Preparation and in vitro evaluation of pH, time-based and enzyme-degradable pellets for colonic drug delivery.
The preparation of pH-dependent, time-based and enzyme degradable pellets was investigated for use as an oral colonic drug delivery system. It was expected that drug would be released immediately once the pellets reached the colon. The pellets were prepared using extrusion-spheronizing equipment and subsequently coated with three layers of three functional polymers by an air-suspension technique. The core consisted of 5-aminosalicylic acid (5-ASA) as a model drug, CaP as an enzyme-degradable material and microcrystalline cellulose (MCC) as an additive. As far as the three coated layers were concerned, the outer layer was coated with Eudragit L30D-55 for protection against gastrointestinal juices, the intermediate layer was coated with ethylcellulose (EC) to inhibit drug release during passage through the small intestine, and the inner film was coated with pectin for swelling and enzyme-degradation, which required a 30, 10, and 12% weight gain, respectively. Several micromeritic properties of the core pellets, including particle size distribution, particle size, degree of circularity, and friability, were evaluated to investigate the effects of the formulations of the cores and preparation conditions. Also, dissolution testing of the cores showed that the presence of calcium pectinate (CaP) markedly increased the drug release rate from the cores, as determined by scanning electron microscopy (SEM). In-vitro release studies indicated that the coated pellets completely protected the drug release in 0.1 mol/L HCl, while the drug release was delayed for 3-4 hr in pH 6.8 PBS. A synergistic effect of enzyme dependence for the coated pellets was seen following removal of the coated layer and during contact with colonic enzymes. Consequently, it was possible to achieve colon-specific drug delivery using this triple-dependence system.


From Habit-Forming to Habit-Breaking Availability: Experiences on Electronic Gambling Machine Closures During COVID-19.
Electronic gambling machines (EGMs) are among the most harmful forms of gambling. The structural characteristics of EGMs prolong and reinforce gambling similarly to other habit-forming technologies. In Finland, the wide availability of EGMs in non-casino locations is likely to further reinforce the habit-creating nature of gambling offer by incorporating EGMs into everyday practices. The COVID-19 pandemic changed the landscape of gambling in Finland. The most visible change was the closure of land-based EGMs in non-casino environments, arcades, and the casino in March 2020. Since then, the status of EGMs has varied depending on the pandemic situation. The current qualitative study focuses on how Finnish past-year gamblers experience prolonged EGM closures and occasional re-openings 1 year into the pandemic. The data consist of responses to an online questionnaire eliciting experiences (N = 187) as well as interviews (N = 27, conducted in groups or alone). To aid our analysis, we employ the sociological pragmatist theory of the concept of "habit." The analysis focuses on gambler experiences on EGM shutdowns and re-openings, and views on whether closures have contributed to abstaining from gambling or to shifting to other gambling products. Policy implications of the results are discussed.


[Experience of the quality improvement plan for the La Mina Health Centre (1989-2004)].
To describe how well the problems detected by a quality improvement plan (QIP) for a health care team (HCT) were solved; and to analyse the identification methods, the quality causes and dimensions affected by the problems detected, and the participation of professionals. Descriptive study. Evaluation of the situation in December 2004 of the problems identified since 1989. Urban HCT, with 58 professionals caring for a population of 18,897 inhabitants in the La Mina District, Barcelona, Spain. Five-hundred and thirty problems identified. Number and kind of detections and problems; identification methods; quality dimensions; causes; degree of solution, by method and cause; degree of solution of the QIP (of "internal" problems, excluding the problems caused externally or by patients); professional participation. In 312 meetings, there were 963 detections (annual average, 60.1; SD, 18.8), corresponding to 530 problems (annual average, 33.1; SD, 12.4). Of these 530 problems, 411 improved (77.5%). Of the 258 "internal" problems, 225 improved. The degree of solution of the QIP was 87.2%. The identification method that detected most problems (53.02% of the total) was the active listening of the quality improvement group. The quality dimensions most affected by the problems were effectiveness (31.7%) and accessibility (20.4%). The most frequent cause of problems and, at the same time, the category with the highest improvement rate (81.6%) was internal organization; 83.9% of professionals took part in the QIP. Having a QIP at our centre facilitated the management of the quality of care delivery.


Traffic flow simulation of modified cellular automata model based on producer-consumer algorithm.
With the rise of new technologies such as the Internet of Vehicles and the Internet of Things, research on the intelligent connected vehicle has become a hot topic in contemporary times. The modeling and simulation of traffic flow are mainly used to analyze the characteristics of traffic flow and study the formation and dissipation mechanism of traffic congestion to better guide the real traffic. Cellular automata are suitable for the simulation of complex giant systems. Because of the randomness and discreteness of vehicle driving, cellular automata are often used to model and analyze traffic flow. This article mainly studies the traffic flow formed by intelligent connected vehicles. Based on the traditional NaSch model, the producer-consumer algorithm is introduced to form a multi-buffer vehicle information access mode, and an improved cellular automata model with random updates is constructed. The simulation results show that the improved cellular automata model improves the traffic congestion significantly compared with the original NaSch model in the intelligent network environment, which is consistent with the actual traffic situation. Therefore, the algorithm proposed in this article can effectively simulate the traffic flow characteristics of intelligent connected vehicles, and provide a theoretical basis for solving traffic problems.


Prevalence Rates of Major Depressive Disorders: The Effects of Varying the Diagnostic Criteria in an Older Primary Care Population.
Patients age 60 years and older (N = 3,767) were screened for depression using the Center for Epidemiological Studies Depression Scale (CES-D). A random sample of patients scoring ≥ 16 on the CES-D (n = 44) and of patients scoring < 16 (n = 81) were recruited to complete a structured psychiatric interview. The estimated prevalence of major depressive disorder (MDD), using a clinically derived diagnosis with the "etiological" method, was 1.78%. When a computer-generated algorithm for MDD using the "inclusive" method for counting somatic symptoms was applied, the estimated prevalence for MDD rose to 5.84%. All subjects with MDD diagnosed by any method had significantly higher scores on the Sickness Impact Profile (SIP), compared with nondepressed subjects.


Genetic resources for methane production from biomass described with the Gene Ontology.
Methane (CH4) is a valuable fuel, constituting 70-95% of natural gas, and a potent greenhouse gas. Release of CH4 into the atmosphere contributes to climate change. Biological CH4 production or methanogenesis is mostly performed by methanogens, a group of strictly anaerobic archaea. The direct substrates for methanogenesis are H2 plus CO2, acetate, formate, methylamines, methanol, methyl sulfides, and ethanol or a secondary alcohol plus CO2. In numerous anaerobic niches in nature, methanogenesis facilitates mineralization of complex biopolymers such as carbohydrates, lipids and proteins generated by primary producers. Thus, methanogens are critical players in the global carbon cycle. The same process is used in anaerobic treatment of municipal, industrial and agricultural wastes, reducing the biological pollutants in the wastes and generating methane. It also holds potential for commercial production of natural gas from renewable resources. This process operates in digestive systems of many animals, including cattle, and humans. In contrast, in deep-sea hydrothermal vents methanogenesis is a primary production process, allowing chemosynthesis of biomaterials from H2 plus CO2. In this report we present Gene Ontology (GO) terms that can be used to describe processes, functions and cellular components involved in methanogenic biodegradation and biosynthesis of specialized coenzymes that methanogens use. Some of these GO terms were previously available and the rest were generated in our Microbial Energy Gene Ontology (MENGO) project. A recently discovered non-canonical CH4 production process is also described. We have performed manual GO annotation of selected methanogenesis genes, based on experimental evidence, providing "gold standards" for machine annotation and automated discovery of methanogenesis genes or systems in diverse genomes. Most of the GO-related information presented in this report is available at the MENGO website (http://www.mengo.biochem.vt.edu/).


White light-induced sugar distribution controls growth and osmotic properties in the coleoptile and the first leaf in Zea mays seedlings.
The correlation of white light-induced changes in osmotic concentration in the coleoptile and the first leaf and the growth rate of these organs in maize seedlings, was examined in relation to sugar distribution and invertase activity. One hour irradiation with white light decreased the osmotic concentration in basal zones of the coleoptile and increased it in the apical zones of the first leaf. The change in the osmotic concentration was positively correlated with the growth rate of both organs. The amount of total osmotic solutes in each zone was highly correlated with that of soluble sugars. Light decreased the activity of wall-bound invertase in the coleoptile, but increased it in the first leaf. A high correlation existed between the content of soluble sugars and invertase activity in both organs. During 1 h incubation in the light, ca 2 µmol of soluble sugars per seedling was lost from the coleoptile and gained in the first leaf. Light promoted sugar exudation from the excised coleoptile, but the amount of soluble sugar exuded represented 5% of sugar loss from the coleoptile in intact seedlings. These results indicate that in maize seedlings white light controls the growth rate of the coleoptile and the first leaf through the osmotic concentration. Light may have an osmoregulatory function in the control of sugar distribution between the coleoptile and the first leaf by regulating the activity of wall-bound invertase.


Neonatal anatomical correction of transposition of the great arteries: non-invasive assessment of haemodynamic function up to four years after operation.
Intracardiac and great artery blood flow velocities were recorded by pulsed and continuous wave Doppler ultrasound in 18 children aged between eight months and four years (mean 25 months) who had undergone anatomical correction of transposition of the great arteries in the first month of life. Postoperative peak flow velocities across the mitral valve and in the ascending aorta were not significantly different from those in an age matched control population, but tricuspid flow velocities were higher than normal. Aortic regurgitation was detected in only one of the eighteen patients, a markedly lower frequency than that reported after two stage anatomical correction. Peak velocities in the pulmonary artery were higher than normal, and in most cases there was some degree of stenosis of the pulmonary artery at the site of anastomosis.


Physical interaction and mutual transrepression between CCAAT/enhancer-binding protein beta and the p53 tumor suppressor.
The tumor suppressor protein p53 is not only involved in defending cells against genotoxic insults but is also implicated in differentiation processes, a function that it shares with the CCAAT/enhancer-binding protein beta (C/EBPbeta). We previously reported an up-regulation of both factors in the cycle-dependent differentiation process of human endometrial stromal cells, termed decidualization. C/EBPbeta-mediated activation of a decidualization marker, the decidual prolactin promoter, was antagonized by p53. Here we report that C/EBPbeta in turn represses the transcriptional activity of p53. Competition for limiting amounts of coactivator CREB-binding protein/p300 was ruled out as the underlying mechanism of transrepression. Physical interaction between p53 and C/EBPbeta was demonstrated in vitro and in vivo and shown to depend on the C-terminal domains of both proteins. In gel shift experiments, C/EBPbeta reduced complex formation between p53 and its response element. Conversely, p53 strongly inhibited binding of endogenous C/EBPbeta from endometrial stromal cells to the C/EBP-responsive region in the decidual prolactin promoter. The observed negative cross-talk between p53 and C/EBPbeta is likely to impact expression of their respective target genes.


