Encapsulation of selenium-containing peptides in xanthan gum-lysozyme nanoparticles as a powerful gastrointestinal delivery system.
In this study, nanoparticles (NPs) prepared with xanthan gum and lysozyme were established as a powerful delivery system for two Se-containing peptides: TSeMMM (STP) and SeMDPGQQ (SHP). NPs-STP and NPs-SHP had relatively small particle sizes (145 nm and 148 nm) and negative zeta potentials (-47 mV and -49 mV). The encapsulation efficiency of NPs-STP and NPs-SHP was determined to be 34.35% and 41.35%, respectively. The stability and antioxidant activity of Se-containing peptides were greatly enhanced due to encapsulation. NPs-STP and NPs-SHP exhibited controlled release of Se-containing peptides under in vitro gastrointestinal conditions. NPs-STP and NPs-SHP showed low toxicity and entered Caco-2 cells through clathrin-mediated endocytosis, contributing to a significant increase in the apparent permeability coefficient of STP (2.19 × 10-6 cm/s) and SHP (2.21 × 10-6 cm/s). Thus, NPs-STP and NPs-SHP are considered promising delivery systems for Se-containing peptides and have good potential applications in the food and pharmaceutical industries.


Joplin's neuroma or compression neuropathy of the plantar proper digital nerve to the hallux: clinicopathologic study of three cases.
Both nonsurgical and surgical treatment of compressive and/or entrapment neuropathy of the plantar proper digital nerve to the hallux, also known as Joplin's neuroma, are very uncommon in the literature. The condition of perineural fibrosis of this nerve was first described in 1971 by Joplin. Diagnosis of this nerve in a localized pathologic process based on physical exam and surgical pathology and noniatrogenic etiology are discussed. Three case studies of Joplin's neuroma are followed through the treatment course from initial presentation to postoperative follow-up.


Smoking cessation intervention for patients with head and neck cancer: A prospective randomized controlled trial.
To evaluate the effectiveness of a brief smoking cessation intervention in head and neck cancer patients (HNCP). A prospective randomized controlled trial that randomly assigns participants in two groups: a usual care group (UCG), and a standardized intervention group (SIG). Patients with a confirmed diagnosis of head and neck squamous cell carcinoma (HNSCC) and who are active smokers were prospectively approached by one of 4 trained Ear-nose-throat (ENT) residents. Participants were randomized into a UCG, and a SIG consisting of a brief perioperative smoking cessation intervention based on National Institute of Health (NIH) "5A's" model along with an informative motivational document and nicotine patch therapy (NPT) offered for 8 weeks in gradually decreasing doses. The evaluation of abstinence at 3, 6 and 12 months after enrollment. 56 subjects were randomized into the UCG (N = 29, 52%), and the SIG (N = 27, 48%). The overall smoking cessation rates were not statistically different between the two groups; we observed at 3 months cessation rates of 57.1% vs. 57.7% (p = 0.96); at 6 months, 42.9% vs. 24% (p = 0.148); and at 12 months, 33.3% vs. 20.8% (p = 0.318), for the UCG and the SIG respectively. This study failed to show the effectiveness of a combined brief smoking cessation approach led by and ENT resident in HNSCC patients. A multifaceted approach addressing different pharmacological treatments, factors contributing to smoking maintenance, mainly alcohol dependence and mood disturbances and dealing with relapse risks through close face-to-face or phone call follow-ups may have better outcomes and should be evaluated in upcoming trials.


Charge-transport properties of 4-(1,2,2-tri-phenyl-vinyl)-aniline salicylaldehyde hydrazone: tight-packing induced molecular 'hardening'.
Based on first-principles calculations, the relationship between molecular packing and charge-transport parameters has been investigated and analysed in detail. It is found that the crystal packing forces in the flexible organic molecule 4-(1,2,2-triphenylvinyl)-aniline salicylaldehyde hydrazone (A) can apparently overcome the dynamic intramolecular rotations and the intramolecular steric repulsion, effectively enhancing the molecular rigidity and decreasing the internal reorganization energy. The conducting properties of A have also been simulated within the framework of hopping models, and the calculation results show that the intrinsic electron mobility in A is much higher than the corresponding intrinsic hole mobility. These theoretical investigations provide guidance for the efficient and targeted control of the molecular packing and charge-transport properties of organic small-molecule semiconductors and conjugated polymeric materials.


Gingival squamous cell carcinoma appearing as a benign lesion: report of case.
A case of a 37-year-old female who had a squamous cell carcinoma on the attached gingiva is discussed. The report emphasizes the importance of a correct diagnosis of all lesions, including lesions that appear atypical. A brief review of the literature also is presented.


Differences in microplastic abundances within demersal communities highlight the importance of an ecosystem-based approach to microplastic monitoring.
Plastic pollution is prevalent in all habitats and microplastic ingestion has been recorded in several different species examined to date. However, most studies have focused solely on commercial species. This study investigates microplastics (MPs) by assessing the levels present in a mixed demersal trawl at two sites in a coastal embayment. MPs were recovered from species' gastrointestinal tracts and polymers identified with μFTIR spectroscopic analysis. Particles recovered comprised 20% natural fibres. The majority of MPs were identified as PE, PVDF, and PETE. Results show an average MP range of 0.11-4.67 MPs individual-1. Fluctuating trendlines for MPs within species suggest that their bioavailability is influenced by several factors. Individual species show significant differences in ingested MP between trawls; however, when the entire trawl community is assessed there is no significant difference between sites. These results suggest that future studies should follow an ecosystem-based approach to monitor MPs.


Upregulated calcium-binding tyrosine phosphorylation-regulated protein-a/b regulates cell proliferation and apoptosis and predicts poor prognosis in hepatocellular carcinoma.
Calcium-binding tyrosine phosphorylation-regulated protein (CABYR) is a group of isoforms produced by alternative splicing and is overexpressed in human malignancies including hepatocellular carcinoma (HCC). However, the prognostic value and biological functions of its major protein isoforms, named CABYR-a/b (combined CABYR-a and CABYR-b), in HCC remain to be established. CABYR-a/b expression was detected in HCC tissues and cell lines by quantitative real-time polymerase chain reaction and Western blot analysis. The correlation of CABYR-a/b expression with clinical characteristics and its prognosis impact were determined by statistical analysis. Finally, the biological functions and molecular mechanism of CABYR-a/b were also investigated using molecular biology approaches. The present research found that CABYR-a/b was markedly elevated in HCC specimens and cell lines. Upregulated CABYR-a/b level had positive association with tumor size and differentiation in patients. Moreover, cases with elevated CABYR-a/b level had poorer overall survival (OS) and disease-free survival (DFS) than those with reduced CABYR-a/b level. Multivariate analysis and prognostic nomograms demonstrated that CABYR-a/b overexpression was an independent predictive indicator for OS and DFS. The calibration curve for the odds of OS and DFS demonstrated that the prediction by nomograms was in excellent accordance with actual situation. CABYR-a/b downregulation suppressed cell proliferation and induced G1-phase arrest via decreasing cyclin D1 and cyclin dependent kinase 4, while promoted apoptosis by reducing B-cell lymphoma 2 (Bcl-2) and increasing Bcl-2-associated death promoter. Our research indicates that CABYR-a/b exerts an oncogenic effect on HCC development and may become a new prognostic indicator for patients with HCC.


Ulthera: initial and six month results.
The Ulthera system is a facial application of intense focused ultrasound developed for improving noninvasive rejuvenation results. This article describes the Ulthera device, its mechanism of action, the indications and limitations of the device, and the details of treatment. We also review the literature and our personal results, discuss future trends, and conclude with advice for the early user.


Changes induces by haloperidol (antidepressant drug) on the developing retina of the chick embryo.
Morphological and histological studies were done on the retina of chick embryos of 6th, 10th and 16th days of incubation by a single dose of haloperidol (0.25 mg/egg), injected on day zero and 5 of incubation. To get an idea about the extent of the teratogenic effect of this drug on the development retina. Sign of malformation in the chick embryo after administration of haloperidol were seen as absent of the ear vesicles, eyes or decreased size of them. Retardation of growth of the retina at 6th, 10th and 16th days treated chick embryo were observed as evidenced of reduction of the size of the retina, associated with sign of degeneration of the retina cells. The injection of haloperidol drug give rise to several side effects as retardation of growth and degeneration of the cells. The decrease of the thickness of the layers and less density of the cells was related to direct effect of the drug on the cells of this organ. Also on the DNA formation and on the retardation of cellular mitotic activates, therefore the retina appeared decrease in thickness and less cell density with degeneration its cells.


Health and labor-power: a theoretical investigation.
In this historical materialist analysis of health and medical care, health is defined as a component of labor-power (capacity to work). Investment in health, including provision of medical services, represents part of the cost of maintaining the labor force. The primary determined of the level of health and medical care under capitalism is the tendency toward maximization of the rate of exploitation. The absolute level of health and medical care tends to decline as unemployment rises and individual workers become more "replaceable." Health differentials by socioeconomic status are similarly explained by the easier replacement of lesser-skilled workers. Medical care services in the context of the capitalist system constitute a drain on surplus-value. In periods of economic decline, attempts are made to conserve surplus-value through reductions in medical services ("social wages"). Institutional and ideological racism yields additional surplus-value savings and weakness public resistance to medical care retrenchment. The profits of health-related industries are shown to be merely partially recouped surplus-value losses. The social epidemiology of capitalism has been characterized as social murder. "Public health" measures appropriate to this systemic pathology are suggested.


Nosocomial outbreak of Pantoea agglomerans bacteraemia associated with contaminated anticoagulant citrate dextrose solution: new name, old bug?
We describe an outbreak investigation of Pantoea agglomerans bacteraemia associated with anticoagulant citrate-dextrose 46% (ACD) solution prepared in-house. A healthy man presented with septic shock during plasmapheresis for granulocyte donation. The solution used for priming and blood samples were sent for culture. Identification of the isolate to species level was performed by gyrB sequencing. Typing was performed by pulsed-field gel electrophoresis (PFGE). In total, eight cases were identified during a three-week period. P. agglomerans was also cultured from six ACD solution bags. Isolates from patients and ACD bags were identical by PFGE. All isolates were susceptible to ampicillin, cephazolin, gentamicin, ciprofloxacin, cefepime and imipenem.


Pediatric cervicomediastinal hibernoma: a case report.
Hibernoma is a rare lipomatous tumor of brown fat origin. Though uniformly benign in nature these tumors may cause symptoms secondary to extrinsic compression of neighboring structures. Hibernomas may be found anywhere that normal fetal brown fat may be located but are most commonly located in the thigh. We present a case of a hibernoma presenting as an unusual cervicomediastinal mass in a 6-year-old male. This mass was discovered during a diagnostic chest x-ray for pneumonia and treated by resection. Complete surgical resection is considered curative. Hibernoma should be considered in the differential diagnosis of any lipomatous tumor.


