Simultaneous non-thermal saccharification of cassava pulp by multi-enzyme activity and ethanol fermentation by Candida tropicalis.
Cassava pulp, a solid by-product from starch processing, is a promising and underused biomass that can be converted to biofuels and other value-added bio-products. In this study, an alternative cassava pulp saccharification process, which utilizes the multi-activity enzyme from Aspergillus niger BCC17849 and obviates the need for a pre-gelatinization step, was developed. The crude multi-enzyme composed of non-starch polysaccharide hydrolyzing enzyme activities, including cellulase, pectinase and hemicellulase act cooperatively to release the trapped starch granules from the fibrous cell wall structure for subsequent saccharification by raw starch degrading activity. A high yield of fermentable sugars, equivalent to 716 mg glucose and 67 mg xylose/g of cassava pulp, was obtained after 48 h incubation at 40 degrees C and pH 5 using the multi-enzyme, which was greater than the yield obtained from the optimized combinations of the corresponding commercial enzymes. The multi-enzyme saccharification reaction can be performed simultaneously with the ethanol fermentation process using a thermotolerant yeast Candida tropicalis BCC7755. The combined process produced 14.3 g/l ethanol from 4% (w/v) cassava pulp after 30 h of fermentation. The productivity rate of 0.48 g/l/h is equivalent to 93.7% of the theoretical yield based on total starch and cellulose, or 85.4% based on total fermentable sugars. The non-thermal enzymatic saccharification process described is more energy efficient and yields more fermentable sugar than the conventional enzymatic process. Furthermore, the process is applicable for production of various bio-products of economic importance.


Virtual Proprioception for eccentric training.
Wireless inertial sensors enable quantified feedback, which can be applied to evaluate the efficacy of therapy and rehabilitation. In particular eccentric training promotes a beneficial rehabilitation and strength training strategy. Virtual Proprioception for eccentric training applies real-time feedback from a wireless gyroscope platform enabled through a software application for a smartphone. Virtual Proprioception for eccentric training is applied to the eccentric phase of a biceps brachii strength training and contrasted to a biceps brachii strength training scenario without feedback. During the operation of Virtual Proprioception for eccentric training the intent is to not exceed a prescribed gyroscope signal threshold based on the real-time presentation of the gyroscope signal, in order to promote the eccentric aspect of the strength training endeavor. The experimental trial data is transmitted wireless through connectivity to the Internet as an email attachment for remote post-processing. A feature set is derived from the gyroscope signal for machine learning classification of the two scenarios of Virtual Proprioception real-time feedback for eccentric training and eccentric training without feedback. Considerable classification accuracy is achieved through the application of a multilayer perceptron neural network for distinguishing between the Virtual Proprioception real-time feedback for eccentric training and eccentric training without feedback.


DNA stem line heterogeneity in esophageal cancer accurately identified by flow cytometric analysis.
This study was designed to evaluate the importance of DNA stem line heterogeneity in determining the malignant potential of esophageal cancer. Flow cytometric analysis of intratumor heterogeneity of DNA contents was performed on step-sectioned slices of 57 resected esophageal carcinomas. DNA stem line heterogeneity, as assessed by DNA content measurements, was present in 25 (44%) tumors; 6 (11%) were a combination of diploid and aneuploid DNA pattern, and 19 (33%) had two or more aneuploid peaks with different DNA contents (multiploid). Of the remaining 32 homogeneous tumors, 4 showed only a diploid DNA pattern in all samples examined, whereas 28 tumors had only the aneuploid pattern. Tumors with the heterogeneous DNA pattern had a significantly higher frequency of lymph node metastasis than did those with the homogeneous DNA pattern (P < 0.05). For evaluation of the highly malignant potential of esophageal carcinoma by nuclear DNA contents, it is important to identify accurately intratumoral heterogeneity. Because different DNA stem lines were evident in different areas of the lesion, evaluation of multiple specimens from a wide area of each lesion is needed to determine with accuracy the degree of intratumor DNA stem line heterogeneity.


Clinical case of the month. A rare case of Budd Chiari syndrome.
Budd Chiari syndrome is a rare disorder resulting from hepatic venous outflow tract obstruction anywhere from the small hepatic veins to the suprahepatic inferior vena cava. This patient has a hypercoagulable state secondary to heterozygous mutation of factor V and the JAK2 mutation and is being anticoagulated. We hypothesize that the low protein C and low antithrombin III levels seen in this patient resulted from decreased synthetic function of the liver and were not indicative of actual deficiencies. Indeed, reports of coexisting protein C and antithrombin III deficiencies are not existent in the literature and likely are not compatible with life. All patients with BCS warrant a hypercoagulable work up and JAK2 mutation is increasingly recognized as a contributing factor, even in those patients without obvious signs of polycythemia vera.


[Qualification requirements for physician-bacteriologists].
The authors present the qualification requirements to laboratory physicians specialized in bacteriology. The knowledge and skills of a bacteriologist, necessary for his organizations, methodologic, prophylactic, and diagnostic activities, are listed.


Docking ligands into flexible and solvated macromolecules. 3. Impact of input ligand conformation, protein flexibility, and water molecules on the accuracy of docking programs.
Several modifications and additions to Fitted1.5 led to the development of Fitted2.6. Among the novel implementations are a matching algorithm-enhanced genetic algorithm and a ring conformational search algorithm. With these various optimizations, we also hoped to remove the biases and to develop a docking program that would provide results (i.e., poses) as independent as possible to the input ligand and protein conformations and used parameters, although keeping the options to provide additional experimental information. These biases were investigated within Fitted2.6 along with FlexX, GOLD, Glide, and Surflex. The input ligand conformation was found to have a major impact on the program accuracy as drops as large as 10-50% were observed with all the programs but Fitted. This comparative study also demonstrates that the accuracy of Fitted is similar to that of other widely used programs. We have also demonstrated that protein flexibility, displaceable water molecules, and ring conformational search algorithms, three of the main Fitted features, significantly increased its accuracy. Finally, we also proposed potential modifications to the available programs to further improve their accuracy in binding mode prediction.


Characterization of a gyrB mutation responsible for low-level nalidixic acid resistance in Neisseria gonorrhoeae.
Nalidixic acid-resistant derivatives of Neisseria gonorrhoeae WR302 were identified and categorized into two classes on the basis of their susceptibilities to this antimicrobial agent. The MIC of nalidixic acid for the derivative strain MUG116 was fourfold greater than that for its isogenic parental strain WR302 (2 versus 0.5 micrograms/ml, respectively). MUG324 was significantly more resistant to nalidixic acid (greater than 64 micrograms/ml). The MICs of other antimicrobial agents known to interact with either the gyrA or gyrB gene products were determined. Although the nalidixic acid MIC for MUG116 increased, no significant increases in the MICs of other agents that interact with the gyrA gene product were seen. The MICs of all agents that interact with the gyrA gene product were significantly increased for MUG324. The gene that imparts low-level nalidixic acid resistance was cloned from strain MUG116. The DNA sequence of this gene was determined, and by comparing the deduced amino acid sequence with sequences of proteins in data bases, this protein was found to be approximately 70% homologous with the gyrB gene product of Escherichia coli.


Untreated scoliosis in the adult.
Untreated scoliosis affects the quality of life and is a disabling disease in the adult. Most patients can expect back pain, particularly after the age of 30, and one in 4 may be disabled by it. The majority of adults are embarassed by their deformity. Women, in particular, are less likely to marry. Surgical treatment of the adult is difficult and hazardous, and is associated with socioeconomic problems not encountered in the adolescent. Scoliosis should be treated definitively before the end of the period of growth.


The type 3 secretion effector IpgD promotes S. flexneri dissemination.
The bacterial pathogen Shigella flexneri causes 270 million cases of bacillary dysentery worldwide every year, resulting in more than 200,000 deaths. S. flexneri pathogenic properties rely on its ability to invade epithelial cells and spread from cell to cell within the colonic epithelium. This dissemination process relies on actin-based motility in the cytosol of infected cells and formation of membrane protrusions that project into adjacent cells and resolve into double-membrane vacuoles (DMVs) from which the pathogen escapes, thereby achieving cell-to-cell spread. S. flexneri dissemination is facilitated by the type 3 secretion system (T3SS) through poorly understood mechanisms. Here, we show that the T3SS effector IpgD facilitates the resolution of membrane protrusions into DMVs during S. flexneri dissemination. The phosphatidylinositol 4-phosphatase activity of IpgD decreases PtdIns(4,5)P2 levels in membrane protrusions, thereby counteracting de novo cortical actin formation in protrusions, a process that restricts the resolution of protrusions into DMVs. Finally, using an infant rabbit model of shigellosis, we show that IpgD is required for efficient cell-to-cell spread in vivo and contributes to the severity of dysentery.


Three-Dimensional Printing Strategies for Irregularly Shaped Cartilage Tissue Engineering: Current State and Challenges.
Although there have been remarkable advances in cartilage tissue engineering, construction of irregularly shaped cartilage, including auricular, nasal, tracheal, and meniscus cartilages, remains challenging because of the difficulty in reproducing its precise structure and specific function. Among the advanced fabrication methods, three-dimensional (3D) printing technology offers great potential for achieving shape imitation and bionic performance in cartilage tissue engineering. This review discusses requirements for 3D printing of various irregularly shaped cartilage tissues, as well as selection of appropriate printing materials and seed cells. Current advances in 3D printing of irregularly shaped cartilage are also highlighted. Finally, developments in various types of cartilage tissue are described. This review is intended to provide guidance for future research in tissue engineering of irregularly shaped cartilage.


Emergence of colistin-resistant Enterobacter cloacae and Raoultella ornithinolytica carrying the phosphoethanolamine transferase gene, mcr-9, derived from vegetables in Japan.
Plasmid-mediated mobile colistin-resistance genes have been recognized as a global threat because they jeopardize the efficacy of colistin in therapeutic practice. Here, we described the genetic features of two mcr-9.1-carrying Gram-negative bacteria with a colistin-resistant phenotype derived from vegetables in Japan. The colistin-resistant mcr-9.1, which has never been detected in vegetables, was located on a large plasmid in Enterobacter cloacae CST17-2 and Raoultella ornithinolytica CST129-1, suggesting a high chance of horizontal gene transfer. To the best of our knowledge, this is the first report of mcr-9 in R. ornithinolytica. This study indicates that fresh vegetables might be a potential source for the transmission of mcr-9 genes encoding resistance to frontline (colistin) and clinically relevant antimicrobials. The study also provides additional consideration for colistin use and the relevance of routine surveillance in epidemiological perspective to curb the continuous spread of mcr alleles.


