Transplantation for inherited metabolic disorders of the liver.
Inherited metabolic diseases that affect the liver are a frequent cause of liver failure in children, but other disorders more commonly cause liver failure in adulthood where they may present with chronic liver disease and, less frequently, with acute liver failure. The identification of the underlying genetic defect for many of these inherited disorders has improved our understanding of their pathophysiology and impacted on the indications for and timing of liver transplant, yielding better outcomes. Screening for disease and genetic counseling of family members may help prevent adverse outcomes in relatives of affected individuals. Timely liver transplantation offers correction of the inherited metabolic defect and restores liver function when medical therapy is not possible or when complications of liver disease arise. Some inherited metabolic diseases have their defect based in the liver and lead not to liver disease, but to other end organ damage. Earlier detection of these disorders may prevent pathological injury by treatment of the underlying disease or by pre-emptive liver transplant. In some instances where damage of other organs has already occurred, dual organ transplant with liver and another organ may be needed. Improvement in the technical aspects of performing liver transplantation and posttransplant care has led to better outcomes for those with inherited metabolic disorders of the liver.


Surviving the COVID-19 pandemic: navigating the recovery of breast imaging services in a safety-net hospital.
The purpose of this study was to determine the impact of COVID-19 on county safety-net breast imaging services and describe the steps taken to actively manage and mitigate delays. This was an IRB exempt retrospective review of our county safety-net breast imaging practice analyzed for 4 distinct time periods: (1) "Shut-down period": March 17, 2020 to May 17, 2020; (2) "Phased re-opening": May 18, 2020 to June 30, 2020; (3) "Ramp-up": July 1, 2020 to September 30, 2020; and (4) "Current state": October 1, 2020 to September 30, 2021. These time periods were compared to identical time periods 1 year prior. For "Current state," given that the 1-year prior comparison encompassed the first 3 periods of the pandemic, the identical time period 2 years prior was also compared. Our safety-net practice sustained significant volume losses during the first 3 time periods with a 99% reduction in screening mammography in the shut-down period. Cancers diagnosed decreased by 17% in 2020 (n = 229) compared to 2019 (n = 276). By implementing multiple initiatives that targeted improved access to care, including building community-hospital partnerships and engagement through outreach events and a community education roadshow, we were able to recover and significantly exceed our pandemic screening volumes by 48.1% (27,279 vs 18,419) from October 1, 2020 to September 30, 2021 compared to the identical time period 1 year prior, and exceed our pre-pandemic screening volume by 17.4% (27,279 vs 23,234) compared to the identical time period 2 years prior. Through specific community outreach programs and optimized navigation, our safety-net breast imaging practice was able to mitigate the impact of COVID-19 on our patient population by increasing patient engagement and breast imaging services.


Biliary atresia and liver transplantation in the United States: A contemporary analysis.
Biliary atresia (BA) remains the number one indication for paediatric liver transplantation (LT) worldwide but is an uncommon indication for older LT recipients. The impact of recent donor allocation changes, pervasive organ shortage and evolving LT practices on the BA LT population is unknown. We identified patients who underwent LT between January 2010 and December 2021 using the UNOS database. We compared clinical outcomes between patients with BA and those with non-BA cholestatic liver disease. Groups were stratified by age, <12 years (allocated via PELD system) and ≥12 years (allocated via MELD system). Waitlist outcomes were compared using competing-risk regression analysis, graft survival rates were compared using Kaplan-Meier time-to-event analysis and Cox proportional hazards modelling provided adjusted estimates. There were 2754 BA LT waitlist additions and 2206 BA LTs (1937 <12 years [younger], 269 ≥12 years [older]). There were no differences in waitlist mortality between BA and non-BA cholestatic patients. Among BA LT recipients, there were 441 (20.0%) living-donor liver transplantations (LDLT) and 611 (27.7%) split deceased-donor LTs. Five-year graft survival was significantly higher among BA versus non-BA cholestatic patients in the older group (88.3% vs. 79.5%, p < .01) but not younger group (89.3% vs. 89.5%). Among BA LT recipients, improved graft outcomes were associated with LDLT (vs. split LT: HR: 2, 95% CI: 1.03-3.91) and higher transplant volume (volume >100 vs. <40 BA LTs: HR: 3.41, 95% CI: 1.87-6.2). Liver transplant outcomes among BA patients are excellent, with LDLT and higher transplant centre volume associated with optimal graft outcomes.


Functional imaging of the angiogenic switch in a transgenic mouse model of human breast cancer by dynamic contrast enhanced magnetic resonance imaging.
Tumour progression depends on several sequential events that include the microenvironment remodelling processes and the switch to the angiogenic phenotype, leading to new blood vessels recruitment. Non-invasive imaging techniques allow the monitoring of functional alterations in tumour vascularity and cellularity. The aim of this work was to detect functional changes in vascularisation and cellularity through Dynamic Contrast Enhanced (DCE) and Diffusion Weighted (DW) Magnetic Resonance Imaging (MRI) modalities during breast cancer initiation and progression of a transgenic mouse model (BALB-neuT mice). Histological examination showed that BALB-neuT mammary glands undergo a slow neoplastic progression from simple hyperplasia to invasive carcinoma, still preserving normal parts of mammary glands. DCE-MRI results highlighted marked functional changes in terms of vessel permeability (K(trans) , volume transfer constant) and vascularisation (vp , vascular volume fraction) in BALB-neuT hyperplastic mammary glands if compared to BALB/c ones. When breast tissue progressed from simple to atypical hyperplasia, a strong increase in DCE-MRI biomarkers was observed in BALB-neuT in comparison to BALB/c mice (K(trans) = 5.3 ± 0.7E-4 and 3.1 ± 0.5E-4; vp = 7.4 ± 0.8E-2 and 4.7 ± 0.6E-2 for BALB-neuT and BALB/c, respectively) that remained constant during the successive steps of the neoplastic transformation. Consistent with DCE-MRI observations, microvessel counting revealed a significant increase in tumour vessels. Our study showed that DCE-MRI estimates can accurately detect the angiogenic switch at early step of breast cancer carcinogenesis. These results support the view that this imaging approach is an excellent tool to characterize microvasculature changes, despite only small portions of the mammary glands developed neoplastic lesions in a transgenic mouse model.


Stereotactic Radiotherapy in the Management of Ventricular Tachycardias: More Questions than Answers?
Stereotactic body radiotherapy is a recent promising therapeutic alternative in cases of failed catheter ablation for recurrent ventricular tachycardias (VTs) in patients with structural heart disease. Initial clinical experience with a single radiation dose of 25 Gy shows reasonable efficacy in the reduction of VT recurrences with acceptable acute toxicity. Many unanswered questions remain, including unknown mechanism of action, variable time to effect, optimal method of substrate targeting, long-term safety, and definition of an optimal candidate for this treatment."


Dynamics of Fat Mass in DUhTP Mice Selected for Running Performance - Fat Mobilization in a Walk.
Reduction of body fat can be achieved by dietary programs and/or aerobic exercise training. More convenient methods to rid the body of excess fat are needed. However, it is unclear whether it is possible to more easily lose body weight at all. DUhTP mice bred through phenotype selection for high treadmill performance and unselected controls were voluntarily physically active in a running wheel over a period of 3 weeks. Phenotypical data were collected, and subcutaneous fat was analyzed for expression of mitochondria-relevant proteins. Voluntary physical activity over 3 weeks exclusively in DUhTP mice severely reduced subcutaneous (-38%; p < 0.05) and epididymal (-32%; p < 0.05) fat. Following mild physical activity, subcutaneous fat derived from DUhTP mice showed increased levels of long chain acyl dehydrogenase (LCAD; +230%; p < 0.05) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α; p < 0.01). Mitochondrial transcription factor A (Tfam) expression was similar in both sedentary genotypes but physical activity increased Tfam levels exclusively in DUhTP (p < 0.05). Our findings indicate that the mitochondrial mass is highly active in DUhTP mice and responsive even to mild physical activity. While genetic predisposition could not prevent fat accretion in DUhTP mice, voluntary activity was sufficient to reduce excess body fat almost completely.


Multi-targeted dihydrazones as potent biotherapeutics.
Hydrazone compounds were considered as a useful moiety in drug design development. Therefore, these studies were aimed at the synthesis of new dihydrazones and were screened for their in vitro H+/K+-ATPase and anti-inflammatory activities. The results revealed that compounds 9 (22 ± 0.62 µg/mL), 10 (26 ± 0.91 µg/mL), 15 (24 ± 0.44 µg/mL), 16 (28 ± 0.63 µg/mL), 17 (12 ± 0.38 µg/mL), 18 (14 ± 0.47 µg/mL), 19 (26 ± 0.54 µg/mL), 20 (16 ± 0.41 µg/mL), 25 (06 ± 0.68 µg/mL) and 26 (08 ± 0.43 µg/mL) showed excellent H+/K+-ATPase activity and their IC50 value were lower than the standard drug Omerazole (48 ± 0.12 µg/mL). Compounds 5 (28 ± 0.65 µg/mL), 6 (24 ± 0.61 µg/mL), 7 (28 ± 0.64 µg/mL), 8 (26 ± 0.45 µg/mL), 11 (30 ± 0.74 µg/mL), 12 (28 ± 0.40 µg/mL), 13 (32 ± 0.24 µg/mL), 14 (30 ± 0.55 µg/mL) and 21 (08 ± 0.47 µg/mL), 22 (12 ± 0.47 µg/mL), 23 (10 ± 0.51 µg/mL) and 24 (14 ± 0.84 µg/mL) showed better anti-inflammatory activity compared to standard indomethacin (44 ± 0.15 µg/mL). The structure activity relationship (SAR) showed that, electron donating groups (OH, OCH3) favored the H+/K+-ATPase and antioxidants activity, whereas, electron withdrawing groups (F, Cl, Br and NO2) favored the anti-inflammatory activity. Furthermore, molecular docking study was performed to investigate the binding interactions of the most active analogs with the active site of H+/K+-ATPase enzyme. Compounds 25 (G-score = -9.063) and 26 (G-score = -8.977) showed the highest docking G-scores for H+/K+-ATPase inhibition activity.


Prognosis in survivors of acute myocardial infarction occurring at age 70 years or older.
To identify prognostic factors in elderly persons who have survived acute myocardial infarction, 113 patients, aged 70 to 91 years (median 76), were followed for an average of 122 months (range 94 to 170). Eighty-four patients died, 61 (73%) from coronary artery disease. Overall mortality rates were 20.4% at 1 year, 30.1% at 2 years, 31.9% at 3 years, 45.1% at 4 years, 51.3% at 5 years and 69% at 10 years. Almost half (44%) of all deaths from coronary causes occurred in the first 2 years. Univariate analysis of 21 historical and clinical variables found several of prognostic significance: age, prior myocardial infarction, previous diastolic hypertension, history of diabetes mellitus, history of heart failure, presence of rales above the scapula, ventricular gallop, Killip class, cardiomegaly on admission chest x-ray and prescribing digitalis or diuretic at discharge. When these prognostic factors were entered into multivariate analysis, only Killip class (p less than 0.001) emerged as an independent predictor of survival.


