leukapheresis and comparison with intermittent centrifugation leukapheresis.
Fifteen normal donors underwent gravity leukapheresis using a prototype collection and reinfusion harness after receiving dexamethasone for leukocyte stimulation. A mean of 4.6 units of blood were processed, producing a mean granulocyte yield of 10.8 X 10(9), with an average donation time of 261 minutes. Granulocyte collection efficiency was 79.9 per cent, but yield was only 2.5 X 10(9) granulocytes/hour. Granulocytes obtained by gravity leukapheresis were normal morphologically and had normal bactericidal capacity. Serial determinations showed no changes before and after donation of coagulation profile and serum chemistries in the donors. Seven donors underwent leukapheresis using intermittent centrifugation the day following gravity leukapheresis without further leukocyte stimulation. Mean granulocyte yield (16.1 X 10(9)), and yield/hour (5.37 X 10(9)) of donation were significantly greater for the mechanical method (p less than 0.0005). Gravity leukapheresis required considerable blood bag handling and bag entries, even with the prototype harness. Considering the amount of blood handling, the expense of the sedimenting agent, the probable dose response phenomenon of granulocyte transfusions, and the low yield resulting from the limited volume of blood processed, this technique should not be made widely available, especially where regional centers can provide granulocytes obtained by more productive methods.


Seeking professional help for personal problems: black Americans' use of health and mental health services.
This article explored the use of health and mental health services for serious personal problems in a national sample of adult black Americans. The results indicated low usage of the mental health sector in response to problems. Only 9% of the respondents who sought professional help contacted a community mental health center, psychiatrist or psychologist. Mental health usage was low even among respondents who felt their problem brought them to the point of a nervous breakdown and among respondents who conceptualized their distress in "emotional" terms. The traditional health care sector (doctors, hospitals) and ministers were used more often by blacks in distress. When the use of professional help only is considered, there appeared to be a large pocket of unmet need in the black community. When the use of informal help is taken into consideration, however, the percentage of respondents who did not receive help was considerably lower. The implications of these findings for professional service delivery are discussed.


Monitoring tourism flows and destination management: Empirical evidence for Portugal.
We propose the use of a tool recently introduced by Gayer (2010), known as the "economic climate tracer", to analyze and monitor the cyclical evolution of tourism source markets to Portugal. Considering the period 1987-2015, we evaluate how tourism to Portugal has been affected by economic cycles. This tool is useful as it clearly illustrates the evolutionary patterns of different markets, and allows us to identify close relationships with economic fluctuations. We found that German tourism plays a leading role, since its movements are followed with delays by tourism flows from other countries, and exhibits higher resilience to shocks. Also, domestic and Spanish tourism have both displayed less irregular behaviors than tourism from other source markets. On the contrary, tourism from the Netherlands and the UK, have displayed irregular patterns, which demonstrates the urgency to diversify tourism source markets to reduce the country's vulnerability to external shocks and economic cycles.


Cloning and pattern of expression of the shiro-uo vasa gene during embryogenesis and its roles in PGC development.
The vasa genes are expressed in the germ cell lineage in many organisms, but their expression patterns show large variations. Recent studies suggest that vasa transcripts are involved in germ cell lineage development. In this paper, we isolated the vasa cDNA clone from a teleost, shiro-uo, Leucopsarion petersii and examined its expression pattern during embryogenesis. Then, we examined the functional significance of vasa mRNA during the formation of primordial germ cells (PGCs). The amino acid sequence of shiro-uo VASA is 61.1% identical to that of zebrafish. In whole-mount in situ hybridization, vasa transcripts appeared at the 4- and 8-cell stages as four spots at both ends of two cleavage planes between the lower tier of blastomeres and the yolk cell mass. At the 16-cell stage, eight spots were observed. After the blastula stage, shiro-uo vasa transcripts showed similar localization as in the zebrafish. Ultrastructural analysis of 4-cell stage embryos revealed the presence of a subcellular organelle that resembled 'nuage' in the germ cell lineage observed in the embryos of various organisms. We carried out micromanipulation of 4- or 8-cell stage embryos to remove the vasa mRNA-containing spots and then measured the number of the vasa-expressing PGCs in the genital ridge of the manipulated embryos. The numbers decreased when all of the four spots were removed, indicating that the vasa-containing spots at early cleavage stages have important functions in the development of PGCs.


RAVECAB: improving outcome in off-pump minimal access surgery with robotic assistance and video enhancement.
To determine the efficacy of using the harmonic scalpel and robotic assistance to facilitate thoracoscopic harvest of the internal thoracic artery (ITA). A case series. London Health Sciences Centre, University of Western Ontario, London, Ont. Fifteen consecutive patients requiring harvest of the ITA for coronary artery bypass grafting. Robot-assisted, video-enhanced coronary artery bypass (RAVECAB) through limited-access incisions, using the harmonic scalpel and a voice-activated robotic assistant. Ease and duration of the harvesting technique, complications of the procedure, graft flow and patency, and duration of postoperative hospitalization. RAVECAB facilitated thoracoscopic dissection of the ITA with the harmonic scalpel in all cases. There were no conversions to a standard approach and no reoperations for bleeding. The mean (and standard deviation) ITA harvest time was 64.1 (22.9) minutes (range from 40 to 118 minutes). Robotic voice command capture rate was greater than 95%. Mean (and SD) intraoperative graft flows were 33.1 (26.8) mL/min (range from 14 to 126 mL/min). There was 100% graft patency on postoperative angiography. There were no deaths, perioperaive myocardial infarction or arrhythmias. Mean (and SD) postoperative hospitalization was 3.3 (0.8) days. RAVECAB is a demanding procedure that addresses many of the disadvantages of the "conventional" minimally invasive coronary artery bypass. It allows complete pedicle dissection with minimal ITA manipulation and assures sufficient conduit length and a tension-free coronary artery anastomosis. All anastomoses were performed under direct vision through a 5- to 8-cm inferior mammary incision.