Luteimonas soli sp. nov., isolated from farmland soil.
A yellow-pigmented bacterial strain, designated Y2T, was isolated from farmland soil in Bengbu, Anhui province, China. Cells of strain Y2T were Gram-stain-negative, strictly aerobic, non-motile and rod-shaped. Strain Y2T grew optimally at pH 7.0, 30 °C and in the presence of 2 % (w/v) NaCl. The DNA G+C content was 68.9 mol%. The major fatty acids (>5 %) were iso-C15 : 0, iso-C17 : 0, summed feature 9 (C16 : 0 10-methyl and/or iso-C17 : 1ω9c), iso-C11 : 0 3-OH and iso-C11 : 0. The major respiratory quinone was ubiquinone-8 (Q-8), and the major polar lipids were phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. Phylogenetic analysis of the 16S rRNA gene sequences showed that strain Y2T was most closely related to Luteimonas mephitis B1953/27.1T (99.1 % 16S rRNA gene sequence similarity), followed by Luteimonas lutimaris G3T (98.6 %), Luteimonas abyssi XH031T (96.2 %) and Luteimonas aquatica RIB1-20T (96.0 %). Strain Y2T exhibited low DNA-DNA relatedness with Luteimonas mephitis B1953/27.1T (43.6 ± 0.5 %) and Luteimonas lutimaris G3T (43.9 ± 2.1 %). On the basis of phenotypic, genotypic and phylogenetic evidence, strain Y2T represents a novel species of the genus Luteimonas, for which the name Luteimonas soli sp. nov. is proposed. The type strain is Y2T ( = ACCC 19799T = KCTC 42441T).


Systematic reviews of infectious diseases.
The World Wide Web provides ready access to a wealth of information on infectious diseases topics. Systematic reviews and practice guidelines help to focus that evidence with in-depth literature analysis of a specific question. These reviews are typically rigidly structured, often periodically updated, and include critical evaluation of available data. In this article, Web sites of organizations that publish systematic reviews and practice guidelines for infectious diseases are identified and reviewed with regard to ease of use, comprehensiveness, quality of information, and cost. Examples of information available in databases of practice guidelines and systematic reviews are provided. A hypothetical case is used to illustrate the use of electronic resources in evidence-based infectious diseases practice.


[Topiramate and pregnancy. Neonate with bone anomalies].
Topiramate is a new generation, antiepileptic drug used for the treatment of persistent partial crises. To date no specific teratogenic effects have been reported in humans, but they have appeared in experimental animals. We present the case of a neonate whose mother suffered from partial epilepsy, which was treated with topiramate throughout pregnancy at doses of 300 mg per day. When the child was born agenesis of the right thumb, hypoplasia of the left thumb, and syndactylia of the second and third toes of the foot with agnesis of some phalanges, and hypoplasia of the right orbicular muscle in the mouth were observed. No etiologic cause was found. We discuss whether there could have been a causal relationship with topiramate monotherapy.


[Not Available].
It is the aim of the present dissertation to analyze the cultural and pharmaceutical history of the medicinal plant Ruta graveolens L. (rue) beginning in antiquity until the invention of letter-press printing (see Kap. 1). In contrast to other historical works which emphasize descriptive aspects or the transmission of the sources, an analysis of the content of the sources within their contemporaneous context was attempted here. The sources come from different scientific fields and were collected in numerous European and American (USA) libraries (See Kap. 18.104.22.168). In order to evaluate the medicinal uses of the plant as mentioned in the sources, basic knowledge in pharmaceutical botany is necessary. This qualification makes it possible to correlate the traditional indications of ruta with the current knowledge on the constituents of the plant. 1. Dioskurides' Materia medica presents a chapter on rue. The properties of ruta mentioned there can in part be explained by pharmacologically tested constituents (see Kap. 2). 2. Knowledge on rue was passed on to the middle ages by "Rezeptarien", "Antidotarien", and a latinized Dioskurides. Monasteries become important in medicine (see Kap. 3). 3. Garden history demonstrates that rue was actually cultivated and used for healing, seasoning, coloring, and magic (see Kap. 4). 4. Rue became part of the practically oriented textbooks of the Medical School of Salerno (10th-13th century). Thus, the plant is mentioned (see Kap. 5) and illustrated (see Kap. 6.1-6.3) in mnuscripts of this time period. These manuscripts are the predecessors of the modern pharmacopoeia, drug monograph and popular literature on health. 5. Rue is rarely shown in arts. The interpretation of illustrations of rue depends on some of its uses as a medicinal plant (antidote, eye medication, protection from evil; see Kap. 6.4). These results expand our image of ruta. We have shown here, that questions that lie in the fields of both humanities and natural sciences can be well addressed with an interdisciplinary approach.


Social olfaction in male brown lemmings (Lemmus sibiricus = trimucronatus) and collared lemmings (Dicrostonyx groenlandicus): II. Discrimination of mated and unmated females.
When tested in a Y-maze olfactometer, male brown and collared lemmings (Lemmus sibiricus = trimucronatus and Dicrostonyx groenlandicus) preferred the odor of unmated receptive females to the odor of females with which they had just copulated. Similarly, sexually satiated males preferred the odor of an unmated receptive female to that of a strange female that had recently copulated with another male. Sexually experienced males without recent copulatory experience also demonstrated this preference, but sexually naive males did not. Sexually satiated collared lemmings preferred the odor of bedding from a novel estrous female to bedding from the female with which they had just copulated even when the bedding was collected before mating occurred. These results suggest that discrimination between prior mates and unmated females may be based on individual recognition as well as recognition of subclasses of females (i.e., mated vs. unmated, familiar vs. unfamiliar).


Examination of the envelope antigen K1 in Yersinia enterocolitica which was identified as fimbriae.
The envelope antigen K1 found in the majority of Yersinia enterocolica (Y. ent.) strains belonging to the O group 10 as described by WAUTERS, was re-examined under the electron microscope, and identified as being fimbriae. These fimbriae envelop the bacterial cell with a dense fringe. Single filaments show a width of 2.5 to 1.7 nm whilst their length is variable, often many times the size of the bacterial cell. Fimbriated Y. ent. cultures do not form pellicle, and the haemagglutination test is negative. They are O and fimbriae agglutinable. Test results for the acknowledged 3 antigenic differences, i.e. agglutinability, agglutinin-binding capacity and agglutinogenic capacity showed that: 1. there is a certain thermo-lability as to the agglutinability. For its total suppression, half-an-hour's boiling at 120 degrees C of the culture fim+ is necessary. Chemical treatment of such a culture hardly impairs the agglutinability of fimbriae. 2. the agglutinin-binding (= absorbing) capacity of the fimbrial antigen is little affected by continuous heating, even up to 3 hrs. However, at least half-an-hour's boiling at 120 degrees C or alternatively chemical treatment with 50% alcohol or nHC1 practically destroys this ability. 3. The heating process has a significant and progressive effect on the agglutinogenic capacity of the Y. ent. fimbriae which is destroyed irrevocably after 30 mins. boiling at 120 degrees C. Chemical treatment hardly affects this character. It is recommended to use a formalised culture Y. ent. fim+ for the preparation of a specific Y. ent. fimbrial serum. For the elimination of O antibodies, this antiserum should be absorbed with a strain fim- of the same O group. Provided the strain was incubated at 37 degrees C, no H absorption is required, because Y. ent. strains do not form flagella at that incubation temperature.


Fosmidomycin resistance in adenylate cyclase deficient (cya) mutants of Escherichia coli.
Adenylate cyclase deficient (cya) mutants of E. coli K-12 were found to be resistant to fosmidomycin, a specific inhibitor of the non-mevalonate pathway, just like to fosfomycin. E. coli glpT mutants were resistant to fosfomycin and also to fosmidomycin. This fact shows that fosmidomycin was transported inside via the glycerol-3-phosphate transporter, GlpT. DNA micro-array analysis showed that the transcription of glpT and other genes concerning glycerol utilization were highly dependent on the presence of cAMP.


Comparison of pancreas juice proteins from cancer versus pancreatitis using quantitative proteomic analysis.
Pancreatitis is an inflammatory condition of the pancreas. However, it often shares many molecular features with pancreatic cancer. Biomarkers present in pancreatic cancer frequently occur in the setting of pancreatitis. The efforts to develop diagnostic biomarkers for pancreatic cancer have thus been complicated by the false-positive involvement of pancreatitis. In an attempt to develop protein biomarkers for pancreatic cancer, we previously use quantitative proteomics to identify and quantify the proteins from pancreatic cancer juice. Pancreatic juice is a rich source of proteins that are shed by the pancreatic ductal cells. In this study, we used a similar approach to identify and quantify proteins from pancreatitis juice. In total, 72 proteins were identified and quantified in the comparison of pancreatic juice from pancreatitis patients versus pooled normal control juice. Nineteen of the juice proteins were overexpressed, and 8 were underexpressed in pancreatitis juice by at least 2-fold compared with normal pancreatic juice. Of these 27 differentially expressed proteins in pancreatitis, 9 proteins were also differentially expressed in the pancreatic juice from pancreatic cancer patient. Identification of these differentially expressed proteins from pancreatitis juice provides useful information for future study of specific pancreatitis-associated proteins and to eliminate potential false-positive biomarkers for pancreatic cancer.


Development of a tumor-selective approach to treat metastatic cancer.
Patients diagnosed with metastatic cancer have almost uniformly poor prognoses. The treatments available for patients with disseminated disease are usually not curative and have side effects that limit the therapy that can be given. A treatment that is selectively toxic to tumors would maximize the beneficial effects of therapy and minimize side effects, potentially enabling effective treatment to be administered. We postulated that the tumor-tropic property of stem cells or progenitor cells could be exploited to selectively deliver a therapeutic gene to metastatic solid tumors, and that expression of an appropriate transgene at tumor loci might mediate cures of metastatic disease. To test this hypothesis, we injected HB1.F3.C1 cells transduced to express an enzyme that efficiently activates the anti-cancer prodrug CPT-11 intravenously into mice bearing disseminated neuroblastoma tumors. The HB1.F3.C1 cells migrated selectively to tumor sites regardless of the size or anatomical location of the tumors. Mice were then treated systemically with CPT-11, and the efficacy of treatment was monitored. Mice treated with the combination of HB1.F3.C1 cells expressing the CPT-11-activating enzyme and this prodrug produced tumor-free survival of 100% of the mice for >6 months (P<0.001 compared to control groups). The novel and significant finding of this study is that it may be possible to exploit the tumor-tropic property of stem or progenitor cells to mediate effective, tumor-selective therapy for metastatic tumors, for which no tolerated curative treatments are currently available.