Umami detection threshold among children of different ethnicities and its correlation with various indices of obesity and blood pressure.
Sensitivity to savory taste has been linked to high consumption of savory foods and increased risks of obesity and hypertension. However, there are limited studies that investigate whether obesity indices are correlated with the differences in umami taste perception, particularly in children. This study aimed to investigate the umami detection threshold among children of different ethnicities and the threshold's correlation with obesity indices and blood pressure. A total of 140 subjects were recruited and consisted of a nearly equal distribution of children from three main ethnicities (37.2% Malays, 31.4% Chinese, 31.4% Indians). Umami detection threshold was measured using the two-alternative, forced-choice staircase procedure. Body weight, height, waist circumference and blood pressure of children were measured. Body composition was assessed using bioelectrical impedance analysis (BIA). Mean umami detection threshold was 1.22 ± 1.04 mM and there were no observable differences attributable to the subjects' ethnicities. Body fat percentage was negatively correlated (r = -0.171, p < 0.05), while lean body mass percentage was positively correlated (r = 0.171, p < 0.05) with umami detection threshold. These findings revealed that umami taste perception correlated with children's body composition, but not other anthropometric indicators and blood pressure. Future studies should explore the correlation between umami taste perception and children's total dietary intake.


Visible-Light-Driven Thioesterification of Aryl Halides with Potassium Thiocarboxylates: Transition-Metal Catalyst-Free Incorporation of Sulfur Functionalities into an Aromatic Ring.
Reactions of acceptor-substituted aryl iodides and bromides with potassium thiocarboxylates under white light irradiation allow for the preparation of S-aryl thioesters including synthetically versatile S-aryl thioacetates. This transition-metal and external photocatalyst-free method features extremely mild reaction conditions compared with those used in transition-metal-catalyzed protocols. Reactions proceed via the initial formation of an electron donor-acceptor (EDA) complex in the ground state, which was supported by UV-vis spectra. Electron paramagnetic resonance (EPR) spin-trapping experiments using phenyl-N-tert-butylnitrone (PBN) have revealed the radical nature of the reaction.


Clinical and Translational Pharmacology Considerations for Anti-infectives Approved Under the FDA Animal Rule.
The US Food and Drug Administration's Animal Rule provides a pathway for approval of drugs and biologics aimed to treat serious or life-threatening conditions wherein traditional clinical trials are either not ethical or feasible. In such a scenario, determination of safety and efficacy are based on integration of data on drug disposition and drug action collected from in vitro models, infected animals, and healthy volunteer human studies. The demonstration of clinical efficacy and safety in humans based on robust, well-controlled animal studies is filled with challenges. This review elaborates on the challenges in the translation of data from in vitro and animal models to human dosing for antimicrobials. In this context, it discusses precedents of drugs approved under the Animal Rule, along with the approaches and guidance undertaken by sponsors.


Evaluation of Adherence and Persistence Differences Between Adalimumab Citrate-Free and Citrate Formulations for Patients with Immune-Mediated Diseases in the United States.
Our aim was to evaluate patient adherence and persistence with citrate-free adalimumab (ADA-CF), introduced in 2018 to reduce injection-site pain, compared with citrate-containing adalimumab (ADA-C). This was a retrospective cohort study using a US claims database (IBM® MarketScan® Commercial and Medicare Supplemental Claims Database) from February 2018 to January 2020. Patients at least 18 years of age who were naïve to adalimumab 6 months before the index date (date of first adalimumab claim) and with at least 12 months of continuous medical and pharmacy coverage were eligible for the study. Adherence was assessed by determining the proportion of days covered (PDC) and the percentage of patients with PDC ≥ 80% during the 12-month follow-up period. Persistence was evaluated by measuring the rate of discontinuation and days to discontinuation (i.e., time on treatment) from the index date over the 12-month follow-up period. Continuous adherence outcomes (PDC) were evaluated using linear regression models. Binary adherence outcomes (PDC ≥ 80%) were assessed using logistic regression models. Kaplan-Meier analysis and Cox proportional hazards models were used to assess persistence outcomes. There were 2195 and 1005 patients in the ADA-CF and ADA-C cohorts, respectively, with most using adalimumab for rheumatoid arthritis (ADA-CF 29.7%, ADA-C 27.2%) and psoriasis (ADA-CF 24.5%, ADA-C 31.9%). Significantly greater adherence was achieved with ADA-CF compared with ADA-C (mean PDC [standard deviation] 0.68 [0.30] vs 0.61 [0.32], P < 0.0001). A significantly greater percentage of patients receiving ADA-CF (47.2%) vs ADA-C (39.6%) had PDC ≥ 80% (P < 0.0001). The discontinuation rate was significantly lower for the ADA-CF cohort (46.4%) compared with ADA-C (55.9%, P < 0.0001), resulting in a 27% lower likelihood of discontinuation during the 12-month follow-up period (hazard ratio 0.73; 95% confidence interval 0.66, 0.82; P < 0.0001) and longer time on treatment (260 vs 232 days, P < 0.0001). Adherence and persistence are significantly improved with ADA-CF compared with ADA-C.


Iron, zinc and magnesium nutrition and athletic performance.
During the last decade there has been considerable interest in the idea that dietary trace elements supplementation can result in an improvement in athletic performance. The current paper discusses this idea as it relates to 3 elements: iron, zinc and magnesium. Emphasis has been placed on examining the implicit assumptions underlying the idea that mineral supplements help the athlete. These assumptions include the beliefs that the athlete has a higher than normal requirement for minerals; that the athlete consumes a diet inadequate in these minerals; and that a marginal deficiency of these elements has a direct effect on athletic performance. Evidence is presented that both iron deficiency and magnesium deficiency can result in a significant reduction in exercise performance; however, the biochemical lesions underlying the reductions in exercise performance have not been identified. There is evidence that dietary magnesium intake may be suboptimal in some individuals, thus dietary supplementation of this element may be useful in some population groups. Excessive magnesium supplementation is not thought to be a serious health problem. Similar to magnesium dietary iron supplements can improve athletic performance in individuals severely deficient in this element. However, few studies have documented a need for iron supplements in healthy athletes. If iron supplements are used, it is important that the level of supplementation is not excessive, as excess iron in the diet can result in an induced zinc deficiency. In marked contrast to iron and magnesium, there is little evidence for the idea that zinc deficiency influences exercise performance in humans. Despite this fact, zinc supplements have been widely advocated for the athlete, as it is known that intense exercise can result in changes in zinc metabolism. If zinc supplements are used, it is important that they are not excessive, as excess zinc in the diet can result in a secondary copper deficiency.


Discovery of quorum quenchers targeting the membrane-embedded sensor domain of the Staphylococcus aureus receptor histidine kinase, AgrC.
We combined mRNA display technology with lipid-nanodisc based selections and identified high-affinity ligands targeting the integral membrane sensor domain of the histidine kinase AgrC as potent inhibitors of Staphylococcus aureus quorum sensing-modulated virulence. Our study highlights the potential of this integrated approach for identifying functional modulators of integral membrane proteins.


Impact of Tumor Location on Patient Outcomes in Small Bowel Cancers.
Small bowel cancers are rare gastrointestinal malignancies and tumor location impact on outcomes is unclear. A retrospective review was performed on stage I to IV small bowel cancer cases from 2000 to 2017 in British Columbia, Canada. Baseline patient characteristics, disease-free survival (DFS) and overall survival (OS) were evaluated by tumor location and systemic therapy use patterns were summarized. Of 340 patients included, primary tumor distribution was: duodenum (51.2%), ileum (19.1%), jejunum (18.5%), and unspecified (11.2%). Median DFS for stage I to III disease was 37.7, 49.1, and 26.7 months for duodenal, jejunal, and ileal tumors (P = .018). Median OS was 9.6, 35.2, and 20.1 months for duodenal, jejunal, and ileal tumors (P < .0001). Compared to duodenal primaries, both jejunal and ileal tumors were associated with significantly improved OS (HR 0.43, P < .001 for jejunal; HR 0.71, P = .035 for ileal). Adjuvant therapy was given to 21.6% of stage II and 50.6% of stage III cancers. Among patients with metastatic disease, median OS was 4.2, 11.4, and 6.9 months for duodenal, jejunal, and ileal tumors (P = .0019). Jejunal tumors had the best prognosis (HR 0.48, P = .001 vs. duodenum). Survival differences exist when small bowel cancers were assessed by tumor location, and jejunal tumors portended better prognosis overall.


Genome-Wide Identification and Analysis of Collar Region-Preferential Genes in Rice.
The collar region plays a crucial role in leaf angle formation and plant architecture, which is important for improving crop yield given the challenges of diminishing arable land and changing environmental conditions. To determine collar region-preferential genes (CRPGs) affecting plant architecture and crop yield, we conducted genome-wide transcriptomic analysis. By integrating our RNA sequencing data with public rice anatomical expression data, we identified 657 CRPGs. Verification involved testing six randomly selected CRPGs, all of which exhibited collar-preferential expression. The functional significance of CRPGs was assessed via Gene Ontology enrichment analysis, utilizing MapMan and KEGG, and literature analysis provided additional information for characterized CRPGs. Our findings revealed links between manipulating leaf angle and phytohormone-related pathways and stress responses. Moreover, based on the CRPGs, five transcription factors downstream of the liguleless 1 (LG1) gene were identified. Overall, the identified CRPGs provide potential targets for further research and breeding applications aimed at improving crop productivity by manipulating leaf architecture.


Antioxidant effect of Azadirachta indica on high fat diet induced diabetic Charles Foster rats.
Oxidative stress plays a major role in the pathogenesis of both types of diabetes mellitus. Excessively high levels of free radicals cause damage to cellular proteins, membrane lipids and nucleic acids, and eventually cell death. The present study was designed to investigate the possible effect of Azadirachta indica leaf extract in high fat diet induced diabetic Charles Foster rats. The increased level of lipidperoxidation and altered levels of enzymatic (superoxide dismutase, glutathione peroxidase and catalase) and non-enzymatic (glutathione) antioxidants were seen in high fructose fed animals. The treatment with A. indica leaf extract significantly normalized the altered levels of lipid peroxidation and antioxidant status at 400 mg/kg b.w. dose. The A. indica leaf extract was also tested for in vitro inhibition of generation of superoxide anion and hydroxyl free radical in both enzymatic and non-enzymatic systems. The A. indica leaf extract was found to inhibit generation of superoxide anion and hydroxyl free radical significantly at 200 μg/ml concentration. Data of present study demonstrated that the A. indica leaf extract has both antidiabetic and antioxidant properties.