Microscopic study of migration of microbes in food-packaging paper and board.
The microbiological barrier properties of food-packaging paperboards, coated with polyethylene, mineral pigment or a biodegradable polymer and of high-density paper were examined with confocal laser scanning microscopy. The results show that the spatial distribution of microscopically observable bacterial cells was uneven inside the paperboard. The concentration in the interface between the polyethylene coating and the cellulose fibers was 100-200 times higher than inside the cellulose matrix. The bacteria in the interface and the mineral coating layer grew in response to access to food and moisture, whereas no growth was observed inside the fiber web, not even after extended exposure for up to 90 days. The paper and paperboards studied contained soluble nutrients (C:N:P 54:9:1 to 309:3:1) and no measurable antimicrobial activity. The factor limiting growth and migration of bacteria inside the fiber web was most likely limited access to free water, even under conditions of extensive wetting. The studied paperboards functioned as efficient barriers against translocation of microbes. The microbes residing between the paperboard and its polymer coating facing food, was the only potential site from which microbes could leak into food. This emphasizes the need for high hygienic quality of surface-sizing chemicals. Mineral-coating pigments were a source of microbes and their application behind the PE coating facing food is contraindicated.


Ataxia, tremor, intellectual disability: a case of STXBP1 encephalopathy with a new mutation.
Değerliyurt A, Gezgen Kesen G, Ceylaner S. Ataxia, tremor, intellectual disability: a case of STXBP1 encephalopathy with a new mutation. Turk J Pediatr 2019; 61: 757-759. STXBP1 gene mutations are among the most common mutations in earlyonset epileptic encephalopathies. The clinical spectrum of STXBP1 mutations is not limited to epileptic phenotypes and also includes atypical Rett syndrome and non-syndromic sporadic severe intellectual disability. Tremor, dystonia, choreiform movements, stereotypical head movements and ataxia may also be seen. However, the phenotypical spectrum is not as well-known as the other common SCN1A or CDKL5 gene mutations, making the clinical diagnosis difficult and usually requiring gene panel studies or whole exome sequencing for the diagnosis. We present a 17-year-old male patient whose seizures started at the age of 12 years. The patient could only make limited eye contact, would continuously scream, and also had severe intellectual disability, marked ataxic walking and a very significant coarse tremor. The patient was clinically thought to have STXBP1 encephalopathy due to the presence of severe intellectual disability together with tremor, and ataxia. STXBP1 gene analysis revealed a new c.9_13delCATTG (pIle4Profs*12) (p.I4Pfs*12) (heterozygous) frameshift mutation. In conclusion, STXBP1 encephalopathy should be considered if severe intellectual disability is accompanied by severe tremor and ataxia in a patient with epileptic and developmental encephalopathy. A normal head circumference supports the diagnosis in such patients.


Electrically tunable bandpass filter using solid-core photonic crystal fibers filled with multiple liquid crystals.
An electrically tunable bandpass filter is designed and fabricated by integrating two solid-core photonic crystal fibers filled with different liquid crystals in a double silicon v-groove assembly. By separately controlling the driving voltage of each liquid-crystal-filled section, both the short-wavelength edge and the long-wavelength edge of the bandpass filter are tuned individually or simultaneously with the response time in the millisecond range.


Improving the prevention and management of chronic disease in low-income and middle-income countries: a priority for primary health care.
The burden of chronic diseases, such as heart disease, cancer, diabetes, and mental disorders is high in low-income and middle-income countries and is predicted to increase with the ageing of populations, urbanisation, and globalisation of risk factors. Furthermore, HIV/AIDS is increasingly becoming a chronic disorder. An integrated approach to the management of chronic diseases, irrespective of cause, is needed in primary health care. Management of chronic diseases is fundamentally different from acute care, relying on several features: opportunistic case finding for assessment of risk factors, detection of early disease, and identification of high risk status; a combination of pharmacological and psychosocial interventions, often in a stepped-care fashion; and long-term follow-up with regular monitoring and promotion of adherence to treatment. To meet the challenge of chronic diseases, primary health care will have to be strengthened substantially. In the many countries with shortages of primary-care doctors, non-physician clinicians will have a leading role in preventing and managing chronic diseases, and these personnel need appropriate training and continuous quality assurance mechanisms. More evidence is needed about the cost-effectiveness of prevention and treatment strategies in primary health care. Research on scaling-up should be embedded in large-scale delivery programmes for chronic diseases with a strong emphasis on assessment.


Coexistence of sarcopenia and self-reported weight loss is a powerful predictor of mortality in older patients with heart failure.
We examined whether the addition of self-reported weight loss improves the accuracy of prediction of mortality caused by sarcopenia in heart failure (HF) patients. We enrolled 477 HF patients (mean age 77 years) who received combined assessment of sarcopenia and self-reported weight loss. Sarcopenia was diagnosed according to the criteria of the Asian Working Group for Sarcopenia. If the patients answered "yes" to the question "have you lost 2 kg or more in the past 6 months?", they were diagnosed as having self-reported weight loss. Sarcopenia and self-reported weight loss coexisted in 32% of patients. During a median follow-up period of 763 days, 65 patients (15%) died. Kaplan-Meier curves showed a significantly higher rate of mortality in HF patients with both sarcopenia and self-reported weight loss than in HF patients with sarcopenia alone. Multivariate Cox proportional hazards analysis showed that the coexistence of sarcopenia and self-reported weight loss is an independent predictor of mortality in HF patients. Inclusion of the coexistence of sarcopenia and self-reported weight loss in the baseline model consisting of established prognostic markers significantly improved both the net reclassification index and the integrated discrimination index. The coexistence of sarcopenia and self-reported weight loss is a powerful predictor of mortality in HF patients. Geriatr Gerontol Int 2023; ••: ••-••.