The serum concentrations of zinc, copper and selenium in children with inflammatory bowel disease.
To estimate the levels of trace elements in children with inflammatory bowel disease (IBD). Prospective cross sectional study. Gastroentrology Unit, Great Ormond Street Children's Hospital, London, UK. Seventy four children with inflammatory bowel disease confirmed endoscopically and histologically (38 ulcerative colitis and 36 Crohn's disease) and 40 age matched controls had their serum zinc, copper and selenium assayed at presentation. Serum levels of zinc, copper and selenium in children with inflammatory bowel disease and age matched controls. Seventy four children with inflammatory bowel disease confirmed endoscopically and histologically (38 ulcerative colitis and 36 Crohn's disease) and 40 age matched controls had their serum zinc, copper and selenium assayed at presentation. The serum levels of selenium were significantly lower in cases of ulcerative colitis 0.63 +/- 0.25 mmol/L and Crohn's disease 0.69 +/- 0.25 mmol/L than in the controls 0.84 +/- 0.13 mmol/L (p < 0.01). The serum copper concentration was significantly higher in those with Crohn's disease 22.7 +/- 5.49 mmol/L than in those with ulcerative colitis 17.6 +/- 5.15 mmol/L and the controls 20.76 +/- 4.06 mmol/L (p < 0.01). Children with Crohn's disease had a lower serum zinc level 11.01 +/- 2.49 mmol/L compared to the control level of 13.6 +/- 1.63 mmol/L (p < 0.05), but the levels were not significantly different in the controls and ulcerative colitis (p > 0.10). Children with inflammatory bowel disease have abnormal levels of the trace elements which is more marked in those with Crohn's disease. Children with IBD in this study show abnormalities of the trace elements which is probably a result of inadequate intake, reduced absorption, increased intestinal loss due to impairment of the absorption as a result of the inflammatory process. The reduced free radical scavenging action of zinc and selenium as a result of their deficiency may contribute to the continued inflammatory process of IBD. The recommendation of the supplementation of these trace elements in IBD is further supported by the findings of this study in children.


Biocompatible nanoparticles intercalated with anticancer drug for target delivery: pharmacokinetic and biodistribution study.
We have developed new hybrid systems consisting of anticancer drugs such as methotrexate (MTX) or 5-fluorouracil (5-FU) and two-dimensional inorganic delivery carrier like layered double hydroxide (LDH). Such an inorganic vector with biocompatible metal ions can be used to overcome toxicity, immunogenecity and poor integration capacity, which are critical problems caused by conventional viral vectors, cationic liposomes and polymers. Moreover, the intercellular mechanism of LDH nanoparticles is primarily related to clathrin-mediated endocytosis, resultihg in effective delivery and eventually enhancing drug efficacy. In this report, the effect of LDH intercalated with 5-Fu (5-Fu-LDH) was evaluated in whole animal by studying pharmacokinetic behavior and tissue distribution. The results showed that 5-Fu-LDH exhibited favorable blood clearance profiles compared to free 5-Fu, such as sustained drug release, prolonged drug half-life, and increased drug accumulation in target tumor tissue. Furthermore, LDH nanoparticles were rapidly excreted from the body and not accumulated in the organs after administration as 5-Fu-LDH. Therefore, the hybrid system can be promising anticancer chemotherapy agent for tumor targeting with biocompatibility.


Effects of Low-Protein Diets Supplemented with Branched-Chain Amino Acid on Lipid Metabolism in White Adipose Tissue of Piglets.
This study evaluated the effect of branched-chain amino acid (BCAA) supplementation in low-protein diets on lipid metabolism in dorsal subcutaneous adipose (DSA), abdominal subcutaneous adipose (ASA), and perirenal adipose (PRA) tissues. A total of 24 piglets were allotted to four treatments, and each group was fed the adequate protein (AP) diet, low-protein (LP) diet, LP diet supplemented with BCAA (LP + B), or LP diet supplemented with twice BCAA (LP + 2B). Serum concentrations of leptin in the BCAA-supplemented treatments were higher (P < 0.01) than in the AP treatment, but lower (P < 0.01) than in the LP treatment. In DSA, the mRNA and protein levels for lipogenic-related genes were highest in the LP treatment and lowest in the LP + 2B treatment. However, in ASA and PRA, the expression levels for those genes were significantly elevated in the LP + 2B treatment. In conclusion, BCAA supplementation could alter the body fat condition, and this effect was likely modulated by the expression of lipid metabolic regulators in DSA, ASA, and PRA in a depot-specific manner.


Proteome Multimarker Panel With Multiple Reaction Monitoring-Mass Spectrometry for Early Detection of Hepatocellular Carcinoma.
There is an urgent need for new biomarkers that address the shortcomings of current screening methods which fail to detect a large proportion of cases with hepatocellular carcinoma (HCC) at early stage. To develop a robust, multiple-biomarker panel based on multiple reaction monitoring-mass spectrometry with high performance in detecting early-stage HCC within at-risk populations. In the discovery set, 150 samples were analyzed to identify candidate biomarkers. The resulting list of candidates was tested in the training set (713 samples) to establish a multimarker panel, which was evaluated in the validation set (305 samples). We identified 385 serum HCC biomarker candidates in the discovery set and developed a multimarker panel consisting of 28 peptides that best differentiated HCC from controls. The area under the receiver operating characteristic curve of multimarker panel was significantly higher than alpha-fetoprotein (AFP) in the training (0.976 vs. 0.804; P < 0.001) and validation (0.898 vs. 0.778; P < 0.001) sets. In the validation set, this multimarker panel, compared with AFP, showed significantly greater sensitivity (81.1% vs. 26.8%; P < 0.001) and lower specificity (84.8% vs. 98.8%; P < 0.001) in detecting HCC cases. Combining AFP with the multimarker panel did not significantly improve the area under the receiver operating characteristic curve compared with the panel alone in the training (0.981 vs. 0.976; P = 0.37) and validation set (0.906 vs. 0.898; P = 0.75). Conclusion: The multiple reaction monitoring-mass spectrometry multimarker panel consisting of 28 peptides discriminates HCC cases from at-risk controls with high performance and may have potential for clinical application in HCC surveillance.


Modelling the effectiveness and risks of vaccination strategies to control classical swine fever epidemics.
In a recent update of the Dutch contingency plan for controlling outbreaks of classical swine fever (CSF), emergency vaccination is preferred to large-scale pre-emptive culling. This policy change raised two questions: can emergency vaccination be as effective as pre-emptive culling, and what are the implications for showing freedom of infection? Here, we integrate quantitative information available on CSF virus transmission and vaccination effects into a stochastic mathematical model that describes the transmission dynamics at the level of animals, farms and livestock areas. This multilevel approach connects individual-level interventions to large-scale effects. Using this model, we compare the performance of five different control strategies applied to hypothetical CSF epidemics in The Netherlands and, for each of these strategies, we study the properties of three different screening scenarios to show freedom of infection. We find that vaccination in a ring of 2 km radius around a detected infection source is as effective as ring culling in a 1 km radius. Feasible screening scenarios, adapted to the use of emergency vaccination, can reduce the enhanced risks of (initially) undetected farm outbreaks by targeting vaccinated farms. Altogether, our results suggest that emergency vaccination against CSF can be equally effective and safe as pre-emptive culling.


Does gender-specific substance abuse treatment for women promote continuity of care?
Research has stressed the value of providing specialized services to women and suggests the importance of treatment duration. This quasi-experimental retrospective study reports on the continuity of care for women with children who were admitted to long-term residential substance abuse treatment. Women were admitted to 7 agencies offering specialized, women's only treatment (SP, n = 747) or to 9 agencies that provided standard mixed-gender treatment (ST, n = 823). Client and treatment data were gathered from administrative sources. We hypothesized that women in specialized treatment would demonstrate higher continuing care rates after controlling for treatment completion and length of stay. Women in SP programs (37%) were more likely than those in ST programs (14%) to continue care. Multivariate analyses revealed that SP clients who completed treatment with longer stays were most likely to continue care. The findings show that specialized treatment for women promotes continuing care and demonstrate the importance of treatment completion.


Comparative studies on conventional and microwave assisted synthesis of benzimidazole and their 2-substituted derivative with the effect of salt form of reactant.
Benzimidazole and their derivative were reported to have wide biological activities and were synthesized by using different solvents and ring closing agents. The present work deals with the comparative synthesis of 2-alkyl and aryl substituted benzimidazole derivative in the presence of polyphosphoric acid through microwave and conventional methods and also studied the effect of salt form of reactant for completion of the reaction. The 2-substituted aryl and alkyl benzimidazole derivative were synthesized via microwave and was observed to be more beneficial, in respect of yield (increases up to 10 to 50%) and time (96 to 98% was reduced) than conventional method of synthesis. This study was concluded that the salt form of reactant (o-phenylenediamine dihydrochloride) gave reduced colour impurities, homogenous mixing and reduced time for completion of reaction.


Intracellular characterization of DDX39, a novel growth-associated RNA helicase.
DDX39 belongs to the DEAD box RNA helicase family and is overexpressed in human lung squamous cell carcinoma. In this study, in order to seek the biological relevance of DDX39, we conducted its intracellular characterization. When expressed in 293 cells, DDX39 undergoes heavy ubiquitylation and the stability of DDX39 is regulated via a ubiqutin-proteasome pathway. DDX39 tethers ALY, an essential mRNA export factor, in vivo, confirming the role of DDX39 in the RNA splicing/export process. Co-immunoprecipitation and mass spectrometry analyses detected CIP29, a recently discovered growth and cell cycle-related factor, as a main DDX39-interacting protein. CIP29 binds RNA on its own and enhances RNA unwinding activity of DDX39. Thus, CIP29 physically and functionally associates with DDX39, suggesting their cooperation in the RNA metabolism. Extension of the search for the protein-protein interactions encompassing DDX39 identified FUS/TLS, a nucleic acid binding protein participating in both transcription and splicing, as a CIP29-interacting protein. The connections comprising ALY, DDX39, CIP29 and FUS/TLS may be an integral part of transcription, splicing and RNA export. We simultaneously examined the properties of DDX39-S, a C-terminally truncated variant of DDX39 stemmed from alternative splicing, to understand its biological significance.