Exclusion of persistent mutations in splicing factor genes and isocitrate dehydrogenase 2 improves the prognostic power of molecular measurable residual disease assessment in acute myeloid leukemia.
Not available.


Characterization of LP-Z Lipoprotein Particles and Quantification in Subjects with Liver Disease Using a Newly Developed NMR-Based Assay.
Lipoprotein particles with abnormal compositions, such as lipoprotein X (LP-X) and lipoprotein Z (LP-Z), have been described in cases of obstructive jaundice and cholestasis. The study objectives were to: (1) develop an NMR-based assay for quantification of plasma/serum LP-Z particles, (2) evaluate the assay performance, (3) isolate LP-Z particles and characterize them by lipidomic and proteomic analysis, and (4) quantify LP-Z in subjects with various liver diseases. Assay performance was assessed for linearity, sensitivity, and precision. Mass spectroscopy was used to characterize the protein and lipid content of isolated LP-Z particles. The assay showed good linearity and precision (2.5-6.3%). Lipid analyses revealed that LP-Z particles exhibit lower cholesteryl esters and higher free cholesterol, bile acids, acylcarnitines, diacylglycerides, dihexosylceramides, lysophosphatidylcholines, phosphatidylcholines, triacylglycerides, and fatty acids than low-density lipoprotein (LDL) particles. A proteomic analysis revealed that LP-Z have one copy of apolipoprotein B per particle such as LDL, but less apolipoprotein (apo)A-I, apoC3, apoA-IV and apoC2 and more complement C3. LP-Z were not detected in healthy volunteers or subjects with primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis, or type 2 diabetes. LP-Z were detected in some, but not all, subjects with hypertriglyceridemia, and were high in some subjects with alcoholic liver disease. LP-Z differ significantly in their lipid and protein content from LDL. Further studies are needed to fully understand the pathophysiological reason for the enhanced presence of LP-Z particles in patients with cholestasis and alcoholic liver disease.


[Possibilities and limitations in evaluating treatment concepts in lip-jaw-palate clefts].
Recently, government and medical practitioners have shown considerable interest in the discipline of evidence-based medicine. In this study, we investigated the literature concerning treatment concepts in cleft surgery according to criteria of evidence-based medicine. Over the last decade 996 articles on cleft patients were published, 181 of which were studies evaluating the clinical outcome of distinct treatment options. Only 57 studies proved to be classifiable due to a well-described study protocol. One treatment study of cleft patients reached the strength of evidence grade I and strength of recommendation grade A, whereas all other studies had a lower evidence rating. The reasons behind these findings seem to be due to problems faced by the specialty of this disease.


Existing and Developing Preclinical Models for Neurofibromatosis Type 1-Related Cutaneous Neurofibromas.
Neurofibromatosis type 1 (NF1) is caused by a nonfunctional copy of the NF1 tumor suppressor gene that predisposes patients to the development of cutaneous neurofibromas (cNFs), the skin tumor that is the hallmark of this condition. Innumerable benign cNFs, each appearing by an independent somatic inactivation of the remaining functional NF1 allele, form in nearly all patients with NF1. One of the limitations in developing a treatment for cNFs is an incomplete understanding of the underlying pathophysiology and limitations in experimental modeling. Recent advances in preclinical in vitro and in vivo modeling have substantially enhanced our understanding of cNF biology and created unprecedented opportunities for therapeutic discovery. We discuss the current state of cNF preclinical in vitro and in vivo model systems, including two- and three-dimensional cell cultures, organoids, genetically engineered mice, patient-derived xenografts, and porcine models. We highlight the models' relationship to human cNFs and how they can be used to gain insight into cNF development and therapeutic discovery.


Behavior and quality of life measures after anesthesia for tonsillectomy or ear tube insertion in children.
Past research examining the psychosocial impact of general anesthesia and day case surgery on children has been hampered by a lack of valid and reliable assessment tools. The purpose of the current study was to assess the feasibility of using a well-validated scale (i.e. the Pediatric Quality of Life Inventory Generic Core Scales Version 4.0, PedsQL) in the perioperative setting and to establish changes seen in a sample of children having day case surgery when using this scale. Eighty-nine children (aged 3-12 years) scheduled for general anesthesia for day case tonsillectomy or ear tube insertions were recruited into a prospective study in Melbourne, Australia. Parents completed the PedsQL and the Post Hospitalization Behavioral Questionnaire (PHBQ), and children completed the PedsQL (child self-report) at baseline (preanesthesia), 7 days following anesthesia and 30 days following anesthesia. The response rate at day 7 and day 30 was modest but when returned the PedsQL and PHBQ had minimal missing data. On the PedsQL, parents rated children's physical functioning as worse at day 7 than at baseline but psychosocial functioning did not differ significantly from baseline. At 30 days, both physical and psychosocial functioning was rated by parents to be better than baseline levels. From children's perspective, there was little evidence of a change in their physical or psychosocial functioning on the self-report PedsQL at day 7, but by day 30 both physical and psychosocial functioning was above baseline levels. A similar pattern was observed on the PHBQ, with little difference in ratings of behavioral problems between baseline and day 7, but less behavioral problems reported at day 30 compared with baseline. The PedsQL is feasible for use in the perioperative setting. Future studies should take into account the possibility that deterioration of psychosocial functioning is uncommon at 1 -month postsurgery compared to the preoperative baseline.


Economic outcomes of exenatide vs liraglutide in type 2 diabetes patients in the United States: results from a retrospective claims database analysis.
The safety and efficacy of the GLP-1 receptor agonists exenatide BID (exenatide) and liraglutide for treating type 2 diabetes mellitus (T2DM) have been established in clinical trials. Effective treatments may lower overall treatment costs. This study examined cost offsets and medication adherence for exenatide vs liraglutide in a large, managed care population in the US. This was a retrospective cohort analysis comprising adult patients with T2DM who initiated exenatide or liraglutide between 1/1/2010 and 6/30/2010 and had 6 months pre-index and post-index continuous eligibility. Patients were propensity score-matched to controls for baseline differences. Medication adherence was measured by proportion of days covered (PDC). Paired t-test and McNemar's test were used to compare outcomes. Matched exenatide and liraglutide cohorts (n=1347 pairs) had similar average total 6-month follow-up costs ($6688 vs $7346). However, exenatide patients had significantly lower mean pharmacy costs ($2925 vs $3272, p<0.001). Among liraglutide patients, patients receiving the 1.8 mg dose had significantly higher average total costs compared to those receiving the 1.2 mg dose ($8031 vs $6536, p=0.026), with higher mean pharmacy costs in the 1.8 mg cohort ($3935 vs $3146, p<0.001). There were no significant differences in inpatient or outpatient costs or medication adherence between groups (mean PDC: exenatide 56% vs liraglutide 57%, p=0.088). The study assumed that all information needed for case classification and matching of cohorts was present and not differential across cohorts. The study did not control for covariates that were unavailable, such as HbA1c and duration of diabetes. Patients initiating exenatide vs liraglutide for T2DM had similar medication adherence and total healthcare costs; however, exenatide patients had significantly lower total pharmacy costs. Patients prescribed 1.8 mg liraglutide had significantly higher costs compared to those on 1.2 mg.


Staining of Frozen and Formalin-Fixed, Paraffin-Embedded Tissues with Metal-Labeled Antibodies for Imaging Mass Cytometry Analysis.
This unit describes protocols for labeling tissue sections using combinations of metal-tagged antibodies and an iridium-containing DNA intercalator for analysis by imaging mass cytometry. Imaging mass cytometry (IMC) allows the labeling of up to 40 individual markers simultaneously using antibody cocktails. We discuss labeling of both cryostat sections and sections from formalin-fixed, paraffin-embedded (FFPE) tissue blocks. The protocols are similar to those used for optical microscopy techniques, while allowing much higher complexity of analysis. © 2017 by John Wiley & Sons, Inc.


Chemical Variability of Ivoirian Xylopia rubescens Leaf Oil.
Forty-two essential oil samples were isolated from leaves of Xylopia rubescens harvested in three forests of Southern Ivory Coast. All the samples have been submitted to GC-FID and the retention indices (RIs) of individual components have been measured on two capillary columns of different polarity. In addition, 20 oil samples, selected on the basis of their chromatographic profile, were also analyzed by 13 C-NMR and 24 components (78.0 - 92.4% of the whole compositions) have been identified. The content of the main components varied drastically from sample to sample: furanoguaia-1,4-diene (5.7 - 54.1%), furanoguaia-1,3-diene (1.1 - 10.5%), (8Z,11Z,14Z)-heptadeca-8,11,14-trien-2-one (4.3 - 16.0%), and (E)-β-caryophyllene (1.7 - 17.3%). Hierarchical cluster and principal components analysis of the 42 oil compositions allowed the distinction of two well-differentiated groups of unequal importance within the oil samples. Oil samples of the main group (Group II) contained mainly furanoguaia-1,4-diene (mean [M] = 43.1%; standard deviation [SD] = 3.2%) while furanoguaia-1,3-diene (M = 8.4%; SD = 0.9%) and (8Z,11Z,14Z)-heptadeca-8,11,14-trien-2-one (M = 7.1%; SD = 1.5%) were present at appreciable contents. The composition of Group I was dominated by furanoguaia-1,4-diene (M = 17.0%; SD = 8.5%), (8Z,11Z,14Z)-heptadeca-8,11,14-trien-2-one (M = 10.2%; SD = 2.4%) and (E)-β-caryophyllene (M = 9.5%; SD = 5.3%).


KCa3.1 channel mediates inflammatory signaling of pancreatic β cells and progression of type 2 diabetes mellitus.
Chronic islet inflammation is associated with development of type 2 diabetes mellitus (T2DM). Intermediate-conductance calcium-activated K+ (KCa3.1) channel plays an important role in inflammatory diseases. However, the role and regulation of KCa3.1 in pancreatic β cells in progression of T2DM remain unclarified. In the present study, we evaluated the effect of the specific KCa3.1 channel blocker 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34) on diabetic phenotype in the db/db model. In diabetic mice, blockade of KCa3.1 significantly improved glucose tolerance, enhanced secretion of postprandial insulin level, and reduced loss of β-cell mass through attenuating the expression and secretion of inflammatory mediators. Furthermore, in cultured pancreatic β cells, exposure to high levels of glucose or palmitic acid significantly increased expression and current density of the KCa3.1 channel as well as secretion of proinflammatory chemokines, and the effects were similarly reversed by preincubation with TRAM-34 or a NF-κB inhibitor pyrrolidinedithiocarbamate. Additionally, expression of KCa3.1 in pancreas islet cells was up-regulated by activation of NF-κB with IL-1β stimulation. In summary, up-regulated KCa3.1 due to activation of NF-κB pathway leads to pancreatic inflammation via expression and secretion of chemokines and cytokines by pancreatic β cells, thereby facilitating progression of T2DM.-Pang, Z.-D., Wang, Y., Wang, X.-J., She, G., Ma, X.-Z., Song, Z., Zhao, L.-M., Wang, H.-F., Lai, B.-C., Gou, W., Du, X.-J., Deng, X.-L. KCa3.1 channel mediates inflammatory signaling of pancreatic β cells and progression of type 2 diabetes mellitus.