Discovery of Imidazole-Based Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase.
The discovery of new targets for the treatment of malaria, in particular those aimed at the pre-erythrocytic stage in the life cycle, advanced with the demonstration that orally administered inhibitors of Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) could clear infection in a murine model. This enthusiasm was tempered by unsatisfactory safety and/or pharmacokinetic issues found with these chemotypes. To address the urgent need for new scaffolds, this paper presents initial structure-activity relationships in an imidazole scaffold at four positions, representative in vitro ADME, hERG characterization, and cell-based antiparasitic activity. This series of PfPKG inhibitors has good in vitro PfPKG potency, low hERG activity, and cell-based antiparasitic activity against multiple Plasmodium species that appears to be correlated with the in vitro potency.


Primary mucin-producing urothelial-type adenocarcinoma of the prostatic urethra diagnosed on TURP: a case report and review of literature.
Mucin-producing urothelial-type adenocarcinoma of the prostatic urethra is extremely rare. These lesions must be differentiated from other mucinous tumors including mucin-producing prostatic adenocarcinoma and metastases from either colonic or bladder primaries. We report here a case of urothelial-type adenocarcinoma arising from the prostatic urethra. The patient is an 81 year-old man with a history of pT1 urothelial cell carcinoma of the bladder status post trans-urethral resection of bladder tumor (TURBT) who initially presented with irritative lower urinary tract symptoms and mucosuria refractory to Flomax and finasteride. A shared decision was made for the patient to undergo trans-urethral resection of prostate (TURP). At the time of surgery, a papillary tumor emanating from the prostatic urethra was found and no urothelial lesions were noted in the bladder. Pathology of the resected prostatic chips revealed an invasive adenocarcinoma with intestinal-type differentiation that stained positive for CK7, CK20, and villin, but negative for PSA, PSAP, uroplakin, and CDX-2. Colonoscopy was normal and CT scan did not show any evidence of colonic lesions nor visceral or lymph node metastases. Thus, the patient was diagnosed with a primary urothelial-type adenocarcinoma of the prostatic urethra. Herein we review the literature regarding this unusual entity, and discuss the differential diagnosis, immunohistochemistry, and the importance of correctly identifying this rare tumor.


Reinitiation of sensitivity to naloxone by a single narcotic injection in postaddicted mice.
In mice implanted with a morphine pellet for 3 days and subsequently withdrawn for various periods of time, a single injection of morphine results in a rapid and marked sensitization of abstinent mice to naloxone-induced jumping behavior when compared to abstinent mice pretreated with saline or to placebo-withdrawn mice given a single morphine injection. Maximum sensitization of abstinent mice occurs at morphine doses of about 10 to 30 mg/kg and peaks at 0.5 to 2 hours after morphine administration. The ability of morphine to sensitize abstinent mice to naloxone declines with time after pellet removal and appears to consist of two components, one with a short T1/2 and one with a much longer T1/2. Abstinent mice are also sensitized to naloxone by levorphanol and methadone, but not by dextrorphan. It is proposed that the administration of a narcotic drug to abstinent mice uncovers a latent, pre-existing state of physical dependence and restores the responsiveness of this state to naloxone.


The effect of adhesive resin cement, obturation material and root dentin location on the retention of glass fiber-reinforced composite resin posts.
To assess the effects of adhesive resin cement, obturation material and dentin location on the retention of glass fiber-reinforced resin composite (FRRC) posts. 60 root canals in single rooted teeth were obturated with three different protocols (n= 20), including no obturation material (Control), GuttaFlow and Gutta-percha. Spaces were prepared for glass (FRCR) posts. Subgroups of the roots (n=10) were allocated for receiving posts luted with RelyX Unicem or Calibra resin cements. The specimens were mounted in plastic molds using epoxy resin. They were sectioned transversely to obtain three 1 mm-thick coronal, middle and apical slabs. Post retention was measured using a universal testing machine. The push-out test was performed at a crosshead speed of 0.5 mm/minute until post dislodgement occurred. Dislodged posts were examined microscopically to evaluate the mode of failure. Data were analyzed using univariate tests to reveal the effects of dependent variables and their interactions on post retention. Tukey test was used to determine significant differences for post retention in obturation material and dentin location groups. P-values ≤ 0.05 were considered significant. The adhesive resin cement, obturation material, dentin location and cement obturation materials interaction affected post retention. The mean bond strength was higher for posts cemented with RelyX Unicem than for those cemented with Calibra resin cements. Post retention in coronal locations was significantly superior to middle or apical locations. The failure mode was primarily mixed. When using RelyX Unicem cement for luting glass fiber-reinforced root canal posts, complete removal of all obturation materials from the post space significantly improves the retention. Although Calibra cement is less technique sensitive than RelyX Unicem resin cement, it produces notably lower retention of fiber-reinforced glass root canal posts.


Arachnoid membranes in the posterior half of the incisural space: an inverted Liliequist membrane-like arachnoid complex.
The aim of this study was to describe the similarity of configuration between the arachnoid complex in the posterior half of the incisural space and the Liliequist membrane. Microsurgical dissection and anatomical observation were performed in 20 formalin-fixed adult cadaver heads. The origin, distribution, and configuration of the arachnoid membranes and their relationships with the vascular structures in the posterior half of the incisural space were examined. The posterior perimesencephalic membrane and the cerebellar precentral membrane have a common origin at the tentorial edge and form an arachnoid complex strikingly resembling an inverted Liliequist membrane. Asymmetry between sides is not uncommon. If the cerebellar precentral membrane is hypoplastic on one side or both, the well-developed quadrigeminal membrane plays a prominent part in partitioning the subarachnoid space in the posterior half of the incisural space. The arachnoid complex in the posterior half of the incisural space can be regarded as an inverted Liliequist membrane. This concept can help neurosurgeons to gain better understanding of the surgical anatomy at the level of the tentorial incisura.