Ultrasmall iron-quercetin metal natural product nanocomplex with antioxidant and macrophage regulation in rheumatoid arthritis.
Oxidative stress, due to the disruption of the balance between reactive oxygen species (ROS) generation and the antioxidant defense system, plays an important role in the pathogenesis of rheumatoid arthritis (RA). Excessive ROS leads to the loss of biological molecules and cellular functions, release of many inflammatory mediators, stimulate the polarization of macrophages, and aggravate the inflammatory response, thus promoting osteoclasts and bone damage. Therefore, foreign antioxidants would effectively treat RA. Herein, ultrasmall iron-quercetin natural coordination nanoparticles (Fe-Qur NCNs) with excellent anti-inflammatory and antioxidant properties were constructed to effectively treat RA. Fe-Qur NCNs obtained by simple mixing retain the inherent ability to remove ROS of quercetin and have a better water-solubility and biocompatibility. In vitro experiments showed that Fe-Qur NCNs could effectively remove excess ROS, avoid cell apoptosis, and inhibit the polarization of inflammatory macrophages by reducing the activation of the nuclear factor-κ-gene binding (NF-κB) pathways. In vivo experiments showed that the swollen joints of mice with rheumatoid arthritis treated with Fe-Qur NCNs significantly improved, with Fe-Qur NCNs largely reducing inflammatory cell infiltration, increasing anti-inflammatory macrophage phenotypes, and thus inhibiting osteoclasts, which led to bone erosion. This study demonstrated that the new metal-natural coordination nanoparticles could be an effective therapeutic agent for the prevention of RA and other diseases associated with oxidative stress.


SIGIRR deficiency contributes to CD4 T cell abnormalities by facilitating the IL1/C/EBPβ/TNF-α signaling axis in rheumatoid arthritis.
Rheumatoid arthritis (RA) is a complex autoimmune disease with multiple etiological factors, among which aberrant memory CD4 T cells activation plays a key role in the initiation and perpetuation of the disease. SIGIRR (single immunoglobulin IL-1R-related receptor), a member of the IL-1 receptor (ILR) family, acts as a negative regulator of ILR and Toll-like receptor (TLR) downstream signaling pathways and inflammation. The aim of this study was to investigate the potential roles of SIGIRR on memory CD4 T cells in RA and the underlying cellular and molecular mechanisms. Single-cell transcriptomics and bulk RNA sequencing data were integrated to predict SIGIRR gene distribution on different immune cell types of human PBMCs. Flow cytometry was employed to determine the differential expression of SIGIRR on memory CD4 T cells between the healthy and RA cohorts. A Spearman correlation study was used to determine the relationship between the percentage of SIGIRR+ memory CD4 T cells and RA disease activity. An AIA mouse model (antigen-induced arthritis) and CD4 T cells transfer experiments were performed to investigate the effect of SIGIRR deficiency on the development of arthritis in vivo. Overexpression of SIGIRR in memory CD4 T cells derived from human PBMCs or mouse spleens was utilized to confirm the roles of SIGIRR in the intracellular cytokine production of memory CD4 T cells. Immunoblots and RNA interference were employed to understand the molecular mechanism by which SIGIRR regulates TNF-α production in CD4 T cells. SIGIRR was preferentially distributed by human memory CD4 T cells, as revealed by single-cell RNA sequencing. SIGIRR expression was substantially reduced in RA patient-derived memory CD4 T cells, which was inversely associated with RA disease activity and related to enhanced TNF-α production. SIGIRR-deficient mice were more susceptible to antigen-induced arthritis (AIA), which was attributed to unleashed TNF-α production in memory CD4 T cells, confirmed by decreased TNF-α production resulting from ectopic expression of SIGIRR. Mechanistically, SIGIRR regulates the IL-1/C/EBPβ/TNF-α signaling axis, as established by experimental evidence and cis-acting factor bioinformatics analysis. Taken together, SIGIRR deficiency in memory CD4 T cells in RA raises the possibility that receptor induction can target key abnormalities in T cells and represents a potentially novel strategy for immunomodulatory therapy.


Crystal growth in confinement.
The growth of crystals confined in porous or cellular materials is ubiquitous in Nature and forms the basis of many industrial processes. Confinement affects the formation of biominerals in living organisms, of minerals in the Earth's crust and of salt crystals damaging porous limestone monuments, and is also used to control the growth of artificial crystals. However, the mechanisms by which confinement alters crystal shapes and growth rates are still not elucidated. Based on novel in situ optical observations of (001) surfaces of NaClO3 and CaCO3 crystals at nanometric distances from a glass substrate, we demonstrate that new molecular layers can nucleate homogeneously and propagate without interruption even when in contact with other solids, raising the macroscopic crystal above them. Confined growth is governed by the peculiar dynamics of these molecular layers controlled by the two-dimensional transport of mass through the liquid film from the edges to the center of the contact, with distinctive features such as skewed dislocation spirals, kinetic localization of nucleation in the vicinity of the contact edge, and directed instabilities. Confined growth morphologies can be predicted from the values of three main dimensionless parameters.


Adding pyrrolysine to the Escherichia coli genetic code.
Pyrrolysyl-tRNA synthetase and its cognate suppressor tRNA(Pyl) mediate pyrrolysine (Pyl) insertion at in frame UAG codons. The presence of an RNA hairpin structure named Pyl insertion structure (PYLIS) downstream of the suppression site has been shown to stimulate the insertion of Pyl in archaea. We study here the impact of the presence of PYLIS on the level of Pyl and the Pyl analog N-epsilon-cyclopentyloxycarbonyl-l-lysine (Cyc) incorporation using a quantitative lacZ-luc tandem reporter system in an Escherichia coli context. We show that PYLIS has no effect on the level of neither Pyl nor Cyc incorporation. Exogenously supplying our reporter system with d-ornithine significantly increases suppression efficiency, indicating that d-ornithine is a direct precursor to Pyl.


Assembly landscape for the bacterial large ribosomal subunit.
Assembly of ribosomes in bacteria is highly efficient, taking ~2-3 min, but this makes the abundance of assembly intermediates very low, which is a challenge for mechanistic understanding. Genetic perturbations of the assembly process create bottlenecks where intermediates accumulate, facilitating structural characterization. We use cryo-electron microscopy, with iterative subclassification to identify intermediates in the assembly of the 50S ribosomal subunit from E. coli. The analysis of the ensemble of intermediates that spans the entire biogenesis pathway for the 50 S subunit was facilitated by a dimensionality reduction and cluster picking approach using PCA-UMAP-HDBSCAN. The identity of the cooperative folding units in the RNA with associated proteins is revealed, and the hierarchy of these units reveals a complete assembly map for all RNA and protein components. The assembly generally proceeds co-transcriptionally, with some flexibility in the landscape to ensure efficiency for this central cellular process under a variety of growth conditions.


Arthroscopic Anterior Shoulder Capsular Reconstruction Using Human Acellular Dermal Graft in Conjunction With Anatomic Glenoid Reconstruction.
Capsular insufficiency of the shoulder associated with glenoid bone loss poses a major challenge to orthopaedic surgeons in the management of recurrent anterior instability. Multiple surgical techniques have been described in the literature with varying rates of success, and the majority of these are open techniques. We present a complete arthroscopic technique for anterior capsular reconstruction using acellular human dermal allograft patch in conjunction to an anatomic glenoid reconstruction using a distal tibial allograft in the lateral decubitus position. If the capsular insufficiency is determined irreparable after glenoid reconstruction, the acellular human dermal graft patch is prepared, inserted into the shoulder joint, and appropriately fixed using suture anchors on both glenoid and humerus, all through arthroscopic portals.


Predictors of three dose on-time compliance with HPV4 vaccination in a disadvantaged, underserved, safety net population in the US Midwest.
HPV4 is approved as a series of three timed doses expected to result in efficacy against specific HPV infections. Completion rates in the US are quite low at the same time the structure of health care delivery is changing. The aim of this study was to determine how the patient-, clinic- and systems-level characteristics facilitate or hinder the timely completion of three HPV4 doses in both adolescent and adult female populations in a high-risk safety net population. This is a retrospective study in which patient-, clinic- and systems-level data are abstracted from the electronic medical record (EMR) for all females 10-26 years of age receiving at least one dose of HPV4 between July 1, 2006 and October 1, 2009. Adults were more likely to complete the three dose series if they had at least one health care visit in addition to their HPV4 visit, (aOR = 1.54 (95% CI:1.10, 2.15). Adults were less likely to complete the three dose series if they received their second HPV4 dose at an acute health care, preventive care or postpartum visits compared to an HPV4-only visit (aOR = 0.31 (95% CI: 0.13, 0.72), 0.12 (0.04, 0.35), 0.30 (0.14, 0.62), respectively). Hispanic adults were less likely than whites to complete the series (aOR = 0.24 (95% CI:0.10, 0.59). 39% of adolescents who completed two doses completed the series. HPV4 is more likely to be effectively administered to adults in a safety net population if multiple health care needs can be met within the health care system.


The effect of Rb+, Cs+, and T1+ on the gramicidin A-induced conductance changes of the skeletal muscle cell membrane.
The channel-forming antibiotic gramicidin A increases the K+ conductance of frog skeletal muscle fibres in isotonic K2SO4 solution. The conductance of the gramicidin channel is not affected by Rb+ or Cs+, but is reduced by T1+. In contrast, the conductance of the normal K+ channel is decreased by Rb+ and Cs+ but is nearly unaffected by 5 and 10 mM T1+. The results suggest differences in the cation permeation through the gramicidin and the K+ channel of the muscle cell membrane.


Retrospective selection of elite parent trees using paternity testing with microsatellite markers: an alternative short term breeding tactic for Eucalyptus.
The conventional way to drive modifications in old forest tree seed orchards is to establish progeny trials involving each parent tree and then evaluate its contribution to the performance of the progeny by estimating its general and specific combining ability (GCA and SCA). In this work, we successfully applied an alternative parent selection tactic based on paternity testing of superior offspring derived from a hybrid seed orchard established with a single Eucalyptus grandis seed parents and six E. urophylla pollen parents. A battery of 14 microsatellite markers was used to carry out parentage tests of 256 progeny individuals including two independent samples of selected trees and one control unselected sample, all derived from 6-year-old forest stands in eastern Brazil. Paternity determination was carried out for all progeny individuals by a sequential paternity exclusion procedure. Exclusion was declared only when the obligatory paternal allele in the progeny tree was not present in the alleged parent tree for at least four independent markers to avoid false exclusions due to mutation or null alleles. After maternity checks to identify seed mixtures and selfed individuals, the paternity tests revealed that approximately 29% of the offspring was sired by pollen parents outside the orchard. No selfed progeny were found in the selected samples. Three pollen parents were found to have sired essentially all of the offspring in the samples of selected and non-selected progeny individuals. One of these three parents sired significantly more selected progeny than unselected ones ( P< or =0.0002 in a Fisher exact test). Based on these results, low-reproductive-successful parents were culled from the orchard, and management procedures were adopted to minimize external pollen contamination. A significant difference ( P<0.01) in mean annual increment was observed between forest stands produced with seed from the orchard before and after selection of parents and revitalization of the orchard. An average realized gain of 24.3% in volume growth was obtained from the selection of parents as measured in forest stands at age 2-4 years. The marker-assisted tree-breeding tactic presented herein efficiently identified top parents in a seed orchard and resulted in an improved seed variety. It should be applicable for rapidly improving the output quality of seed orchards, especially when an emergency demand for improved seed is faced by the breeder.