Evidence of soluble proteins binding adriamycin by affinity chromatography.
The presence of various tissues of soluble proteins binding adriamycin is evidenced by affinity chromatography.


Developing a personal health record self-efficacy tool.
The purpose of this preliminary work was to develop a new short tool to assess personal health records (PHRs) self-efficacy. Prior work had found 4 distinct skills related to creating, updating, tracking symptoms, and sharing information with health care providers using PHR. Although PHRs have great promise, their uptake has been rather limited, especially in economically limited populations. A convenience sample of community-living persons with HIV/AIDS (N = 100) was asked to complete the new tool along with other self-efficacy measures. Preliminary work indicated more confidence about paper-based PHRs compared with computer-based PHRs. The paper-based subscale was significantly correlated to chronic illness and HIV treatment self-efficacy scales as expected, but there were no relationships for the computer-based subscale. This simple screening tool could identify interested clients and their preference either for a paper-based or computer-based PHR. Further research is needed with larger sample sizes and different chronically ill populations to further explore the psychometrics of the instrument.


Circadian variation in an amphetamine induced motor response.
Significant diurnal variation in occurrence and duration of D-amphetamine induced head-shaking were observed in 9-day-old rats. The lowest values were obtained near noon, and the highest around midnight. These variations should be considered if head-shaking is to be used as a quantitative neuropharmacological test.


Do primary care physicians underprescribe antibiotics for peptic ulcer disease? Report from an Italian research network.
To determine how often primary care physicians prescribe eradication therapy for peptic ulcer disease (PUD) and nonulcer dyspepsia (NUD). During a 2-year period (1998-2000) we analyzed data concerning patients with PUD or NUD seen by 80 Italian primary care physicians uniformly distributed throughout the country. We classified patients as having a definitive or a presumptive diagnosis on the basis of the completeness of the diagnostic workup and interpreted the prescription of antibiotics for dyspepsia as evidence of attempted eradication of Helicobacter pylori. Consecutive ambulatory patients. The frequency with which predefined groups of patients received eradication therapy. Of 6866 patients, 690 (10%) received eradication therapy. Of 2162 patients with PUD, 596 (27.6%) received eradication therapy; of 4704 patients with NUD, however, only 94 (2%) received this treatment (P =.0001). A total of 341 (37.7%) of 904 PUD patients with a definitive diagnosis were given eradication therapy and 255 (20.3%) of 1258 PUD patients with a presumptive diagnosis were given therapy (P &lt.0001). In NUD patients, 7 of 743 (0.9%) with a definitive diagnosis received eradication therapy, while 87 (2.2%) of 3961 of those with a presumptive diagnosis were given the same therapy (P =.025). While Italian primary care physicians appropriately target eradication therapy for H pylori infection in patients with peptic ulcer disease rather than nonulcer disease, the intervention was still underused in these patients. Improvements in this prescribing behavior are needed.


Diving behaviour of southern elephant seals: new models of behavioural and ecophysiological adjustments of oxygen store management.
Among pinnipeds, southern elephant seals (SESs, Mirounga leonina) are extreme divers that dive deeply and continuously along foraging trips to restore their body stores after fasting on land during breeding or moulting. Their replenishment of body stores influences their energy expenditure during dives and their oxygen (O2) reserves (via muscular mass), yet how they manage their O2 stores during their dives is not fully understood. In this study, 63 female SESs from Kerguelen Island were equipped with accelerometers and time-depth recorders to investigate changes in diving parameters through their foraging trips. Two categories of dive behaviour were identified and related to the body size of individuals, with smaller SESs performing shallower and shorter dives requiring greater mean stroke amplitude compared with larger individuals. In relation to body size, the larger seals had lower estimated oxygen consumption levels for a given buoyancy (i.e. body density) compared with smaller individuals. However, both groups were estimated to have the same oxygen consumption of 0.079±0.001 ml O2 stroke-1 kg-1 for a given dive duration and at neutral buoyancy when the cost of transport was minimal. Based on these relationships, we built two models that estimate changes in oxygen consumption according to dive duration and body density. The study highlights that replenishing body stores improves SES foraging efficiency, as indicated by increased time spent at the bottom of the ocean. Thus, prey-capture attempts increase as SES buoyancy approaches the neutral buoyancy point.


Fast three-dimensional superimposition of cone beam computed tomography for orthopaedics and orthognathic surgery evaluation.
The aim of this study was to validate a method for fast three-dimensional (3D) superimposition of cone beam computed tomography (CBCT) in growing patients and adults (surgical cases). The sample consisted of CBCT scans of 18 patients. For 10 patients, as the gold standard, the spatial position of the pretreatment CBCT was reoriented, saved as a reoriented volume, and then superimposed on the original image. For eight patients, four non-growing and four growing, the pre- and post-treatment scans were superimposed. Fast voxel-based superimposition was performed, with registration at the anterior cranial base. This superimposition process took 10-15s. The fit of the cranial base superimposition was verified by qualitative visualization of the semi-transparent axial, sagittal, and coronal cross-sectional slices of all corresponding anatomical structures. Virtual 3D surface models of the skull were generated via threshold segmentation, and superimposition errors in the reoriented models and the results of treatment for the treated cases were evaluated by 3D surface distances on colour-coded maps. The superimposition error of the spatial reorientation and for growing and non-growing patients was <0.5mm, which is acceptable and clinically insignificant. The voxel-based superimposition method evaluated was reproducible in different clinical conditions, rapid, and applicable for research and clinical practice.


Behavioral Indexes of Thermal Nociceptive Sensitivity in Rats after Melatonin Administration.
We studied the effect of melatonin (10 mg/kg intraperitoneally) on behavioral indexes reflecting changes in nociceptive sensitivity of rats in response to thermal stimulation in the hot plate test. Administration of melatonin to animals suppressed the perceptual component of nociception, which was manifested in an increase in the perception threshold of noxious thermal stimulus. In the follow-up period, exogenous melatonin contributed to a decrease in the latency of avoidance reactions and enhanced the behavior of escaping the thermal nociceptive stimulation. Our results suggest that the involvement of melatonin in goal-directed behavior of mammals during nociceptive treatment is related to an increase in orientation and exploratory activity, facilitation of memory storage, and improvement of memory retrieval for environmental signals, action program, and reinforcing effect of avoiding the painful stimulus.


Health behaviours and well-being among older adults with a Surinamese migration background in the Netherlands.
This study aims to identify the relationships between health behaviours (healthy diet, physical activity, not smoking and social activity) and well-being among older adults with a Surinamese background. Community-dwelling older adults (≥ 70 years) with a Surinamese background living in Rotterdam, the Netherlands, were identified by the municipal register. A survey study was conducted to assess background information, health behaviours (healthy diet, physical activity, not smoking and social activity) and well-being. Multiple regression analyses were performed to assess the relationships of health behaviours with well-being while controlling for background characteristics. Average age of participants was 76.2 (4.9) years, slightly more than half of them were female (54.2%). Almost half of the participants had a low-income level (49.6%). More than half of the participants met the Dutch guidelines of fruit intake (63.0%) and vegetable intake (62.8%). Less than half of the participants met the guidelines of fish intake (40.9%) and physical activity (39.8%). The majority of the participants were non-smokers (87.9%). Most of the participants had daily contact with family/friends (90.9%) and slightly more than half of the participants visited family/friends often (53.6%). Looking at the health behaviours, a positive relationship was found between eating enough fruit (β = .109; p ≤ 0.05) and vegetables (β = .135; p ≤ 0.01), physical activity (β = .164; p ≤ 0.001) and often visiting family/friends (β = .158; p ≤ 0.001) with well-being. This study suggests that next to traditional health behaviours also social activity is an essential health behaviour for the well-being of older Surinamese adults. Research about health promotion should expand its focus by including social activity as health behaviour.


Diagnostic value of mucin-like carcinoma-associated antigen (MCA) in breast cancer.
The diagnostic value of mucin-like carcinoma-associated antigen (MCA) was compared to that of carcinoembryonic antigen (CEA) and/or CA 15.3 in patients with breast cancer. A total of 368 patients with breast cancer were studied, of whom 253 were free of metastases, whereas 94 had either skeletal or visceral metastases or diffuse metastatic disease. The diagnostic sensitivity of MCA proved to be comparable to that of CA 15.3 and superior to that of CEA in patients with metastatic breast cancer. In contrast, the specificity of MCA was superior to that of CA 15.3. Finally, the diagnostic sensitivity of each of the tested tumour markers, i.e. MCA, CEA and CA 15.3, could be improved by their combined use. We conclude that MCA, either alone or in combination with CA 15.3 and CEA, can improve the monitoring of disease progression in patients with metastatic breast cancer.


Increase in the prevalence of follicular regulatory T cells correlates with clinical efficacy of sublingual immunotherapy with house dust mites.
Allergic rhinitis (AR) impairs quality of life and affects nearly 40% of the Japanese population. Sublingual immunotherapy (SLIT) is the disease-modifying treatment for AR, but requires the selection of a biomarker associate with clinical efficacy in patients with AR who are treated with SLIT. The present study sought to examine objective biomarkers used for assessing the clinical efficacy of SLIT. The authors examined the effects of 1 year of SLIT treatment with house dust mites (HDMs) using peripheral blood mononuclear cells (PBMCs) and serum from patients with AR. The prevalences of follicular regulatory T (Tfr), type 2 follicular helper T (Tfh2), type 2 helper T (Th2), conventional regulatory T (Treg), and type 1 regulatory T (Tr1) cells were examined by flow cytometry. Serum concentrations of HDM-specific IgA, IgE, and IgG4 antibodies, and HDM-induced production of interleukin (IL) 5 and IL-10 from cultured PBMCs were evaluated by enzyme-linked immunosorbent assay. Following 1 year of SLIT, the prevalences of Tfr, conventional Treg, and Tr1 cells were significantly increased, whereas that of Th2 cells and Tfh2 cells were significantly decreased; the serum concentration of HDM-specific IgG4 was significantly increased; and HDM-induced production of IL-5 from PBMCs was significantly decreased, while that of IL-10 was significantly increased. The increase in the prevalence of Tfr cells after SLIT correlated positively with the improvement of clinical symptom scores. An increase in Tfr cells may play an important role in SLIT, and may be a useful indicator for the clinical efficacy of SLIT.