Documentation of medial rotation accompanying shoulder flexion. A case report.
We dissected a fresh cadaver to determine which glenohumeral structures causes medial rotation of the humerus during flexion in the sagittal plane. All structures associated with both shoulders were dissected thoroughly. Both elbows were disarticulated to expose the distal end of each humerus to be used as measurement landmarks. We used a universal goniometer for measurements of shoulder flexion. To determine which structures cause passive medial rotation, the associated shoulder muscles, ligaments, and the capsule were individually reflected from the humerus. Passive shoulder flexion to the point where medial rotation started was measured after each structure was resected. The end passive glenohumeral flexion without rotation was 60 degrees after reflection of all musculature and other periarticular shoulder structures. Our results support Steindler's conclusion that during flexion of the humerus beyond the horizontal there is forced rotation caused by ligamentous tension. We also found that the bony configuration of the glenohumeral joints also plays an important role in medial rotation accompanying shoulder flexion.


Natronolimnobius sulfurireducens sp. nov. and Halalkaliarchaeum desulfuricum gen. nov., sp. nov., the first sulfur-respiring alkaliphilic haloarchaea from hypersaline alkaline lakes.
Eight pure cultures of alkaliphilic haloaloarchaea capable of growth by dissimilatory sulfur reduction (previously only shown for neutrophilic haloarchaea) were isolated from hypersaline alkaline lakes in different geographic locations. These anaerobic enrichments, inoculated with sediments and brines, used formate, butyrate and peptone as electron donors and elemental sulfur as an electron acceptor 4 M total Na+ and at pH 9-10. According to 16S rRNA gene sequencing, the isolates fell into two distinct groups. A major group, comprising seven obligate alkaliphilic isolates from highly alkaline soda lakes, represents a new species-level branch within the genus Natronolimnobius (order Natrialbales), while a single moderately alkaliphilic isolate from the less alkaline Searles Lake forms a novel genus-level lineage within the order Haloferacales. The cells of the isolates are either flat rods or coccoid. They are facultative anaerobes using formate or H2 (in the presence of acetate or yeast extract as carbon source), C4-C9 fatty acids or peptone (the major group) as electron donors and either sulfur or DMSO (the major group) as electron acceptors. Aerobic growth is only possible with organic acids and peptone-yeast extract. All isolates are extreme halophiles, growing optimally at 4 M total Na+. On the basis of their unique physiological properties and distinct phylogeny, we propose that the seven isolates from the soda lakes are placed into a novel species, Natronolimnobiussulfurireducens sp. nov. (type strain AArc1T=JCM 30663T=UNIQEM U932T), and the Searles Lake isolate, AArc-SlT, into a new genus and species Halalkaliarchaeum desulfuricum (=JCM 30664T=UNIQEM U999T).


Relation between local acoustic parameters and protein distribution in human and porcine eye lenses.
The purpose of this study is to characterize the eye lens (human, porcine) by acoustic measurements and to investigate whether relations exist with the local protein content. The acoustic measurements were performed with a 'scanning acoustic microscope' (SAM), operating at a frequency of 20 MHz. At this frequency the lateral resolution in the acoustic images was 150 microns. A double-transmission pulse-echo technique was employed to obtain acoustic parameter images of a central, 1-mm-thick slice of the lenses. The two-dimensional images were derived by ultrasonic spectroscopy displaying the ultrasound velocity, the attenuation at 20 MHz and the slope of the attenuation coefficient between 17 and 23 MHz. The images were summarized by profiles along the optical and equatorial axes of these parameters. Acoustic parameters were obtained from human lenses (n = 13) and porcine lenses (n = 10). The protein contents of human lenses were obtained from literature. Additionally, Raman microspectroscopy was used to measure the local protein content of porcine lenses (n = 3). Profiles along the optical and equatorial axes were obtained. The relation between the protein content and the acoustic parameters was obtained qualitatively by comparison of the shape of the profiles and, where possible, quantitatively by calculating the Pearson correlation coefficients. Furthermore, the results have been related to a statistical metastudy found in literature in which the relation between collagen, protein and acoustic velocity in various biological tissues was investigated. The results show a gradual decrease of the magnitude of the acoustic parameters from the centre to the periphery of the porcine eye lens, which is clearly equivalent to the decrease in profiles of the protein content. For the human lenses the acoustic characteristics and the protein content exhibit the same profile, fairly constant in the lens nucleus and decreasing towards the periphery of the lens cortex. Strong positive correlation coefficients for acoustic parameters and protein content for the porcine lens are found. It is concluded that protein concentration related phenomena can be investigated by measuring the acoustic parameters.


Do Patients Retain their Family Physicians after Long-Term Care Entry? A Retrospective Cohort Study.
Older adults value and benefit from the long-standing relationship they have with their family physicians. This dynamic has not been researched in a long-term care (LTC, ie, nursing home) setting. We sought to determine the proportion of LTC residents who retain their community family physician within the first 180 days of LTC, and the resident, physician, and LTC home factors that may influence retention. Population-based retrospective cohort study. Individuals from Ontario, Canada, aged 60 years or older who were newly admitted to a LTC home between April 1, 2014 and March 31, 2017. Residents were indexed upon LTC admission, and their data was linked across ICES databases. Residents were matched to their rostered family physician, and physician retention was defined as having at least 1 visit by their matched physician within 0 to 90 days and 90 to 180 days of LTC admission. Out of 50,089 LTC residents, 12.1% retained their family physicians post-LTC admission. Resident factors associated with reduced odds of retention included physical impairment [odds ratio OR (95% confidence interval, CI) = 0.59 (0.42‒0.83)], cognitive impairment [0.39 (0.33‒0.47)], and a dementia diagnosis [0.80 (0.74‒0.86)]. Physician factors associated with lower retention included a greater distance from the LTC home to the family physician's clinic [30+ kilometers 0.41 (0.35‒0.48)], having a physician who is female [0.90 (0.83‒0.98)], an international medical graduate [0.89 (0.81‒0.97)] or someone who practices in a capitation-based Family Health Organization [0.86 (0.78‒0.95)]. Factors associated with greater odds of retention were residing in a rural LTC home [2.23 (1.78‒2.79)], having a rural family physician [1.70 (1.52‒1.90)], or a family physician who has billed LTC fee codes in the past year [2.64 (2.45‒2.85)]. Few LTC residents retained their family physician post-LTC admission, underscoring this healthcare transition as a breakdown point in relational continuity. Factors that influenced retention included resident health, LTC home geography, and family physician demographics and practice patterns.