Thermogenic effects of the antiglucocorticoid RU-486 in the rat: involvement of corticotropin-releasing factor and sympathetic activation of brown adipose tissue.
Acute injection (sc) of the antiglucocorticoid RU-486 (5-10 mg/kg) stimulated oxygen consumption (VO2) and brown adipose tissue (BAT) activity (mitochondrial GDP binding) in the rat. A peak effect was seen 60-80 min after injection. The rise in VO2 was prevented by prior injection of the beta-adrenergic antagonist propranolol, and the effect on BAT was abolished by surgical denervation of the sympathetic supply to the tissue. Central injection (cerebroventricular) of a much lower dose (3-8 micrograms/kg) of RU-486 also stimulated VO2, and this effect was inhibited by a CRF receptor antagonist [alpha-helical CRF-(9-41)]. Peripheral injection of RU-486 also elicited acute thermogenic responses in older (greater than 12 months) rats and in genetically obese (Zucker) rats. In lean animals, daily injection of RU-486 inhibited weight gain and stimulated BAT without affecting food intake. The thermogenic effects of RU-486 appear to be due to central stimulation of sympathetic outflow and may involve CRF release. The data support previous studies on the effects of adrenalectomy and CRF on thermogenesis in the rat.


Assessment of diastolic function by cardiovascular magnetic resonance.
The assessment of diastolic heart function has been hampered by multiple difficulties. Cardiovascular magnetic resonance (CMR) is a new, noninvasive technique to study cardiac function. The literature on CMR for the analysis of diastolic function and its clinical applications is extensively reviewed. Analysis of ventricular filling velocity and volume flow, volumetric assessment of ventricular chamber volume, analysis of 3-dimensional myocardial strains, and assessment of myocardial energy content are numerous validated applications of CMR. With the advent of real-time imaging and automated analysis of myocardial strains, CMR tagging is a promising method to assess regional diastolic function. Today, many CMR techniques are leaving the experimental or developmental stage rapidly and becoming clinically available for the evaluation of diastolic function in heart disease. CMR is emerging as a highly accurate and reproducible noninvasive 3-dimensional technique for the assessment of diastolic function.


Smoking, acute mountain sickness and altitude acclimatisation: a cohort study.
The relationship between cigarette smoking and acute mountain sickness (AMS) is not clear. To assess AMS risk and altitude acclimatisation in relation to smoking. 200 healthy non-smokers and 182 cigarette smokers were recruited from Han lowland workers. These were men without prior altitude exposure, matched for age, health status and occupation, who were transported to an altitude of 4525 masl. AMS, smoking habits, arterial saturation (SpO2), haemoglobin (Hb), lung function and mean pulmonary artery pressure (PAPm) were assessed upon arrival and after 3 and 6 months. Compared with non-smokers, smokers had a lower incidence of AMS and lower AMS scores than non-smokers upon arrival; higher Hb and PAPm associated with lower SpO2 at 3 and 6 months at altitude; and lower forced expiratory volume in 1 s and maximal voluntary ventilation at 3 and 6 months. Smoking slightly decreases the risk of AMS but impairs long-term altitude acclimatisation and lung function during a prolonged stay at high altitude.


A rare case of bilateral malignant otitis externa and osteomyelitis with lower cranial nerve sequelae.
The authors present the case of a 76-year-old male who presented with right-sided recurrent malignant otitis externa (MOE) and skull-base osteomyelitis. His management involved aggressive antimicrobial therapy and multiple hyperbaric oxygen treatments. After resolution of his right-sided infection, the patient returned a short time later with symptoms and findings consistent with new, left-sided MOE with involvement of the left skull-base. With repeat treatment, the patient is now cured of his infection but poses a challenge to the treating team about future management.


Use of Electronic Versus Print Textbooks by Chilean Dental Students: A National Survey.
Electronic textbooks have become available in recent decades as replacements or alternatives for print versions. The aim of this descriptive cross-sectional study was to evaluate the use of electronic versus print textbooks by Chilean dental students. The target population was students from 14 Chilean dental schools. The questionnaire was adapted and translated to Spanish from a previous survey used in a similar study. It consisted of the following variables: preferred type, type used, frequency of use, source, electronic devices used to read, and disposal after use. The use of textbooks was analyzed and compared by gender and course (p≤0.05). The final sample consisted of 3,256 students (21.38±2.5 years of age, 50.8% women). Most of the participants reported using both types of texts, with most (63.9%) preferring print over electronic texts, including significantly more women (p<0.001) and first-year students (p<0.001). Most of the participants (82.8%), more women (p<0.001), and with variations over years of study (p<0.001) reported that they printed out their electronic texts, and 91.8% kept their printed material. Most of the students used electronic books on a daily basis (47.3%) or at least twice a week (30.7%). The main source of electronic textbooks was the Internet (43.8%). A personal computer was the most widely used device for reading electronic texts (95.0%), followed by a cell phone (46.4%) and a tablet (24.5%). Overall, these Chilean dental students preferred print over electronic textbooks, despite having available electronic devices.


The Cervical Arteries: An Anatomical Study with Application to Avoid the Nerve Root and Spinal Cord Blood Supply.
Injury to the vascular supply to the cervical spinal cord can lead to the anterior spinal artery syndrome, which is often associated with transforaminal corticosteroid injections to the cervical foramina. The purpose of this cadaveric study was to examine the morphology of the cervical arteries and to emphasize their clinical importance. Five formalin-fixed human cadavers were used to determine the morphology of the radicular arteries from the vertebral, ascending and deep cervical arteries in the cervical foraminal region. The mean diameter of the vertebral arteries was 5.50 mm. The radicular arteries arose from the vertebral artery originating from its posterior aspect at each level and the C6 radicular artery was larger in diameter than others. Their diameters ranged from 0.75 mm to 1.02 mm. The mean diameter of the ascending cervical artery was 1.5 mm (range 1.21 to 1.80 mm). Its arising spinal branches were located at the C3-4 or C4-5 levels. The diameters of radicular branches arising from the ascending cervical artery ranged from 0.80 mm to 1.40 mm. The mean diameter of the deep cervical artery was 1.71 mm (range 1.3 to 2.1 mm) and was usually slightly larger than the ascending cervical arteries. These deep cervical radicular arteries always entered the C5-6, C6-7 and C7-T1 foramens and those of the radicular branches arising from the deep cervical artery ranged from 0.43 mm to 1.49 mm (mean, 1.08 mm). Understanding the vascular supply to the cervical spinal cord is important for preventing serious complications such as spinal cord ischemia.


Eating disorders in adolescents and young women with spina bifida.
This is the first report of the association of spina bifida and eating disorders. Five patients were diagnosed rather late in the course of their illness. They all had been overweight premorbidly and had been urged to lose weight for years in order to improve their mobility. As they dieted, they experienced their weight loss as a source of power that could somehow compensate for their losses and neurologic limitations. They responded to a multidisciplinary intervention. Clinicians taking care of patients with spina bifida need to be cognizant that they may be at risk of developing an eating disorder. Such awareness should influence the quality of nutritional counseling (prevention aspect) and the clinical assessment of sudden weight loss (early intervention).


[Pediatric traumatic brain injury due to civil gunshot wounds at a General Hospital in Cali, Colombia].
Traumatic brain injury (TBI) due to gunshot-wounds (GSW) is a critical situation in the pediatric population. The aim of this study is to characterize TBI in this population since there are few reports that describe it especially in Colombia where its incidence is high, also to determine which were the main mortality predictor within our population. We conducted a retrospective cross-sectional study in which we reviewed pediatric medical records of patients that had consulted at the Fundacion Valle del Lili pediatric Emergency Room between January of 2011 and December of 2015 because of TBI due to GSW. A descriptive statistical analysis was performed. In our sample of 32 patients the average age was of 13.3 (SD ± 5.4) and with 75% male patients. In our sample the Glasgow Coma Scale (GCS) at entry was less than 8 in 59.38%, a 15.6% needed craniotomy and 81.2% were admitted to the Intensive Care Unit (ICU). Death occurred in 43.75% of cases. The following mortality predictors were obtained: GCS at entry, pupillary exam and light reflexes, ISS, Marshal Score, absence of basal cisterns and presence of subarachnoid hemorrhage in CT scan, and APACHE II. TBI due to GSW is a devastating entity, especially in the pediatric population, they are responsible of high mortality and disability rates. There were no significant findings regarding infection rates and the use of surgery as a preventive method, therefore there's a chance it might not be indicated.


Use of the Lotus Transcatheter Valve to Treat Severe Native Aortic Regurgitation.
Transcatheter aortic valve implantation (TAVI) has become the standard treatment for aortic stenosis in high-risk patients. TAVI for native valve aortic regurgitation is technically more demanding because of a lack of anchoring calcification, a lower index incidence, heterogeneous causes, and larger anatomy. We present 3 cases in which the Lotus TAV was used to treat severe native aortic regurgitation (AR) successfully.


Forest management could counteract distribution retractions forced by climate change.
Climate change is expected to drive the distribution retraction of northern species. However, particularly in regions with a history of intensive exploitation, changes in habitat management could facilitate distribution expansions counter to expectations under climate change. Here, we test the potential for future forest management to facilitate the southward expansion of an old-forest species from the boreal region into the boreo-nemoral region, contrary to expectations under climate change. We used an ensemble of species distribution models based on citizen science data to project the response of Phellinus ferrugineofuscus, a red-listed old-growth indicator, wood-decaying fungus, to six forest management and climate change scenarios. We projected change in habitat suitability across the boreal and boreo-nemoral regions of Sweden for the period 2020-2100. Scenarios varied in the proportion of forest set aside from production, the level of timber extraction, and the magnitude of climate change. Habitat suitabilities for the study species were projected to show larger relative increases over time in the boreo-nemoral region compared to the boreal region, under all scenarios. By 2100, mean suitabilities in set-aside forest in the boreo-nemoral region were similar to the suitabilities projected for set-aside forest in the boreal region in 2020, suggesting that occurrence in the boreo-nemoral region could be increased. However, across all scenarios, consistently higher projected suitabilities in set-aside forest in the boreal region indicated that the boreal region remained the species stronghold. Furthermore, negative effects of climate change were evident in the boreal region, and projections suggested that climatic changes may eventually counteract the positive effects of forest management in the boreo-nemoral region. Our results suggest that the current rarity of this old-growth indicator species in the boreo-nemoral region may be due to the history of intensive forestry. Forest management therefore has the potential to compensate for the negative effects of climate change. However, increased occurrence at the southern range edge would depend on the dispersal and colonization ability of the species. An increase in the amount of set-aside forest across both the boreal and boreo-nemoral regions is therefore likely to be required to prevent the decline of old-forest species under climate change.