An economic analysis of a system wide Lean approach: cost estimations for the implementation of Lean in the Saskatchewan healthcare system for 2012-2014.
The costs of investing in health care reform initiatives to improve quality and safety have been underreported and are often underestimated. This paper reports direct and indirect cost estimates for the initial phase of the province-wide implementation of Lean activities in Saskatchewan, Canada. In order to obtain detailed information about each type of Lean event, as well as the total number of corresponding Lean events, we used the Provincial Kaizen Promotion Office (PKPO) Kaizen database. While the indirect cost of Lean implementation has been estimated using the corresponding wage rate for the event participants, the direct cost has been estimated using the fees paid to the consultant and other relevant expenses. The total cost for implementation of Lean over two years (2012-2014), including consultants and new hires, ranged from $44 million CAD to $49.6 million CAD, depending upon the assumptions used. Consultant costs accounted for close to 50% of the total. The estimated cost of Lean events alone ranged from $16 million CAD to $19.5 million CAD, with Rapid Process Improvement Workshops requiring the highest input of resources. Recognizing the substantial financial and human investments required to undertake reforms designed to improve quality and contain cost, policy makers must carefully consider whether and how these efforts result in the desired transformations. Evaluation of the outcomes of these investments must be part of the accountability framework, even prior to implementation.


Near fatal percutaneous paraquat poisoning.
A fatal paraquat poisoning can occur when relatively large areas of skin are contaminated with a concentrated solution of paraquat (Gramoxone). A paraquat absorption takes place of the same magnitude as that with an equal dose per os. In the presence of mechanical or chemical lesion of the skin the percutaneous paraquat absorption is distinctly enhanced.


Postnatal subventricular zone of the neocortex contributes GFAP+ cells to the rostral migratory stream under the control of Sip1.
The rostral migratory stream (RMS) is composed of neuroblasts migrating from the striatal SVZ to the olfactory bulb through a meshwork of GFAP- expressing astrocytes called the glial tube. So far, the origin of the glial tube astrocytes was attributed to differentiation of Type-B stem cells of the striatal SVZ. The true identity of these cells (Type-B stem cells versus immature/mature astrocytes) is also unclear. By analyzing a neocortex-specific conditional knockout of the transcriptional repressor Sip1 (Smad-interacting protein 1), we have now identified a novel pool of progenitors located within the dorsal SVZ (dSVZ) at early postnatal stages that differentiate into GFAP+ cells of the glial tube. We show that Sip1, expressed in postmitotic cortical neurons, controls the size of this dorsal progenitor pool possibly through cell-extrinsic mechanisms. Lack of Sip1 in the neocortex causes an expansion of this population leading to an increased production of GFAP+ astrocytes/Type-B stem cells in the glial tube, and a denser intercalation of these cells with Dcx+ neuroblasts of the RMS, the consequence of which is not yet clear. Neocortex-specific Sip1 deletion also led to an expansion of Dcx+ and Tbr2+ progenitor populations in the dSVZ. We show that the dSVZ progenitors (possibly remnants of embryonic radial glia) differentiate exclusively into BLBP+ cells which migrate into the RMS and mature into GFAP+ astrocytes/Type-B stem cells at around two weeks of postnatal development. In summary, our work shows that Sip1 controls the generation of GFAP+ cells of the RMS by regulating the size of a novel progenitor pool located in the postnatal dSVZ.


Characterization of kinase inhibitors using reverse phase protein arrays.
Using the reverse protein array platform in combination with planar waveguide technology, which allows detection of proteins in spotted cell lysates with high sensitivity in a 96-well microtiter-plate format for growing, treating, and lysing cells was shown to be suitable for this approach and indicates the usefulness of the technology as a screening tool for characterization of large numbers of kinase inhibitors. In this study, we have used reverse protein arrays to profile kinase inhibitors in various cellular pathways in order to unravel their MoA. Multiplexing and simultaneous analysis of several phospho-proteins within the same lysate allows (1) the estimation of inhibitor concentrations needed to shut down an entire pathway, (2) the estimation of inhibitor selectivity, and (3) the comparison of inhibitors of different kinases within one assay. For example, parallel analysis of p-InsR, p-PKB, p-GSK-3, p-MEK, p-ERK, and p-S6rp in insulin treated A14 cells allows profiling for inhibitors of the InsR, PI3K, PKB, mTor, RAF, and MEK. Selective kinase inhibitors revealed different specific inhibitory pattern of the analyzed phospho-read outs. Altogether, multiplexed analysis of reverse (phase) protein arrays is a powerful tool to characterize kinase inhibitors in a semi-automated low to medium throughput assay format.


Positively Charged Residues in the Head Domain of P2X4 Receptors Assist the Binding of ATP.
P2X receptors are a family of trimeric cationic channels located in the membrane of mammalian cells. They open in response to the binding of ATP. The differences between the closed and open structures have been described in detail for some members of the family. However, the order in which the conformational changes take place as ATP enters the binding cleft, and the residues involved in the intermediate stages, are still unknown. Here, we present the results of umbrella sampling simulations aimed to elucidate the sequence of conformational changes that occur during the reversible binding of ATP to the P2X4 receptor. The simulations also provided information about the interactions that develop in the course of the process. In particular, they revealed the existence of a metastable state which assists the binding. This state is stabilized by positively charged residues located in the head domain of the receptor. Based on these findings, we propose a novel mechanism for the capture of ATP by P2X4 receptors.


Liver-specific in vivo base editing of Angptl3 via AAV delivery efficiently lowers blood lipid levels in mice.
Gene editing has emerged as an exciting therapeutic development platform for numerous genetic and nongenetic diseases. Targeting lipid-modulating genes such as angiopoietin-related protein 3 (ANGPTL3) with gene editing offers hope for a permanent solution to lower cardiovascular disease risks associated with hypercholesterolemia. In this study, we developed a hepatocyte-specific base editing therapeutic approach delivered by dual adeno-associated virus (AAV) to enable hepatocyte-specific targeting of Angptl3 to lower blood lipid levels. Systemic AAV9-mediated delivery of AncBE4max, a cytosine base editor (CBE), targeting mouse Angptl3 resulted in the installation of a premature stop codon in Angptl3 with an average efficiency of 63.3 ± 2.3% in the bulk liver tissue. A near-complete knockout of the ANGPTL3 protein in the circulation were observed within 2-4 weeks following AAV administration. Furthermore, the serum levels of triglyceride (TG) and total cholesterol (TC) were decreased by approximately 58% and 61%, respectively, at 4 weeks after treatment. These results highlight the promise of liver-targeted Angptl3 base editing for blood lipid control.


A pediatric case of autoimmune encephalitis with chronologically moving seizure foci and cortical lesions: A case report.
Autoimmune encephalitis (AIE) is a relatively newly described category of immune-mediated diseases involving the central nervous system with a wide spectrum of clinical presentations, ranging from relatively mild or insidious onset of cognitive impairment to more complex forms of encephalopathy with medically refractory seizures. Single or multifocal seizures accompanied by neuropsychiatric symptoms and cognitive or memory impairments are suggestive of clinical features at AIE onset. A six-year-old boy presented with repetitive focal seizures, slowly progressive emotional liability, and attention-deficit/hyperactivity disorder-like symptoms. Seizure types varied during the clinical course, sometimes emerging as clusters or statuses. MRI performed during seizure clustering/status revealed moving signal abnormalities. We successfully treated the patient with high-dose intravenous methylprednisolone. Cerebrospinal fluid analysis revealed pleocytosis and marked elevation of antibodies against N-terminals of N-methyl-d-aspartate type glutamate receptor subunits and granzyme B. We report a case of moving seizure foci with abnormal MRI findings. Although the onset of psychiatric symptoms slowly progressed to those atypical for AIE, responsiveness to immunotherapy, cerebrospinal fluid pleocytosis, and autoantibodies all indicated AIE. We thus suggest that moving seizure foci and abnormal MRI signals may be findings of AIE.


Mutations in the rpIJ leader of Escherichia coli that abolish feedback regulation.
We have isolated mutants that fail to exhibit biosynthetic feedback regulation of a rpIJ-lacZ fusion. Analysis of these mutants and of others that were isolated earlier indicates that crucial sequences for both translational feedback regulation and efficient translation lie closely intermingled in the central region of the rpIJ mRNA leader 70-195 bases upstream from the translation start of rpIJ. We suggest that our point mutations define a region of the rpIJ leader mRNA to which L10 binds in effecting autogenous translational regulation.


Hip fracture management in the emergency department and its impact on hospital outcomes: a retrospective cross-sectional analysis.
The emergency department (ED) plays an important role in initiating early treatment for hip fractures and ensuring prompt transfer to orthopaedic wards. This study reported on the care delivered in a tertiary centre ED in Malaysia and the association between time spent in ED with hospital outcomes. Patients aged ≥ 65 years with fragility hip fractures and seen by the geriatric team were recruited. Data were collected on patient characteristics, key time points for treatment and hospital outcomes. Median time in ED was used to dichotomise long and short waiting time. 447 patients were recruited. The mean (SD) age was 80.5 (7.0) years and 69.8% were women. 74.9% were prescribed analgesia within 30 min. Median (Q1,Q3) time to diagnostic imaging was 27.0 (24.0-43.0) minutes, clinician confirmation of fracture was 83.0 (49.0-129.0) minutes, and time in ED was 4.8 (3.5-6.9) h. A weekday, weekend, in-hour or out-of-hour admission did not demonstrate a difference in the time important care was delivered. Patients who spent ≥ 5 h in ED had more cardiac events (4.6 vs 10.1%, p = 0.023) and more spent ≥ 14 days in hospital (17.5 vs 29.0%, p = 0.004) compared to those < 5 h. No significant increase in inpatient complications (43.5 vs 34.6%, p = 0.054), length of stay (median, 8 vs 7 days, p = 0.119), care home discharge (5.3 vs 4.6%, p = 0.772), or in-hospital death (6.3 vs 4.2%, p = 0.313) were observed. Time to early hip fracture pain relief and diagnosis was adequate in this ED. Time ≥ 5 h in ED was associated with cardiac events and 2 weeks or more inpatient stay.