Reduced Expression of the Cell Cycle Regulator p27Kip1 within the Invasion Front of Renal Cell Carcinomas Proved to be a Significant Marker for Disease-specific Survival.
The expression of the negative cell cycle regulator p27Kip1 is frequently found to be deregulated in various human cancer types. Whether the expression of p27Kip1 can be used as a prognostic marker for renal cell cancer patients still remains to be clarified. Therefore, in the present investigation the expression of protein within different tissue areas obtained from renal cell carcinomas, their invasion front and corresponding histologically benign renal parenchyma was determined and statistically correlated with several tumor and patient characteristics including the disease-specific long-term survival following surgical treatment. For analysis of p27Kip1 expression in 420 tumor nephrectomy specimens obtained from 420 consecutively included patients, tissue microarrays were used comprising 1260 tissue samples each obtained from the tumor itself, the invasive front as well as the non-malignant surrounding parenchyma. A sufficient follow-up after surgical therapy was available in 251 cases In total, 88 out of 251 patients (35%) had died from tumor progression after a median follow-up of 138 (36-240) months. In univariate survival analysis, decreased expression of p27Kip1 within tissue cores obtained from the invasion front was significantly correlated with the patients' disease-specific long-term survival (p=0.02, log rank test). In contrast, expression of p27Kip1 within the primary tumors was not identified to reveal any prognostically important information. In Cox regression analysis, histological stage and grade (p<0.01), the presence of regional lymph node (p<0.01) or distant metastases at the time of surgery (p<0.01) as well as decreased expression of p27Kip1 (p=0.04) within the invasion front tissue samples independently predicted the disease-specific long-term survival following surgery. Our analysis demonstrated that p27Kip1 is heterogeneously expressed in renal cell carcinomas. Moreover, the results of the present study supports the prognostic value of p27Kip1 protein expression for patients diagnosed with renal cell carcinoma.


Anticoagulant therapy in patients undergoing dental interventions: a critical review of the literature and current perspectives.
Patients treated with oral anticoagulant therapy (OAT) represent an issue to the dentist, as an increasing number of people are using anticoagulant drugs for cardiovascular disease. The choice of an eventual suspension or continuation of anticoagulant therapy is important when considering an efficient management of the patient. Patients in anticoagulant therapy and requiring dental procedures sometimes represent therapeutic concerns especially concerning the suspension of the anticoagulant treatment. At the moment there is no consensus among international experts of a possible discontinuation of therapy before invasive dental procedures. In this paper, the authors try to focus on this topic through a critical review of the literature. Most of the studies suggest the continuation of the anticoagulant treatment with heparin before invasive oral surgical interventions. Based on the data of the literature, two rules must be adopted in clinical practice: 1) maintenance of anticoagulation related to the international normalized ratio (INR); 2) local application of antifibrinolytic agents to ensure a proper hemostatic process. Given the widespread use of anticoagulant drugs in cardiovascular disease, dentists must often face the problem of the therapy and, since there is no consensus on the management of these patients, the authors propose, after a thorough critical review of the literature, the implementation of a multiphase protocol of surgical approach to be implemented with safety in daily clinical practice.


Skill Movement Trajectory Recognition of Freestyle Skiing U-Shaped Field Based on Deep Learning and Multitarget Tracking Algorithm.
Freestyle skiing U-shaped field is a snow sport that uses double boards to perform a series of action skills in a U-shaped pool, which requires very high skills for athletes. In this era of deep learning, in order to develop a more scientific training method, this paper combines multitarget tracking algorithm and deep learning to conduct research in freestyle skiing U-shaped venue skills motion capture. Therefore, this paper combines the convolutional neural network and multitarget tracking algorithm in deep learning to study the human action recognition technology, and then uses the LSTM module to study the freestyle skiing U-shaped venue skills. Finally, this paper designs the training method of the action recognition algorithm of the freestyle U-shaped skiing skills multitarget tracking algorithm based on deep learning. This paper also designs multitarget tracking dataset experiments and model updating experiments. Based on the data of experimental analysis, the training method designed in this paper is optimized, and finally compared with the traditional training method. Compared with the traditional freestyle U-shaped skiing skills training method, the experimental results show that the training method of the freestyle U-shaped skiing skills multitarget tracking algorithm action recognition algorithm is based on deep learning designed in this paper and this improves the skill score by 14.48%. Most professional students are very satisfied with the training method designed in this paper.