Peptide fusion inhibitors targeting the HIV-1 gp41: a patent review (2009 - 2014).
As the first peptide HIV fusion inhibitor targeting gp41, enfuvirtide (T20) was approved by the US FDA in 2003 as a salvage therapy for HIV/AIDS patients who failed to respond to the then existing antiretroviral therapeutics. However, its clinical application is limited by its relatively low potency, low genetic barrier to drug resistance and short half-life. Therefore, it is essential to develop new peptide HIV fusion inhibitors with improved antiviral efficacy, drug-resistance profile and pharmaceutical properties. In this paper, we reviewed the patents, patent applications and related research articles for the development of new peptide fusion inhibitors targeting the HIV-1 gp41 published between 2009 and 2014. To improve enfuvirtide's anti-HIV efficacy, drug-resistance profile, half-life and pharmaceutical properties, the best approaches include the addition of the pocket-binding domain (PBD) to the N-terminus of T20 and linking of the M-T hook to the N-terminus of PBD, as well as conjugation of cholesterol, serum albumin-binding motif or gp120-binding fragment with a PBD-containing C-terminal heptad repeat-peptide. Therefore, sifuvirtide from Tianjin FusoGen Pharmaceuticals, Inc., albuvirtide from Frontier Biotechnologies Co., Ltd., cholesterol-conjugated HIV fusion inhibitor from the Institute of Pathogen Biology, Chinese Academy of Medical Science, 2DLT, a bivalent HIV fusion inhibitor/inactivator, and an enfuvirtide/sifuvirtide combination regimen from the New York Blood Center may all have potential as next-generation HIV fusion inhibitors targeting gp41 for clinical use.


[Sepsis in HIV-positive patients--own observation].
In the period of 1988-2001 (June) 24 HIV-positive patients with symptoms of sepsis were observed. Most of them (17 persons) were intravenous drug addicts, six patients were infected HIV trough sexual contact and one person-via blood transfusion. There were 26 cases analyzed (one of the patients went trough three episodes of sepsis). Bacterial sepsis dominated (22 cases). In three patients fungoid etiology was diagnosed, and one case was of mixed character. The highest risk factors of sepsis were: intravenous drug addiction and advanced stage of HIV infection.


Simulation of Laser-assisted Directed Energy Deposition of Aluminum Powder: Prediction of Geometry and Temperature Evolution.
One of the main current challenges in the field of additive manufacturing and directed energy deposition of metals, is the need for simulation tools to prevent or reduce the need to adopt a trial-and-error approach to find the optimum processing conditions. A valuable help is offered by numerical simulation, although setting-up and validating a reliable model is challenging, due to many issues related to the laser source, the interaction with the feeding metal, the evolution of the material properties and the boundary conditions. Indeed, many attempts have been reported in the literature, although some issues are usually simplified or neglected. Therefore, this paper is aimed at building a comprehensive numerical model for the process of laser-assisted deposition. Namely: the geometry of the deposited metal is investigated in advance and the most effective reference shape is found to feed the simulation as a function of the governing factors for single- and multi-track, multi-layer deposition; then, a non-stationary thermal model is proposed and the underlying hypotheses to simulate the addition of metal are discussed step-by-step. Validation is eventually conducted, based on experimental evidence. Aluminum alloy 2024 is chosen as feeding metal and substrate.


Healthy shopper? Blood pressure testing in a shopping centre Pop-Up in England.
Improving detection of elevated blood pressure (BP) remains a public health need. We present results from a Pop-Up health check stationed in shopping centres in England. We hypothesise the rate of case detection is related to measurable 'unhealthiness' of the shopping centres. A Pop-Up health check was sited in four and three shopping centres sampled from the top ten unhealthiest and top 15 healthiest shopping regions respectively, following a report ranking towns/cities based on their unhealthy and healthy retail outlets. On one day in each shopping centre, people were approached and consented to BP testing. Outcome measure was people flagged with BP ≥ 140/90 mmHg (cases). We detected 45 (22.6%) and 20 (13.1%) cases from testing 199 and 152 adults in the unhealthy and healthy locations respectively (relative risk 1.72; 95% confidence interval: 1.06 to 2.78). A measure of unhealthy retail outlets (e.g. fast-food outlets) within each shopping centre was associated with detection rate (R2 = 0.61; p = 0.04). An association exists between cases of suspect hypertension found in a health check Pop-Up and measured 'unhealthiness' of the shopping centre site. Results hint at strategies for public testing of BP, potentially in the context of reducing health inequalities.


Community pharmacy practice related to the COVID-19 pandemic: barriers and facilitators.
Community pharmacies provide an important healthcare service. Their significant value has been further highlighted during the COVID-19 pandemic crisis. To identify and categorize potential barriers and facilitators to the role of community pharmacists during the pandemic and their association with demographic factors. A cross-sectional survey of community pharmacists was conducted using a self-administered questionnaire during April 2020 across all regions of Egypt. Respondents (n = 1018; 98.4% response rate) revealed practical and psychological barriers, including inadequate levels of pandemic preparedness (mean 61.43%; ±SD 0.47), inadequate working environments (mean 56.23%; ±SD 0.49) and uncooperative behaviour from stakeholders (mean 65.3%; ±SD 0.47).The majority of respondents emphasized the universal, region-independent necessity for facilitators, including the availability of timely (94.9%) guidance (97.4%) published by the Egyptian healthcare authority (94.6%), in electronic format (82.1%), through smartphone application (80.0%) and the provision of a dedicated telephone hotline (89.5%). Furthermore, authorities must use the media to manage public perceptions (97.2%) and increase public trust (94.8%) towards the pharmacist. The barriers and facilitators identified herein could improve service provision in an integrated manner by overcoming the reported inadequate level of preparedness (barrier) through the provision of electronic guidance (facilitator), and the use of the media in managing public perceptions and trust (facilitators) to reduce the panic that negatively affects the working environment (barrier) for pharmacy staff. The varied level of healthcare authority cooperation reported in many regions requires further investigation.


Studies on Isotope Ratio Measurement of Cl by Inductively Coupled Plasma Triple-quad Mass Spectrometry.
Fundamental studies on isotope ratio measurement of Cl were carried out using inductively coupled plasma triple-quad mass spectrometry (ICP-MS/MS) and the analytical performance obtained was compared to that obtained by ICP sector field mass spectrometer (ICP-SFMS). Though the polyatomic ion interferences of 16O18O1H and 36Ar1H with respect to 35Cl and 37Cl, respectively, made a negative effect on the accuracy and the precision for isotope ratio measurements of Cl, the ICP-SFMS could eliminate these interferences by medium mass resolution mode (m/Δm = 4000) and achieved the isotope ratio measurements with 0.2 - 0.5% of relative standard deviation (RSD) at the concentrations of Cl from 1 to 10 mg kg-1. In the case of ICP-MS/MS, both the single-MS mode without collision reaction gas and the MS/MS mode with collision reaction gases such as oxygen (O2) and hydrogen (H2) were examined and compared their analytical sensitivities as well as the precisions of isotope ratio measurement of Cl. The precisions of Cl isotope ratio measurements were 3 - 14% of RSD at the concentrations of Cl from 5 to 100 mg kg-1, when single-MS mode was carried out, even though the similar isotope ratios of 35Cl/37Cl could be obtained. In the case of O2 gas for MS/MS mode with mass-shift method, precisions of 0.3 - 2% of RSD were obtained at the concentration range of 1 - 100 mg kg-1. In the case of H2 gas, similar sensitivities as those obtained by ICP-SFMS and the precisions of 0.2 - 0.5% of RSD at the concentration range of 1 - 10 mg kg-1 were obtained. From these results, it was evaluated that the ICP-MS/MS in MS/MS mode with collision reaction gas could be used for Cl isotope ratio measurements for such studies as stable isotope tracers, isotope abundance measurements in nuclear chemistry and accurate determinations by isotope dilution mass spectrometry.


Regioselective bond cleavage in the dissociative electron transfer to benzyl thiocyanates.
The electrochemical reduction of benzyl thiocyanate and p-nitrobenzyl thiocyanate was investigated in acetonitrile at an inert electrode. These two compounds reveal a change in the reductive cleavage mechanism, and more interestingly, they show a clear-cut example of a regioselective bond dissociation. Both phenomena may be understood on the basis of the dissociative ET theory and its extension to the formation/dissociation reactions of radical ions. While the effect of the standard oxidation potential of the leaving group seems to be predominant in understanding the change in the ET mechanism by changing the driving force, the regioselective cleavage is dictated by changes in the intrinsic barrier related to the nature of the substituent on the aryl moiety.


Occlusal contact wear of prosthodontic materials. An in vivo study.
The wear of gold, porcelain, and heat- and light-cured resins in occlusal contact with resin and porcelain teeth has been studied in vivo. Both weighing of removable segments of fixed partial prostheses and a replica technique allowing scanning electron microscope observations of the worn surfaces were used. The results showed that all materials had the greatest loss of substance when the opposing teeth were of porcelain. The heat-cured, unfilled resin was the least wear-resistant material, followed by light-cured resin, porcelain, and gold. The heat-cured resin showed a combined tribochemical and fatigue type of wear. The light-cured resin and porcelain showed mainly a fatigue type of wear, whereas gold showed a combined abrasive and fatigue type of wear.


The metalloproteinase ADAM-12 regulates bronchial epithelial cell proliferation and apoptosis.
The ADAMs (a disintegrin and metalloproteinase) enzymes compose a family of membrane-bound proteins characterized by their multi-domain structure and ADAM-12 expression is elevated in human non-small cell lung cancers. The aim of this study was to investigate the roles played by ADAM-12 in critical steps of bronchial cell transformation during carcinogenesis. To assess the role of ADAM-12 in tumorigenicity, BEAS-2B cells were transfected with a plasmid encoding human full-length ADAM-12 cDNA, and then the effects of ADAM-12 overexpression on cell behaviour were explored. Treatment of clones with heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) neutralizing antibodies as well as an EGFR inhibitor allowed the dissection of mechanisms regulating cell proliferation and apoptosis. Overexpression of ADAM-12 in BEAS-2B cells promoted cell proliferation. ADAM-12 overexpressing clones produced higher quantities of HB-EGF in their culture medium which may rely on membrane-bound HB-EGF shedding by ADAM-12. Targeting HB-EGF activity with a neutralizing antibody abrogated enhanced cell proliferation in the ADAM-12 overexpressing clones. In sharp contrast, targeting of amphiregulin, EGF or transforming growth factor-alpha failed to influence cell proliferation; moreover, ADAM-12 transfectants were resistant to etoposide-induced apoptosis and the use of a neutralizing antibody against HB-EGF activity restored rates of apoptosis to be similar to controls. ADAM-12 contributes to enhancing HB-EGF shedding from plasma membranes leading to increased cell proliferation and reduced apoptosis in this bronchial epithelial cell line.