15-Deoxy-delta12,14-prostaglandin-J(2) up-regulates cyclooxygenase-2 but inhibits prostaglandin-E(2) production through a thiol antioxidant-sensitive mechanism.
15-Deoxy-delta12,14-prostaglandin-J(2) (15d-PGJ(2)) has potent anti-inflammatory effects including the inhibition of interleukin-1beta (IL-1beta)-induced expression of cyclooxygenase-2 (COX-2) and prostaglandin E(2) (PGE(2)) production in several cell types. 15d-PGJ(2) contains an alpha,beta-unsaturated electrophilic ketone and several evidences suggest that thiol reducing agents prevent or revert the cellular effects of 15d-PGJ(2). The present study was devoted to analyze the effect of 15d-PGJ(2) on COX-2 expression in cultured human mesangial cells (HMC). 15d-PGJ(2) induced an increase in the reduced glutathione (GSH) content and up-regulated COX-2 protein expression, but not COX-1, in a manner which was unaffected by selective peroxisome proliferator-activated receptor gamma (PPARgamma) blockade nor mimicked by ciglitazone, a PPARgamma agonist. N-acetylcysteine (NAC), a thiol reducing agent, but not reactive oxygen species scavengers, prevented 15d-PGJ(2)-induced COX-2 up-regulation. Depletion of GSH by buthionine sulfoximine, which diminishes thiol antioxidant activity, cooperated with 15d-PGJ(2) to accumulate COX-2. Therefore, 15d-PGJ(2) up-regulated COX-2 through a thiol antioxidant-sensitive mechanism. Interestingly, NAC did not inhibit the COX-2 expression induced by the electrophilic alpha,beta-unsaturated compound PGA(2). Up-regulation of COX-2 by 15d-PGJ(2) did not result in increased PGE(2) production. Furthermore, preincubation with 15d-PGJ(2) inhibited IL-1beta-induced PGE(2) production although IL-1beta-induced COX-2 expression remained unaffected by the treatment with 15d-PGJ(2). On the contrary, PGA(2) elicited an increase in PGE(2) production and it acted synergistically with IL-1beta to enhance PGE(2) production. These results indicate for the first time that 15d-PGJ(2) inhibits PGE(2) production independently of its effect on COX-2 expression.


EVALUATION OF FREEZE DRIED ALOE VERA AND NOPAL CACTUS FOR POSSIBLE HEALTH TREATMENTS BY COMPARISON OF ANTIOXIDANT PROPERTIES AND FREE RADICAL INHIBITION.
The goal of this project was to characterize the antioxidant powers of lyophilized Aloe Vera (Aloe barbadensis) and Nopal Cactus (Opuntia ficus-indica) by quantifying the phenolics content and radical scavenging abilities of preparations derived from these plants. Extracts of these lyophylized succulents were assayed for phenolic compounds by the Folin Ciocalteau method and compared for free radical scavenging capability by the DPPH method. We found that even though the Aloe lyophilizate extract contained more phenolic content, the Nopal lyophilizate exhibited better free radical scavenging ability. Aloe Vera extract contained 0.278 g/L of phenolic content and exhibited 11.1% free radical inhibition, with a free radical scavenging rate constant of 0.177±0.015 min-1. Nopal Cactus extract contained 0.174 g/L of phenolic content and exhibited 13.2% free radical inhibition, with a free radical scavenging rate constant of 0.155±0.009 min-1. These results showed Nopal to have greater antioxidant potency than Aloe.


A Study on Pharmacokinetics of Acetylsalicylic Acid Mini-Tablets in Healthy Adult Males-Comparison with the Powder Formulation.
Children with Kawasaki disease are prescribed acetylsalicylic acid powder as an antipyretic analgesic and antiplatelet agent; however, some of it remains in the mouth, leading to a bitter or sour taste. To address this issue, an in-hospital mini-tablet formulation of acetylsalicylic acid was developed. In order to use the mini-tablets safely and effectively, dissolution tests alone are not sufficient. Therefore, an open-label crossover study on six healthy participants was conducted to evaluate comparative pharmacokinetic parameters. The pharmacokinetic parameters of salicylic acid were Cmax: 4.80 ± 0.79 mg/L (powder; P), 5.03 ± 0.97 mg/L (mini-tablet; MT), AUC0-12: 18.0 ± 3.03 mg-h/L (P), 18.9 ± 4.59 mg-h/L (MT), those of acetylsalicylic acid Cmax: 0.50 ± 0.20 mg/L (P), 0.41 ± 0.24 mg/L (MT), AUC0-12: 0.71 ± 0.27 mg-h/L (P), 0.61 ± 0.36 mg-h/L (MT), with no significant differences between the mini-tablet and powder formulations. Although pharmacokinetic results obtained from adults cannot be directly applied to children, the results of this study are important for predicting pharmacokinetics. Furthermore, a formulation that can improve medication adherence in children who have difficulty taking acetylsalicylic acid powder, thus contributing to pediatric drug therapy.


The hepatic adenylate cyclase system. II. Substrate binding and utilization and the effects of magnesium ion and pH.
The kinetic characteristics of substrate utilization by hepatic adenylate cyclase were investigated under a variety of incubation conditions, including veriations in pH, [substrate], [Mg2+], and in the absence or presence of glucagon. Activities were compared with ATP and 5'-adenylylimidodiphosphate (App(NH)p) as substrates. The Km for both substrates was about 50 muM; Vmax given with App(NH)p was about 40% lower than obtained with ATP as substrate. In the presence of a saturating concentration of substrate (1 mM), basal activity was increased 4-fold by increasing [Mg2+] from 5 to 50 mM. The stimulatory effect of Mg2+ was not due to an allosteric action since basal activity was only marginally enhanced (40%) when the substrate concentration was reduced to 10 muM. As suggested by deHaen ((1974 J. Biol. Chem. 249, 2756), it is likely that Mg2+ increases enzyme activity by decreasing the concentration of an inhibitory, unchelated form of substrate that competes with the productive magnesium-substrate complex at the active site. Activity-pH profiles differed with ATP and App(NH)p as substrates; a shift in pH optimum was observed which correlated with the different pKa of the terminal phosphate groups of ATP and App(nh)p, and which reflect the concentration of protonated substrate (ATPH-3 minus) present in the incubation medium. Accordingly, protonated substrate is the predominant inhibitory species of unchelated substrate and probably has a considerably higher affinity for the active site than does the magnesium-substrate complex. Glucagon-stimulated activity was less susceptible to inhibition by protonated substrate than is the basal state as evidenced by lower stimulatory effect when the [Mg2+] was increased from 5 to 20 mM. However, increasing the [Mg2+] from 20 to 50 mM resulted in marked inhibition of glucagon-stimulated activity, particularly in the presence of 10 muM substrate. Conversely, at a fixed [Mg2+], concentrations of substrate at least 20-fold higher than the Km were required to achieve maximal hormone-stimulated activity. These findings suggest that the unchelated, fully ionized form of substrate serves as an activating ligand, as has been observed with guanine nucleotides at considerably lower concentrations. Thus, Mg2+ affects adenylate cyclase activity by forming the productive substrate complex and by titrating the inhibitory protonated and activating free forms of substrate. As a result of these effects of unchelated substrate, it proved difficult to evaluate the kinetic parameters involved in substrate binding and utilization and the effects of hormone thereon when substrate was added as the only source of activating ligand. However, linear Michaelis kinetic data were obtained by adding the activating ligand 5'-guanylylimidodiphosphate with glucagon and by making appropriate adjustments of pH and [Mg2+]. Vmax was increased 4-fold without changes in Km by the actions of 5'-guanylylimidodiphosphate and glucagon.


Cango Lyec (Healing the Elephant): HIV incidence in post-conflict Northern Uganda.
Civil war in Northern Uganda resulted in widespread atrocities, human rights violations, and death, and caused millions to flee to internally displaced persons camps. War-related traumas combined with difficulties accessing HIV prevention and health services has led to extreme HIV-related vulnerability among conflict-affected people who survived the war. Objectives were to (1) determine HIV incidence among conflict-affected people in Northern Uganda and (2) identify vulnerabilities associated with HIV infection. The Cango Lyec (Healing the Elephant) Project is a prospective cohort involving conflict-affected populations in three districts in Northern Uganda. In 2011, eight randomly selected communities were mapped, and a census was conducted. Consenting participants aged 13-49 years were followed over three rounds of follow-up. Longitudinal data collected included war-related experiences, sexual vulnerabilities, and sociodemographics. Blood samples were tested for HIV-1 at baseline and each 12-month follow-up. Multivariable Cox proportional hazard models determined factors associated with HIV incidence. Overall, 1920 baseline HIV-negative participants with at least one follow-up contributed 3877 person-years (py) for analysis. Thirty-nine (23 female, 16 male) participants contracted HIV during follow-up. Age- and gender-standardised HIV incidence rate was 10•2 per 1000py (95%CI: 7•2-14•0). Stratified by sex, the age-adjusted HIV incidence was 11•0 per 1000py (95%CI: 6•9-16•6) among women and 9•4 per 1000py (95%CI: 5•3-15•3) among men. Adjusting for confounders, factors associated with risk of HIV included: having been abducted (HR: 3•70; 95%CI: 1•87-7•34), experiencing ≥12 war-related traumatic events (HR: 2•91 95%CI: 1•28-6•60), suicide ideation (HR: 2•83; 95%CI: 1•00-8•03), having ≥2 sexual partners (HR: 4•68; 95%CI: 1•36-16•05), inconsistent condom use (HR: 6•75; 95%CI: 2•49-18•29), and self-reported genital ulcers (HR: 4•39; 95%CI: 2•04-9•45). Conflict-affected participants who had experienced abduction and multiple traumas during the war were at greater risk of HIV infection. Trauma-informed HIV prevention and treatment services, and culturally-safe mental health initiatives, are urgent for Northern Uganda.


Learning clinical skills: an interprofessional approach.
The professions of nursing and medicine are committed to interprofessional education, in the belief that through this, patient care and satisfaction will be improved. Most initiatives involving nurses have been at post-qualification level, in primary health care, and concerning interpersonal or information management skills. Much of this collaboration has been with professions allied to medicine or social services. This paper discusses an innovative programme of shared learning in acute care, involving final year medical students and newly qualified staff nurses. The programme, developed in response to the blurring of professional roles between nurses and junior doctors, took place in our interprofessional Clinical Skills Centre. It was based around a developing patient scenario which was pertinent to the participants' area of practice. Each session was led by an experienced nurse lecturer and doctor, supported by specialist contributors. The style of learning was participative, with small interprofessional groups addressing a range of patient management issues. In this way, relevant clinical and communication skills were integrated within the context of holistic patient care. The course was well evaluated by both professional groups of participants and their managers. Subsequent research and curriculum development are leading to the expansion of this successful initiative.