Palearctic predator invades North American Great Lakes.
Bythotrephes cederstroemii Schoedler, a predatory freshwater zooplankter (Crustacea: Cladocera), was first found in the Laurentian Great Lakes in December 1984. The first individuals were from Lake Huron, followed in 1985 with records from Lakes Erie and Ontario. By late August, 1986 the species had spread to southern Lake Michigan (43°N). Bythotrephes has not previously been reported from North America, but has been restricted to a northern and central Palearctic distribution. Its dramatic and widespread rise in abundance in Lake Michigan was greatest in offshore regions. Bythotrephes appears to be invading aggressively, but avoiding habitats presently occupied by glacio-marine relict species that became established in deep oligotrophic North American lakes after the Wisconsin glaciation. Because it is a voracious predator its invasion may lead to alterations in the native zooplankton fauna of the Great Lakes. It offers the chance to study how invading plankton species join an existing community. Judging from its persistence and success in deep European lakes, Bythotrephes may now become a permanent member of zooplankton communities in the Nearctic.


Attenuated Salmonella typhimurium carrying the hepatocyte growth factor and keratinocyte growth factor genes repairs gastrointestinal mucosal damage caused by chemotherapy.
Radiotherapy and chemotherapy are the main therapeutic approaches for patients with malignant tumours, especially advanced tumours. However, they can cause adverse effects, one of which is gastrointestinal mucosal damage, which can greatly affect patients' quality of life. Until now, there have been no effective therapies to avoid or treat these adverse effects. In this study, we used attenuated Salmonella typhimurium (S. typhimurium) to deliver the hepatocyte growth factor (HGF) or keratinocyte growth factor (KGF) to murine gastrointestinal mucosa. We found that attenuated S. typhimurium carrying the HGF or KGF genes can effectively reduce the ratio of tumour to non-tumour carcass weight, repair damage to the gastrointestinal mucosal from chemotherapy, improve the immune response, and reduce the mortality rate of mice. Oral administration of attenuated S. typhimurium with HGF and KGF may be promising as a way of improving the quality of life of patients undergoing radiotherapy and chemotherapy.


Some effects of method on the measured conspicuity of chest lesions.
Both the magnitude and the precision of the conspicuity of a series of solitary chest nodules depends on the number and spacing of the measurement points. Observer accuracy in detecting 1.0 cm and 1.5 cm psuedo chest lesions does not correlate well with conspicuity.


Angiotensin-induced cyclic GMP production is mediated by multiple receptor subtypes and nitric oxide in N1E-115 neuroblastoma cells.
Angiotensin II (AngII) elicited a rapid and dose-related production of intracellular cyclic GMP (cGMP) in murine neuroblastoma N1E-115 cells. The agonist-induced rise in cGMP levels was blocked in a monophasic fashion by the AT1-selective antagonist DuP 753 or the nonselective antagonist [Sarc1,Ile8]-AngII, and both antagonists produced complete inhibition of the cGMP response elicited by submaximal concentrations of AngII. In contrast, the AT2-selective antagonist CGP 42112A inhibited the cGMP response biphasically. At lower antagonist concentrations, agonist-induced cGMP production was only partially inhibited, whereas complete inhibition was observed only when the concentration of CGP 42112A was increased sufficiently to interact with both AT1 and AT2 receptor subtypes. AngII also increased inositol trisphosphate (InsP3) levels in N1E-115 cells. However, the InsP3 response was mediated exclusively by the AT1 receptor subtype because it was inhibited by lower, AT1-selective concentrations of DuP 753, whereas only higher, nonselective concentrations of CGP 42112A were effective. Finally, the stimulatory effects of AngII on cGMP production appeared to be mediated by the intracellular formation of nitric oxide in that they were attenuated by the nitric oxide synthase inhibitor, N-monomethyl-L-arginine. Collectively, these results suggest that the AngII-elicited rise in cGMP levels may require an interaction between AT1-mediated mobilization of intracellular Ca2+, as well as some partial role of AT2 receptors.


The effect of lactoferrin on complement mediated modulation of immune complex size.
Earlier we showed that human lactoferrin is capable of inhibiting the complement-mediated lysis of antibody-coated erythrocytes due to an inhibition of the formation of the classical C3 convertase. In this report the effect of lactoferrin on complement mediated modulation of immune complex size was studied. Lactoferrin was shown to inhibit the complement-dependent solubilization of immune precipitates with kinetics resembling that seen by others using C2 deficient serum. Lactoferrin, however, did not affect the complement-dependent inhibition of immune precipitation. These findings confirm our earlier observations that lactoferrin has no effect on the activation of the very early complement components (C1 and C4), but inhibits C3 deposition on immune complexes which is a crucial mechanism in immune precipitate solubilization.


Biophysical and biochemical properties of PHGDH revealed by studies on PHGDH inhibitors.
The rate-limiting serine biogenesis enzyme PHGDH is overexpressed in cancers. Both serine withdrawal and genetic/pharmacological inhibition of PHGDH have demonstrated promising tumor-suppressing activities. However, the enzyme properties of PHGDH are not well understood and the discovery of PHGDH inhibitors is still in its infancy. Here, oridonin was identified from a natural product library as a new PHGDH inhibitor. The crystal structure of PHGDH in complex with oridonin revealed a new allosteric site. The binding of oridonin to this site reduced the activity of the enzyme by relocating R54, a residue involved in substrate binding. Mutagenesis studies showed that PHGDH activity was very sensitive to cysteine mutations, especially those in the substrate binding domain. Conjugation of oridonin and other reported covalent PHGDH inhibitors to these sites will therefore inhibit PHGDH. In addition to being inhibited enzymatically, PHGDH can also be inhibited by protein aggregation and proteasome-mediated degradation. Several tested PHGDH cancer mutants showed altered enzymatic activity, which can be explained by protein structure and stability. Overall, the above studies present new biophysical and biochemical insights into PHGDH and may facilitate the future design of PHGDH inhibitors.


Cancers of the eye.
Ocular cancers are unique among the diseases of the eye, threatening both vision and life. In most cases, the diagnosis can be made utilizing a careful clinical history and specialized ocular examination. Eye cancer diagnosis relies heavily on imaging techniques such as high-frequency ultrasound, fluorescein angiography, anterior and posterior segment optical coherence tomography, computed tomography (CT), and magnetic resonance imaging (MRI). Once the diagnosis is established, treatment decisions depend on the tumor's location, size, local extension, patterns of growth, and secondary complications. Treatment options include observation, local resection, chemotherapy (topical, intravenous, intra-arterial, or intravitreal), and radiation (ophthalmic plaque or external beam). Enucleation or exenteration is only employed if these eye- and vision-sparing treatments are not possible. The core of this comprehensive review is a consecutive series of the most common ocular tumor of each structure of the eye, anterior to posterior, including basal cell carcinoma of the eyelid, squamous conjunctival neoplasia, choroidal melanoma, retinoblastoma, ocular adnexal lymphoma, and metastatic orbital tumors.


Antibody coated conductive polymer for the electrochemical immunosensing of Human Cardiac Troponin I in blood plasma.
Cardiac troponin I (cTnI) is a sensitive biomarker for cardiovascular disease (CVD). Rapid determination of cTnI concentration in blood can greatly reduce the potential of significant heart damage and heart failure. Herein, we demonstrate a new electrochemical immunosensor for selective affinity binding and rapid detection of cTnI in blood plasma by an electrochemical method. A conductive film of "poly 2,5-bis(2-thienyl)3,4-diamine-terthiophene (PDATT)" was deposited onto an Indium Tin Oxide (ITO) electrode using chronoamperometry. Anti-cardiac troponin I antibody was then attached to the two amine (NH2) groups substituted on the central thiophene of terthiophene repeating unit of the polymer chain via amide bond formation. The gaps on the surface of the antibody coated immunosensor were backfilled with bovine serum albumin (BSA) to prevent nonspecific binding of interfering molecules. Differential pulse voltammetry (DPV) was used to determine cTnI upon the formation of cTnI immunocomplex on the sensing surface, appearing a peak at 0.27 V. The response range was 0.01-100 ng mL-1 with limit of quantification down to 0.01 ng mL-1. The developed immunosensor was used to determine cTnI in spiked blood plasma without interference from cardiac troponin T (cTnT). Therefore, this new sensor can be utilised for the detection of cTnI biomarker in pathological laboratories and points of care in less than 15 min.


Optimization of two-joint arm movements: a model technique or a result of natural selection?
The fossil record of early hominids suggests that their Arm length, and presumably stature and weight, had a tendency to increase. Using the minimum jerk principle and a related formulation of averaged specific power, ASP, with regard to selected two-joint Arm movements, the current paper explores relationships between ASP, hand trajectory length (or Arm length, or body mass) and mean movement speed, deriving relationships which indicate that ASP is proportional to cubic mean movement speed, but inversely proportional to hand trajectory length (or Arm length, or 1/3 power of body mass). Accordingly, an ;ecological niche' is modeled in a three-parameter space. Either ASP maximization for fixed movement time, or ASP minimization for fixed mean movement speed, taken as selective optimization criterion, allows the increasing of human Arm length during evolution, regardless of the arm-to-forearm length ratio.


The vascular nature of hemorrhoids.
The arterial blood supply of the internal hemorrhoidal plexus is commonly believed to be associated with the pathogenesis of hemorrhoids. Ultrasound-supported proctoscopic techniques with Doppler-guided ligature of submucosal rectal arteries have been introduced for the therapy of hemorrhoids. The present investigation focuses on caliber and flow changes of the terminal branches of the superior rectal artery (SRA) supplying the corpus cavernosum recti (CCR) in patients with hemorrhoids. Forty-one outpatients (17 female, 24 male; mean age 48 years) with hemorrhoids of Goligher grades I-IV were compared with 17 healthy volunteers (nine female, eight male; mean age 29 years) by means of transperineal color Doppler ultrasound. The mean caliber of the arterial branches in the study group with hemorrhoids was 1.87 +/- 0.68 mm (range, 0.6 to 3.60 mm) and 0.92 +/- 0.15 mm (range, 0.6 to 1.2 mm) in the control group (P < 0.001). The arterial blood flow was significantly higher in patients with hemorrhoids than in the control group (mean 33.9 vs. 11.9 cm/second, P < 0.01). Our findings demonstrate that increased caliber and arterial blood flow of the terminal branches of the SRA are correlated with the appearance of hemorrhoids. We suggest that the hypervascularization of the anorectum contributes to the growth of hemorrhoids rather than being a consequence of hemorrhoids. Transperineal color Doppler ultrasound (CDUS) is an appropriate method to assess these findings in patients with hemorrhoids.