SOS2-LIKE PROTEIN KINASE5, an SNF1-RELATED PROTEIN KINASE3-Type Protein Kinase, Is Important for Abscisic Acid Responses in Arabidopsis through Phosphorylation of ABSCISIC ACID-INSENSITIVE5.
Abscisic acid (ABA) plays an essential role in seed germination. In this study, we demonstrate that one SNF1-related protein kinase3-type protein kinase, SOS2-like protein kinase5 (PKS5), is involved in ABA signal transduction via the phosphorylation of an interacting protein, abscisic acid-insensitive5 (ABI5). We found that pks5-3 and pks5-4, two previously identified PKS5 superactive kinase mutants with point mutations in the PKS5 FISL/NAF (a conserved peptide that is necessary for interaction with SOS3 or SOS3-like calcium binding proteins) motif and the kinase domain, respectively, are hypersensitive to ABA during seed germination. PKS5 was found to interact with ABI5 in yeast (Saccharomyces cerevisiae), and this interaction was further confirmed in planta using bimolecular fluorescence complementation. Genetic studies revealed that ABI5 is epistatic to PKS5. PKS5 phosphorylates a serine (Ser) residue at position 42 in ABI5 and regulates ABA-responsive gene expression. This phosphorylation was induced by ABA in vivo and transactivated ABI5. Expression of ABI5, in which Ser-42 was mutated to alanine, could not fully rescue the ABA-insensitive phenotypes of the abi5-8 and pks5-4abi5-8 mutants. In contrast, mutating Ser-42 to aspartate rescued the ABA insensitivity of these mutants. These data demonstrate that PKS5-mediated phosphorylation of ABI5 at Ser-42 is critical for the ABA regulation of seed germination and gene expression in Arabidopsis (Arabidopsis thaliana).


[Transposition of mobile dispersed genes (MDG) after substitution of various chromosome pairs in inbred Drosophila melanogaster strains].
Transpositions of MDG-1, MDG-3 and copia were detected as a result of crosses of the inbred maladaptive LA stock with laboratory stocks, in order to construct the genomes carrying different combinations of the LA or non-La chromosomal pairs. Changes of the mobile gene distributions were revealed in chromosomes of hybrid genotypes, as compared to parental chromosomal pairs. A trivial source of variability of chromosomal molecular structure ensured by crossing over was excluded by inversions which serve as suppressors of crossing over in corresponding crosses. Multiple transpositions of mobile genes in definite chromosomal sites were detected in genotypes carrying chromosomal pair 2 originated from the LA stock. No such transpositions were observed, when the pair 2 was substituted by the chromosome 2 originated from the Swedish-b line or in control crosses, where the LA stock was not involved. Both LA chromosomes 2 and 3 were shown to be the targets of transpositions. Comparison of hot spot transposition sites of MDG-1, as a result of crosses, with the earlier described rare events of spontaneous transpositions in the LA stock, coupled with its fitness increase, revealed that the hot spot sites were shared in both series of experiments. The data obtained show that transpositions of mobile genetic elements may change the genetic and molecular structure of the chromosome involved in crosses, in spite of suppression of crossing over by inversions usually suggested as a tool for keeping chromosomal genetic structure intact.


Estrogen receptor-α and aryl hydrocarbon receptor involvement in the actions of botanical estrogens in target cells.
Botanical estrogen (BE) dietary supplements are consumed by women as substitutes for loss of endogenous estrogens at menopause. To examine the roles of estrogen receptor α (ERα) and aryl hydrocarbon receptor (AhR) and their crosstalk in the actions of BEs, we studied gene regulation and proliferation responses to four widely used BEs, genistein, daidzein, and S-equol from soy, and liquiritigen from licorice root in breast cancer and liver cells. BEs and estradiol (E2), acting through ERα, stimulated proliferation, ERα chromatin binding and target-gene expression. BEs but not E2, acting through AhR, bound to xenobiotic response element-containing chromatin sites and enhanced AhR target-gene expression (CYP1A1, CYP1B1). While E2 and TCDD acted quite selectively through their respective receptors, BEs acted via both receptors, with their AhR activity moderated by negative crosstalk through ERα. Both ERα and AhR should be considered as mediators of the biology and pharmacology of BEs.


Racial regularities: Setting-level dynamics as a source of ethnic-racial socialization.
A substantial literature has focused on how ethnic-racial socialization from parents shapes youths' racial identities and the meanings they attach to their own and others' racial group membership. We argue that a critically important source of information to youth about the meaning and significance of race, and therefore a key source of ethnic-racial socialization, resides in youths' exposure to repeated patterns in the relative social experiences, opportunities, roles, and outcomes experienced by two or more racial groups across levels of the ecological environment. Drawing on Seidman's concept of a "social regularity" we propose the concept of a "racial regularity" to name, describe and define pervasive and repeated intergroup patterns that youth observe through their daily transactions across settings. Additionally, drawing from the socio-cognitive developmental literature, we consider why and how racial regularities may inform youths' racial knowledge. Finally, we illustrate our perspective using existing ethnographies of racial dynamics in schools and neighborhoods vis-à-vis youths' racial knowledge.


Masticatory hypofunction effects induced by BTXA injection of hippocampal neurons in developing rats.
In clinical practice, malocclusion is often encountered during the period of growth and development of individuals. In addition to nutritional imbalance, some studies have found that mastication affects learning and memory ability. Tooth loss and masticatory hypofunction have been suggested as risk factors of Alzheimer disease. However, relatively little research has been done in developing animals. The present study evaluated the relationship between masticatory hypofunction and neuropathological changes of the hippocampus in developing rats. Four-week-old Wistar rats were randomly divided into saline-injected and botulinum toxin type A (BTXA)-injected groups. After an experiment period of 4 weeks, the rats were sacrificed for evaluation of neuropathological changes in the hippocampus through Nissl staining and phosphorylated cyclic AMP (cAMP) response element binding protein (CREB) immunohistochemistry. Nissl staining revealed a significant reduction in the density of neurons in the BTXA-injected rats. The BTXA-injected rats exhibited a decreased level of CREB phosphorylation. The degree of p-CREB immunoreactivity differed significantly between the two groups. The BTXA-injected rats exhibited a reduction in neuron density and phosphorylated CREB, indicating that mastication might influence the learning and memory ability during the growth period. Therefore, it is strongly suggested that malocclusion be corrected as soon as possible during growth and development.