Smad4-deficient T cells promote colitis-associated colon cancer via an IFN-γ-dependent suppression of 15-hydroxyprostaglandin dehydrogenase.
Immune cells and the cytokines they produce are important mediators of the transition from colitis to colon cancer, but the mechanisms mediating this disease progression are poorly understood. Interferon gamma (IFN-γ) is known to contribute to the pathogenesis of colitis through immune modulatory mechanisms, and through direct effects on endothelial and epithelial homeostasis. Here we explore whether IFN-γ influences tumor progression by expanding the effector memory T cells (TEM) population and restricting the expression of tumor suppressors in a preclinical model of spontaneous colitis-associated colorectal cancer (CAC). We show that IFN-γ expression is significantly increased both in the T cells and the colonic mucosal epithelia of mice with a T cell-restricted deletion of the TGF-β intermediate, SMAD4 (Smad4TKO). The increase of IFN-γ expression correlates with the onset of spontaneous CAC in Smad4TKO mice by 6 months of age. This phenotype is greatly ameliorated by the introduction of a germline deletion of IFN-γ in Smad4TKO mice (Smad4TKO/IFN-γKO, DKO). DKO mice had a significantly reduced incidence and progression of CAC, and a decrease in the number of mucosal CD4+ TEM cells, when compared to those of Smad4TKO mice. Similarly, the colon epithelia of DKO mice exhibited a non-oncogenic signature with a decrease in the expression of iNOS and p-STAT1, and a restoration of the tumor suppressor gene, 15-hydroxyprostaglandin dehydrogenase (15-PGDH). In vitro, treatment of human colon cancer cells with IFN-γ decreased the expression of 15-PGDH. Our data suggest that Smad4-deficient T cells promote CAC through mechanisms that include an IFN-γ-dependent suppression of the tumor suppressor 15-PGDH.


Estimating Drug Efficacy with a Diet-Induced NASH Model in Chimeric Mice with Humanized Livers.
Nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is the most common liver disorder in developed countries. Although many new therapeutics for NASH are present in the drug development pipeline, there are still no approved drugs. One of the reasons that makes NASH drug development challenging is the lack of appropriate animal NASH models that resolve issues arising from inter-species differences between humans and rodents. In the present study, we developed a choline-deficient, L-amino-acid-defined, high-fat-diet (CDAHFD)-induced human NASH model using human liver chimeric mice. We demonstrated human hepatocyte injury by an elevation of plasma human alanine aminotransferase 1 in mice fed CDAHFD. Histological analysis showed that CDAHFD feeding induced similar histological changes to human NASH patients, including ballooning, inflammation, apoptosis, regeneration of human hepatocytes, and pericellular and perisinusoidal fibrosis. The chimeric mice fed CDAHFD were treated with a peroxisome-proliferator-activated receptor α/δ agonist, Elafibranor. Elafibranor ameliorated steatosis, ballooning of hepatocytes, and preserved fibrosis progression. We developed a novel humanized NASH model that can elucidate pathophysiological mechanisms and predict therapeutic efficacy in human NASH. This model will be useful in exploring new drugs and biomarkers in the early stages of human NASH.


Experimental Investigation on Dynamic Tensile Behaviors of Engineered Cementitious Composites Reinforced with Steel Grid and Fibers.
Engineered cementitious composites (ECC) used as runway pavement material may suffer different strain rate loads such as aircraft taxiing, earthquakes, crash impacts, or blasts. In this paper, the dynamic tensile behaviors of the steel grid-polyvinyl alcohol (PVA) fiber and KEVLAR fiber-reinforced ECC were investigated by dynamic tensile tests at medium strain rates. The mixture was designed with different volume fractions of fibers and layer numbers of steel grids to explore the reinforcement effectiveness on the dynamic performance of the ECC. The volume fractions of these two types of fibers were 0%, 0.5%, 1%, 1.5%, and 2% of the ECC matrix, respectively. The layer numbers of the steel grid were 0, 1, and 2. The dynamic tensile behaviors of the PVA fiber and the KEVLAR fiber-reinforced ECC were also compared. The experimental results indicate that under dynamic tensile loads, the PVA-ECC reveals a ductile and multi-cracking failure behavior, and the KEVLAR-ECC displays a brittle failure behavior. The addition of the PVA fiber and the KEVLAR fiber can improve the tensile peak stress of the ECC matrix. For the specimens A0.5, A1, A1.5, and A2.0, the peak stress increases by 84.3%, 149.4%, 209.6%, and 237.3%, respectively, compared to the matrix specimen. For the specimens K0.5, K1, K1.5, and K2, the peak stress increases by about 72.3%, 147.0%, 195.2%, and 263.9%, respectively, compared to the matrix specimen. The optimum fiber volume content is 1.5% for the PVA-ECC and the KEVLAR-ECC. The KEVLAR-ECC can supply a higher tensile strength than the PVA-ECC, but the PVA-ECC reveals more prominent deformation capacity and energy dissipation performance than the KEVLAR-ECC. Embedding steel grid can improve the tensile peak stress and the energy dissipation of the ECC matrix. For the strain rate of 10-3 s-1, the peak stress of the A0.5S1 and A0.5S2 specimens increases by about 49.1% and 105.7% compared to the A0.5 specimen, and the peak stress of the K0.5S1 and K0.5S2 specimens increases by about 61.5% and 95.8%, respectively, compared to the K0.5 specimen.


Congenital anomalies of the hand. The Asian perspective.
To have a better understanding of teratogenic mechanisms of congenital absence of digits, ulnar and radial deficiencies, cleft hand, and symbrachydactyly were analyzed in clinical cases. The same anomalies were induced in rat fetuses by busulfan, and their characteristics were investigated. The formation process of longitudinal deficiency also was observed histologically. There seemed to be 4 teratogenic mechanisms of congenital absence of digits. Ulnar and radial deficiencies have the same clinical features, and the cause of these deficiencies is related closely to a deficit of mesenchymal cells in the limb bud caused by the impairment before the formation of the limb bud. Cleft hand, central polydactyly, and osseous syndactyly were induced by the same treatment at the same developmental stage in rats. Cleft hand formation process from osseous syndactylies and central polydactylies was supposed. The teratogenic mechanism of cleft hand seemed to be failure of induction of digital rays in the hand plate. The sequence of anomalies from brachysyndactyly, or the atypical cleft hand, to the transverse deficiency can be regarded as equivalent to the category of bony dysplasia of the hand. Congenital constriction ring syndrome does appear after the formation of the digital rays.


Anxiety in Hospice Inpatients With Advanced Cancer, From the Perspective of Their Informal Caregivers: A Qualitative Study.
Anxiety is a common symptom in patients with advanced cancer. Early recognition of anxiety is difficult, especially when the physical condition of patients declines and patients are not able to verbally express about their concerns. Under these circumstances, informal caregivers may be a valuable source of information. The aim of this study was to explore anxiety in hospice inpatients with advanced cancer from the perspective of their informal caregivers. Fourteen informal caregivers were interviewed; 64% were women and the median age was 55 years. Informal caregivers assessed patients' anxiety as moderate to severe and identified a negative impact of anxiety on physical, psychological, social, and spiritual dimensions of the patients' lives. They indicated a variety of expressions of anxiety and mentioned physical and mental deterioration as an important source of anxiety. Informal caregivers recognized patients' needs as having a safe environment, presence of people around, and a sense of control over the situation. Although the patients' perspective is the gold standard, informal caregivers can be a valuable source of information in identifying anxiety and providing personalized support. Therefore, informal caregivers should be more involved in the care for anxious patients to improve early recognition of anxiety and to ameliorate anxiety management for this vulnerable patient population.


Occurrence of No-Harm Incidents and Adverse Events in Hospitalized Patients with Ischemic Stroke or TIA: A Cohort Study Using Trigger Tool Methodology.
Adverse events (AEs)-healthcare caused events leading to patient harm or even death-are common in healthcare. Although it is a frequently investigated topic, systematic knowledge on this phenomenon in stroke patients is limited. To determine cumulative incidence of no-harm incidents and AEs, including their severity and preventability, a cohort study using trigger tool methodology for retrospective record review was designed. The study was carried out in a stroke center at a university hospital in the German speaking part of Switzerland. Electronic records from 150 randomly selected patient admissions for transient ischemic attack (TIA) or ischemic stroke, with or without acute recanalization therapy, were used. In total, 170 events (108 AEs and 62 no-harm incidents) were identified, affecting 83 patients (55.3%; 95% CI 47 to 63.4), corresponding to an event rate of 113 events/100 admissions or 142 events/1000 patient days. The three most frequent AEs were ischemic strokes (n = 12, 7.1%), urinary tract infections (n = 11, 6.5%) and phlebitis (n = 10, 5.9%). The most frequent no-harm incidents were medication events (n = 37, 21.8%). Preventability ranged from 12.5% for allergic reactions to 100% for medication events and pressure ulcers. Most of the events found (142; 83.5%; 95% CI 76.9 to 88.6) occurred throughout the whole stroke care. The remaining 28 events (16.5%; 95% CI 11.4 to 23.1) were detected during stroke care but were related to care outside the stroke pathway. Trigger tool methodology allows detection of AEs and no-harm incidents, showing a frequent occurrence of both event types in stroke and TIA patients. Further investigations into events' relationships with organizational systems and processes will be needed, first to achieve a better understanding of these events' underlying mechanisms and risk factors, then to determine efforts needed to improve patient safety.


Expression of human papilloma virus E7 protein causes apoptosis and inhibits DNA synthesis in primary hepatocytes via increased expression of p21(Cip-1/WAF1/MDA6).
The impact of human papilloma virus (HPV16) E7 proteins and retinoblastoma (RB) antisense oligonucleotides upon mitogen-activated protein kinase (MAPK)-mediated inhibition of DNA synthesis via p21(Cip-1/WAF1/MDA6) (p21) was determined in primary hepatocytes. Prolonged activation of the MAPK pathway in p21(+/+) or p21(-/-) hepatocytes caused a large decrease and increase, respectively, in DNA synthesis. Either transfection with RB antisense oligonucleotides, expression of wild type E7, or RB binding mutant E7 (C24S) proteins increased p21 levels and reduced DNA synthesis in p21(+/+) hepatocytes. RB antisense oligonucleotides and E7 proteins increased apoptosis in p21(+/+), but not p21(-/-), hepatocytes. Expression of wild type E7 increased DNA synthesis above control levels in p21(-/-) cells, which was additive with prolonged MAPK activation. In contrast, expression of mutant E7 did not alter DNA synthesis above control levels in p21(-/-) cells and was supra-additive with prolonged MAPK activation. Antisense ablation of RB in p21(-/-) hepatocytes had a weak stimulatory effect upon DNA synthesis itself but enhanced the capacity of mutant E7 protein to stimulate DNA synthesis to the same level observed using wild type E7. The ability of prolonged MAPK activation to stimulate DNA synthesis in the presence of mutant E7 and antisense RB was additive. Collectively, the present data demonstrate that loss of RB function together with loss of p21 function plays an important role in the E7- and MAPK-dependent modulation of apoptosis and DNA synthesis in primary hepatocytes.