Susceptibility genes for asthma and allergy: hits and questions.
Allergy and asthma are closely related conditions which result from a complex interaction between several genetic and environmental factors. On the basis of familial linkage analysis data from different populations, some chromosomal regions containing a series of susceptibility loci have been identified. To date, genome-wide search studies have reported a group of chromosomal regions which include most likely several candidate genes for asthma and allergy. Some of these genes are excellent candidates, as they are known to modulate the immune response and airways inflammation processes. So, by focusing efforts on the analysis of those chromosomal regions, the characterization of the potentially important genes can be achieved. This will undoubtedly provide a clue for a better understanding of those pathologic components involved in the onset and development of asthma and allergic disorders.


Ultrasound or CT in splenic diseases?
To compare the value of US and CT for the detection and analysis of splenic abnormalities, we reviewed the medical records and imaging findings of 93 patients with 93 proven textural lesions of the spleen, which were visualized by US and/or CT. US revealed the abnormality in 91 (97.8%) patients and CT in 74 (79.6%) patients. US was more sensitive than CT in the detection of malignant lesions, particularly splenic lymphoma, while US and CT were equally effective in benign lesions. In 2 patients, one with sarcoidosis and the other with an acute infarct, the lesion was visualized by CT but not by US. On CT, i.v. injection of contrast material improved both the sensitivity of the examination and the delineation of the abnormality. The echogenicity or the attenuation of the lesions did not usually allow differentiation between the various benign and malignant splenic lesions. US is recommended as the method of choice for splenic imaging.


Titration of antibodies to Paracoccidioides brasiliensis by erythro-immunoassay (EIA).
The erythro-immunoassay, a new serological procedure in which a hybrid antibody conjugate is able to bind erythrocytes, was used for the titration of antibodies against P. brasiliensis in sera from patients with paracoccidioidomycosis. A peptide-polysaccharide and a lyophilized yeast culture filtrate of P. brasiliensis were used as antigens. Absorption with dead Candida albicans whole cells was necessary to decrease cross reactions observed with heterologous sera. Erythro-immunoassay provides a sensitive system for titration of antibodies in paracoccidioidomycosis with serum dilutions up to 1:102000.


The concept of pain in the 17th century.
The 17th century is very important in the history of sensation and pain. Philosophers, as Descartes, Hobbes, Spinoza, defined a new philosophy of science. Physicians of the iatro-chemical school introduced the first principles of biochemistry, tied to the sensations. Physicians of the iatro-mechanical school postulated a really modern concept: the importance of nerve juices in sensibility and pain.


Determinants of needle sharing among intravenous drug users.
Data from 110 IV-drug abusing persons in methadone maintenance were analyzed to determine the correlates of needle sharing. Sharing was directly related to peer group behavior, attitudes conducive to sharing, economic motivation to share, not owning injection equipment, and fatalism about developing AIDS. Sharers were aware of their AIDS risk. Indicated measures to reduce needle sharing would be positive peer support groups to help resist pressures to share, legal and free access to fresh injection equipment, education on the utility of risk reduction, and increased treatment options for IV cocaine users.


A mathematical model of the use of supplemental oxygen to combat surgical site infection.
Infections are a common complication of any surgery, often requiring a recovery period in hospital. Supplemental oxygen therapy administered during and immediately after surgery is thought to enhance the immune response to bacterial contamination. However, aerobic bacteria thrive in oxygen-rich environments, and so it is unclear whether oxygen has a net positive effect on recovery. Here, we develop a mathematical model of post-surgery infection to investigate the efficacy of supplemental oxygen therapy on surgical-site infections. A 4-species, coupled, set of non-linear partial differential equations that describes the space-time dependence of neutrophils, bacteria, chemoattractant and oxygen is developed and analysed to determine its underlying properties. Through numerical solutions, we quantify the efficacy of different supplemental oxygen regimes on the treatment of surgical site infections in wounds of different initial bacterial load. A sensitivity analysis is performed to investigate the robustness of the predictions to changes in the model parameters. The numerical results are in good agreement with analyses of the associated well-mixed model. Our model findings provide insight into how the nature of the contaminant and its initial density influence bacterial infection dynamics in the surgical wound.


Toward an Enhanced Sampling Molecular Dynamics Method for Studying Ligand-Induced Conformational Changes in Proteins.
Current enhanced sampling molecular dynamics methods for studying large conformational changes in proteins suffer from certain limitations. These include, among others, the need for user defined collective variables, the prerequisite of both start and end point structures of the conformational change, and the need for a priori knowledge of the amount by which to boost specific parts of the potential. In this paper, a framework is proposed for a molecular dynamics method for studying ligand-induced conformational changes, in which the nonbonded interactions between the ligand and the protein are used to calculate a biasing force. The method requires only a single input structure, and does not entail the use of collective variables. We provide a proof-of-concept for accelerating conformational changes in three simple test molecules, as well as promising results for two proteins known to undergo domain closure upon ligand binding. For the ribose-binding protein, backbone root-mean-square deviations as low as 0.75 Å compared to the crystal structure of the closed conformation are obtained within 50 ns simulations, whereas no domain closures are observed in unbiased simulations. A skewed closed structure is obtained for the glutamine-binding protein at high bias values, indicating that specific protein-ligand interactions might suppress important protein-protein interactions.


Mobilization of state program resources for a steel mill accident.
Radioactive materials in scrap metal are a serious problem for dealers and processors as well as for state radiation protection programs. Most large dealers and processors have monitoring devices that detect radiation sources at their scale house or feed to the furnaces. For example, in Florida since July 1995, a fiscal year average of 41 such alarms has been reported to the Department of Health's Bureau of Radiation Control. The majority of these alarms involve small amounts of radioactive material, usually naturally occurring radioactive material such as 226Ra, contained in luminous dials or scale associated with mining activities in the state. Occasionally, industrial devices that contain radioactive source material are found. The Bureau classifies these alarms as incidents, and inspectors are dispatched to help identify the source and determine the disposition of the material. On 13 July 2001, a steel mill in north Florida reported that a 137Cs source had been melted in their furnace. This paper describes the actions undertaken by the Bureau in assessing the extent of contamination and subsequent cleanup activities undertaken by the mill.


Work satisfaction, stressors and support experienced by community health nurses.
This study sought to describe the support, work-related stressors, job satisfaction, and burnout experienced by community health nurses (CHNs). Four standardized measures were administered to CHNs in Nova Scotia. One hundred and one CHNs completed the questionnaires. Spouse, family, friends and work associates were the key sources of support for CHNs. The three main sources of stress identified by participants were insufficient time for client care, poor work environment, and difficult clients; perceived lack of support from supervisors and heavy workload were additional sources of stress. The two primary sources of job satisfaction for these CHNs were enjoyment of work and provision of quality care. Strain and illness were the major dimensions of burnout. All five hypotheses were supported; for example, as support increased, burnout and illness decreased and job satisfaction increased. Programs and policies that provide support for Canadian CHNs are timely.


Identifying Structural Determinants of Product Specificity in Leishmania major Farnesyl Diphosphate Synthase.
Farnesyl diphosphate synthase (FPPS) is an isoprenoid chain elongation enzyme that catalyzes the sequential condensation of dimethylallyl diphosphate (C5) with isopentenyl diphosphate (IPP; C5) and the resulting geranyl diphosphate (GPP; C10) with another molecule of IPP, eventually producing farnesyl diphosphate (FPP; C15), which is a precursor for the biosynthesis of a vast majority of isoprenoids. Previous studies of FPPS have highlighted the importance of the structure around the hydrophobic chain elongation path in determining product specificity. To investigate what structural features define the final chain length of the product in FPPS from Leishmania major, we designed and expressed six mutants of LmFPPS by replacing small amino acids around the binding pocket with bulky residues. Using enzymatic assays, binding kinetics, and crystallographic studies, we analyzed the effects of these mutations on the activity and product specificity of FPPS. Our results revealed that replacement of Thr-164 with tryptophan and phenylalanine completely abolished the activity of FPPS. Intriguingly, the T164Y substitution displayed dual product specificity and produced a mixture GPP and FPP as final products, with an activity for FPP synthesis that was lower than that of the wild-type enzyme. These data indicate that Thr-164 is a potential regulator of product specificity.


The accumulation and subcellular distribution of arsenic and antimony in four fern plants.
In the present study, Pteris cretica 'Albo-Lineata' (PC), Pteris fauriei (PF), Humata tyermanii Moore (HT), and Pteris ensiformis Burm (PE), were selected to explore additional plant materials for the phytoremediation of As and Sb co-contamination. To some extent, the addition of As and Sb enhanced the growth of HT, PE, and PF. Conversely, the addition of As and Sb negatively affected the growth of PC and was accompanied with the accumulation of high levels of As and Sb in the roots. The highest concentration of Sb was recorded as 6405 mg kg(-1) in the roots of PC, and that for As was 337 mg kg(-1) in the rhizome of PF. To some degree, As and Sb stimulated the uptake of each other in these ferns. Arsenic was mainly stored in the cytoplasmic supernatant (CS) fraction, followed by the cell wall (CW) fraction. In contrast, Sb was mainly found in the CW fraction and, to a lesser extent, in the CS fraction, suggesting that the cell wall and cytosol play different roles in As and Sb accumulation by fern plants. This study demonstrated that these fern plants show a good application potential in the phytoremediation of As and Sb co-contaminated environments.