To Refer or Not to Refer in Teledermoscopy: Retrospective Study.
Challenges remain for general practitioners (GPs) in diagnosing (pre)malignant and benign skin lesions. Teledermoscopy (TDsc) supports GPs in diagnosing these skin lesions guided by teledermatologists' (TDs) diagnosis and advice and prevents unnecessary referrals to dermatology care. However, the impact of the availability of TDsc on GPs' self-reported referral decisions to dermatology care before and after the TDsc consultation is unknown. The objective of this study is to assess and compare the initial self-reported referral decisions of GPs before TDsc versus their final self-reported referral decisions after TDsc for skin lesions diagnosed by the TD as (pre)malignant or benign. TDsc consultations requested by GPs in daily practice between July 2015 and June 2020 with a TD assessment and diagnosis were extracted from a nationwide Dutch telemedicine database. Based on GP self-administered questions, the GPs' referral decisions before and their final referral decision after TDsc consultation were assessed for (pre)malignant and benign TD diagnoses. GP self-administered questions and TD diagnoses were evaluated for 6364 TDsc consultations (9.3% malignant, 8.8% premalignant, and 81.9% benign skin lesions). In half of the TDsc consultations, GPs adjusted their initial referral decision after TD advice and TD diagnosis. Initially, GPs did not have the intention to refer 67 (56.8%) of 118 patients with a malignant TD diagnosis and 26 (16.0%) of 162 patients with a premalignant TD diagnosis but then decided to refer these patients after the TDsc consultation. Furthermore, GPs adjusted their decision from referral to nonreferral for 2534 (74.9%) benign skin lesions (including 676 seborrheic keratosis and 131 vascular lesions). GPs adjusted their referral decision in 52% (n=3306) of the TDsc consultations after the TD assessment. The availability of TDsc is thus of added value and assists GPs in their (non)referral for patients with skin lesions to dermatology care. TDsc resulted in referrals of patients with (pre)malignant skin lesions that GPs would not have referred directly to the dermatologist. TDsc also led to a reduction of unnecessary referrals of patients with low complex benign skin lesions (eg, seborrheic keratosis and vascular lesions).


Characterization of a complete cycle of acetylcholinesterase catalysis by ab initio QM/MM modeling.
The reaction mechanism of acetylcholine hydrolysis by acetylcholinesterase, including both acylation and deacylation stages from the enzyme-substrate (ES) to the enzyme-product (EP) molecular complexes, is examined by using an ab initio type quantum mechanical - molecular mechanical (QM/MM) approach. The density functional theory PBE0/aug-6-31+G* method for a fairly large quantum part trapped inside the native protein environment, and the AMBER force field parameters in the molecular mechanical part are employed in computations. All reaction steps, including the formation of the first tetrahedral intermediate (TI1), the acylenzyme (EA) complex, the second tetrahedral intermediate (TI2), and the EP complex, are modeled at the same theoretical level. In agreement with the experimental rate constants, the estimated activation energy barrier of the deacylation stage is slightly higher than that for the acylation phase. The critical role of the non-triad Glu202 amino acid residue in orienting lytic water molecule and in stabilizing the second tetrahedral intermediate at the deacylation stage of the enzymatic process is demonstrated.


Transport and cytotoxicity of the anticancer drug 3-bromopyruvate in the yeast Saccharomyces cerevisiae.
We have investigated the cytotoxicity in Saccharomyces cerevisiae of the novel antitumor agent 3-bromopyruvate (3-BP). 3-BP enters the yeast cells through the lactate/pyruvate H(+) symporter Jen1p and inhibits cell growth at minimal inhibitory concentration of 1.8 mM when grown on non-glucose conditions. It is not submitted to the efflux pumps conferring Pleiotropic Drug Resistance in yeast. Yeast growth is more sensitive to 3-BP than Gleevec (Imatinib methanesulfonate) which in contrast to 3-BP is submitted to the PDR network of efflux pumps. The sensitivity of yeast to 3-BP is increased considerably by mutations or chemical treatment by buthionine sulfoximine that decrease the intracellular concentration of glutathione.


Perspectives for establishment and reorganization of carbohydrate-directed CD antibodies. Report of the carbohydrate section.
Complex glycosylated glycoproteins, glycolipids and proteoglycans are expressed on the cell surface and are also found as constituents of the extracellular matrix (ECM). Interactions of the carbohydrate moiety of these macromolecules with specific receptors (lectins) are involved in many functions of immune cells such as cell-cell or cell-ECM adhesion, recognition, and neutralization of pathogens and regulation of apoptosis. For studies on live cells mAbs recognizing distinct oligosaccharide structures are useful tools because in contrast to other analytical methods of carbohydrate biochemistry they are able to react with glycans in the complex sterical context of the cell surface. In general expression patterns of carbohydrate mAbs depend on (i) the number and type of carriers to which the glycans are linked (glycoproteins, glycolipids), (ii) the steric situation on the cell surface, and (iii) modifications of the basic glycotope (different branching, chain length, masking by sialylation, sulphation or fucosylation).


Determination of the standard value of circulating blood volume during anesthesia using pulse dye-densitometry: a multicenter study in Japan.
The standard value for circulating blood volume (BV) during anesthesia was determined by a multicenter study in Japan. The significance of BV on the reduction of blood pressure after the induction of anesthesia was also examined. The study included 184 patients from eight university hospitals. After the induction of anesthesia, pulse dye-densitometry was performed according to a uniform protocol. Factors contributing to reduced blood pressure after induction of anesthesia were examined by multiple logistic regression analysis. The mean and standard deviation of BV was 80.0 +/- 13.9 ml x kg(-1); for females and 84.2 +/- 15.3 ml x kg(-1) for males (P > 0.05). There was no age difference in terms of BV. After adjusting for the effects of height, weight, and age, the factors predisposing to a reduction in blood pressure of >20 mmHg after induction of anesthesia were found to be age (P < 0.01) and BV (ml x kg(-1)) (P < 0.001). We determined the BV of anesthetized patients before surgery in Japan using pulse dye-densitometry. It is suggested that age is not a factor regarding BV, and that blood pressure tends to be reduced in hypovolemic patients after induction of anesthesia.


Paraoxonase 2 (PON2) plays a limited role in murine lung tumorigenesis.
Paraoxonase 2 (PON2) is a multifunctional intracellular enzyme that has received growing attention for its ability to modulate various aspects of normal and malignant cellular physiology. Recent research has revealed that PON2 is upregulated in tissues from patients with various types of solid tumors and hematologic cancers, likely due to its ability to suppress oxidative stress and evade apoptosis. However, the effects of PON2 on pulmonary oncogenesis are unknown. Here, we conducted studies to investigate how PON2 influences lung cancer cell proliferation in vitro and lung tumorigenesis in vivo using a variety of cellular and animal models. It was found that PON2 expression deficiency hampered the proliferation of cultured lung cancer cells with concomitant cell cycle arrest at the G1 phase. In addition, the loss of endogenous PON2 expression impaired key aspects of oxidative metabolism in lung adenocarcinoma cells. Moreover, we investigated how the interplay between PON2 expression in lung tumors and host mice influences lung tumor initiation and progression. PON2 status in both transplanted tumor cells and mice failed to influence the development of subcutaneously grafted Lewis lung carcinoma (LLC) tumors, orthotopically implanted LLC tumors, and oncogenic Kras-driven primary lung adenocarcinoma tumors. Importantly, the frequencies of tumor-infiltrating myeloid subsets that include myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages were not impacted by PON2 expression in LLC tumor-bearing mice. Overall, our studies indicate that PON2 plays a limited role in murine lung tumorigenesis.


Early and intermediate results of the Fontan procedure at moderately high altitude.
At higher elevations, alveolar hypoxia increases pulmonary vascular resistance and may limit the cardiac output of individuals without a subpulmonary ventricle. Thus, we reviewed the outcome of definitive palliation for tricuspid atresia and other forms of single ventricle in 60 consecutive Fontan patients living at a mean elevation of 1,370 m (range, 910 to 2,130 m). There were four early deaths (6.7%; 70% confidence limits, 4.1% to 10.7%) and six late deaths. Kaplan-Meier actuarial survival (+/- standard error) is 79.6% +/- 8.2% at 5 years. Survival was significantly decreased in patients with a preoperative mean pulmonary arterial pressure greater than or equal to 15 mm Hg unless the Fontan procedure was performed with a residual fenestration. Exercise tolerance was significantly worse at higher elevations in a subgroup of patients who have traveled to altitudes of 1,680 to 3,350 m. We conclude that the early and intermediate results of the Fontan procedure at moderately high altitude are similar to results reported at sea level. However, exercise tolerance may be impaired at higher elevations in many patients.


Chasing Histone Biology from Sea Urchins to Yeast.
Together with David Allis, Michael Grunstein just received the Lasker Basic Medical research award. The article that follows is a transcript of a conversation with Jacques Deguine, scientific editor at Cell, that was edited for length. Annotated excerpts from this conversation are presented below, and the full conversation is available with the article online.


Alterations of the FMLP-induced Ca2+ efflux from human monocytes with aging.
The Ca2+ with the calmodulin system plays a major role in the receptor-induced intracellular biochemical events. Thus, as in our previous studies, we found an altered postreceptorial coupling in the case of elderly, we were interested to elucidate the Ca2+ transport in the case of healthy young (less than 25 years) and aged (greater than 65 years) subjects. The chemotactic peptide FMLP was used for receptor stimulation. Our data show that both spontaneous and FMLP-triggered Ca2+ extrusion measured on monocyte monolayers is decreased with aging. The FMLP-triggered Ca2+ extrusion nevertheless did not occur through the TFP-sensitive pathway. These alterations of Ca2+ transport seem to indicate an impaired Ca2+-calmodulin function in monocytes with aging.


A short version of the International Hip Outcome Tool (iHOT-12) for use in routine clinical practice.
The purpose of this study was to develop and validate a shorter version of the 33-item International Hip Outcome Tool (iHOT-33) that could be easily used in routine clinical practice to measure both health-related quality of life and changes after treatment in young, active patients with hip disorders. A development dataset (104 patients) was explored with forward-selection linear regression analysis to choose a reduced item set for the new scale. This was tested in a validation dataset (1,833 patients) and responsiveness subset (80 patients) to measure agreement between the shorter and longer versions and to test the sensitivity of the shorter instrument to change after treatment. Twelve items were chosen for a short version of the International Hip Outcome Tool (iHOT-12). The iHOT-12 showed excellent agreement with the long version (iHOT-33). It captured 95.9% (95% confidence interval, 95.0% to 96.8%) of the variation of the iHOT-33 and showed equivalent sensitivity to change with a standardized effect size of 0.98 (95% confidence interval, 0.67 to 1.28). A short version of the International Hip Outcome Tool (iHOT-12) has been developed. It has very similar characteristics to the original rigorously validated 33-item questionnaire, losing very little information despite being only one-third the length. It is valid, reliable, and responsive to change. We suggest that it be used for initial assessment and postoperative follow-up in routine clinical practice.