Comparison of six microcomputer dietary analysis systems with the USDA Nutrient Data Base for Standard Reference.
We compared the general operating features and nutrient databases of six microcomputer dietary analysis systems. A 3-day food record with 73 food items was entered into each program; nutrient averages were compared with the US Department of Agriculture Nutrient Data Base for Standard Reference (USDA NDB), full version, release 9, for microcomputers. The six programs were found to vary widely in cost, number of foods and nutrients in the database, use of non-USDA data and imputation of data for missing values, number of print/export options, time to analyze the 3-day food record, and overall ease of use. Although all of the microcomputer dietary analysis systems were within 7% of the USDA NDB for energy, protein, total fat, and total carbohydrates, the proportion of other nutrients varying more than 15% from the USDA NDB varied considerably between programs. Variance among programs for 3-day food record nutrient values occurred because of differences in the number of food items included in the database (leading to varying degrees of substitution), the recency of the nutrient data (whether or not the most recent USDA releases had been incorporated), and the number of missing values (the degree to which non-USDA sources or estimated calculations were used to fill in the blanks from the USDA standard). Our results demonstrate that it is important for each dietitian to carefully choose a microcomputer dietary analysis system that is suitable to specific and predetermined needs.


High Serum Estradiol and Heavy Metals Responsible for Human Spermiation Defect-A Pilot Study.
Spermiation is a process of releasing sperm into the lumen of seminiferous tubules. Failure in releasing sperm into the lumen is designated as spermiation defect. Spermiation defect cases present as oligo-azoospermia or azoospermia despite normal gonadotropins and testicular histology/cytology. Human spermiation defect never got attention to investigate infertility practice. Most of the information on spermiation defect, so far is from animal experiments. We assume some cases of non-obstructive azoospermia with normal gonadotropins and testicular histology/cytology could be due to spermiation defect. The aim of the study was to find out the underlying aetiology in cases of human spermiation defect. A total of 13 cases of spermiation defect and 20 fertile men as control constituted study material. Cases were studied for chromosomal abnormalities by conventional karyotyping, sex chromosome mosaicism by interphase XY FISH, Yq microdeletion by STS PCR, sertoli cell quality (function) and quantity (numbers) by serum Anti-Mullerian Hormone (AMH) and inhibin B besides other hormones like Follicular Stimulating Hormone (FSH), prolactin, testosterone and estradiol. Vitamin A concentration in serum was also measured. Presence of heavy metal was investigated by elemental electron microscopy in seminal cells (eight cases) & by spectrometry in serum as well as seminal plasma. Chromosomal and Yq microdeletion study failed to detect any abnormalities. AMH, inhibin B and vitamin A were also normal. Estradiol level was high in 6 out of 13 cases (46%) while platinum in seminal cells was high in 4 cases (50%). High (four times or more) serum level of lead and nickel was observed in 11 (85%) and 6 (46%) cases, respectively. High serum concentration of heavy metals like lead & nickel or high platinum accumulation in seminal cells or high serum estradiol alone or in combinations may be underlying aetiologic factors in human spermiation defect.


Bayesian model choice for epidemic models with two levels of mixing.
This paper considers the problem of choosing between competing models for infectious disease final outcome data in a population that is partitioned into households. The epidemic models are stochastic individual-based transmission models of the susceptible-infective-removed type. The main focus is on various algorithms for the estimation of Bayes factors, of which a path sampling-based algorithm is seen to give the best results. We also explore theoretical properties in the case where the within-model prior distributions become increasingly uninformative, which show the need for caution when using Bayes factors as a model choice tool. A suitable form of deviance information criterion is also considered for comparison. The theory and methods are illustrated with both artificial data, and influenza data from the Tecumseh study of illness.


Generational differences in spatial mobility: A study with mobile phone data.
This article focuses on generational differences in spatial mobility. Assuming that the ability to cope with the social transformations related to growing mobility varies significantly across generations, we use mobile positioning data collected in Estonia during 2014 providing four main indicators, namely, the number of locations visited and the distances between visited locations, within Estonia and abroad. The results indicate that spatial mobility declines linearly with age; however, a high degree of heterogeneity exists within age groups. Whereas the spatial mobility of the most active members of the younger generation takes place mostly within Estonia, among the most active older generation focus their activity beyond its borders. The study reveals "delayed mobility" patterns among the most active groups of the older generation and a new "immobility culture" among the younger generation in terms of cross-border activities in a transition society.


Micropreparative ligand fishing with a cuvette-based optical mirror resonance biosensor.
We have previously demonstrated the role of an optical biosensor (BIAcore 2000) as a specific detector to monitor chromatographic fractions during the purification and characterisation of ligands for orphan biomolecules. We have now extended this application to perform micropreparative ligand fishing directly on the sensor surface using an automated cuvette-based optical biosensor (Iasys Auto+) equipped with a high-capacity carboxymethyldextran surface (surface area 16 mm2). Using a F(ab)2' fragment of the A33 monoclonal antibody as bait, we have recovered microgram quantities of essentially homogeneous A33 ligand from the sensor surface in a form suitable for subsequent sensitive and specific down stream analysis (micropreparative HPLC, sodium dodecyl sulphate-polyacrylamide gel electrophoresis and Western blotting). The design of the cuvette-based system facilitates recovery of desorbed material from the constrained workspace in small volumes at high concentration. The use of on-surface detection allows the surface viability to be continuously monitored and permits direct quantitation of both bound and recovered material.


Comparative phenotypic and transcriptomic analysis of Victoria and flame seedless grape cultivars during berry ripening.
Grape berry development is a highly coordinated and intricate process. Herein, we analyzed the phenotypic and transcriptomic patterns of Victoria (VT) and Flame Seedless (FS) grape varieties during berry development. Physiological analysis and transcriptomic sequencing were performed at four berry developmental phases. VT berry size was comparatively larger to the FS variety. At maturity, 80 days postanthesis (DPA), the FS soluble solids were 61.8% higher than VT. Further, 4889 and 2802 differentially expressed genes were identified from VT and FS 40 DPA to 80 DPA development stages, respectively. VvSWEET15, VvHXK, and MYB44 genes were up-regulated during the postanthesis period, while bHLH14, linked to glucose metabolism, was gradually down-regulated during berry development. These genes may have significant roles in berry development, ripening, and sugar accumulation.


The effects of chlordiazepoxide and d-amphetamine during a three-component multiple schedule.
Multiple schedules have been used in behavioral pharmacology research to show that a drug's effect on behavior can be a function of the schedule of reinforcement that supports that behavior. However, less research has examined whether the context of the schedule of reinforcement in a multiple schedule can change the drug's effect on behavior. We examined the effects of acute chlordiazepoxide and d-amphetamine injections on the behavior of two groups of pigeons trained on a three-component multiple schedule with identical schedules of reinforcement in the first and last components. For one group of pigeons reinforcement was unavailable during the middle component (decreased-middle-component). For the second group reinforcement rate was higher during the middle component than during the first or third components (increased-middle-component). In the decreased-middle-component group, chlordiazepoxide (3.2-32 mg/kg) decreased third-component response rates less than it decreased responding in the first component. Conversely, in the increased-middle-component group, chlordiazepoxide (3.2-10 mg/kg) decreased third-component response rates more than in the first component. In both groups, d-amphetamine did not differentially affect response rates across components. These results are consistent with previous research showing that drugs can differentially affect responding to two different schedules of reinforcement during the same session, and suggest that pharmacological preparations may be helpful in elucidating the mechanisms that control multiple schedule interactions.


[Nursing staff downsizing at a university hospital].
The developed investigation in this type of case study, had as main goal to measure the nursing personnel at a university hospital. The adopted methodology comprizes the identification of some specific variables, among them the patient classification according to the nursing care category and the index of the predicted and not predicted absences. The medical clinic admission and surgical units were studied. Results demonstrated that the current nursing personnel corresponds to 50% of what was expected, whereas the nursing aides personnel has shown an overage of 29.2%. The redefinition of the nurses quantitative in the hospital will create possibilities to reorganize the work with the minimization of the working load, in such a way to assure the quality of delivered nursing care.


Assaying ornithine and arginine decarboxylases in some plant species.
A release of (14)CO(2) not related to ornithine decarboxylase activity was found in crude leaf extracts from Lycopersicon esculentum, Avena sativa, and especially from the pyrrolizidine alkaloid-bearing Heliotropium angiospermum when incubated with [1-(14)C]- or [U-(14)C]ornithine. The total (14)CO(2) produced was about 5- to 100-fold higher than that due to ornithine decarboxylase activities calculated from labeled putrescine (Put) found by thin-layer electrophoresis in the incubation mixtures. Partial purification with (NH(4))(2)SO(4) did not eliminate completely the interfering decarboxylation. When incubated with labeled arginine, a very significant (14)CO(2) release not related to arginine decarboxylase activity was observed only in extracts from H. angiospermum leaves, especially in Tris.HCl buffer. Under the assay conditions, these extracts exhibited oxidative degradation of added Put and agmatine (Agm) and also revealed a high arginase activity. Amino-guanidine at 0.1 to 0.2 millimolar prevented Put degradation and greatly decreased oxidative degradation of Agm; ornithine at 15 to 20 millimolar significantly inhibited arginase activity. A verification of the reliability of the standard (14)CO(2)-based method by assessing labeled Put and/or Agm-formed in the presence of added aminoguanidine and/or ornithine when needed-is recommended especially when crude or semicrude plant extracts are assayed.When based on Put and/or Agm formed at 1.0 to 2.5 millimolar of substrate, the activities of ornithine decarboxylase and arginine decarboxylase in the youngest leaves of the tested species ranged between 1.1 and 3.6 and 1 and 1600 nanomoles per hour per gram fresh weight, respectively. The enzyme activities are discussed in relation to the biosynthesis of pyrrolizidine alkaloids.


Beyond illness and treatment.
Peer support workers or peer experts are a new workforce in the mental health services of Hong Kong. As two of the few peer support workers in mental health services, we share our experience in working in a regional hospital. We share the amazing benefit of this new workforce to service users and service providers as well as the obstacles in the further development of this service. We hope our experience can help to examine the implementation of peer support services in Hong Kong. As this service is still in its preliminary stage in Hong Kong, we are looking forward to establish a win-win situation for both our peers and the service providers for the enhancement of mental health services in Hong Kong.