Reversion of breast epithelial polarity alterations caused by obesity.
Molecular links between breast cancer risk factors and pro-oncogenic tissue alterations are poorly understood. The goal of this study was to characterize the impact of overweight and obesity on tissue markers of risk, using normal breast biopsies, a mouse model of diet-induced obesity, and cultured breast acini. Proliferation and alteration of epithelial polarity, both necessary for tumor initiation, were quantified by immunostaining. High BMI (>30) and elevated leptin were associated with compromised epithelial polarity whereas overweight was associated with a modest increase in proliferation in human and mice mammary glands. Human serum with unfavorable adipokine levels altered epithelial polarization of cultured acini, recapitulating the effect of leptin. Weight loss in mice led to metabolic improvements and restored epithelial polarity. In acini cultures, alteration of epithelial polarity was prevented by antioxidants and could be reverted by normalizing culture conditions. This study shows that obesity and/or dietary factors modulate tissue markers of risk. It provides a framework to set target values for metabolic improvements and to assess the efficacy of interventional studies aimed at reducing breast cancer risk.


Intraoperative Squash and Touch Preparation Cytology of Brain Lesions Stained with H+E and Diff-Quik™: A 20-Year Retrospective Analysis and Comparative Literature Review.
Squash preparation (SP) is a rapid technique for the intraoperative assessment of brain lesions. Only a few studies have employed touch preparation (TP) cytology and Diff-QuikTM (DQ) staining in conjunction with SP. Our study aimed to assess the diagnostic efficacy of SP of brain lesions at our institution, ascertain the additional effect of TP and DQ staining, examine factors affecting the sensitivity and specificity of our methods, and compare our findings with those of previous investigations. Our database was searched for all SP/TP of brain lesions examined from January 1996 to December 2016. During this 20-year study period, our search revealed 400 brain lesions diagnosed by SP/TP cytology. There were 338 (84.5%) neoplasms and 62 (15.5%) nonneoplastic lesions. The most common neoplasms were glioblastoma multiforme (24.6%), metastatic cancer (18.3%), meningioma (16.9%), astrocytoma (11.5%), lymphoma (8.3%), oligoastrocytoma (3.3%), and pituitary adenoma (3.3%). There was discordance between the SP/TP and histological diagnoses in 19/338 (5.6%) cases, i.e., 12 misclassifications of tumor subtype and 7 sampling errors. No false-positive cases were detected. Brain SP/TP stained with H+E/DQ demonstrated high sensitivity (97.9%), specificity (100%), and overall diagnostic accuracy (95.3%). The combined methods, in particular, aided in the diagnosis of brain tumors prone to smearing artifacts and certain metastatic malignancies.


Ultrafast imaging of terahertz electric waveforms using quantum dots.
Microscopic electric fields govern the majority of elementary excitations in condensed matter and drive electronics at frequencies approaching the Terahertz (THz) regime. However, only few imaging schemes are able to resolve sub-wavelength fields in the THz range, such as scanning-probe techniques, electro-optic sampling, and ultrafast electron microscopy. Still, intrinsic constraints on sample geometry, acquisition speed and field strength limit their applicability. Here, we harness the quantum-confined Stark-effect to encode ultrafast electric near-fields into colloidal quantum dot luminescence. Our approach, termed Quantum-probe Field Microscopy (QFIM), combines far-field imaging of visible photons with phase-resolved sampling of electric waveforms. By capturing ultrafast movies, we spatio-temporally resolve a Terahertz resonance inside a bowtie antenna and unveil the propagation of a Terahertz waveguide excitation deeply in the sub-wavelength regime. The demonstrated QFIM approach is compatible with strong-field excitation and sub-micrometer resolution-introducing a direct route towards ultrafast field imaging of complex nanodevices in-operando.


Posttraumatic stress disorder in eating disorder patients: The roles of psychological distress and timing of trauma.
Exposure to traumatic events may be a risk factor for subsequent development of an eating disorder (ED). In a previous study, we showed that trauma exposure impacted symptom load in ED patients. We also saw an effect of trauma on general psychological distress. The aim of the present study was to investigate the association between Posttraumatic stress disorder (PTSD) and ED severity, to focus on the mediating role of psychological distress for the association, and to assess the role of timing of trauma in relation to emergence of ED. Participants were Swedish adult ED patients with a history of traumatic exposure (N=843, Mean age 27.2, 97.3% female). One fourth (24.1%) of the participants had a lifetime diagnosis of PTSD. PTSD had an impact on ED severity, but the impact was mediated by psychological distress. When stratifying the sample based on timing of trauma a significant effect was present only in those with trauma within a year of emergence of ED. The results suggest emotion regulation as a possible underlying factor of interest in future research.


Aldosterone induces rapid sodium intake by a nongenomic mechanism in the nucleus tractus solitarius.
The purpose of this study was to determine whether aldosterone has a rapid action in the nucleus tractus solitarius (NTS) that increases sodium intake, and to examine whether this effect of aldosterone, if present, is mediated by G protein-coupled estrogen receptor (GPER). Adult male Sprague-Dawley rats with a stainless-steel cannula in the NTS were used. Aldosterone was injected into the NTS at the doses of 1, 5, 10 and 20 ng 0.1 μl-1. A rapid dose-related increase of 0.3 M NaCl intake was induced within 30 min and this increase was not suppressed by the mineralocorticoid receptor (MR) antagonist spironolactone (10 ng 0.1 μl-1). Water intake was not affected by aldosterone. The GPER agonist G-1 produced a parallel and significant increase in sodium intake, while pre-treatment with GPER antagonist G15 (10 ng 0.1 μl-1) blocked the G-1 or aldosterone-induced rapid sodium intake. In addition, sodium intake induced by sodium depletion or low-sodium diet fell within 30 min after injection into the NTS of the MR antagonist spironolactone, while G15 had no effect. Our results confirm previous reports, and support the hypothesis that aldosterone evokes rapid sodium intake through a non-genomic mechanism involving GPER in NTS.


Effects of testosterone and estradiol on stress-induced adrenal and hippocampal weight changes in female rats.
To examine the impact of circulating testosterone (T) and the T/Estradiol (T/Ediol) ratio on chronic stress-induced changes of adrenal and hippocampal weight during proestrus (PE) and estrus (E) in female rats. Stress was composed of repeated vaginal smear screening (VSS) and measured by the emotional reactivity score (ERS). Adrenal and hippocampal weight and the T, Ediol and T/Ediol ratio were assessed in PE and E controls as well as 20 h after sham or left adrenalectomy performed on diestrus-2 (DE-2) and PE, respectively. T was measured in ovariectomized (OVX) rats treated with estradiol benzoate (EB) or vehicle (VEH) and in non-OVX EB-treated rats. In OVX rats EB treatment increased adrenal weight and T levels. After separation of VEH- and EB-treated rats into the low and high T-range (below and above the mean, respectively), it was observed that higher T was accompanied by higher adrenal weight in EB- compared to VEH-treated rats only in the low T-range. Non-OVX EB-treated rats with high T had lower adrenal weight compared to low T. Cycling rats assigned to the high T-range presented higher T/Ediol ratio but similar ERS and Ediol levels compared to rats in the low T-range, and were characterized by reduced adrenal weight, higher hippocampal weight and prevalence of PE versus E. High T and high T/Ediol ratios are prominent in PE compared to E and exert a protective effect on hippocampal neuronal degeneration after similar chronic stress through T-mediated lessening of stress response thus counteracting the stress-promoting effects of Ediol.


Gordon Coupler with Inductive or Capacitive Iris for Small EPR Resonators for Aqueous Samples.
The Gordon coupler was introduced for use in EPR experiments at liquid helium temperatures. It provides an evanescent wave incident on the iris of a microwave resonator. Match of power incident on the coupler to the resonator is obtained by variation of the amplitude of an evanescent wave that arises from displacement of a dielectric wedge in a tapered waveguide. Reduced microphonics from helium bubbling was reported. The Gordon coupler was subsequently extended from cavity resonators to loop-gap resonators, initially at helium temperatures but later for aqueous samples. Plastics with low dielectric constants, usually Teflon, were used. Here, we extend the Gordon coupler for application in X-band five-loop-four-gap resonators using fused quartz, sapphire, or rutile dielectrics, noting that the size of the coupler can then be commensurate with dimensions of dielectric loop-gap resonators as well as dielectric tube resonators. Finite element modeling of electromagnetic fields has been carried out, and use of a capacitive iris that interfaces with the Gordon coupler reduces pulling of the resonant frequency when matching the resonator.


Mouse macrophage hybridomas secreting a cytotoxic factor and interleukin 1.
Stable mouse macrophage hybridomas were produced by somatic cell fusion between proteose peptone-elicited peritoneal macrophages and NS-1 myeloma cells. Three cloned hybrid cell lines, designated as N/P-5-3, -6-2, and -7-1, exhibited typical macrophage-like morphology. Moreover, their macrophage characteristics were confirmed by the manifestation of intracellular nonspecific esterase, the detection of Mac-1 antigens and Fc-receptors on the cell surface, and the demonstration of phagocytic and antigen-presenting activities. Furthermore, these cell lines, stimulated with LPS, secreted considerable amounts of a cytotoxic factor and interleukin 1. Cultured cells of various tumor cell lines were sensitive to the cytotoxic factor, but normal thymocytes, spleen cells, and liver cells were not killed by the factor.


In vitro and in vivo drug release from a novel in situ forming drug delivery system.
The objective of this work was to investigate the influence of various preparation and formulation parameters on the in vitro and in vivo release of bupivacaine hydrochloride from an injectable in situ forming microparticle system (ISM). The in vitro drug release of ISM was investigated as a function of various formulation and process parameters and was compared to the drug release from in situ forming implants and conventional microparticles. In vivo studies were carried out in male Sprague-Dawley rats. Upon contact with an aqueous medium, the internal polymer phase of the ISM system solidified and formed microparticles. The initial drug release from ISM systems was reduced with decreasing polymer phase/external oil phase ratio. An advantage of the ISM system compared to in situ implant systems was the significantly reduced burst effect, resulting in drug release profiles comparable to microparticles prepared by conventional methods. The in vivo drug release studies were in good agreement with the in vitro drug release. With the ISM system, the analgesic effect of the bupivacaine hydrochloride was prolonged when compared to the injection of a drug solution or drug-polymer solution. ISM are an attractive alternative for parenteral drug delivery systems.