Extended lateral transsylvian approach for basilar bifurcation aneurysms.
The surgical management of aneurysms of the basilar apex is one of the most challenging areas in neurosurgery. Successful treatment of this subgroup of aneurysms is dependent on the mastery of technical nuances that have been pioneered and advanced over the past 4 decades. Although both the traditional transsylvian and subtemporal approaches have distinct advantages, each is associated with significant limitations. In this article, the senior author shares his insights into a hybrid approach: the extended lateral transsylvian approach. This approach combines the assets of the two traditional approaches while eliminating their liabilities.


Contributors to Screening Positive for Mental Illness in Lebanon's Shatila Palestinian Refugee Camp.
This study evaluates contributors to the mental health status of Palestinians, Syrians, and nonrefugee residents of Lebanon's Shatila Refugee Camp. Primary health care clinic patients in Shatila were screened for mental illness between 2012 and 2013 using the K6, the Primary Care Posttraumatic Stress Disorder (PTSD), and the Modified Mini International Neuropsychiatric Interview. Logistic regressions enabled the consideration of potential contributors to participants' positive mental illness screens. The sample (n = 254) included 63.4% Palestinians, 18.5% Syrians, and 18.1% nonrefugees. People lived in the camp for 21.1 years (±17), 63% had stable housing and 78% had war event exposure. Mental illness prevalence was 51.6% in total (34.8% serious mental illness [SMI] alone, 5.1% PTSD alone, 11.4% comorbid SMI/PTSD, and 0.08% comorbid psychotic spectrum disorder SMI/PTSD). For Palestinians and nonrefugees, respectively, stable housing accounted for a 79% and a 98% reduction in positive SMI screen risk. For Syrians, access to paid employment accounted for a 66% risk reduction. Stable living situations and economically productive employment for those trapped in a refugee situation, even in the face of war trauma, seem most important for ensuring reduced mental disorder risk.


Failure of naloxone to modify electroencephalogram interictal epileptiform discharges in patients with primary generalized epilepsy after slation.
Sleep deprivation (SD) is a method widely used to activate EEG epilept oform activity, but the basis of this effect remains unknown. One possibilty is that SD shares a common mechanism with physical and psychological stresses that also precipitate seizures. Because endogenous opioids are released during stress, opioids may play a role in enhancing epileptiform EEG patterns after SD. We report the effects of SD on EEG epileptiform activity in a small but highly homogeneous population of 13 epileptic patients with idiopathic (primary) generalized epilepsy (IGE). SD increased EEG interictal epileptiform discharges (IEDs); this activation was not modified by naloxone (NAL). Our results, in contrast to those of previous investigations of localization-related epilepsy, which showed an increase in IEDs after NAL administration, suggest a possible difference in the mechanism whereby SD enhances IEDs in IGE and localization-related epilepsy.


Serum sodium alterations in SARS CoV-2 (COVID-19) infection: impact on patient outcome.
Hyponatremia is the most common electrolyte disorder in hospitalized patients and occurs in about 30% of patients with pneumonia. Hyponatremia has been associated with a worse outcome in several pathologic conditions The main objective of this study was to determine whether serum sodium alterations may be independent predictors of the outcome of hospitalized COVID-19 patients. In this observational study, data from 441 laboratory-confirmed COVID-19 patients admitted to a University Hospital were collected. After excluding 61 patients (no serum sodium at admission available, saline solution infusion before sodium assessment, transfer from another hospital), data from 380 patients were analyzed. 274 (72.1%) patients had normonatremia at admission, 87 (22.9%) patients had hyponatremia and 19 (5%) patients had hypernatremia. We found an inverse correlation between serum sodium and IL-6, whereas a direct correlation between serum sodium and PaO2/FiO2 ratio was observed. Patients with hyponatremia had a higher prevalence of non-invasive ventilation and ICU transfer than those with normonatremia or hypernatremia. Hyponatremia was an independent predictor of in-hospital mortality (2.7-fold increase vs normonatremia) and each mEq/L of serum sodium reduction was associated with a 14.4% increased risk of death. These results suggest that serum sodium at admission may be considered as an early prognostic marker of disease severity in hospitalized COVID-19 patients.


A modified transmission tip-enhanced Raman scattering (TERS) setup provides access to opaque samples.
The combination of scanning probe microscopy and Raman spectroscopy enables chemical characterization of surfaces at highest spatial resolution. This so-called tip-enhanced Raman scattering (TERS) can be employed for a variety of samples where a label-free characterization or identification of constituents on the nanometer scale is pursued. Present TERS setup geometries are always a compromise for specific dedicated applications and show different advantages and disadvantages: Transmission back-reflection setups, when using immersion objectives with a high numerical aperture, intrinsically provide the highest collection efficiency but cannot be applied for opaque samples. Those samples demand upright setups, at the cost of lower collection efficiency, even though very efficient systems using a parabolic mirror for illumination and collection have been demonstrated. In this contribution it is demonstrated that the incorporation of a dichroic mirror to a transmission TERS setup provides easy access to opaque samples without further modification of the setup.


Effects of a Flipped Classroom Curriculum on Inpatient Cardiology Resident Education.
The flipped classroom is designed to reinvigorate education and utilizes "at-home" time to learn concepts and "in-class" time for clinical application. While some studies have shown positive effects of the flipped classroom in undergraduate medical education, there is a paucity of data on its use in graduate medical education. We hypothesized that a flipped classroom curriculum of Medical Knowledge Self-Assessment Program (MKSAP) content with group case discussions could improve resident knowledge and preparedness in cardiology. Ninety-eight internal medicine residents who rotated on the inpatient cardiology service from March to October 2017 were quasi-randomized into control and intervention groups, with the intervention group assigned MKSAP readings and cases to review on their own, accompanied by weekly case discussion. Pre-post surveys evaluated for change in knowledge and preparedness, quantity of teaching received, and use of MKSAP. A total of 93 of 98 residents (95%) participated in the curriculum. There were 37 of 51 residents (73%) in the control group and 37 of 47 residents (79%) in the intervention group who responded to pre-post assessments. In paired analysis, knowledge score did not improve significantly between the groups, nor did self-reported preparedness, number of teaching sessions per week, or reported MKSAP use. However, all participants had positive perceptions of the curriculum, and the majority felt it should be continued. This flipped classroom curriculum did not affect knowledge, preparedness, or number of teaching sessions for internal medicine residents on a cardiology rotation when compared to usual teaching, although residents experiencing the new model expressed high satisfaction.