Neurologic cause of idiopathic incontinence.
The relationship between the pudendal and perineal nerve terminal motor latencies and descent (weakness) of the perineum on straining was investigated in 31 patients with idiopathic fecal incontinence, and in 30 patients with double incontinence. Pelvic floor descent was correlated with increased pudendal nerve terminal motor latency in both groups of patients. In the patients with double incontinence, there was a less significant correlation between perineal descent and increased perineal nerve terminal motor latency. In the patients with fecal incontinence, but without urinary incontinence, there was no correlation between perineal descent and perineal nerve terminal motor latency. These data support the concept that pelvic floor weakness can result in damage to the pudendal and perineal nerves, leading to fecal and urinary incontinence. In patients with isolated fecal incontinence the perineal nerves are relatively spared. Thus these common types of incontinence probably have a neurologic cause, and neurophysiologic methods can be used in their assessment.


Mussel-Inspired Anisotropic Nanocellulose and Silver Nanoparticle Composite with Improved Mechanical Properties, Electrical Conductivity and Antibacterial Activity.
Materials for wearable devices, tissue engineering and bio-sensing applications require both antibacterial activity to prevent bacterial infection and biofilm formation, and electrical conductivity to electric signals inside and outside of the human body. Recently, cellulose nanofibers have been utilized for various applications but cellulose itself has neither antibacterial activity nor conductivity. Here, an antibacterial and electrically conductive composite was formed by generating catechol mediated silver nanoparticles (AgNPs) on the surface of cellulose nanofibers. The chemically immobilized catechol moiety on the nanofibrous cellulose network reduced Ag⁺ to form AgNPs on the cellulose nanofiber. The AgNPs cellulose composite showed excellent antibacterial efficacy against both Gram-positive and Gram-negative bacteria. In addition, the catechol conjugation and the addition of AgNP induced anisotropic self-alignment of the cellulose nanofibers which enhances electrical and mechanical properties of the composite. Therefore, the composite containing AgNPs and anisotropic aligned the cellulose nanofiber may be useful for biomedical applications.


Phase I study of paclitaxel by three-hour infusion: hypotension just after infusion is one of the major dose-limiting toxicities.
The primary objectives of this study were to determine the maximum tolerated dose (MTD) of paclitaxel administered by 3-h infusion to patients with solid tumors, and to characterize the pharmacokinetics of a 3-h infusion in comparison with those of a 24-h infusion. Twenty-seven patients each received one of six levels of paclitaxel, 105, 135, 180, 210, 240 and 270 mg/m2, with premedication. Two patients given 240 mg/m2 and one patient given 270 mg/m2 unexpectedly had grade 3/4 hypotension just after finishing the paclitaxel infusion. Peripheral neuropathy was also dose-limiting at 270 mg/m2. Although granulocytopenia was significantly less severe than with a 24-h infusion, more than half of the patients experienced grade 4 toxicity at doses of 240 or 270 mg/m2. Severe hypersensitivity reactions (HSRs) were not observed. Pharmacokinetic studies using high performance liquid chromatography demonstrated proportionally greater increases in the peak plasma concentration and area under the curve, and decreases in clearance and volume of distribution with increasing dose, suggesting non-linear pharmacokinetics of paclitaxel when given by 3-h infusion. The MTD of paclitaxel given as a 3-h infusion was determined to be 240 mg/m2 with dose-limiting toxicities of granulocytopenia, peripheral neuropathy and hypotension. Hypotension just after infusion, induced by 3-h infusion of paclitaxel, is a new observation which has not been reported previously. The recommended dose for phase II study is 210 mg/m2. Although hypotension was observed as an unexpected toxic effect, paclitaxel could be administered safely over 3 h with premedication and proper monitoring, resulting in reduced myelotoxicity and with no increase in the incidence of HSRs as compared with a 24-h infusion.


Theoretical Methods for Studying DNA Structural Transitions under Applied Mechanical Constraints.
Recent progress in single-molecule manipulation technologies has made it possible to exert force and torque on individual DNA biopolymers to probe their mechanical stability and interaction with various DNA-binding proteins. It was revealed in these experiments that the DNA structure and formation of nucleoprotein complexes by DNA-architectural proteins can be strongly modulated by an intricate interplay between the entropic elasticity of DNA and its global topology, which is closely related to the mechanical constraints applied to the DNA. Detailed understanding of the physical processes underlying the DNA behavior observed in single-molecule experiments requires the development of a general theoretical framework, which turned out to be a rather challenging task. Here, we review recent advances in theoretical methods that can be used to interpret single-molecule manipulation experiments on DNA.


Dose-Response Curves for Intrathecal Bupivacaine, Levobupivacaine, and Ropivacaine Given for Labor Analgesia in Nulliparous Women.
Bupivacaine, levobupivacaine, and ropivacaine are often given intrathecally for labor analgesia, but limited data are available for their dose-response properties in this context. The objective of this study was to describe the dose-response curves of these local anesthetics when given intrathecally for labor analgesia, to determine values for D50 (dose producing a 50% response) and to compare the calculated values of D50 for levobupivacaine and ropivacaine with those for bupivacaine. With ethics approval and written consent, we randomized 270 nulliparous laboring patients requesting neuraxial analgesia at 5-cm cervical dilation or less to receive a single dose of intrathecal local anesthetic without opioid as part of a combined spinal-epidural technique. Patients received either bupivacaine, levobupivacaine, or ropivacaine at a dose of 0.625, 1.0, 1.5, 2.5, 4.0, or 6.25 mg (n = 15 per group). Visual analog scale pain scores were measured for 15 minutes, after which further analgesia and management were at the clinician's discretion. The primary end point was percentage reduction of pain score at 15 minutes. Logistic sigmoidal dose-response curves were fitted to the data using nonlinear regression, and D50 values were calculated for each drug. Data were analyzed from 270 patients. Patient characteristics were similar between groups. The calculated D50 and 95% confidence interval values were as follows: bupivacaine, 1.56 mg (1.25-1.94 mg); ropivacaine, 1.95 mg (1.57-2.43 mg); and levobupivacaine, 2.20 mg (1.76-2.73 mg). The results of this study support previous work showing that intrathecal levobupivacaine and ropivacaine are less potent than bupivacaine. Chinese Clinical Trial Registry (identifier: ChiCTR-TRC-09000773) and Centre of Clinical Trials Clinical Registry of the Chinese University of Hong Kong (identifier: CUHK_CCT00245).


A role for Mac-1 (CDIIb/CD18) in immune complex-stimulated neutrophil function in vivo: Mac-1 deficiency abrogates sustained Fcgamma receptor-dependent neutrophil adhesion and complement-dependent proteinuria in acute glomerulonephritis.
Mac-1 (alphambeta2), a leukocyte adhesion receptor, has been shown in vitro to functionally interact with Fcgamma receptors to facilitate immune complex (IC)-stimulated polymorphonuclear neutrophil (PMN) functions. To investigate the relevance of Mac-1-FcgammaR interactions in IC-mediated injury in vivo, we induced a model of Fc-dependent anti-glomerular basement membrane (GBM) nephritis in wild-type and Mac-1-deficient mice by the intravenous injection of anti-GBM antibody. The initial glomerular PMN accumulation was equivalent in Mac-1 null and wild-type mice, but thereafter increased in wild-type and decreased in mutant mice. The absence of Mac-1 interactions with obvious ligands, intercellular adhesion molecule 1 (ICAM-1), and C3 complement, is not responsible for the decrease in neutrophil accumulation in Mac-1- deficient mice since glomerular PMN accumulation in mice deficient in these ligands was comparable to those in wild-type mice. In vitro studies showed that spreading of Mac-1-null PMNs to IC-coated dishes was equivalent to that of wild-type PMNs at 5-12 min but was markedly reduced thereafter, and was associated with an inability of mutant neutrophils to redistribute filamentous actin. This suggests that in vivo, Mac-1 is not required for the initiation of Fc-mediated PMN recruitment but that Mac-1-FcgammaR interactions are required for filamentous actin reorganization leading to sustained PMN adhesion, and this represents the first demonstration of the relevance of Mac-1-FcgammaR interactions in vivo. PMN-dependent proteinuria, maximal in wild-type mice at 8 h, was absent in Mac-1 mutant mice at all time points. Complement C3-deficient mice also had significantly decreased proteinuria compared to wild-type mice. Since Mac-1 on PMNs is the principal ligand for ic3b, an absence of Mac-1 interaction with C3 probably contributed to the abrogation of proteinuria in Mac-1-null mice.


Ultra-high-frequency ultrasound monitoring of plaque psoriasis during ixekizumab treatment.
High-frequency ultrasound (HFUS) is a non-invasive method that detects superficial skin features. Ultra-high frequencies (50-100 MHz) can reveal epidermis and dermis structures. In this study, we describe the psoriatic plaque using a new device equipped with a 70 MHz probe (VEVO® MD, Fujifilm, VisualSonics) and we assess the lesion before and after ixekizumab. We examined the superficial hyperechoic band, the subepidermal hypoechoic band (SLEB), and the vascularization of the plaque in ten patients affected by plaque psoriasis. The average superficial hyperechoic band thickness was 0.2157 mm before treatment, 0.1611 mm after 15 days, and 0.1354 mm (P < .05) after 30 days. The SLEB thickness was 0.7535 mm at baseline, 0.3300 mm after 15 days (P < .05), and 0.2007 mm (P < .05) after 30 days. The average percentage vascularization was 50.21% at baseline, 13.15% after 15 days (P < .05), and 5.97% after 30 days. UHFUS assessment highlighted the rapid action of the drug in terms of the decrease in vascularization after 15 days. It revealed a statistically significant reduction in SLEB thickness after 15 days and a significant reduction in the hyperechoic superficial band after 30 days. VEVO® MD provides physicians with high-resolution details of the psoriatic plaque, thus enabling tailored-made treatments.