Prescription Opioid Misuse and Use of Alcohol and Other Substances Among High School Students - Youth Risk Behavior Survey, United States, 2019.
Adolescence is an important period of risk for substance use initiation and substance use-related adverse outcomes. To examine youth substance use trends and patterns, CDC analyzed data from the 2009-2019 Youth Risk Behavior Survey. This report presents estimated prevalence of current (i.e., previous 30-days) marijuana use, prescription opioid misuse, alcohol use, and binge drinking and lifetime prevalence of marijuana, synthetic marijuana, cocaine, methamphetamine, heroin, injection drug use, and prescription opioid misuse among U.S. high school students. Logistic regression and Joinpoint analyses were used to assess 2009-2019 trends. Prevalence of current and lifetime substance use by demographics, frequency of use, and prevalence of co-occurrence of selected substances among students reporting current prescription opioid misuse are estimated using 2019 data. Multivariable logistic regression analysis was used to determine demographic and substance use correlates of current prescription opioid misuse. Current alcohol, lifetime cocaine, methamphetamine, heroin, and injection drug use decreased during 2009-2019. Lifetime use of synthetic marijuana (also called synthetic cannabinoids) decreased during 2015-2019. Lifetime marijuana use increased during 2009-2013 and then decreased during 2013-2019. In 2019, 29.2% reported current alcohol use, 21.7% current marijuana use, 13.7% current binge drinking, and 7.2% current prescription opioid misuse. Substance use varied by sex, race/ethnicity, grade, and sexual minority status (lesbian, gay, or bisexual). Use of other substances, particularly current use of alcohol (59.4%) and marijuana (43.5%), was common among students currently misusing prescription opioids. Findings highlight opportunities for expanding evidence-based prevention policies, programs, and practices that aim to reduce risk factors and strengthen protective factors related to youth substance use, in conjunction with ongoing initiatives for combating the opioid crisis.


Correlates and risk markers for sleep disturbance in participants of the Autism Treatment Network.
We explored possible cognitive, behavioral, emotional, and physiological risk markers for sleep disturbance in children with autism spectrum disorders. Data from 1,583 children in the Autism Treatment Network were analyzed. Approximately 45 potential predictors were analyzed using hierarchical regression modeling. As medication could confound findings, it was included in the analyses as a covariate. Results revealed that anxiety, autism symptom severity, sensory sensitivities, and GI problems were associated with sleep disturbance. IQ positively predicted sleep disturbance, and children with Asperger's Disorder were more vulnerable than others. The amount of variance in sleep outcomes explained by predictor variables was modest (i.e., R (2) from .104 to .201). Predictor variables were evaluated in the context of a bidirectional theoretical framework.


Increased levels of interleukin-33 associated with bone erosion and interstitial lung diseases in patients with rheumatoid arthritis.
To analyze the levels of interleukin-33 (IL-33) in the serum of patients with rheumatoid arthritis (RA) and investigated its possible pathophysiological importance. The concentrations of IL-33 and matrix metalloproteinase (MMP)-3 were measured by enzyme-linked immunosorbent assay (ELISA) in the serum of 121 patients with RA and 47 controls. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), and anticyclic citrullinated peptide (anti-CCP) were measured by standard laboratory techniques. Interstitial lung disease (ILD) was identified on high-resolution computed tomography. Disease activity in RA was scored with the Disease Activity Score 28 based on C-reactive protein levels (DAS28-CRP). The bone erosion of RA patients was evaluated by modified Sharp Score (MSS). Serum levels of IL-33 and MMP-3 were significantly higher in RA patients than in healthy controls. Significant higher levels of IL-33 were found in CCP-positive group and in patients with ILD. There was positive correlation between the levels of IL-33 and RF. Moreover, there was also positive correlation between IL-33 and MMP-3, MSS. These data support the hypothesis that IL-33 may be involved in RA pathogenesis and it may partly contribute to the bone erosion in RA patients.


Integrin specificity of the cyclic Arg-Gly-Asp motif and its role in integrin-targeted gene transfer.
Targeted gene transfer, addressing the alphavbeta3 integrin by coupling the appropriate ligand, cRGD (S(2)-bridged cyclic Arg-Gly-Asp containing peptide) motif, on to a DNA condensing sequence was described as early as 1995 by Hart, Harbottle, Cooper, Miller, Williamson and Coutelle [(1995) Gene Ther. 2, 552-554]. Their work was followed by a series of publications, introducing the cRGD motif in polycationic DNA carriers, such as peptides, proteins and liposomes. Polyethylenimine and even adenoviruses were additionally ligated using the cRGD motif. 'Integrin specificity' has been determined from the significantly improved transfection efficiency compared with the DNA carriers with control ligands, mainly the cRGE (S(2)-bridged cyclic-Arg-Gly-Glu-containing peptide) motif. However, by observing the physicochemical appearance of the resulting complexes and their controls such as the poly(L-lysine)-DNA complexes carrying the cRGD and the cRGE motifs, we doubted the integrin-mediated specificity of the increased transfection efficiency. To clarify this contradiction, we investigated the suitability of the cRGD motif for targeted gene transfer. We proved the specificity of the RGD motif and its controls using computational docking procedures and molecular modelling methods. Since we were confident of the motifs used, we improved our transfection method. Since aggregation of the RGD-ligated poly(L-lysine)-DNA complexes under physiological conditions caused an enormous amount of unspecific cell uptake and transfection, a method had to be designed to exclude aggregation processes of the motif-polycation-DNA complexes. Small complex sizes are necessary for receptor-specific uptake. The complexes were therefore recharged using poly(vinyl sulphate). Inhibited aggregation of the targeted DNA carriers under physiological conditions is a necessary prerequisite for successful in vivo gene transfer.


Incorporating Carotid Plaque Imaging into Routine Clinical Carotid Magnetic Resonance Angiography.
The incorporation of a short, easy-to-acquire and simple to read sequence to visualize the vessel wall and detect intraplaque hemorrhage (IPH) is achievable now. Demonstration of IPH may be helpful in primary or secondary prevention of neuroischemic events, assessment prior to carotid intervention and the general definition of an individual's vascular phenotype. The addition of an IPH-detecting vessel wall sequence only adds 5 to 6 minutes to a standard carotid MRI examination making clinical translation feasible and achievable.


Assessment of the Preserved Biceps Tendon After Arthroscopic Rotator Cuff Repair in Patients ≤ 55 Years.
We assessed hypertrophy of preserved long head of the biceps tendon (LHBT) and vascularity in the bicipital groove after arthroscopic rotator cuff repair in ≤55-year-old patients and compared postoperative pain between shoulders with or without vascularity in the bicipital groove. Patients who underwent arthroscopic rotator cuff repair between 2015 and 2017 were reviewed. Inclusion criteria were arthroscopic rotator cuff repair and ≤55 years old. Exclusion criteria were a history of contralateral rotator cuff repair, revision surgery, partial repair or superior capsular reconstruction, shoulder dislocation or fracture, torn LHBT at surgery, LHBT tenodesis, retears, <1-year follow-up, and incomplete follow-up data. Cross-sectional area (CSA) of the LHBT and vascularity in the bicipital groove were examined preoperatively and 1 year after surgery using ultrasonography. Shoulder pain at postoperative 1 year was assessed using the pain subscore of the University of California at Los Angeles scale. The data were compared between shoulders with negative and positive vascularity. Fifty-seven shoulders were included in this study. There was no side-to-side difference in preoperative CSA. No difference was found between preoperative and postoperative CSA in the affected shoulders. Postoperative vascularity was identified in 28 (49%) shoulders. Mean pain score was significantly higher in the negative vascularity group than the positive vascularity group (9 and 8, respectively; P = .002). The preserved LHBT did not show hypertrophy 1 year after arthroscopic repair of medium-sized or smaller posterosuperior rotator cuff tear in ≤55-year-old patients. However, 49% of the shoulders postoperatively demonstrated lower-grade vascularity in the bicipital groove. Healthy LHBT can be preserved in ≤55-year-old patients with posterosuperior medium-sized or smaller rotator cuff tears. III, retrospective comparative prognostic trial.


Chemical modulation of physiological adaptation and cross-protective responses against oxidative stress in soil bacterium and phytopathogen, Xanthomonas.
Soil bacteria need to adapt quickly to changes in the environmental conditions. Physiological adaptation plays an important role in microbial survival, especially under stressful conditions. Here the abilities of chemicals and pesticides to modulate physiological adaptive and cross-protective responses, that make the bacteria more resistant to oxidative stress, are examined in the soil bacterium and phytopathogen, Xanthomonas. The genetic basis for the observed stress resistance, as well as the regulatory mechanisms controlling gene expression during the process, has begun to be elucidated.


Mutagenicity of bi-, tri- and tetra-cyclic aromatic hydrocarbons in the "taped-plate assay" and in the conventional salmonella mutagenicity assay.
Aromatic hydrocarbons in the range of 1-4 nuclear rings were examined for mutagenicity in the so-called "taped-plate assay". This modification of the Ames assay is particularly equipped for the detection of volatile mutagens. Of the many compounds tested only phenanthrene, pyrene, benzo[c]phenanthrene and benzoacenaphthylene were positive in this assay. The present data underline the exceptional behaviour of fluoranthene by being a rather potent bacterial mutagen with a volatile nature (as found in a previous study).


Structural Adaptive, Self-Separating Material for Removing Ibuprofen from Waters and Sewage.
β-Cyclodextrin nanosponge (β-CD-M) was used for the adsorption of ibuprofen (IBU) from water and sewage. The obtained material was characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), Brunauer-Emmett-Teller (BET), Barrett-Joyner-Halenda (BJH), Harkins and Jura t-Plot, zeta potential, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and elementary analysis (EA). Batch adsorption experiments were employed to investigate the effects of the adsorbent dose, initial IBU concentration, contact time, electrolyte ions and humic acids, and sewage over adsorption efficiency. The experimental isotherms were show off using Langmuir, Freundlich, Hill, Halsey and Sips isotherm models and thermodynamic analysis. The fits of the results were estimated according to the Sips isotherm, with a maximum adsorption capacity of 86.21 mg g-1. The experimental kinetics were studied by pseudo-first-order, pseudo-second-order, Elovich, modified Freundlich, Weber Morris, Bangham's pore diffusion, and liquid film diffusion models. The performed experiments revealed that the adsorption process fits perfectly to the pseudo-second-order model. The Elovich and Freundlich models indicate chemisorption, and the kinetic adsorption model itself is complex. The data obtained throughout the study prove that this nanosponge (NS) is extremely stable, self-separating, and adjusting to the guest structure. It also represents a potential biodegradable adsorbent for the removal IBU from wastewaters.