The XPB Subunit of the TFIIH Complex Plays a Critical Role in HIV-1 Transcription and XPB Inhibition by Spironolactone Prevents HIV-1 Reactivation from Latency.
HIV transcription requires assembly of cellular transcription factors at the HIV-1promoter. The TFIIH general transcription factor facilitates transcription initiation by opening the DNA strands around the transcription start site and phosphorylating the C-terminal domain for RNA polymerase II (RNAPII) for activation. Spironolactone (SP), an FDA approved aldosterone antagonist, triggers the proteasomal degradation of the XPB subunit of TFIIH, and concurrently suppresses acute HIV infection in vitro Here we investigated SP as a possible block-and-lock agent for a functional cure aimed at the transcriptional silencing of the viral reservoir. The long-term activity of SP was investigated in primary and cell line models of HIV-1 latency and reactivation. We show that SP rapidly inhibits HIV-1 transcription by reducing RNAPII recruitment to the HIV-1 genome. shRNA knockdown of XPB confirmed XPB degradation as the mechanism of action. Unfortunately, long-term pre-treatment with SP does not result in epigenetic suppression of HIV upon SP treatment interruption, since virus rapidly rebounds when XPB reemerges; however, SP alone without ART maintains the transcriptional suppression. Importantly, SP inhibits HIV reactivation from latency in both cell line models and resting CD4+T cells isolated from aviremic infected individuals upon cell stimulation with latency reversing agents. Furthermore, long-term treatment with concentrations of SP that potently degrade XPB does not lead to global dysregulation of cellular mRNA expression. Overall, these results suggest that XPB plays a key role in HIV transcriptional regulation and XPB degradation by SP strengthens the potential of HIV transcriptional inhibitors in block-and-lock HIV cure approaches.IMPORTANCE Antiretroviral therapy (ART) effectively reduces an individual's HIV loads to below the detection limit, nevertheless rapid viral rebound immediately ensues upon treatment interruption. Furthermore, virally suppressed individuals experience chronic immune activation from ongoing low-level virus expression. Thus, the importance of identifying novel therapeutics to explore in block-and-lock HIV functional cure approaches, aimed at the transcriptional and epigenetic silencing of the viral reservoir to block reactivation from latency. We investigated the potential of repurposing the FDA-approved spironolactone (SP), as one such drug. SP treatment rapidly degrades a host transcription factor subunit, XPB, inhibiting HIV transcription and blocking reactivation from latency. Long-term SP treatment does not affect cellular viability, cell cycle progression or global cellular transcription. SP alone blocks HIV transcription in the absence of ART but does not delay rebound upon drug removal as XPB rapidly reemerges. This study highlights XPB as a novel drug target in block-and-lock therapeutic approaches.


The added value of multi-state modelling in a randomized controlled trial: The HOVON 102 study re-analyzed.
Clofarabine is an active antileukemic drug for subgroups of patients with acute myeloid leukemia (AML). Multi-state models can provide additional insights to supplement the original intention-to-treat analysis of randomized controlled trials (RCT). We re-analyzed the HOVON102/SAKK30/09 phase III RCT for newly diagnosed AML patients, which randomized between standard induction chemotherapy with or without clofarabine. Using multi-state models, we evaluated the effects of induction chemotherapy outcomes (complete remission [CR], measurable residual disease [MRD]), and post-remission therapy with allogeneic stem cell transplantation [alloSCT] on relapse and death. Through the latter a consistent reduction in the hazard of relapse in the clofarabine arm compared to the standard arm was found, which occurred irrespective of MRD status or post-remission treatment with alloSCT, demonstrating a strong and persistent antileukemic effect of clofarabine. During the time period between achieving CR and possible post-remission treatment with alloSCT, non-relapse mortality was higher in patients receiving clofarabine. An overall net benefit of treatment with clofarabine was identified using the composite endpoint current leukemia-free survival (CLFS). In conclusion, these results enforce and extend the earlier reported beneficial effect of clofarabine in AML and show that multi-state models further detail the effect of treatment on competing and series of events.


The time-dependent expressions of IL-1beta, COX-2, MCP-1 mRNA in skin wounds of rabbits.
In this study, we investigated the time-dependent expression of IL-1beta, COX-2, MCP-1 mRNA after incised wounds in rabbit skin using real-time fluorescent quantitative PCR. The tested wound ages were distributed as following: <0.5h, 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 2d, 3d, and 7d. The expressions of three markers in postmortem wounds were determined. Comparison of each wound age with control group, expression of IL-1beta mRNA showed that the significant increase occurred at <0.5h (p<0.01), and the peak level at 2h. The expression was almost normalized at 2d. But for COX-2 and MCP-1 mRNA, the significant increase occurred at 1h for COX-2 mRNA, and 3h for MCP-1 mRNA. The expression peak levels were at 3h and 5h, and were almost normalized at 3d and 7d, respectively. There was no significant increase in all postmortem samples for IL-1beta, COX-2, MCP-1 mRNA compared with control group. Thus, the results of these cytokines and enzyme significant increase at different early wound ages implied that the combined investigation could make wound age determination more objective and accurate. Moreover, the three markers could also be used to distinguish the supravital injuries.


Inhibins A and B are regulated differentially in the early post-partum period.
The early postpartum period is characterized endocrinologically by a rapid fall in the levels of oestradiol (E2) and immunoreactive inhibin, and a delayed rise in serum follicle stimulating hormone (FSH). No description is currently available of changes in serum inhibins A and B. The present study aimed to examine the levels of inhibin A and B during the early weeks of postpartum lactational amenorrhoea, to determine whether there was evidence for differential regulation of the two hormones at a time when no dominant follicle was developing in the ovary. Serum samples were available from 12 subjects aged 29-38 in whom postpartum levels of FSH, immunoreactive inhibin, E2 and prolactin had been examined previously. Samples for hormone assays had been obtained prior to delivery, daily for the 3-5 days postpartum, and weekly thereafter. Inhibins A and B were measured by specific ELISA assays, and results were calculated as 10 day averages for samples obtained on days 1-10, 11-20, 21-30, etc. postpartum. Normal hormone concentrations for reference were obtained from volunteers, also aged 29-38, sampled on days 3-5 of a normal menstrual cycle. Inhibin A in the predelivery sample ranged from 62 to 1243 ng/l, geometric mean 592. Concentrations fell rapidly postpartum and reached a nadir in the low follicular phase range between days 5 and 37 postdelivery, mean 13.6 days. The concentrations of both inhibin B and FSH rose 14-27 days postpartum from their initially low postdelivery levels, to reach the normal follicular phase range. These increases in concentration were significantly correlated in all individual subjects. The secretion of inhibin A and B is regulated differentially during the early stages of lactational amenorrhoea, just as it is in the late luteal phase of the normal menstrual cycle. Whilst inhibin A falls postpartum, reflecting cessation of placental function, and remains low until ovulatory cycles are resumed, FSH and inhibin B rise after a delay of two weeks or more. It is postulated that the rise of inhibin B is the result of secretion from a cohort of small follicles stimulated by rising FSH levels.


Association of Neighborhood Disadvantage With Cardiovascular Risk Factors and Events Among Refugees in Denmark.
Refugees are among the most disadvantaged individuals in society, and they often have elevated risks of cardiovascular risk factors and events. Evidence is limited regarding factors that may worsen cardiovascular health among this vulnerable group. To test the hypothesis that refugee placement in socioeconomically disadvantaged neighborhoods is associated with increased cardiovascular risk. The study population of this quasi-experimental, registry-based cohort study included 49 305 adults 18 years and older who came to Denmark as refugees from other countries during the years of Denmark's refugee dispersal policy from 1986 to 1998. Refugees were dispersed to neighborhoods with varying degrees of socioeconomic disadvantage in an arbitrary manner conditional on observed characteristics. The association of neighborhood disadvantage on arrival with several cardiovascular outcomes in subsequent decades was evaluated using regression models that adjusted for individual, family, and municipal characteristics. Health outcomes were abstracted from the inpatient register, outpatient specialty clinic register, and prescription drug register through 2016. Data analysis was conducted from May 2018 to July 2019. A composite index of neighborhood disadvantage was constructed using 8 neighborhood-level socioeconomic characteristics derived from Danish population register data. Primary study outcomes included hypertension, hyperlipidemia, type 2 diabetes, myocardial infarction, and stroke. Before data analysis commenced, it was hypothesized that higher levels of neighborhood disadvantage were associated with an increased risk of cardiovascular risk factors and events. A total of 49 305 participants were included (median [interquartile range] age, 30.5 [24.9-39.8] years; 43.3% women). Participant region of origin included 6318 from Africa (12.8%), 7253 from Asia (14.7%), 3446 from Eastern Europe (7.0%), 5416 from Iraq (11.0%), 6206 from Iran (12.6%), 5558 from Palestine (via Lebanon, Israel, Occupied Palestinian Territories; 11.3%), and 15 108 from Yugoslavia (30.6%). Adjusted models revealed an association between placement in disadvantaged neighborhoods and increased risk of hypertension (0.71 [95% CI, 0.30-1.13] percentage points per unit of disadvantage index; P < .01), hyperlipidemia (0.44 [95% CI, 0.06-0.83] percentage points; P = .01), diabetes (0.45 [95% CI, 0.09-0.81] percentage points; P = .01), and myocardial infarction (0.14 [95% CI, 0.03-0.25] percentage points; P = .01). No association was found for stroke. Individuals who arrived in Denmark before age 35 years had an increased risk of hyperlipidemia (1.16 [95% CI, 0.41-1.92] percentage points; P < .01), and there were no differences by sex. In this quasi-experimental cohort study, neighborhood disadvantage was associated with increased cardiovascular risk in a relatively young population of refugees. Neighborhood characteristics may be an important consideration when refugees are placed by resettlement agencies and host countries. Future work should examine additional health outcomes as well as potential mediating pathways to target future interventions (eg, neighborhood ease of walking, employment opportunities).


Differences among health care settings in utilization and type of physical rehabilitation administered to patients receiving workers' compensation for musculoskeletal disorders.
There is a paucity of data describing the relationship between practice setting and the delivery of physical rehabilitation to injured workers. To determine differences in the number of visits, the number of treatment units, and the proportion of billing for physical agents over an episode of care between different practice settings' providing physical rehabilitation to patients receiving workers' compensation for a musculoskeletal problem. A large administrative database was evaluated retrospectively. Practice settings were classified as physician office, corporate physical therapy clinic, occupational medicine clinic, hospital-based outpatient clinic, or private physical therapy practice. 70,306 subjects (72.7 % male; mean age = 44.6, SD = 11.8 years) were included in this study. Corporate physical therapy clinics had the highest mean values for total visits (13.1, SD = 12.7) and for total units (66.8, SD = 85.5), and the lowest mean values for proportion of physical agents during the episode of care (.22, SD = .18). Occupational medicine clinics had the lowest mean values for total visits (6.8, SD = 7.9) and for total units (30.4, SD = 36.5), and the highest mean value for proportion of physical agents during the episode of care (.41, SD = .22). When controlling for ICD-9-CM codes, body-part treated, surgical status, and geographical region there were small changes in effect size; however, the significance and directionality of differences between practice settings were not changed. There were significant differences in billing for physical rehabilitation services between practice settings for patients receiving workers' compensation. Corporate physical therapy clinics billed for more total visits and total units over an episode of care than did other practice settings; however they also billed for a lower proportion of physical agents indicating a greater use of those interventions supported by evidence-based guidelines (exercise and manual therapy) compared to other practice settings.