An insoluble frontotemporal lobar degeneration-associated TDP-43 C-terminal fragment causes neurodegeneration and hippocampus pathology in transgenic mice.
Frontotemporal dementia (FTD) causes progressive personality, behavior and/or language disturbances and represents the second most common form of dementia under the age of 65. Over half of all FTD cases are classified pathologically as frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein of 43 kDa (TDP-43) pathology (FTLD-TDP). In FTLD-TDP brains, TDP-43 is phosphorylated, C-terminally cleaved, lost from the nucleus and accumulates in the cytoplasm and processes of neurons and glia. However, the contribution of TDP-43 C-terminal fragments (CTFs) to pathogenesis remains poorly understood. Here, we developed transgenic (Tg) mice with forebrain Camk2a-controlled doxycycline-suppressible expression of a TDP-43 CTF (amino acids 208-414, designated 208 TDP-43 CTF), previously identified in FTLD-TDP brains. In these 208 TDP-43 Tg mice, detergent-insoluble 208 TDP-43 CTF was present in a diffuse punctate pattern in neuronal cytoplasm and dendrites without forming large cytoplasmic inclusions. Remarkably, the hippocampus showed progressive neuron loss and astrogliosis in the dentate gyrus (DG). This was accompanied by phosphorylated TDP-43 in the CA1 subfield, and ubiquitin and mitochondria accumulations in the stratum lacunosum moleculare (SLM) layer, without loss of endogenous nuclear TDP-43. Importantly, 208 TDP-43 CTF and phosphorylated TDP-43 were rapidly cleared when CTF expression was suppressed in aged Tg mice, which ameliorated neuron loss in the DG despite persistence of ubiquitin accumulation in the SLM. Our results demonstrate that Camk2a-directed 208 TDP-43 CTF overexpression is sufficient to cause hippocampal pathology and neurodegeneration in vivo, suggesting an active role for TDP-43 CTFs in the pathogenesis of FTLD-TDP and related TDP-43 proteinopathies.


Tamm-Horsfall Protein is a Potent Immunomodulatory Molecule and a Disease Biomarker in the Urinary System.
Tamm-Horsfall protein (THP), or uromodulin (UMOD), is an 80-90-kDa phosphatidylinositol-anchored glycoprotein produced exclusively by the renal tubular cells in the thick ascending limb of the loop of Henle. Physiologically, THP is implicated in renal countercurrent gradient formation, sodium homeostasis, blood pressure regulation, and a defense molecule against infections in the urinary system. Investigations have also revealed that THP is an effective binding ligand for serum albumin, immunoglobulin G light chains, complement components C1 and C1q, interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, and interferon-γ through its carbohydrate side chains for maintaining circulatory and renal immune homeostasis. Thus, THP can be regarded as part of the innate immune system. UMOD mutations play crucial roles in congenital urolithiasis, hereditary hyperuricemia/gout, and medullary cystic kidney diseases. Recent investigations have focused on the immunomodulatory effects of THP on immune cells and on THP as a disease biomarker of acute and chronic kidney diseases. Our studies have suggested that normal urinary THP, through its epidermal growth factor (EGF)-like domains, binds to the surface-expressed EGF-like receptors, cathepsin G, or lactoferrin to enhance polymorphonuclear leukocyte phagocytosis, proinflammatory cytokine production by monocytes/macrophages, and lymphocyte proliferation by activating the Rho family and mitogen-activated protein kinase signaling pathways. Furthermore, our data support both an intact protein core structure and carbohydrate side chains are important for the different protein-binding capacities of THP. Prospectively, parts of the whole THP molecule may be used for anti-TNF-α therapy in inflammatory diseases, autoantibody-depleting therapy in autoimmune disorders, and immune intensification in immunocompromised hosts.


Mining soil metagenomes to better understand the evolution of natural product structural diversity: pentangular polyphenols as a case study.
Sequence-guided mining of metagenomic libraries provides a means of recovering specific natural product gene clusters of interest from the environment. In this study, we use ketosynthase gene (KS) PCR amplicon sequences (sequence tags) to explore the structural and biosynthetic diversities of pentangular polyphenols (PP). In phylogenetic analyses, eDNA-derived sequence tags often fall between closely related clades that are associated with gene clusters known to encode distinct chemotypes. We show that these common "intermediate" sequence tags are useful for guiding the discovery of not only novel bioactive metabolites but also collections of closely related gene clusters that can provide new insights into the evolution of natural product structural diversity. Gene clusters corresponding to two eDNA-derived KSβ sequence tags that reside between well-defined KSβ clades associated with the biosynthesis of (C24)-pradimicin and (C26)-xantholipin type metabolites were recovered from archived soil eDNA libraries. Heterologous expression of these gene clusters in Streptomyces albus led to the isolation of three new PPs (compounds 1-3). Calixanthomycin A (1) shows potent antiproliferative activity against HCT-116 cells, whereas arenimycins C (2) and D (3) display potent antibacterial activity. By comparing genotypes and chemotypes across all known PP gene clusters, we define four PP subfamilies, and also observe that the horizontal transfer of PP tailoring genes has likely been restricted to gene clusters that encode closely related chemical structures, suggesting that only a fraction of the "natural product-like" chemical space that can theoretically be encoded by these secondary metabolite tailoring genes has likely been sampled naturally.


In vivo confocal microscopy of pre-Descemet corneal dystrophy associated with X-linked ichthyosis: a case report.
Pre-Descemet corneal dystrophy (PDCD) is characterized by the presence of numerous, tiny, polymorphic opacities immediately anterior to Descemet membrane, which is a rare form of corneal stromal dystrophy and hard to be diagnosed. In vivo confocal microscopy (IVCM) is a useful tool to examine the minimal lesions of the cornea at the cellular level. In this article, we report a rare case of PDCD associated with X-linked ichthyosis and evaluate IVCM findings. We present a 34-year-old male Chinese patient with PDCD associated with X-linked ichthyosis. Slit-lamp biomicroscopy showed the presence of tiny and pleomorphic opacities in the posterior stroma immediately anterior to Descemet membrane bilaterally. IVCM revealed regular distributed hyperreflective particles inside the enlarged and activated keratocytes in the posterior stroma. Hyperreflective particles were also observed dispersedly outside the keratocytes in the anterior stroma. Dermatological examination revealed that the skin over the patient's entire body was dry and coarse, with thickening and scaling of the skin in the extensor side of the extremities. PCR results demonstrated that all ten exons and part flanking sequences of STS gene failed to produce any amplicons in the patient. IVCM is useful for analyzing the living corneal structural changes in rare corneal dystrophies. We first reported the IVCM characteristics of PDCD associated with X-linked ichthyosis, which was caused by a deletion of the steroid sulfatase (STS) gene, confirmed by gene analysis.


EMG analysis of the upper and lower fascicles of the orbicularis oris muscle in deaf individuals.
The aim of this study was to analyze electromyographically the upper and lower fascicles of the orbicularis oris muscle in deaf patients comparing them with clinically normal patients. These patients present several disorders in facial muscles, temporomandibular joints disorders and constantly headache in virtue of not the use of the face expression muscles. This was performed in 30 patients from both sexes with a mean age of 18.5 years, divided into 3 groups of 10 patients each: 1. deaf patients with buccal breathing and incompetent lips; 2. in deaf patients with nasal breathing and competent lips; 3. clinically normal patients, in 7 clinical conditions: at rest with and without labial contact, sucking water, blowing, pursing and reciprocal compression of the lips and the emission of the syllabi "PA". It was observed that in the deaf patients group, both fascicles of the orbiculares oris muscles presented hyperactivity in most of the analyzed movements, mainly in buccal breathing with incompetent lips, and the lower fascicle demonstrated the highest electromyographic activity.


Assessment of DNA damage in a group of professional dancers during a 10-month dancing season.
Despite the numerous health benefits of physical activity, some studies reported that increased intensity and duration may induce oxidative stress in several cellular components including DNA. The aim of this study was to assess the level of basal DNA damage as well as oxidative DNA damage in a group of professional dancers before and after a 10-month dancing season. A group of individuals from general population was also assessed as a control. The alkaline version of the comet assay was the method selected to measure both basal DNA damage and oxidative stress, since this method quantifies both endpoints. In order to measure oxidative stress, the comet assay was coupled with a lesion-specific endonuclease (formamidopyrimidine glycosylase) to detect oxidized purines. The levels of oxidative DNA damage in dancers were significantly increased after the dancing season. Pre-season levels of oxidative DNA damage were lower in dancers than those obtained from the general population, suggesting an adaptation of antioxidant system in dancers. Results of the present biomonitoring study indicate the need for more effective measures to protect ballet dancers from potentially occupational health risks related to regular intensive physical exercise.


Carriage of antibiotic resistant bacteria flora and its role in the guidance of clinical decision making.
There is considerable literature on the threat of antibiotic resistance and its impact on morbidity. However, an under-studied consideration is how carriage of these antibiotic resistant bacteria persist in an individual. The duration that a person harbors a resistant organism is critical in guiding future antimicrobial therapy. Key unexplored questions are the rate of clearance of these organisms and what drives their persistence. This paper attempts to examine these questions and offers some initial answers as well as avenues for further study.


Wastewater surveillance uncovers regional diversity and dynamics of SARS-CoV-2 variants across nine states in the USA.
Wastewater-based epidemiology (WBE) is a non-invasive and cost-effective approach for monitoring the spread of a pathogen within a community. WBE has been adopted as one of the methods to monitor the spread and population dynamics of the SARS-CoV-2 virus, but significant challenges remain in the bioinformatic analysis of WBE-derived data. Here, we have developed a new distance metric, CoVdist, and an associated analysis tool that facilitates the application of ordination analysis to WBE data and the identification of viral population changes based on nucleotide variants. We applied these new approaches to a large-scale dataset from 18 cities in nine states of the USA using wastewater collected from July 2021 to June 2022. We found that the trends in the shift between the Delta and Omicron SARS-CoV-2 lineages were largely consistent with what was seen in clinical data, but that wastewater analysis offered the added benefit of revealing significant differences in viral population dynamics at the state, city, and even neighborhood scales. We also were able to observe the early spread of variants of concern and the presence of recombinant lineages during the transitions between variants, both of which are challenging to analyze based on clinically-derived viral genomes. The methods outlined here will be beneficial for future applications of WBE to monitor SARS-CoV-2, particularly as clinical monitoring becomes less prevalent. Additionally, these approaches are generalizable, allowing them to be applied for the monitoring and analysis of future viral outbreaks.


Varicella pneumonia in immunocompetent adults: report of two cases, with emphasis on high-resolution computed tomography findings.
We report two cases of varicella pneumonia in immunocompetent patients, with emphasis on high-resolution computer tomography manifestations. The predominant findings consisted of multiple bilateral nodules, ranging from 1-10 mm in diameter, with or without a surrounding halo of ground-glass attenuation. Other findings include ground-glass opacities, focal areas of consolidation and small pleural effusions.


Knowing me, knowing you: theory of mind in AI.
Artificial intelligence has dramatically changed the world as we know it, but is yet to fully embrace 'hot' cognition, i.e., the way an intelligent being's thinking is affected by their emotional state. Artificial intelligence encompassing hot cognition will not only usher in enhanced machine-human interactions, but will also promote a much needed ethical approach. Theory of Mind, the ability of the human mind to attribute mental states to others, is a key component of hot cognition. To endow machines with (limited) Theory of Mind capabilities, computer scientists will need to work closely with psychiatrists, psychologists and neuroscientists. They will need to develop new models, but also to formally define what problems need to be solved and how the results should be assessed.