Fibrosing cholestatic hepatitis after living related-donor renal transplantation.
A 43-year-old man underwent living related-donor renal transplantation because of chronic renal failure in 1991. During the transplant period, both donor and recipient were seronegative for hepatitis B surface antigen (HBsAg). The donor was seropositive for antibody to hepatitis B surface antigen (anti-HBs) due to hepatitis B virus (HBV) vaccination. After transplantation, FK506 and methylprednisolone had been administered to the patient as immunosuppressants. In 1993, HBsAg appeared in his serum. His alanine aminotransferase level elevated gradually during 1995 and then in 1996, general fatigue, ascites and jaundice developed. At this time his serum was positive for hepatitis B e antibody, contained more than 100000 Meq/mL HBV-DNA and 100% precore mutant. Despite subsequent intensive therapy, liver dysfunction progressed and this patient died of hepatic failure 2 months following admission. At autopsy, the liver exhibited cholestasis, fibrosis extending from the portal tracts, mild inflammation and hepatocytes with a ground-glass appearance. In addition, HBsAg and hepatitis B core antigens had accumulated in the hepatocytes. Consequently, the final diagnosis was fibrosing cholestatic hepatitis (FCH) due to precore mutant HBV infection contracted after renal transplantation. It is unclear when and where the recipient liver became HBV infected. Nevertheless, after renal transplantation, while receiving immunosuppressive drugs, HBV appeared to have the potential to cause hepatic failure and FCH may have been a fatal complication for the recipient.


Development of highly potent melanogenesis inhibitor by in vitro, in vivo and computational studies.
The present work describes the synthesis of few hydroxylated amide derivatives as melanogenesis inhibitors. In vitro, in vivo and computational studies proved that compound 6d is a highly potent melanogenesis inhibitor compared to standard kojic acid. The title amides 4a-e and 6a-e were synthesized following simple reaction routes with excellent yields. Most of the synthesized compounds exhibited good mushroom tyrosinase inhibitory activity, but compound 6d showed excellent activity (IC50 0.15 µM) compared to standard kojic acid (IC50 16.69 µM). Lineweaver-Burk plots were used for the determination of kinetic mechanism, and it was found that compounds 4c and 6d showed non-competitive inhibition while 6a and 6b showed mixed-type inhibition. The kinetic mechanism further revealed that compound 6d formed irreversible complex with the target enzyme tyrosinase. The Ki values determined for compounds 4c, 6a, 6b and 6d are 0.188, 0.84, 2.20 and 0.217 µM respectively. Results of human tyrosinase inhibitory activity in A375 human melanoma cells showed that compound 6d exhibited 91.9% inhibi-tory activity at a concentration of 50 µg/mL. In vivo cytotoxicity evaluation of compound 6d in zebrafish embryos showed that it is non-toxic to zebrafish. Melanin depigmentation assay performed in zebrafish indicated that compound 6d possessed greater potential in decreasing melanin contents compared to kojic acid at the same concentration. Computational studies also supported the wet lab findings as compound 6d showed a highest binding affinity with the target protein (PDBID: 2Y9X) with a binding energy value of -7.90 kcal/mol. Molecular dynamic simulation studies also proved that amide 6d formed the most stable complex with tyrosinase. Based upon our in vitro, in vivo and computational studies, we propose that compound 6d is a promising candidate for the development of safe cosmetic agent.


The remarkable axial lability of iron(III) corrole complexes.
Flash photolysis of nitrosyl tris(aryl)corrolate complexes of iron(III), Fe(Ar(3)C)(NO) (Ar(3)C(3-) = 5,10,15-tris(4-nitro-phenyl)corrolate (TNPC(3-)), 5,10,15-tris(phenyl)corrolate (TPC(3-)) or 5,10,15-tris(4-tolyl)corrolate (H(3)TTC(3-))) leads to NO labilization. This is followed by the rapid reaction of NO with Fe(III)(C) to regenerate the starting complex. The second-order rate constants for the back reactions (k(NO)) were determined to be many orders of magnitude faster than the corresponding reactions of ferric porphyrin complexes and indeed are reminiscent of the very large values seen for those of the corresponding ferrous porphyrin analogues. These data are interpreted in terms of the strongly electron-donating character of the trianionic corrolate ligand and the likely triplet electronic configuration of the iron(III) complex. These reduce the affinity of the metal centers to Lewis bases to the extent that axial ligands bind very weakly or not at all. This property is illustrated by the nearly identical k(NO) values ( approximately 10(9) M(-1) s(-1) at 295 K) recorded for the back reaction of Fe(III)(TNPC) with NO after flash photolysis of Fe(TNPC)(NO) in toluene solution and in THF solution. Softer Lewis bases have a somewhat greater effect; for example, studies in 1:9 (v:v) acetonitrile:toluene and 1:9 pyridine:toluene gave k(NO) values decreased approximately 33% and approximately 85%, respectively, but these both remain >10(8) M(-1) s(-1). The potential roles of Lewis bases in controlling the dynamics of NO addition to Fe(TNPC) in toluene was investigated in greater detail by determining the rates as a function of pyridine concentration over a wide range (10(-4) to 2.5 M). These data suggest that, while a monopyridine complex, presumably Fe(TNPC)(py), is readily formed (K approximately 10(4) M), this species is about one-sixth as reactive as Fe(TNPC) itself. It appears that a much less reactive bis(pyridine) complex also is formed at high [py] but the equilibrium constant is quite small (<1 M(-1)).