Purification and characteristics of a novel milk-clotting metalloprotease from Bacillus velezensis DB219.
Milk-clotting enzyme (MCE) is the essential active agents in dairy processing. The traditional MCE is mainly obtained from animal sources, in which calf rennet is the most widely used in cheese industry. Traditional MCE substitute is becoming necessary due to its limited production and increased cheese consumption. A novel traditional MCE substitute was produced from Bacillus velezensis DB219 in this study. The DB219 MCE exhibited a notable specific activity of 6,110 Soxhlet units/mg and 3.16-fold purification yield with 28.87% recovery through ammonium sulfate fractionation and DEAE-Sepharose Fast Flow. The purified DB219 MCE was a metalloprotease with a molecular weight of 36 kDa. The DB219 MCE was weak acid resistance and stable at pH 6.0 to 10.0 and temperature <45°C. The highest milk-clotting activity was observed in substrate at pH 5.5 added with 20 to 30 mM CaCl2. The Michaelis constant and maximal velocity for casein were 0.31 g/L and 14.22 μmol/min. The DB219 MCE preferred to hydrolyze β-casein instead of α-casein. The DB219 MCE hydrolyzed α-casein, β-casein, and κ-casein to generate significantly different peptides in comparison with calf rennet and ES6023 MCE (fungal MCE) through SDS-PAGE and reversed-phase HPLC analysis. The DB219 MCE mainly cleaved Thr124-Ile125 and Ser104-Phe105 bonds in κ-casein and had unique casein cleavage sites and peptide composition through LC-MS/MS analysis. The DB219 MCE was potential to be a new milk coagulant and enriched kinds of traditional MCE substitute.


LncRNA FAM13A-AS1, transcriptionally regulated by PHOX2B, modulates hepatocellular carcinoma chemoresistance via stabilizing PPARγ.
Hepatocellular carcinoma (HCC) is a major global public health concern, with approximately 79 million new cases and 75 million HCC-related deaths occurring annually worldwide. Among the drugs, cisplatin (DDP) is considered a cornerstone and has been shown to significantly inhibit cancer progression. However, the mechanism underlying DDP-resistance in HCC remains unclear. This study aimed to identify a novel lncRNA. FAM13A Antisense RNA 1 (FAM13A-AS1), that promotes the proliferation of DDP-resistant HCC cells and to elucidate its downstream and upstream mechanisms in the progression of HCC DDP-resistance. Our results suggest that FAM13A-AS1 interacts directly with Peroxisome Proliferator Activated Receptor γ (PPARγ), stabilizing its protein through de-ubiquitination. Moreover, our findings indicate that Paired Like Homeobox 2B (PHOX2B) transcriptionally regulates the expression of FAM13A-AS1 in HCC cells. These results shed new light on the understanding of the progression of HCC DDP-resistance.


Plant-derived cis-β-ocimene as a precursor for biocompatible, transparent, thermally-stable dielectric and encapsulating layers for organic electronics.
This article presents low-temperature, one-step dry synthesis of optically transparent thermally-stable, biocompatible cis-β-ocimene-based thin films for applications as interlayer dielectric and encapsulating layer for flexible electronic devices, e.g. OLEDs. Morphological analysis of thin films shows uniform, very smooth (Rq < 1 nm) and defect-free moderately hydrophilic surfaces. The films are optically transparent, with a refractive index of ~1.58 at 600 nm, an optical band gap of ~2.85 eV, and dielectric constant of 3.5-3.6 at 1 kHz. Upon heating, thin films are chemically and optically stable up to at least 200 °C, where thermal stability increases for films manufactured at higher RF power as well as for films deposited away from the plasma glow. Heating of the sample increases the dielectric constant, from 3.7 (25 °C) to 4.7 (120 °C) at 1 kHz for polymer fabricated at 25 W. Polymers are biocompatible with non-adherent THP-1 cells and adherent mouse macrophage cells, including LPS-stimulated macrophages, and maintain their material properties after 48 h of immersion into simulated body fluid. The versatile nature of the films fabricated in this study may be exploited in next-generation consumer electronics and energy technologies.


Biofilms on central venous catheters: is eradication possible?
Biofilms on indwelling medical devices such as central venous catheters result in significant morbidity and mortality and have a substantial impact on healthcare delivery. Because routine systemic treatment of patients with catheter-associated bloodstream infections is often ineffective, due to the tolerance of biofilm organisms on these devices, other strategies such as the antimicrobial lock treatment (ALT) have been used. This approach involves the instillation of high concentrations of the antimicrobial agent directly into the biofilm-containing catheter for exposure (i.e., dwell) times sufficient to eradicate the biofilm. Results from human studies, animal studies, and laboratory studies using in vitro model systems have suggested that eradication of a biofilm is possible, depending on the organisms in the biofilm, biofilm age, the antimicrobial agent used, and the dwell/ duration of the treatment. The most effective antimicrobial agents are those (1) that are less affected by the extracellular polymeric substance matrix of the biofilm, (2) that have a more rapid bactericidal effect, or (3) for which the mechanism of action is not dependent upon the growth rates of the organisms. Combining agents may also provide synergy. Fungal biofilms have proven to be much more difficult to treat using the ALT, though newer fungicidal drugs such as the echinocandins hold promise in this regard. However, a serious drawback with the ALT is the potential for the development of resistance. Newer treatments, incorporating agents not classified as antibiotics, appear to effectively eradicate biofilms in in vitro models and should be evaluated in animal and patient studies. Promising technologies that incorporate novel approaches such as ultrasound, bacteriophage, quorum-sensing inhibitors, or enzymes may also provide useful approaches in the future.


Autobiographical memory for the differential diagnosis of cognitive pathology in aging.
The present study distinguishes three memory stages across the lifespan, and aims to compare episodic and semantic autobiographical memory in healthy older adults, with amnesic mild cognitive impairment, and with Alzheimer's disease. This information can offer evidence about the way semantic and episodic autobiographical memory work, and how the disease affects them. The sample was composed of 56 people, all aged over 60 years; 15 with amnestic mild cognitive impairment, 12 with Alzheimer's disease and 29 healthy older people. Participants were evaluated with the Autobiographical Memory Interview. A mixed anova showed significant main effects of memory and time-period, and significant interactions of memory × group, time-period × group and memory × time × group. Assessment of autobiographical memory provides information to differentiate amnestic mild cognitive impairment patients from Alzheimer's disease patients. Although the decline in episodic memory starts with the onset of the disease, semantic memory is maintained until moderate stages of dementia. Geriatr Gerontol Int 2016; 16:1220-1225.


A review of the effects of aircraft noise on wildlife and humans, current control mechanisms, and the need for further study.
Military and civilian aircraft overflights are an issue that may impact the quality of life for millions of United States residents. Aircraft noise annoys many people worldwide and is generally thought to adversely affect some wildlife species. In light of increasing demands being placed on airspace, and because of technological improvements in acoustical testing, there is a need to reexamine the effects of aircraft noise exposure on humans and wildlife. This paper reviews past research, current laws and legislation, and presents an argument for the need to revisit the effects of aircraft noise on humans and wildlife. Some evidence suggests that noise may adversely impact wildlife and humans, however, many of the past studies were inconclusive and based on relatively small sample sizes. Given that aircraft noise abatement legislation has been enacted and because of the recent promulgation of community-based noise awareness programs, future studies should be conducted to resolve public policy problems and debates associated with aircraft noise. The need to further study the effects of aircraft noise on humans and wildlife is critical for creating sustainable land use policies near aircraft installations. Data derived from these studies will be used to create sound public policies that enhance the operational capacity of military and civilian aircraft while reducing the opportunity for human and wildlife exposure to aircraft noise.


Neurolaw: Challenges and limits.
This chapter canvasses the current relevance of behavioral neuroscience to the law, especially to issues of criminal responsibility and competence. It begins with an explanation of the legal doctrines at stake. I then explore the source of the often-inflated claims for the legal relevance of neuroscience. The next section discusses the scientific status of behavioral neuroscience. Then, it addresses two radical challenges to current conceptions of criminal responsibility that neuroscience allegedly poses: determinism and the death of agency. The question of the specific relevance of neuroscience to criminal law doctrine, practice, and institutions is considered next. This is followed by a discussion of how neuroscience evidence is being used in criminal cases in five different countries, including the United States. The penultimate section points to some areas warranting modest optimism. A brief conclusion suggests that neuroscience is at present of limited legal relevance, and advances in the science might alter that judgment.


Transdermal delivery of chloroquine by amidated pectin hydrogel matrix patch in the rat.
The aim of the present study was to investigate the suitability of amidated pectin matrix patch for transdermal chloroquine delivery in an effort to mask the bitter taste when orally administered. Chloroquine has easily measurable outputs that are linked to increased renal Na+ excretion. We thus monitored urinary Na+ output in separate groups intravenously administered chloroquine or topically applied pectin hydrogel chloroquine matrix patch. Male groups of anesthetized Sprague-Dawley rats were placed on a continuous jugular infusion of 0.077 M NaCl at 150 microL min(-1). After 3 h equilibration period, consecutive 20 min urine collections were made over the subsequent 4 h of 1 h control, 1 h 20 min treatment, and 1 h 40 min recovery periods for measurements of urine flow and Na+ and K+ excretion rates. The effects of intravenous chloroquine infusion or topical application of pectin hydrogel chloroquine matrix patch were examined in rats in which the drug was added to the infusate or patch applied onto the shaved area during the 1 h 20 min treatment period. The animals were switched back to the infusate alone for the final 1 h 40 min recovery period. Vehicle infused animals acted as controls. Trunk blood was collected after the treatment period from parallel groups for chloroquine measurements. The plasma chloroquine concentrations following iv chloroquine or application of pectin chloroquine hydrogel matrix patch were 9.3 +/- 0.8 mg L(-1) and 7.3 +/- 1.1 mg L(-1) respectively (n = 7 in both groups). Chloroquine infusion and pectin chloroquine patch significantly (p < 0.01) increased Na+ excretion to peak values of 14.1 +/- 0.9 micromol min(-1). and 20.35 +/- 1.0 micromol min(-1), respectively by comparison with controls (9.1 +/- 0.9 micromol min(-1)), at the corresponding period. The results suggest that the pectin chloroquine patch matrix preparation has potential applications for transdermal delivery of chloroquine and perhaps in the management of malaria.


Can the common bile duct drain into the fourth part of the duodenum?
An interesting case masqueraded as a case of the common bile duct entering the fourth part of the duodenum; this is an extremely rare anomaly. A review of the literature was performed. Surgeons should be cautioned about this anomaly with regard to operative procedures for treatment.