Forearm bone mineral density changes during postpartum and the effects of breastfeeding, amenorrhea, body mass index and contraceptive use.
Prospective cohort study performed to evaluate bone mineral density (BMD) changes up to 12 months postpartum of healthy women and its association with breastfeeding, contraceptive methods, amenorrhea, and body mass index (BMI). There is a trend in bone loss during the first 6 months with posterior recovery, with evidence of a protective effect of hormonal contraception. This study was conducted to evaluate bone mineral density (BMD) changes during postpartum period among healthy women and its association with breastfeeding, use of contraceptive methods, amenorrhea and body mass index (BMI). A prospective cohort study including 100 healthy women. Distal BMD was measured 7-10 days, 3, 6, and 12 months postpartum at the nondominant forearm using dual-energy X-ray absorptiometry. Data about breastfeeding duration, amenorrhea, contraceptive use and BMI were collected. Seventy-eight women had a complete set of BMD measurements. The mean duration of exclusive breastfeeding was 125.9 (±66.6) days, with a median total lactation period of 263.5 days. The mean duration of amenorrhea was 164.2 (±119.2) days. BMD measurements showed a significant decrease in the distal radius, however with no significance in the ultradistal radius. When considering only the nonhormonal contraceptive users, the difference at 12 months was significant. Multivariate analysis of variance showed that both BMI and contraceptive use were significantly correlated with BMD. Multiple linear regression analysis showed significant correlation of distal radius with baseline BMD at the same site, pregestational BMI, age, years of schooling and difference in BMI. For ultradistal radius, there was a significant direct correlation with its baseline BMD and pregestational BMI. There was a trend in bone loss during the first 6 months postpartum with posterior recovery. Also, hormonal contraceptive methods provided protection of bone loss. However, the long duration of breastfeeding and the follow-up were not sufficient to draw definitive conclusions on postweaning BMD conditions.


Stromal striae: a new insight into corneal physiology and mechanics.
We uncover the significance of a previously unappreciated structural feature in corneal stroma, important to its biomechanics. Vogt striae are a known clinical indicator of keratoconus, and consist of dark, vertical lines crossing the corneal depth. However we detected stromal striae in most corneas, not only keratoconus. We observed striae with multiple imaging modalities in 82% of 118 human corneas, with pathology-specific differences. Striae generally depart from anchor points at Descemet's membrane in the posterior stroma obliquely in a V-shape, whereas in keratoconus, striae depart vertically from posterior toward anterior stroma. Optical coherence tomography shear wave elastography showed discontinuity of rigidity, and second harmonic generation and scanning electron microscopies showed undulation of lamellae at striae locations. Striae visibility decreased beyond physiological pressure and increased beyond physiological hydration. Immunohistology revealed striae to predominantly contain collagen VI, lumican and keratocan. The role of these regions of collagen VI linking sets of lamellae may be to absorb increases in intraocular pressure and external shocks.


Dysfunctional eating behaviors, anxiety, and depression in Italian boys and girls: the role of mass media.
Extensive research has implicated identification with characters in mass media in the emergence of disordered eating behavior in adolescents. We explored the possible influence of the models offered by television (TV) on adolescents' body image, body uneasiness, eating-disordered behavior, depression, and anxiety. Three hundred and one adolescents (aged 14-19) from southern Italy participated. They completed a questionnaire on media exposure and body dissatisfaction, the Eating Disorder Inventory-2, the Body Uneasiness Test, the Beck Depression Inventory, and the State-Trait Anxiety Inventory - Form Y. The main factors contributing to females' eating-disordered behaviors were their own desires to be similar to TV characters, the amount of reality and entertainment TV they watched, and the discrepancy between their perceptions of their bodies and those of TV characters. Friends' desire to be similar to TV characters contributed most to depression, anxiety, body uneasiness, and eating disorders for both males and females. Our data confirm that extensive watching of reality and entertainment TV correlates with eating-disordered behavior among females. Moreover, the well-known negative effects of the media on adolescents' eating-disordered behaviors may also be indirectly transmitted by friends who share identification with TV characters.


Risk factors for avascular bone necrosis in patients with systemic lupus erythematosus.
The objective was to investigate the predictive factors for avascular necrosis (AVN) of bone in patients with systemic lupus erythematosus (SLE). The records of 868 patients with SLE from four centers were reviewed retrospectively. Forty-nine patients with AVN were identified. A total of 154 patients with SLE who did not have clinically apparent AVN during the follow-up were evaluated as a control group. The demographic, clinical, laboratory and management characteristics of these two groups of patients were recorded according to predefined protocol and compared. The prevalence of AVN was detected 6% in our SLE population. The highest dose corticosteroid administered within 4 months and total cumulative prednisolone dose were significantly higher in the SLE patients with AVN. The use of cytotoxic agent significantly higher proportion of patients with AVN. AVN tends to develop more frequently in male gender and younger patients. Oral ulcer, pleuritis, Raynaud's phenomenon, cutaneous vasculitis, lymphadenopathy, autoimmune thyroiditis, peripheral neuropathy and Sjögren's syndrome were higher incidence in SLE patients with AVN. The bilateral femoral heads were the commonest site of involvement of AVN in our patients with SLE.


Effects of Methyl Donors on L-Tryptophan Fermentation.
Methyl donors, a class of compounds that supply methyl groups to methyl acceptors, play important roles in the function, growth, and proliferation of cells; however, the methyl donor content in cells is not sufficient to meet their normal needs. In L-tryptophan production with E. coli, the growth and acid-producing ability of E. coli cells are weak due to the presence of exogenous plasmids that inhibit the growth of E. coli, and reduce the efficiency of exogenous gene expression. Therefore, the effect of methyl donors on L-tryptophan production was investigated. Among the methyl donors tested, choline chloride showed the most significant effect in promoting fermentation, followed by methionine. The optimum addition method involved the addition of 1.5 g/L methionine to the culture medium, combined with continuous feeding with a glucose solution containing 1 g/L choline chloride. The final tryptophan titer reached 53.5 g/L; the highest biomass of bacteria reached 51.8 g/L; and the main by-product, acetic acid, was reduced to 2.23 g/L, which had a significant impact on the fermentation results.


PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity.
CD8+ T cell exhaustion is a state of dysfunction acquired in chronic viral infection and cancer, characterized by the formation of Slamf6+ progenitor exhausted and Tim-3+ terminally exhausted subpopulations through unknown mechanisms. Here we establish the phosphatase PTPN2 as a new regulator of the differentiation of the terminally exhausted subpopulation that functions by attenuating type 1 interferon signaling. Deletion of Ptpn2 in CD8+ T cells increased the generation, proliferative capacity and cytotoxicity of Tim-3+ cells without altering Slamf6+ numbers during lymphocytic choriomeningitis virus clone 13 infection. Likewise, Ptpn2 deletion in CD8+ T cells enhanced Tim-3+ anti-tumor responses and improved tumor control. Deletion of Ptpn2 throughout the immune system resulted in MC38 tumor clearance and improved programmed cell death-1 checkpoint blockade responses to B16 tumors. Our results indicate that increasing the number of cytotoxic Tim-3+CD8+ T cells can promote effective anti-tumor immunity and implicate PTPN2 in immune cells as an attractive cancer immunotherapy target.


Nicotine activates and desensitizes midbrain dopamine neurons.
Tobacco use in developed countries is estimated to be the single largest cause of premature death. Nicotine is the primary component of tobacco that drives use, and like other addictive drugs, nicotine reinforces self-administration and place preference in animal studies. Midbrain dopamine neurons normally help to shape behaviour by reinforcing biologically rewarding events, but addictive drugs such as cocaine can inappropriately exert a reinforcing influence by acting upon the mesolimbic dopamine system. Here we show that the same concentration of nicotine achieved by smokers activates and desensitizes multiple nicotinic receptors thereby regulating the activity of mesolimbic dopamine neurons. Initial application of nicotine can increase the activity of the dopamine neurons, which could mediate the rewarding aspects of tobacco use. Prolonged exposure to even these low concentrations of nicotine, however, can cause desensitization of the nicotinic receptors, which helps to explain acute tolerance to nicotine's effects. The effects suggest a cellular basis for reports that the first cigarette of the day is the most pleasurable, whereas the effect of subsequent cigarettes may depend on the interplay between activation and desensitization of multiple nicotinic receptors.


Same-day contralateral implantation of a permanent device after lead extraction for isolated pocket infection.
The purpose of this study is to examine the safety and outcomes of same-day reimplantation at the contralateral pectoral site in patients with device extraction for pocket infection but with negative blood cultures and no signs of systemic infection. Clinical and procedure-related data were retrospectively collected on 15 (11 male, mean age 77) device-dependent patients who underwent device and complete lead extraction (mean 2.5 leads per patient, mean implant duration 6.2 years) for local pocket infection, and who had a new contralateral device implanted on the same day. Temporary pacing via the femoral vein was used during extraction. The infected pocket was managed with an elliptical skin incision, debridement, full capsule resection, and primary wound closure with the end of the wound left open for a Penrose drain. Intravenous antibiotics were used prior to and through the procedure, and continued for a mean of 2 days post-procedure, with oral antibiotics used thereafter for a mean course of 2 weeks. No infections of the new device system occurred, with a mean follow-up of 39.6 months (range 12-74 months). In the setting of device erosion and isolated pocket infection without systemic or bloodstream involvement, a new contralateral device may be implanted on the same day as pocket debridement and system extraction without developing infection of the new permanent hardware. This strategy can be useful in patients with pacemaker-dependence, as an alternative to using a temporary pacing system.


Stability of an ultrathin plasma polymerized film in aqueous solution: in situ detection by surface plasmon resonance.
Recently, surface plasmon resonance (SPR) has been successfully implemented to characterize the film stability in real time: a radio frequency (RF) plasma polymerized film was monitored by swelling or extracting behaviors in aqueous solution. The high-resolution SPR revealed that film stability strongly depended on the monomers, plasma mode, and substrate locations as well as plasma polymerization conditions: incident power and working pressure. By Fourier transform infrared (FTIR), the possible reasons of film stabilization affected by plasma conditions and sample locations are explained. It is recommended that as an adhesive layer for future applications the plasma polymerized polymer shall be prepared in low working pressure pulsed plasma.


