miR-4286 promotes prostate cancer progression by targeting the expression of SALL1.
Prostate cancer (PCa) is a serious health threat for humans worldwide. Recent studies have revealed that microRNAs are associated with the progression of human cancers, including PCa. However, no study has been performed aiming to investigate the role of microNA-4286 (miR-4286) on PCa. A quantitative reverse transcriptase-polymerase chain reaction was conducted to analyze the expression level of miR-4286 in PCa cells. The connection of miR-4286 and spalt like transcription factor 1 (SALL1) was analyzed with a bioinformatic analysis tool, a dual-luciferase activity reporter assay and western blotting. The effects of miR-4286 and SALL1 on PCa cell behaviors were examined in vitro. We showed miR-4286 expression was significantly increased in PCa cells compared to a normal cell line. Knockdown of miR-4286 could inhibit PCa cell proliferation but promote cell apoptosis by targeting SALL1. The results of the present study suggest that miR-4286 overexpression represents a tumor promoter role in PCa.


Superporous polyacrylate/chitosan IPN hydrogels for protein delivery.
In this study, poly(acrylamide), poly(AAm), and poly(acrylamide-co-acrylic acid), poly(AAm-co-AA) superporous hydrogels (SPHs) were synthesized by radical polymerization in the presence of gas blowing agent, sodium bicarbonate. In addition, ionically crosslinked chitosan (CH) superporous hydrogels were synthesized to form interpenetrating superporous hydrogels, i.e. poly(AAm)-CH and poly(AAm-co-AA)-CH SPH-IPNs. The hydrogels have a structure of interconnected pores with pore sizes of approximately 100-150 μm. Although the extent of swelling increased when AA were incorporated to the poly(AAm) structure, the time to reach the equilibrium swelling (~30 s) was not affected so much. In the presence of chitosan network mechanical properties significantly improved when compared with SPHs, however, equilibrium swelling time (~30 min) was prolonged significantly as due to the lower porosities and pore sizes of SPH-IPNs than that of SPHs. Model protein bovine serum albumin (BSA) was loaded into SPHs and SPH-IPNs by solvent sorption in very short time (<1 h) and very high capacities (~30-300 mg BSA/g dry gel) when compared to conventional hydrogels. BSA release profiles from SPHs and SPH-IPNs were characterized by an initial burst of protein during the first 20 min followed by a completed release within 1 h. However, total releasable amount of BSA from SPH-IPNs was lower than that of SPHs as due to the electrostatic interactions between chitosan and BSA.


Investigating the effects of the core nitrogen atom configuration on the thermodynamic solubility of 6,5-bicyclic heterocycles.
Physicochemical properties, such as solubility, are important when prioritising compounds for progression on a drug discovery project. There is limited literature around the systematic effects of core changes on thermodynamic solubility. This work details the synthesis of nitrogen containing 6,5-bicyclic heterocyclic cores which are common scaffolds in medicinal chemistry and the analysis of their physicochemical properties, particularly, thermodynamic solubility. Crystalline solids were obtained where possible to enable a robust comparison of the thermodynamic solubility. Other parameters such as pKa, melting point and lipophilicity were also measured to determine the key factors affecting the observed solubility.


The effect of different debonding techniques on the enamel surface: an in vitro qualitative study.
The purpose of this in vitro study was to evaluate the enamel surface structure subjected to various techniques of debonding orthodontic attachments and to develop a technique for residual adhesive removal that restores the enamel surface as closely as possible to its pretreatment condition without introducing iatrogenic damage. Enamel surface structure was examined with a scanning electron microscope before bonding of twin metal brackets to 60 previously extracted premolars with two heavily filled composite resins. Two groups, each consisting of 30 teeth, were equally subdivided into 10 subgroups. The first three subgroups were used to compare the efficacy of three bracket removing instruments. Since there were no differences in the debonding properties between the two resins, the two groups were combined. In this way, each subgroup (n = 6) could be used for a more meaningful comparison. On the basis of the results of this comparison, the bracket removing instrument that produced the most consistent separation at the bracket-adhesive interface was used in the remainder of the study. After appliance removal, the teeth were again examined microscopically and photographed, and seven different procedures for residual resin removal were compared. After resin removal, the final polished enamel surface was followed by microscopic evaluation. Results of this study show the bracket removing plier produced the most consistent separation at the bracket-adhesive interface, leaving the enamel surface intact. Carbide burs at high speed and air coolant proved to be efficient in residual resin removal, but when used alone, failed to produce a satisfactory enamel surface. After the removal of residual resin, graded medium, fine, and superfine Sof-Lex finishing disks (Unitek Corp., Monrovia, Calif.) produced surfaces that could be readily restored satisfactorily after receiving a final polish with a rubber cup and Zircate paste.