Impact of etanercept tapering on work productivity in patients with early rheumatoid arthritis: results from the PRIZE study.
To assess changes in work productivity in patients who have achieved response using etanercept (ETN) 50 mg+methotrexate (MTX) (phase I) are randomised to ETN 25 mg+MTX versus MTX versus placebo (phase II) and then withdrawn from treatment (phase III). Patients included in the analysis were in employment entering phase II of the PRIZE trial and had one or more follow-ups. Phase II was a 39-week, randomised and double-blind comparison of the 3 dose-reduction treatments. Phase III was a 26-week observational study where treatment was withdrawn. The Valuation of Lost Productivity was completed approximately every 13 weeks to estimate productivity impacts from a societal perspective. A total of 120 participants were included in our analyses. During phase II, ETN25+MTX or MTX improved paid work productivity by over 100 hours compared with placebo, amounting to a gain of €1752 or €1503, respectively. ETN25+MTX compared with placebo gains €1862 in total paid/unpaid productivity. At week 52, the 3-month paid work productivity loss was 21.8, 12.8 and 14.0 hours, respectively. The productivity loss increased at week 64 from week 52, dropped at week 76 for all treatment groups and then continued rising after week 76 for the placebo group (71.9 hours at week 91) but not for the other 2 groups (21.9 hours for ETX25+MTX and 27.6 hours for MTX). The work productivity gain in phase I as a result of ETN50+MTX was marginally lost in the dose-reduction treatment groups, ETN25+MTX and MTX, but substantially lost in the placebo group during phase II. NCT00913458; Results.


Does vitamin D mediate the protective effects of time outdoors on myopia? Findings from a prospective birth cohort.
More time outdoors is associated with a lesser risk of myopia, but the underlying mechanism is unclear. We tested the hypothesis that 25-hydroxyvitamin D (vitamin D) mediates the protective effects of time outdoors against myopia. We analyzed data for children participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) population-based birth cohort: noncycloplegic autorefraction at age 7 to 15 years; maternal report of time outdoors at age 8 years and serum vitamin D2 and D3 at age 10 years. A survival analysis hazard ratio (HR) for incident myopia was calculated for children spending a high- versus low-time outdoors, before and after controlling for vitamin D level (N = 3677). Total vitamin D and D3, but not D2, levels were higher in children who spent more time outdoors (mean [95% confidence interval (CI)] vitamin D in nmol/L: Total, 60.0 [59.4-60.6] vs. 56.9 [55.0-58.8], P = 0.001; D3, 55.4 [54.9-56.0] vs. 53.0 [51.3-54.9], P = 0.014; D2, 5.7 [5.5-5.8] vs. 5.4 [5.1-5.8], P = 0.23). In models including both time outdoors and sunlight-exposure-related vitamin D, there was no independent association between vitamin D and incident myopia (Total, HR = 0.83 [0.66-1.04], P = 0.11; D3, HR = 0.89 [0.72-1.10], P = 0.30), while time outdoors retained the same strong negative association with incident myopia as in unadjusted models (HR = 0.69 [0.55-0.86], P = 0.001). Total vitamin D and D3 were biomarkers for time spent outdoors, however there was no evidence they were independently associated with future myopia.


[Is "the resistance to negative reinforcement" a feature of alcohol dependence syndrome?].
In 1979, "Alcoholism Diagnosis Committee, the Ministry of Health and Welfare" established the diagnostic criteria for alcohol dependence syndrome, which included "the resistance to negative reinforcement". The author raises a question about this criterion which indicates the condition that "an individual continues to drink despite alcohol-related physical diseases, rejection by his/her family or economic poverty and drinking-related criminal problem." The author defines this condition not as "resistance to negative reinforcement" but as "resistance to punishment." Furthermore, the author can not find the data supporting that "the resistance to negative reinforcement" in the correct sense exists in the individuals with alcohol dependence syndrome. In a theoretical sense, an opposite idea seems to exist. There is an observed fact that can be regarded as a phenomenon that explains the involvement of "negative reinforcement" in enhancement of psychological dependence as in the case of the secondary development of psychological dependence. Consequently, the author would have to say that defining "the resistance to negative reinforcement" as one of common features of alcohol dependence syndrome or one of diagnostic criteria for alcohol dependence syndrome is inappropriate.


Timing of food introduction and atopy prevention.
The apparent increase in atopic disease, particularly food allergy, over the past 2 decades has resulted in reconsideration of prevention strategies aimed at the infant's diet. Early advice to have atopy-prone infants delay ingestion of potential food allergens, such as egg, cow's milk, and peanut, was rescinded, as new evidence emerged that did not support these approaches. More recently, randomized controlled trials have provided data to support an opposite strategy, promoting early ingestion of allergens as a means of food allergy prevention. Specifically, new guidelines suggest early ingestion of peanut as a means to prevent peanut allergy. Additional dietary approaches regarding breastfeeding, early introduction of other types of food allergens, formula feeding, dietary nutrients, and probiotics are also under scrutiny as potential preventative strategies. This review focuses on the timing of food introduction as a preventative strategy for food allergy and also discusses other aspects of the infant diet that may provide opportunities for prevention of atopic disease.


Selective C-F/C-H bond activation of fluoroarenes by cobalt complex supported with phosphine ligands.
The reactions of pentafluoropyridine C5NF5, hexafluorobenzene C6F6, and perfluoronaphthalene C10F8 with cobalt(0) complex, Co(PMe3)4, were investigated. The Co(I) complexes (4-C5NF4)Co(PMe3)3 (1), (C6F5)Co(PMe3)3 (2), (C10F7)Co(PMe3)3 (3), (4-C5NF4)Co(PMe3)4 (4) and (C10F7)Co(PMe3)4 (6) were obtained by selective activation of the C–F bonds. The reactions of 1 and 2 with CO afforded dicarbonyl cobalt(I) complexes (4-C5NF4)Co(CO)2(PMe3)2 (7), (C6F5)Co(CO)2(PMe3)2 (8). Under similar reaction conditions, 2 as a C–H bond activation product was obtained from the reaction of pentafluorobenzene, C6F5H, with Co(PMe3)4. The byproducts, hydrodefluorination product 1,2,4,5-C6F4H2 and F2PMe3 from the reaction of C6F5H and Co(PMe3)4 were also observed. The reaction mechanism of C6F5H with Co(PMe3)4 is proposed and partly-experimentally verified. The reaction of C6F5H with Co(PMe3)4 under 1 bar of CO at room temperature afforded hydrido dicarbonyl cobalt(II) complex (C6F5)Co(H)(CO)2(PMe3)2 (11). Treatment of the mixtures of C6F5H/Co(PMe3)4 with hexachlorobenzene, C6Cl6, resulted in (C6F5)CoCl(PMe3)3 (12) via C–H bond cleavage with the hydrodechlorination product pentachlorobenzene, C6Cl5H, and 1,2,4,5-tetrachlorobenzene, C6Cl4H2. The structures of complexes 1, 2, 6, 7, 8, 11 and 12 were determined by X-ray diffraction.


Assessment of respirable dust exposures in an opencast coal mine.
All major opencast mining activities produce dust. The major operations that produce dust are drilling, blasting, loading, unloading, and transporting. Dust not only deteriorates the environmental air quality in and around the mining site but also creates serious health hazards. Therefore, assessment of dust levels that arise from various opencast mining operations is required to prevent and minimize the health risks. To achieve this objective, an opencast coal mining area was selected to generate site-specific emission data and collect respirable dust measurement samples. The study covered various mining activities in different locations including overburden loading, stock yard, coal loading, drilling, and coal handling plant. The dust levels were examined to assess miners' exposure to respirable dust in each of the opencast mining areas from 1994 to 2005. The data obtained from the dust measurement studies were evaluated by using analysis of variance (ANOVA) and the Tukey-Kramer procedure. The analyses were performed by using Minitab 14 statistical software. It was concluded that, drilling operations produce higher dust concentration levels and thus, drill operators may have higher incidence of respiratory disorders related to exposure to dust in their work environment.


Privatization, price and cross-border liquor purchases.
Self-report survey data were used to investigate the effects of liquor sales privatization on cross-border liquor purchases. A state survey sample representing the Iowa age 18+ noninstitutionalized population was interviewed in April 1989, some 25 months after retail spirits sales were privatized. Despite a privatization induced 6.1% increase in retail liquor prices, there was little, if any, change in the self-reported amount of liquor purchased outside the state of Iowa.


Mouse models: the ketogenic diet and polyunsaturated fatty acids.
Literature on the anticonvulsant effects of the ketogenic diet (KD) in mouse seizure models is summarized. Recent data show that a KD balanced in vitamin, mineral, and antioxidant content is anticonvulsant in mice, confirming that the KD's effect in mice can be attributed to the composition of the diet and not other dietary factors. Given that the anticonvulsant mechanism of the KD is still unknown, the anticonvulsant profile of the diet in different seizure models may help to decipher this mechanism. The implications of the findings that the KD is anticonvulsant in electrical seizure models are indicated. Further, the potential involvement of polyunsaturated fatty acids (PUFA) in the KD's anticonvulsant mechanism is discussed.


The in vitro effect of kynurenic acid on the rainbow trout (Oncorhynchus mykiss) leukocyte and splenocyte activity.
Kynurenic acid (KYNA), an endogenous neuroprotectant formed along the kynurenine pathway of tryptophan degradation, is a selective ligand of the GPR35 receptor, which can be found on the surface of various populations of human immune cells. In infections and inflammations, KYNA produces an anti-inflammatory effect through this receptor, by depressing the synthesis of reactive oxygen species and pro-inflammatory cytokines. However, it is still unrecognized whether receptors for kynurenic acid are also localized on immune cells of poikilothermic animals, or whether KYNA is able to affect these cells. The objective of this study has been to determine the effect of different concentrations of kynurenic acid (12.5 microM to 10 mM) on the viability and mitogenic response of lymphocytes and on the activity of phagocytic cells isolated from blood and the spleen of rainbow trout. The results imply low toxicity of kynurenic acid towards fish immune cells, and the proliferative effect observed at the two lowest concentrations of KYNA (12.5 microM and 25 microM) seems indicative of endogenous kynurenic acid being capable of activating fish lymphocytes. Non-toxic, micromole concentrations of KYNA, however, had no influence on the mitogenic response of lymphocytes nor on the activity of phagocytes in rainbow trout under in vitro conditions. There is some likelihood that such an effect could be observed at lower, nanomole concentrations of KYNA.