A double-blind, randomized, placebo-controlled, pilot clinical trial examining buspirone as an adjunctive medication during buprenorphine-assisted supervised opioid withdrawal.
Successful management of opioid withdrawal improves long-term treatment outcomes and reduces opioid use-related morbidity and mortality. Mechanistically supported pharmacotherapeutic approaches are needed to effectively manage acute and protracted opioid withdrawal. Buspirone is a D2 antagonist and 5-HT1a agonist that may decrease opioid withdrawal. Individuals (n = 15) admitted to a residential treatment center for opioid use disorder (OUD) were enrolled into a double-blind randomized clinical trial to assess the efficacy and acceptability of buspirone (45 mg/day) as an adjunctive medication to buprenorphine-assisted, supervised opioid withdrawal. Participants completed daily questionnaires which consisted of the Subjective Opiate Withdrawal Scale (SOWS) and a consensus sleep diary, which assessed total sleep time, time to sleep onset, and sleep quality. Total SOWS scores, individual opioid withdrawal symptoms and sleep outcomes were assessed between treatment groups (Placebo and Buspirone) and over time in a repeated measures linear mixed model. Total SOWS scores significantly decreased across study phases for both groups but decreased to a greater extent among individuals assigned to buspirone during both the first and second week of stable buspirone. Greater decreases in withdrawal were observed during Week 2 of stable buspirone relative to Week 1 of stable buspirone. Participants also reported significant increases in sleep duration and significant decreases in latency to sleep onset. This study provides further support that buspirone can help mitigate opioid withdrawal during a supervised opioid taper. Buspirone may confer unique benefits during protracted withdrawal periods. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Pressure-tuned collapse of the Mott-like state in Ca(n+1)Ru(n)O(3n+1) (n=1,2): Raman spectroscopic studies.
We report a Raman scattering study of the pressure-induced collapse of the Mott-like phases of Ca3Ru2O7 (T(N)=56 K) and Ca2RuO4 (T(N)=110 K). The pressure dependence of the phonon and two-magnon excitations in these materials indicate (i) a T approximately 0 pressure-induced collapse of the antiferromagnetic (AF) insulating phase above P(*) approximately 55 kbar in Ca3Ru2O7 and P(*) approximately 5-10 kbar in Ca2RuO4, (ii) a remarkable insensitivity of the exchange interaction to pressure in both systems, and (iii) evidence for persistent AF correlations above the critical pressure of Ca2RuO4, suggestive of phase separation involving AF insulator and ferromagnetic metal phases.


Multiple abnormalities in permanent incisors diagnosed six years after a severe intrusive injury in the primary dentition: A case report.
Severe intrusion injuries of primary teeth are frequently associated with serious developmental disorders. This report describes the diagnostic procedures and the multidisciplinary approach for multiple sequelae to permanent incisors due to a severe intrusive injury of the primary maxillary anterior teeth at the age of 18 months in a 7-year-old girl. Clinical examination revealed hypoplasia of tooth 22, and radiographic examination showed crown-root malformation of tooth 21, impaction of tooth 11, and the presence of an odontoma-like malformation on tooth 12. The affected tooth 12 had a poor prognosis, as highlighted by CBCT, and it was extracted. While for the impacted 11, a surgical extraction followed by an orthodontic treatment is scheduled. Aesthetic and functional problems were solved by a functional space maintainer using a removable partial denture. The occurrence of multiple abnormalities in permanent teeth as a result of intrusive injuries in the primary dentition enhances the need for creating awareness among dentists not only of the importance of appropriate immediate management of trauma but also of the importance of establishing a long-term follow up and subsequent management of any sequelae.


Differentially expressed genes in resistant and susceptible Bombyx mori strains infected with a densonucleosis virus.
We investigated variations in the gene expression of Bombyx mori following infection with a densonucleosis virus (BmDNV-Z). Two B. mori near-isogenic lines, Jingsong and Jingsong.nsd-Z.NIL, which are highly susceptible and completely resistant to BmDNV-Z, respectively, were used in this study. The infection profiles of BmDNV-Z in the midguts of the B. mori Jingsong and Jingsong.nsd-Z.NIL larvae revealed that the virus invaded the midguts of both of these strains. However, its proliferation was notably inhibited in the midgut of the resistant strain. By using the suppression subtractive hybridization method, three cDNA libraries were constructed to compare BmDNV-Z responsive gene expression between the two silkworm lines. In total, 151 differentially expressed genes were obtained. Real-time qPCR analysis confirmed that 11 genes were significantly up-regulated in the midgut of the Jingsong.nsd-Z.NIL strain following BmDNV-Z infection. Our results imply that these up-regulated genes might be involved in B. mori immune responses against BmDNV infection.


The adhesion of anti-CD3-activated mouse T cells to syngeneic colon adenocarcinoma cells is differentially regulated by protein tyrosine kinase-, protein kinase C-, and cAMP-dependent pathways in the effector cell.
The adhesion of anti-CD3-activated mouse T cells (AK-T cells) to syngeneic colon adenocarcinoma (MCA-38) cells is mediated principally through the integrin VLA-4 (alpha4beta1). We investigated the signalling pathways through which this adhesive interaction might be regulated. The protein tyrosine kinase inhibitors genistein and methyl 2,5-dihydroxycinnamate (MDHC) markedly inhibited the adhesion of AK-T cells to MCA-38 cells. Furthermore, pretreatment of the AK-T cells alone (but not the MCA-38 targets) with MDHC inhibited adhesion to a comparable extent as when MDHC was present during the assay. Calphostin C, an inhibitor of protein kinase C, also inhibited the adhesion of AK-T cells to MCA-38 monolayers. However, the phosphatidylinositol 3-kinase inhibitor wortmannin failed to alter AK-T cell adhesion to MCA-38 tumour cells. Inhibition of protein kinase A with the Rp diastereomer of adenosine cyclic 3',5'-phosphorothioate had no effect on adhesion, but the adenylyl cyclase activator forskolin and the cell-permeable cAMP analogues 8-Br-cAMP and dibutyryl-cAMP significantly suppressed adhesion. Pretreatment of AK-T cells alone with forskolin also inhibited adhesion. The adhesion of AK-T cells to MCA-38 tumour targets is therefore promoted by protein tyrosine kinases and protein kinase C, but inhibited by cAMP-dependent pathways, and the predominant location of the regulatory pathways is within the effector cell.


Sustained cocaine abstinence in methadone maintenance patients through voucher-based reinforcement therapy.
Chronic cocaine abuse remains a serious and costly public health problem. This study assessed the effectiveness of a voucher-based reinforcement contingency in producing sustained cocaine abstinence. A randomized controlled trial compared voucher-based reinforcement of cocaine abstinence to noncontingent voucher presentation. Patients were selected from 52 consecutively admitted injecting heroin abusers in a methadone maintenance treatment program. Patients with heavy cocaine use during baseline period (N = 37) participated. Except where otherwise indicated, the term cocaine abuse is used in this article in a generic sense and not according to the DSM-III-R definition. Patients exposed to abstinence reinforcement received a voucher for each cocaine-free urine sample (ie, negative for benzoylecgonine) provided three times per week throughout a 12-week period; the vouchers had monetary values that increased as the number of consecutive cocaine-free urine samples increased. Control patients received noncontingent vouchers that were matched in pattern and amount to the vouchers received by patients in the abstinence reinforcement group. Patients receiving vouchers for cocaine-free urine samples achieved significantly more weeks of cocaine abstinence (P = .007) and significantly longer durations of sustained cocaine abstinence (P = .001) than controls. Nine patients (47%) receiving vouchers for cocaine-free urine samples achieved between 7 and 12 weeks of sustained cocaine abstinence; only one control patient (6%) achieved more than 2 weeks of sustained abstinence. Among patients receiving vouchers for cocaine-free urine samples, those who achieved sustained abstinence ( > or = 5 weeks) had significantly lower concentrations of benzoylecgonine in baseline urine samples than those who did not achieve sustained abstinence (P < or = .01). Patients receiving voucher reinforcement rated the overall treatment quality significantly higher than controls (P = .002). Voucher-based reinforcement contingencies can produce sustained cocaine abstinence in injecting polydrug abusers.


Synbiotic (probiotic and ginger extract) loaded floating beads: a novel therapeutic option in an experimental paradigm of gastric ulcer.
This study investigated the use of a bioactive phytochemical, namely ginger extract (GE), for its antioxidant and antiulcer effects, and also for supporting probiotic growth and activity. Use of probiotics is limited in therapy because of their transience and inability to survive the adverse physiological conditions of the gastrointestinal tract. Packaging probiotics in a suitably designed pharmaceutical system with GE may facilitate their establishment in the stomach mucosa. A probiotic (Lactobacillus acidophilus) and GE were simultaneously and individually encapsulated/immobilized in alginate floating beads. The developed system was evaluated for diameter, buoyancy, entrapment, porosity, in-vitro viability/release and pharmacodynamics in a cold restraint stress induced gastric ulcer model in rats. The developed floating beads stayed in the stomach for more than 10 h and both agents were released slowly and over a prolonged period from these beads. Significant and promising results were obtained for the combination (synbiotic) system in terms of ulcer index, mucus secretion, oxidative stress and histopathological parameters, as compared with the individual agents. The developed system could completely revert the damage induced in ulcerated stomachs at physiological (ulcer index and mucus secretion), biochemical (oxidative stress) and histological levels. This study establishes that suitable packaging of GE and Lactobacillus acidophilus together in floating beads can help exploit their prospects as therapeutic curative agents rather than potential preventive agents.


Integrating automated patient letter generation into the electronic medical record.
This poster describes the design and functionality of StarLetter, an electronic patient letter generation tool. StarLetter is integrated into the new results feature of the electronic medical record front end allowing the clinicians to generate electronic letters to patients within their workflow.


Recognition of the Qa-2k tumor antigen by T cell receptor gamma/delta of an immunopotentiator-induced tumoricidal T cell of mice.
Tumor-specific expression of Qa-2k antigen coded by the Q5k gene on various mouse tumor cells and immunological response of the host mice to the antigen have been demonstrated [Seo et al. (1992) J Exp Med 175: 547; Tanino et al. (1992) Cancer Immunol Immunother 35: 230]. The possibility was examined that Qa-2 antigen is one of the recognition target molecules of immunopotentiator-induced, H-2-nonrestricted tumoricidal lymphocytes of Qa-2-mice. Lymphocytes stimulated in vivo with P. acnes or culture-induced anomalous killers of B6.K1 mice did not exhibit significant in vitro cytotoxicity against B6.K1 lymphoblasts but lysed their Qa-2,3-congenic counterpart B6 lymphoblasts. To demonstrate the Qa-2 specificity of such cytotoxic cells more precisely, an L cell transformant clone (LQ7b/Kb), which expressed the alpha 1 and alpha 2 domains of the Qa-2 antigen (Q7b gene product), was generated by transfecting a cloned plasmid DNA containing a hybrid gene constructed from the 5' half of the Q7b gene and the 3' half of the H-2Kb gene (pQ7b/Kb). Using LQ7b/Kb cells as the target cells and the nylon-wool-nonadherent fraction of lymphocytes from P. acnes-stimulated (C3H/He x B6.K1)F1 mice (H-2k, Qa-2-) as the effector cells of the in vitro cytotoxicity reaction, the presence of cytotoxic cells that recognize the alpha 1/alpha 2 region of the Q7b gene product was demonstrated. The cytotoxic activity was dependent on T cells bearing T cell receptors of the gamma/delta type (TCR gamma/delta). The (C3H/He x B6.K1)F1 effector cells, as well as the B6.K1 effector cells also lysed BW5147 lymphoma cells (Qa-2k+) derived from AKR mice (Qa-2-, H-2k). By target-competition experiments it was shown that some of the effector cells lytic to BW5147 were identical to those that lysed LQ7b/Kb. Therefore some of the tumoricidal cells induced by the immunopotentiator interact with the target tumor cells through recognition of the alpha 1/alpha 2 region of the Qa-2k tumor antigen by TCR gamma/delta.