Effect of different challenge doses after repeated citalopram treatment on extracellular serotonin level in the medial prefrontal cortex: in vivo microdialysis study.
In order to elucidate the relevance between the delayed onset of clinical efficacy of selective serotonin re-uptake inhibitors (SSRI) and extracellular 5-HT levels in the medial prefrontal cortex, the present study compared the ability of low-dose (3 mg/kg) and high-dose (30 mg/kg) citalopram to increase extracellular 5-HT levels in the medial prefrontal cortex following repeated citalopram treatment using in vivo microdialysis. An SSRI, citalopram, was given 10 mg/kg, s.c. twice daily for 6 days and once on the seventh day in rats. On the eighth day, rats received a single injection of citalopram (3 or 30 mg/kg s.c.), and extracellular 5-HT levels were assessed in the medial prefrontal cortex of rats using in vivo brain microdialysis. There was no significant difference in basal extracellular 5-HT levels between the repeated citalopram group and the repeated saline group. The low-challenge dose of citalopram (3 mg/kg) produced significantly greater increases (170-200% at each time point) in the repeated citalopram group than in the repeated saline group (150%). The high-challenge dose of citalopram (30 mg/kg), however, increased extracellular 5-HT levels by 200-250% of basal levels in the repeated citalopram group, which was similar to the increases in the repeated saline group. Repeated SSRI treatment enhances the effect of low-dose SSRI on extracellular 5-HT levels but not that of high-dose SSRI.


Nucleic acid import into mitochondria: New insights into the translocation pathways.
Mitochondria have retained indispensable but limited genetic information and they import both proteins and nucleic acids from the cytosol. RNA import is essential for gene expression and regulation, whereas competence for DNA uptake is likely to contribute to organellar genome dynamics and evolution. Contrary to protein import mechanisms, the way nucleic acids cross the mitochondrial membranes remains poorly understood. Using proteomic, genetic and biochemical approaches with both plant and yeast organelles, we develop here a model for DNA uptake into mitochondria. The first step includes the voltage-dependent anion channel and an outer membrane-located precursor fraction of a protein normally located in the inner membrane. To proceed, the DNA is then potentially recruited in the intermembrane space by an accessible subunit of one of the respiratory chain complexes. Final translocation through the inner membrane remains the most versatile but points to the components considered to make the mitochondrial permeability transition pore. Depending on the size, DNA and RNA cooperate or compete for mitochondrial uptake, which shows that they share import mechanisms. On the other hand, our results imply the existence of more than one route for nucleic acid translocation into mitochondria.


The polyadenylate polymerases from yeast.
Poly(A) polymerase activity was first detected in yeast extracts, primarily in association with the ribosomal fraction, by Twu and Bretthauer in 1971 (Twu, J. S., and Bretthauer, RK. (1971) Biochemistry 10, 1576-1582). This activity has now been separated into three distinct enzymes by chromatography on DEAE-cellulose. Each of the three enzymes can catalyze the incorporation of adenylate residues from ATP into a polyadenylate (poly(A)) tract at the 3' terminus of a primer RNA. Enzyme I elutes at 0.07 M ammonium sulfate from the DEAE-cellulose column, utilizes the mixed polynucleotide poly(A,G,C,U) or ribosomal RNA most efficiently in vitro, and may be responsible in vivo for the initiation of the poly(A) tracts found on yeast messenger RNA. Enzyme II elutes from the column at 0.20 M ammonium sulfate, requires poly(A) itself or an RNA primer containing a 3'-oligo(A) tract, and may be responsible in the nucleus for the elongation of tracts initiated by enzyme I. Enzyme III elutes from the column at 0.56 M ammonium sulfate and is present in low amounts in nuclear extracts. It may be involved in adding poly(A) tracts to messenger RNA in mitochondria. These enzymes also have the intrinsic capacity for the incorporation of cytidylate residues from CTP, which correlates with the finding of cytidylate residues in the poly(A) tracts present in the yeast RNA which is rapidly labeled in vivo. About 75% of the total poly(A) polymerase activity of yeast is enzyme I, most of which is present in the soluble protein fraction of the whole yeast extract. About 20% of the total poly(A) polymerase is enzyme II, and 1 to 5% is enzyme III. All three of the yeast poly(A) polymerases require an RNA primer with a free 3'-hydroxyl group, show no requirement for a DNA template, require Mn-2+ for optimal activity, have pH optima of 8.5, and are inhibited by GTP, CTP, UTP, and native yeast DNA. Polymerases I and II have similar molecular weights by gel filtration.


Quantitative factors of unenhanced CT for predicting fragmenting efficacy of extracorporeal shock wave lithotripsy on pancreatic duct stones.
To find potential predictors at unenhanced computed tomography (CT) to evaluate the stone clearance rate (SCR) of pancreatic duct stones (PDS) by extracorporeal shock wave lithotripsy (ESWL). A total of 106 consecutive patients with multiple stones of maximal transverse length (MTL) 0.3-3.6 cm in pancreatic head region were enrolled. Unenhanced CT was performed both before and after ESWL therapy. All patients underwent ESWL therapy using an electromagnetic lithotripter, and were divided into three groups with threshold values of >90%, 50-90% and <50% of SCR. Factors including sex, age, MTL, mean stone density (MSD), standard deviation of stone density (SDSD), variation coefficient of stone density (VCSD), attenuation density (AD), pancreatic duct diameter (PDD), skin-to-stone distance (SSD), and number of ESWL sessions were analysed, and their impact on SCR was evaluated by univariate and multivariate analyses. The diagnostic threshold of the independent predicting index was further calculated, and its relationship with SCR and ESWL was analysed by drawing a trend line. The only significant predictor of SCR by ESWL was MSD (p<0.05). More courses of ESWL therapy are required in PDS patients with an MSD higher than the cut-off value of 375.4 HU (mean, 2.6 versus 1.8), but with a relatively lower SCR (mean, 43.96 versus 88.68%) . MSD on pre-treatment unenhanced CT is an independent predictor for SCR of PDS patients treated with ESWL. Using a cut-off value of 375.4 HU, patients with low MSD are good candidates for ESWL therapy.


A long-acting GDF15 analog causes robust, sustained weight loss and reduction of food intake in an obese nonhuman primate model.
Growth Differentiation Factor-15 (GDF15) is a circulating polypeptide linked to cellular stress and metabolic adaptation. GDF15's half-life is ~3 h and activates the glial cell line-derived neurotrophic factor family receptor alpha-like (GFRAL) receptor expressed in the area postrema. To characterize sustained GFRAL agonism on food intake (FI) and body weight (BW), we tested a half-life extended analog of GDF15 (Compound H [CpdH]) suitable for reduced dosing frequency in obese cynomolgus monkeys. Animals were chronically treated once weekly (q.w.) with CpdH or long-acting GLP-1 analog dulaglutide. Mechanism-based longitudinal exposure-response modeling characterized effects of CpdH and dulaglutide on FI and BW. The novel model accounts for both acute, exposure-dependent effects reducing FI and compensatory changes in energy expenditure (EE) and FI occurring over time with weight loss. CpdH had linear, dose-proportional pharmacokinetics (terminal half-life ~8 days) and treatment caused exposure-dependent reductions in FI and BW. The 1.6 mg/kg CpdH reduced mean FI by 57.5% at 1 week and sustained FI reductions of 31.5% from weeks 9-12, resulting in peak reduction in BW of 16 ± 5%. Dulaglutide had more modest effects on FI and peak BW loss was 3.8 ± 4.0%. Longitudinal modeling of both the FI and BW profiles suggested reductions in BW observed with both CpdH and dulaglutide were fully explained by exposure-dependent reductions in FI without increase in EE. Upon verification of the pharmacokinetic/pharmacodynamic relationship established in monkeys and humans for dulaglutide, we predicted that CpdH could reach double digit BW loss in humans. In summary, a long-acting GDF15 analog led to sustained reductions in FI in overweight monkeys and holds potential for effective clinical obesity pharmacotherapy.


Autonomic symptom burden is an independent contributor to multiple sclerosis related fatigue.
To investigate a possible association between autonomic dysfunction and fatigue in people with multiple sclerosis. In 70 people with multiple sclerosis early in the disease course (51 females, mean age 33.8 ± 9.1), quantitative sudomotor axon reflex tests, cardiovascular reflex tests (heart rate and blood pressure responses to the Valsalva maneuver and heart rate response to deep breathing), and the tilt table test were performed. Participants completed the Composite Autonomic Symptom Score 31, the Modified Fatigue Impact Scale, and the Epworth Sleepiness Scale, as well as the Beck Depression Inventory. Cutoff scores of ≥ 38 or ≥ 45 on the Modified Fatigue Impact Scale were used to stratify patients into a fatigued subgroup (N = 17 or N = 9, respectively). We found clear associations between fatigue and scores in subjective tests of the autonomic nervous system: fatigued patients scored significantly worse on Composite Autonomic Symptom Score 31, and there was a strong correlation between the Modified Fatigue Impact Scale and the Composite Autonomic Symptom Score 31 (rs = 0.607, p < 0.001). On the other hand, we found only modest associations between fatigue and scores in objective tests of the autonomic nervous system: there was a clear trend for lower sweating outputs at all measured sites, which reached statistical significance for the distal leg and foot. We found weak correlations between the Modified Fatigue Impact Scale and the Valsalva ratio (rs = - 0.306, p = 0.011), as well as between the Modified Fatigue Impact Scale and quantitative sudomotor axon reflex tests of the forearm, proximal, and distal lower leg (rs = - 0.379, p = 0.003; rs = - 0.356, p = 0.005; and rs = - 0.345, p = 0.006, respectively). A multiple regression model showed that the Composite Autonomic Symptom Score 31, Beck Depression Inventory, and Epworth Sleepiness Scale were independent predictors of fatigue (p = 0.005, p = 0.019, and p = 0.010, respectively). These results suggest that-even early in the course of the disease-people with multiple sclerosis suffer from objective and subjective impairments of the autonomic nervous system. The results also point to an association between autonomic nervous system impairment and multiple sclerosis related fatigue.


Evaluating Organizational Performance of Public Hospitals using the McKinsey 7-S Framework.
This study examined non-financial aspects of the organizational performance of public hospitals from the perspective of hospital physicians; the obtained results were analyzed to identify the necessary improvements in organizational performance. This was a cross-sectional study of multidisciplinary public hospitals on a group of 249 randomly selected physicians from 22 in-patient departments or clinics operating in the Warsaw region. The study data was collected using the structured World Health Organization questionnaires (to be filled out by respondents) assessing the hospital's organizational performance variables qualified according to the McKinsey 7-S Framework. Epidata software version 3.1 was used for data entry, and the analysis was carried out in the SPSS software, version 19. The results of the organization evaluation are presented in the McKinsey 7-S Framework diagram. Key elements of the performance factors were grouped into 'stens', and the sten values were expressed as arithmetic means. Normal distribution of the stens was validated with the Kolmogorov-Smirnov test. 95% confidence intervals were calculated. The significance of differences between the analyzed stens was compared with the paired Student t-test. The interdependence of the variables was determined using the Pearson's correlation coefficient. The results revealed a significant difference (p <0.05) in the respondents' assessment of social (a mean score of 2.58) and technical (a mean score of 2.80) organizational aspects of the hospital operation. Scores for all variables were low. The social elements of an organization with the lowest score included 'staff', and in it the aspect - 'efforts are made to inspire employees at the lowest levels of the organization', 'skills' involving the learning style followed by the management/managerial staff, and 'management style' (average scores of 2.38, 2.56, 2.61, respectively). Consistently with the existing literature, social factors were shown to play a more significant role in the management and they therefore deserve careful attention and more recognition when identifying and improving the key aspects affecting the organizational performance of public hospitals. Technical elements (strategy, structure, system) are important, but were demonstrated to have limited effect on the organizational operations geared towards ensuring effective functioning of a public hospital.