Marine iguanas die from trace oil pollution.
An oil tanker ran aground on the Galapagos island of San Cristóbal on 17 January 2001, spilling roughly three million litres of diesel and bunker oil. The slick started to spread westwards and was dispersed by strong currents, so only a few marine animals were killed immediately as a result. Here we draw on the long-term data sets gathered before the spill to show that a population of marine iguanas (Amblyrhychus cristatus) on Sante Fe island suffered a massive 62% mortality in the year after the accident, due to a small amount of residual oil contamination in the sea. Another population on the more remote island of Genovesa was unaffected.


Effects of ceramide on apoptosis, proteoglycan degradation, and matrix metalloproteinase expression in rabbit articular cartilage.
Cartilage loss in osteoarthritis is characterized by matrix degradation and chondrocyte death. The lipid messenger ceramide is implicated in signal transduction of the catabolic cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1), as well as in apoptosis. The aim of this study was to examine the in vitro effects of ceramide on proteoglycan degradation, matrix-metalloproteinase (MMP) expression and activity, and chondrocyte apoptosis in rabbit articular cartilage. Cell-permeant ceramide C(2) stimulated proteoglycan degradation in cartilage explants starting from 3 x 10(-5) M, with 100% increase at the dose of 10(-4) M. This effect was probably due to MMPs since it was blocked by the MMP inhibitor batimastat. Furthermore, in isolated chondrocytes, C(2) stimulated the expression of MMP-1, 3, and 13 at the mRNA level, MMP activity, and MMP-3 production. Ceramide also caused chondrocyte apoptosis at doses ranging from 10(-5) to 10(-4) M. This study supports the hypothesis that ceramide might play a mediatory role in both matrix degradation and apoptosis in processes of cartilage loss such as those observed in osteoarthritis.


Potential prediction of formulation performance in paediatric patients using biopharmaceutical tools and simulation of clinically relevant administration scenarios of nifedipine and lorazepam.
This study explores the impact of paediatric patient related factors and choice of formulation on the dissolution characteristics of nifedipine and lorazepam, 2 drug substances regularly applied in very young patients and in compounded formulations. Dissolution experiments were designed to reflect clinical practice in a paediatric hospital, with respect to dosage forms, feeding regimens and methods of administration. Solubility studies addressed the influence of age and prandial state. Drug solubility and dissolution experiments were conducted in biorelevant media and adapted age-specific (neonate and infant) media. Dissolution studies were performed with the mini-paddle apparatus and the flow-through cell apparatus. Dissolution of nifedipine formulations was not affected by age-related changes of the fasted state simulated gastrointestinal fluids, and by disintegration of the formulation before administration. However, a significant difference in nifedipine's dissolution rate from commercial tablets and compounded capsules was observed. The dissolution of lorazepam tablets was affected by fasted- vs fed-state media, but it was deemed less likely to be clinically relevant. The significant effect of fed-state media on nifedipine's solubility was considered to have possible clinical relevance since very young patients are almost continuously in a fed state. The in vitro results obtained from these studies reveal the potential of biorelevant solubility and dissolution studies reflecting clinical practice to predict drug performance in paediatric patients.


A novel nine-microRNA-based model to improve prognosis prediction of renal cell carcinoma.
With the improved knowledge of disease biology and the introduction of immune checkpoints, there has been significant progress in treating renal cell carcinoma (RCC) patients. Individual treatment will differ according to risk stratification. As the clinical course varies in RCC, it has developed different predictive models for assessing patient's individual risk. However, among other prognostic scores, no transparent preference model was given. MicroRNA as a putative marker shown to have prognostic relevance in RCC, molecular analysis may provide an innovative benefit in the prophetic prediction and individual risk assessment. Therefore, this study aimed to establish a prognostic-related microRNA risk score model of RCC and further explore the relationship between the model and the immune microenvironment, immune infiltration, and immune checkpoints. This practical model has the potential to guide individualized surveillance protocols, patient counseling, and individualized treatment decision for RCC patients and facilitate to find more immunotherapy targets. Downloaded data of RCC from the TCGA database for difference analysis and divided it into a training set and validation set. Then the prognostic genes were screened out by Cox and Lasso regression analysis. Multivariate Cox regression analysis was used to establish a predictive model that divided patients into high-risk and low-risk groups. The ENCORI online website and the results of the RCC difference analysis were used to search for hub genes of miRNA. Estimate package and TIMER database were used to evaluate the relationship between risk score and tumor immune microenvironment (TME) and immune infiltration. Based on Kaplan-Meier survival analysis, search for immune checkpoints related to the prognosis of RCC. There were nine miRNAs in the established model, with a concordance index of 0.702 and an area under the ROC curve of 0.701. Nine miRNAs were strongly correlated with the prognosis (P < 0.01), and those with high expression levels had a poor prognosis. We found a common target gene PDGFRA of hsa-miR-6718, hsa-miR-1269b and hsa-miR-374c, and five genes related to ICGs (KIR2DL3, TNFRSF4, LAG3, CD70 and TNFRSF9). The immune/stromal score, immune infiltration, and immune checkpoint genes of RCC were closely related to its prognosis and were positively associated with a risk score. The established nine-miRNAs prognostic model has the potential to facilitate prognostic prediction. Moreover, this model was closely related to the immune microenvironment, immune infiltration, and immune checkpoint genes of RCC.


Anti-VEGF in treatment of diabetic macular edema.
Diabetic macular edema is the leading cause of moderate visual deterioration in patients with diabetic retinopathy. Ranibizumab) blocks vascular endothelial growth factor (VEGF) induced hyperpermeability of blood vessels. In this prospective case series we investigated the efficacy and safety of anti-VEGF treatment in reduction of central retinal thickness (CRT) and improvement in visual acuity (VA) in patients with diabetic macular edema (DME). 9 patients were followed up for 6 months and treated monthly with intravitreal ranibizumab. VA and CRT were measured at each visit. Treatment was discontinued as the peak improvement of either parameter was reached and reinstituted in case of deterioration/recurrence of edema. Study endpoints included: VA using ETDRS chart, CRT and number of injections at 6 months. Mean VA from all 9 patients increased by 0.3 lines of logMAR (p < 0.05 compared to baseline), and CRT decreased from 515 +/- 123 microm to 310 +/- 110 microm. The improvement of VA after ranibizumab injection was in correlation with a decrease in CRT. Mean of 4 injections were needed to control the disease during the follow-up period. Ranibizumab treatment was effective in VA and reducing CRT. Several injections were needed to control the disease. Regular OCT examinations and retreatment are advised in order to maintain initially reached VA.


IDH2 knockdown sensitizes tumor cells to emodin cytotoxicity in vitro and in vivo.
Although reactive oxygen species (ROS) work as second messengers at sublethal concentrations, higher levels of ROS can kill cancer cells. Since cellular ROS levels are determined by a balance between ROS generation and removal, the combination of ROS generators, and the depletion of reducing substances greatly enhance ROS levels. Emodin (1,3,8-trihydroxy-6-methyl anthraquinone), a natural anthraquinone derivative from the root and rhizome of numerous plants, is a ROS generator that induces apoptosis in cancer cells. The major enzyme to generate mitochondrial NADPH is the mitochondrial isoenzyme of NADP+-dependent isocitrate dehydrogenase (IDH2). In this report, we demonstrate that IDH2 knockdown effectively enhances emodin-induced apoptosis of mouse melanoma B16F10 cells through the regulation of ROS generation. Our findings suggest that suppression of IDH2 activity results in perturbation of the cellular redox balance and, ultimately, exacerbate emodin-induced apoptotic cell death in B16F10 cells. Our results strongly support a therapeutic strategy in the management of cancer that alters the intracellular redox status by the combination of a ROS generator and the suppression of antioxidant enzyme activity.


Identification of cis-regulatory sequence variations in individual genome sequences.
Functional contributions of cis-regulatory sequence variations to human genetic disease are numerous. For instance, disrupting variations in a HNF4A transcription factor binding site upstream of the Factor IX gene contributes causally to hemophilia B Leyden. Although clinical genome sequence analysis currently focuses on the identification of protein-altering variation, the impact of cis-regulatory mutations can be similarly strong. New technologies are now enabling genome sequencing beyond exomes, revealing variation across the non-coding 98% of the genome responsible for developmental and physiological patterns of gene activity. The capacity to identify causal regulatory mutations is improving, but predicting functional changes in regulatory DNA sequences remains a great challenge. Here we explore the existing methods and software for prediction of functional variation situated in the cis-regulatory sequences governing gene transcription and RNA processing.


Determinants of birth size in Northeast Spain.
To update knowledge on determinants of newborn body size in Northeast of Spain considering gestational, parental and socio-cultural variables. Cross-sectional assessment of 1442 infants from Aragón (Spain), born at term between March 2009 and March 2010. Obstetric, neonatal, socio-demographic and parental anthropometry data were collected during the first infant scheduled health examination. Hierarchical linear regression models were used to explore associations between newborn anthropometry and included variables. Birth weight was significantly higher in males than in females (130.7 g), when mother did not smoke during pregnancy (126.3 g), in immigrant mothers (113.1 g) and when parity increased (67.1 g per additional birth). Body weight at birth was 16.9 g higher per kg of maternal weight gain during pregnancy, 5.4 g higher per kg of maternal pre-pregnancy weight and 5.1 g higher per cm of maternal height. Birth length was also significantly higher in males than in females (0.87 cm), when mother did not smoke (0.48 cm), in immigrant mothers (0.64 cm), and it was positively associated with parity, maternal anthropometry and paternal height. Newborn anthropometry was not associated with maternal age, educational level or living location. Independently of gestational age and newborn sex, the main predictors of birth weight and length were maternal pre-pregnancy anthropometry and weight gain during gestation, to smoke during pregnancy, parity and maternal origin. Our results identify potential modifiable factors influencing newborn body size.