Production of alternarioi and alternariol monomethyl ether in natural substrates in comparison with semisynthetic culture medium.
The comparison In toxins production and growth byAlternarla strains in liquid, solid culture media and natural substrates (rice and sunflower) was evaluated. Ground rice- corn steep liquor medium (GRCS) was the more suitable medium for production of alternariol (AOH) and alternariol monomethyl ether(AME). The maximum levels produced were 676 μg/50ml AOH and 1570/50ml AME. Rice was better than sunflower In supporting toxins production. Different ratios AOH/AME were found according to the substrate evaluated.


Effects of diet on the neurologic development of children at 5 years of age: the STRIP project.
To evaluate the effects of diet, serum cholesterol concentrations, and apolipoprotein E phenotype on neurodevelopment of 5-year-old children. Prospective, 4.4-year cohort study in 496 children. Fat-modified diet was introduced to intervention families of 7-month-old infants. Control children consumed an unrestricted diet. Nutrient intakes, serum cholesterol, and neurodevelopment were studied. The groups were combined in univariate and stepwise multivariate logistic regression analyses. In 13-month-old boys (girls), energy intake was 996 (938) kcal, fat intake 26.6 (26.4) percent of energy (E%), and protein intake 17.2 (17.4) E%. In 5-year-old boys (girls), the intakes were 1484 (1364) kcal, 32.1 (31.9) E%, and 15.5 (15.9) E%, respectively. The intakes of total fat and saturated fat and serum cholesterol were not associated with neurodevelopment. In boys, high intake of protein at 5 years, high intakes of protein at 4 years and cholesterol at 2 years, and high intake of polyunsaturated fatty acids at 3 years predicted favorable outcomes in the tests of speech and language skills, gross motor function and perception, and visual motor skills, respectively. Apolipoprotein E phenotype did not influence the test performance. Moderate restriction of dietary fat has no unfavorable effects on neurodevelopment in early childhood. However, the quality of fat and the relative intake of protein may influence neurodevelopment of the boys.


Epiretinal membrane removal in eyes with good visual acuities.
To evaluate the results of vitrectomy for epiretinal membrane in eyes with a preoperative visual acuity of 20/50 or better. The visual results and complications of vitrectomy for epiretinal membranes were analyzed in a retrospective, consecutive case series of 40 eyes of 40 patients treated by a single surgeon. The mean preoperative visual acuity was 20/50 + 2 (range 20/30 + 1 to 20/50 -3). The mean visual acuity improved to 20/40 + 2 (P = 0.02) by the final examination at a mean of 2.4 years following surgery. The status of the lens at the final examination was correlated with the visual results of surgery. Twenty-one eyes were phakic preoperatively and 14 of these eyes had cataracts removed by the final examination. The mean preoperative visual acuity in 7 eyes which were still phakic at the final examination was 20/50 and this decreased to 20/50 -2 (P = 0.82). The mean preoperative visual acuity was 20/50 + 2 in 33 eyes which were pseudophakic by the final examination and this improved to 20/32 -2 (P = 0.005). There were no other serious complications such as retinal detachment or infectious endophthalmitis. Vitrectomy for epiretinal membranes is safe in eyes with relatively good preoperative visual acuities but cataract surgery is necessary in phakic eyes to achieve long-term visual acuity improvement.


High Temperature and Power Dependent Photoluminescence Analysis on Commercial Lighting and Display LED Materials for Future Power Electronic Modules.
Commercial light emitting diode (LED) materials - blue (i.e., InGaN/GaN multiple quantum wells (MQWs) for display and lighting), green (i.e., InGaN/GaN MQWs for display), and red (i.e., Al0.05Ga0.45In0.5P/Al0.4Ga0.1In0.5P for display) are evaluated in range of temperature (77-800) K for future applications in high density power electronic modules. The spontaneous emission quantum efficiency (QE) of blue, green, and red LED materials with different wavelengths was calculated using photoluminescence (PL) spectroscopy. The spontaneous emission QE was obtained based on a known model so-called the ABC model. This model has been recently used extensively to calculate the internal quantum efficiency and its droop in the III-nitride LED. At 800 K, the spontaneous emission quantum efficiencies are around 40% for blue for lighting and blue for display LED materials, and it is about 44.5% for green for display LED materials. The spontaneous emission QE is approximately 30% for red for display LED material at 800 K. The advance reported in this paper evidences the possibility of improving high temperature optocouplers with an operating temperature of 500 K and above.


Beyond the disability: recognizing mental health issues among persons with intellectual and developmental disabilities.
Current societal changes mean increased possibilities for individuals with I/DD to participate in work, family, and community life. However, as individuals with I/DD have at least the same prevalence of mental health disorders as the general population and possibly an increased susceptibility to some mental health disorders, their ability to participate in work, housing, and social opportunities is hampered. It is important to improve nursing education about the specific issues of mental health care of individuals with I/DD. An important area for nursing research and education are improved clinical and practice guidelines. Research on medications and other therapies in mental health care of individuals with I/DD is limited and has methodological limitations. Nursing education and training are holistic, and nursing has the potential of positive impact on practice, education, and research that will improve the mental health care of individuals with I/DD.


Monitoring of moisture contents and rehydration rates of microwave vacuum and hot air dehydrated beef slices and splits using hyperspectral imaging.
Effects of food microstructure and processing methods on moisture migration in food during processing are important for improving product quality. This study evaluated the effects of fibre directions and dehydration methods on beef dehydration and rehydration behaviours using near-infrared hyperspectral imaging. Beef slices (transversal cut) and splits (longitudinal cut) were dehydrated by hot air drying (HAD) and microwave vacuum drying (MVD). Results indicated the moisture in the slices evaporated faster than that in the splits during HAD and MVD processed samples exhibited higher rehydration rates than HAD ones. Principal component analysis showed great performance in clustering samples based on fibre directions, processing methods and time. The established simplified RC-SG-PLSR and RC-2nd Der-PLSR models possessed good prediction accuracies for moisture (R2p = 0.994) and rehydration rate (R2p = 0.889), respectively. Chemical distribution maps also confirmed the influence of fibre directions and dehydration methods on moisture migration in samples.


Hypolipidemic action of chrysin on Triton WR-1339-induced hyperlipidemia in female C57BL/6 mice.
Chrysin (5,7-dihydroxyflavone) is a flavonoid, natural component of traditional medicinal herbs, present in honey, propolis and many plant extracts. The objective of this study was to investigate the hypolipidemic properties of chrysin on Triton WR-1339-induced hyperlipidemia in female C57BL/6 mice. Triton WR-1339 was administered intraperitoneally (400 mg/kg) to overnight-fasted mice to develop acute hyperlipidemia. Chrysin was administered orally (10 mg/kg) 30 min before Triton WR-1339. At 24 h after Triton WR-1339 injection, blood samples were collected to measure plasma lipid levels. The hepatic thiobarbituric acid reactive substances (TBARS), carbonyl content, non-protein sulfhydryl (NPSH) and ascorbic acid (AA) levels, as well as catalase (CAT) and superoxide dismutase (SOD) activity were recorded. Chrysin administration significantly decreased total cholesterol levels. In addition, it partially decreased non-high density lipoprotein-cholesterol and triglycerides levels in plasma of hyperlipidaemic mice. In addition chrysin administration prevented the increase on TBARS levels and prevented the decrease in SOD activity induced by Triton WR-1339. These findings indicated that chrysin was able to decrease plasma lipids concentration and that its antioxidant properties was, at least in part, involved in the hypolipidaemic action of chrysin.


The Joubert Syndrome Gene arl13b is Critical for Early Cerebellar Development in Zebrafish.
Joubert syndrome is characterized by unique malformation of the cerebellar vermis. More than thirty Joubert syndrome genes have been identified, including ARL13B. However, its role in cerebellar development remains unexplored. We found that knockdown or knockout of arl13b impaired balance and locomotion in zebrafish larvae. Granule cells were selectively reduced in the corpus cerebelli, a structure homologous to the mammalian vermis. Purkinje cell progenitors were also selectively disturbed dorsomedially. The expression of atoh1 and ptf1, proneural genes of granule and Purkinje cells, respectively, were selectively down-regulated along the dorsal midline of the cerebellum. Moreover, wnt1, which is transiently expressed early in cerebellar development, was selectively reduced. Intriguingly, activating Wnt signaling partially rescued the granule cell defects in arl13b mutants. These findings suggested that Arl13b is necessary for the early development of cerebellar granule and Purkinje cells. The arl13b-deficient zebrafish can serve as a model organism for studying Joubert syndrome.


Molecular design, synthesis and biological evaluation of cage compound-based inhibitors of hepatitis C virus p7 ion channels.
The hepatitis C caused by the hepatitis C virus (HCV) is an acute and/or chronic liver disease ranging in severity from a mild brief ailment to a serious lifelong illness that affects up to 3% of the world population and imposes significant and increasing social, economic, and humanistic burden. Over the past decade, its treatment was revolutionized by the development and introduction into clinical practice of the direct acting antiviral (DAA) agents targeting the non-structural viral proteins NS3/4A, NS5A, and NS5B. However, the current treatment options still have important limitations, thus, the development of new classes of DAAs acting on different viral targets and having better pharmacological profile is highly desirable. The hepatitis C virus p7 viroporin is a relatively small hydrophobic oligomeric viral ion channel that plays a critical role during virus assembly and maturation, making it an attractive and validated target for the development of the cage compound-based inhibitors. Using the homology modeling, molecular dynamics, and molecular docking techniques, we have built a representative set of models of the hepatitis C virus p7 ion channels (Gt1a, Gt1b, Gt1b_L20F, Gt2a, and Gt2b), analyzed the inhibitor binding sites, and identified a number of potential broad-spectrum inhibitor structures targeting them. For one promising compound, the binding to these targets was additionally confirmed and the binding modes and probable mechanisms of action were clarified by the molecular dynamics simulations. A number of compounds were synthesized, and the tests of their antiviral activity (using the BVDV model) and cytotoxicity demonstrate their potential therapeutic usefulness and encourage further more detailed studies. The proposed approach is also suitable for the design of broad-spectrum ligands interacting with other multiple labile targets including various viroporins.