Prevalence of common sleep disorders in a middle-aged community sample.
There is a paucity of contemporary prevalence estimates for common sleep disorders of insomnia, obstructive sleep apnea (OSA), and restless legs syndrome. We aimed to assess the prevalence of clinically significant common sleep disorders in a middle-aged community sample. Parents of participants in the community-based Raine Study underwent assessments between 2015 and 2017, including comprehensive questionnaires, anthropometric measures, and in-laboratory polysomnography. Clinically significant sleep disorders were defined as chronic insomnia using the Pittsburgh Sleep Symptom Questionnaire-Insomnia with duration criterion ≥ 3 months; OSA as apnea-hypopnea index ≥ 5 events/h with excessive sleepiness (Epworth Sleepiness Scale ≥ 11) or apnea-hypopnea index ≥ 15 events/h (even in the absence of symptoms); restless legs syndrome when participants endorsed the International Restless Legs Syndrome Study Group diagnostic criteria (2003) with symptoms ≥ 5 times/month involving moderate-severe distress. At least 1 sleep-related assessment was completed by 1,005 (female = 586, 58.3%) middle-aged (45-65 years) participants, 72.5% of eligible Raine Study parents. The respective prevalences for clinically significant disease in females and males were as follows: OSA, 24.0% (95% confidence interval [CI]: 20.5-27.7) and 47.3% (95% CI: 42.2-53.4); insomnia, 15.8% (95% CI: 13.1-19.0) and 9.3% (95% CI: 6.8-12.4); restless legs syndrome, 3.7% (95% CI: 2.4-5.4) and 2.2% (95% CI: 1.1-3.9). At least 1 sleep disorder was present in 42.9% of those with complete data on all assessments (n = 895). Common sleep disorders are highly prevalent, to a clinically important extent, in an Australian community sample of middle-aged adults. Contemporary OSA prevalence is notably higher than previously reported and further work is needed to determine the communal impact of OSA. McArdle N, Reynolds AC, Hillman D, et al. Prevalence of common sleep disorders in a middle-aged community sample. J Clin Sleep Med. 2022;18(6):1503-1514.


Relationship between renal function and outcomes in high-risk patients with non-ST-segment elevation acute coronary syndromes: results from SYNERGY.
Chronic kidney disease (CKD) is a risk factor for coronary heart disease and bleeding with antithrombotic therapy in patients with acute coronary syndromes (ACS). We evaluated the effect of renal function on efficacy and outcomes in high-risk patients with NSTE ACS in the SYNERGY trial. Creatinine clearance (CrCl) at the time of randomization was analyzed as a continuous variable added to multivariable logistic regression models for 30-day death or MI, non-CABG-associated TIMI major bleeding, GUSTO severe bleeding, and transfusion in the overall study population, patients undergoing coronary angiography, and patients undergoing PCI. Of 9838 patients with a CrCl value, 70.6% (N=6950) had CrCl≥60 mL/min, 27.8% (N=2732) had CrCl 30-59 mL/min, and 1.6% (N=156) had CrCl<30 mL/min. No randomized treatment by CrCl interaction test was found to be statistically significant, suggesting renal insufficiency affected enoxaparin and unfractionated heparin outcomes similarly. After adjustment, CrCl was an independent predictor of 30-day death or MI (OR 1.06, 95% CI 1.03-1.09), TIMI major bleeding (OR 1.06, 95% CI 1.02-1.10), GUSTO severe bleeding (OR 1.10, 95% CI 1.03-1.17), and transfusion (OR 1.07, 95% CI 1.04-1.11). Patients with CKD had higher rates of 30-day death or MI and bleeding than those without CKD, regardless of randomized antithrombin therapy. While this analysis suggests that there is a rise in bleeding events as CrCl falls for patients in either treatment group, it is unknown whether a reduction in dose would decrease bleeding risk.


Advances in Thymidine Kinase 2 Deficiency: Clinical Aspects, Translational Progress, and Emerging Therapies.
Defects in the replication, maintenance, and repair of mitochondrial DNA (mtDNA) constitute a growing and genetically heterogeneous group of mitochondrial disorders. Multiple genes participate in these processes, including thymidine kinase 2 (TK2) encoding the mitochondrial matrix protein TK2, a critical component of the mitochondrial nucleotide salvage pathway. TK2 deficiency (TK2d) causes mtDNA depletion, multiple deletions, or both, which manifest predominantly as mitochondrial myopathy. A wide clinical spectrum phenotype includes a severe, rapidly progressive, early onset form (median survival: < 2 years); a less severe childhood-onset form; and a late-onset form with a variably slower rate of progression. Clinical presentation typically includes progressive weakness of limb, neck, facial, oropharyngeal, and respiratory muscle, whereas limb myopathy with ptosis, ophthalmoparesis, and respiratory involvement is more common in the late-onset form. Deoxynucleoside monophosphates and deoxynucleosides that can bypass the TK2 enzyme defect have been assessed in a mouse model, as well as under open-label compassionate use (expanded access) in TK2d patients, indicating clinical efficacy with a favorable side-effect profile. This treatment is currently undergoing testing in clinical trials intended to support approval in the US and European Union (EU). In the early expanded access program, growth differentiation factor 15 (GDF-15) appears to be a useful biomarker that correlates with therapeutic response. With the advent of a specific treatment and given the high morbidity and mortality associated with TK2d, clinicians need to know how to recognize and diagnose this disorder. Here, we summarize translational research about this rare condition emphasizing clinical aspects.


Cardiac autonomic control and treatment of hostility: a randomized controlled trial.
To test whether reduction in hostility increases autonomic regulation of the heart. In this randomized controlled trial, participants were 158 healthy adults, aged 20 years to 45 years, who were 1 standard deviation (SD) above national norms on the Cook-Medley Hostility and the Spielberger Trait Anger Indices. Participants also were interviewed, using the Interpersonal Hostility Assessment Technique (IHAT). They were randomly assigned to a 12-week cognitive behavior therapy program for hostility reduction or a wait-list control condition. The main outcome measure was cardiac autonomic modulation, measured as RR interval variability (RRV) derived from 24-electrocardiographic recordings. In a multivariate analysis of variance assessing psychological outcomes of hostility, anger, and IHAT scores, there was a significant treatment effect with an average reduction across the three outcomes that was approximately 0.7 SD (ES = 0.685, SE = 0.184, p < .001) greater for the intervention group than for the control group. In contrast, the change in heart rate was -0.14 beat/min (95% Confidence Interval [CI] = -2.43, 2.14) in treatment participants and -1.36 beat/min (95% CI = -3.28, 0.61) in wait-list participants. High-frequency RRV, an index of cardiac parasympathetic modulation, increased by 0.07 ln ms(2) (95% CI = -0.10, 0.24) for participants in the treatment condition and decreased by 0.04 ln ms(2) (95% CI = -0.18, 0.10) for participants in the wait-list condition. These differences were not significant. The findings for other indices of RRV were similar. Reduction of hostility and anger was not accompanied by increases in cardiac autonomic modulation. These findings raise questions about the status of disordered autonomic nervous system regulation of the heart as a pathophysiological mechanism underlying the hostility-heart disease relationship and about whether hostility itself is a mechanism or merely a marker of elevated risk of heart disease.


Lymph node hypertrophy following Leishmania major infection is dependent on TLR9.
Control of the protozoan parasite Leishmania major is dependent on establishing a robust T cell response. An early event in the development of an effective T cell response is the expansion (or hypertrophy) of the lymph node draining the site of infection, although the mechanisms involved in this response are not completely understood. In this study, we show that lymph node hypertrophy following L. major infection in mice is associated with increased recruitment of lymphocytes to the lymph node from the blood, and that CD62L-deficient mice, which are unable to recruit cells to the lymph node, develop a chronic infection with L. major. Injection of L. major-activated dendritic cells promoted lymph node hypertrophy, and this correlated with an increase in the expression of CCR7 on dendritic cells, although the upregulation of CCR7 occurred on the bystander (uninfected) dendritic cells rather than those containing parasites. We found that increased CCR7 expression was TLR9-dependent, that TLR9(-/-) dendritic cells migrated less efficiently to the draining lymph node, and that TLR9(-/-) mice exhibited a deficit in lymph node expansion following L. major infection, as well as increased susceptibility. Taken together, to our knowledge, these results are the first to demonstrate that activation of dendritic cells via TLR9 is essential for the induction of lymph node hypertrophy in leishmaniasis.


Effect of in utero growth retardation on lung function at follow-up of prematurely born infants.
The aim of the study was to determine if prematurely born children who had suffered intra-uterine growth retardation (IUGR) had more severe lung function abnormalities than those born an appropriate weight for gestational age (AGA). Analysis of the lung function results of 119 infants (median (range) gestational age of 30 (23-35) weeks) was undertaken. In total, 31 of the infants had suffered IUGR and were born small for gestational age (SGA). Functional residual capacity and airways resistance (Raw) were measured at a median post-natal age of 10 (6-24) months. Specific airway conductance (sGaw) was calculated from thoracic gas volume and Raw. The SGA children were born at a greater gestational age and had a lower body weight at testing than the AGA children. Raw and sGaw differed between the SGA and AGA children. Regression analysis demonstrated that lung volumes were significantly related to body weight at testing, Raw was related to IUGR, maternal smoking and bronchopulmonary dysplasia, and sGaw to maternal smoking. In conclusion, these results suggest that prematurely born infants who have suffered intra-uterine growth retardation may be at increased risk of impaired lung function at follow-up.


Increasing adherence to a community-based guideline for acute sinusitis through education, physician profiling, and financial incentives.
To implement a large-scale multifaceted intervention consisting of physician education, profiling, and a financial incentive, to improve treatment quality for acute sinusitis. Cohort trial using a historical control of treatment patterns among approximately 500 internists, 200 family practitioners, and 200 pediatricians in a northeastern community-wide individual practice association. Episode treatment group methods were adapted to identify cases (episodes) and to assess care patterns for acute sinusitis among 420,000 health maintenance organization patients seen between January 1, 1999, and December 31, 2001. The intervention consisted of care pathway development, physician and patient education, physician profiling, and a financial incentive. A statistical process control chart showed a shift toward recommended treatment patterns after our intervention. The rate of exceptions per episode of acute sinusitis decreased 20%, from 326 exceptions per 1000 episodes between January 1, 1999, and October 31, 2000, to 261 between November 1, 2000, and December 31, 2001. Decreased use of less effective or inappropriate antibiotics accounted for most of the change (199 to 136 exceptions per 1000 episodes [32% change]). Azithromycin use decreased 30%, from 97 to 68 prescriptions per 1000 episodes. Firstline antibiotic (amoxicillin and doxycycline) use increased 14%, from 451 to 514 prescriptions per 1000 episodes. Inappropriate radiology use decreased 20%, from 15 to 12 per 1000 episodes. These changes were significant at P < .005. A multifaceted program, including education, physician profiling with actionable recommendations, and a financial incentive, significantly increased physicians' adherence to a community-developed care pathway and was successful at improving adherence to recommended patterns of antibiotic use in acute sinusitis.