Refractoriness to chemotherapy and poor survival related to abnormalities of chromosomes 17 and 7 in lymphoma.
Lymphoma cells usually show cytogenetic abnormalities, but their relationship to prognosis has not been as extensively studied as in leukemia. A group of previously untreated cases of lymphoma with evaluable metaphases was examined for the association between cytogenetic abnormalities and clinical outcome. The study consisted of 104 patients, from whom fresh tumor samples were obtained for cytogenetic tests. Because of the complexity of lymphoma karyotypes, the cases were divided into four patterns according to the type of abnormality of chromosome 17 or 7 present. Treatment of patients was given based on histologic grade and stage of disease. Response to treatment was evaluated according to previously described methods. Patients with true abnormalities of chromosome 17 or 7 (defined as those with either structural abnormalities of the short arm of these chromosomes or monosomy of these chromosomes with no associated unidentified markers) were observed to have an adverse prognosis. The overall response rate and tumor-related mortality were less favorable for patients with these cytogenetic abnormalities. By applying multivariate analysis, we found that this observation was independent of the effect of serum lactic dehydrogenase level, histologic grade, or tumor burden. True abnormalities of chromosome 17 or 7 in patients with lymphoma are associated with a poor response to chemotherapy, short time to treatment failure, and high tumor-related mortality rate. These findings raise the question of the potential involvement of some gene or oncogene, perhaps the p53 oncogene, which might impart a survival advantage to the malignant cells.


Glucose repression on RIM1, a gene encoding a mitochondrial single-stranded DNA-binding protein, in Saccharomyces cerevisiae: a possible regulation at pre-mRNA splicing.
The mitochondrial single-stranded DNA-binding protein (SSB) encoded by anuclear gene, RIM1, is a homolog of Escherichia coli SSB. The addition of glucose decreased the amount of RIM1-mRNA in cells growing in a glycerol medium, but increased the amount of the immature RIM1-mRNA. The changes in the amounts of both mature and immature RIM1-mRNAs were dependent on SRN1/REG1/HEX2, a gene relating to pre-mRNA-splicing and glucose repression. These observations suggest that the expression of the mitochondrial SSB is regulated, at least in part, by pre-mRNA splicing under the control of glucose repression.


Amphibian embryo protease inhibitors. IV. Studies on an inhibitor of chymotrypsin and papain.
Amphibian embryo chymotrypsin and papain inhibitor (ACPI) purified by the procedure described in this paper produces a single band on sodium dodecyl sulfate (SDS) gel electrophoresis and a single peak on Sephadex G-75 chromatography. Except for its enzyme specificity, ACPI is very similar to amphibian embryo trypsin inhibitor (ATI). Its molecular weight is about 10,500 and its amino acid composition is typical of many naturally occurring protease inhibitors. Inhibition develops slowly, is retarded by the presence of substrate and is temporary. ACPI is localized in the yolk platelets and its disappearance both from whole embryos and from select tissue types corresponds closely with that of ATI. Possible roles for amphibian embryo proteases and protease inhibitors in development are discussed.


Endogenously produced 20-HETE modulates myogenic and TGF response in microperfused afferent arterioles.
Previous studies have indicated that 20-hydroxyeicosatetraeonic acid (20-HETE) modulates vascular tone in large cerebral and renal arteries through inhibition of the large conductance, calcium sensitive potassium (BK) channel activity. However, the role of 20-HETE in modulating tubuloglomerular feedback (TGF) and the myogenic response in the afferent arteriole (Af-Art) is unknown. The present study examined the effects of inhibitors of the synthesis and action of 20-HETE on the myogenic and TGF responses of isolated rabbit and mouse Af-Arts. Luminal diameter decreased by 9.2±0.5% in mice and 8.9±1.3% in rabbit Af-Art when the perfusion pressure was increased from 60 to 120 mmHg. Administration of a 20-HETE synthesis inhibitor, HET0016 (1 μM), or a selective 20-HETE antagonist, 6, 15-20-hydroxyeicosadienoic acid (6, 15-20-HEDE, 10 μM) completely blocked the myogenic response of both rabbit and mouse Af-Art, while addition of 5, 14-20-HEDE (10 μM), a 20-HETE agonist, restored the myogenic response in vessels treated with HET0016. Increases in NaCl concentration from 10 to 80 mM of the solution perfusing the macula densa constricted the Af-Art of rabbits by 6.0±1.4 μm (n=5). Addition of a 20-HETE agonist to the tubular perfusate potentiated the TGF-mediated vasoconstrictor response. This response was blocked by addition of a 20-HETE antagonist (6, 15-20-HEDE, 10 μM) to the vascular perfusate. These studies indicate that locally produced 20-HETE plays an important role in modulating the myogenic and TGF responsiveness of the Af-Art and may help explain how deficiencies in the renal formation of 20-HETE could promote the development of hypertension induced glomerular injury.


Okadaic acid induces the rapid and reversible disruption of the neurofilament network in rat dorsal root ganglion neurons.
Treatment of 15-17 day old dissociated cultures of rat dorsal root ganglia with 1 microM okadaic acid caused a reduction in the mobilities of neurofilament subunits on SDS-polyacrylamide gels, signifying an increase in their phosphorylation levels. When cultures were exposed to okadaic acid for 0.5 hrs and harvested in buffer containing Triton X-100, NF-H was nearly completely redistributed to the detergent- soluble fraction while NF-M and NF-L required a longer exposure to the drug before undergoing a similar shift. This redistribution of subunits corresponded with striking changes in the immunofluorescence staining pattern for neurofilaments. Upon removal of okadaic acid from the culture medium following a 0.5 hr treatment, NF-L and NF-M returned to the Triton X-100 insoluble fraction within 2 hrs while NF-H required 10 hrs for recovery.


Empiric vs. preemptive antifungal treatment: an appraisal of treatment strategies in haematological patients.
Neutropenic patients are at high risk to develop invasive fungal infections (IFI). Immediate antifungal treatment has been considered necessary for the treatment of these patients. However, only a minority of patients have 'probable' or 'proven' IFI according to EORTC-/MSG-criteria. The majority of the patients present with ongoing fever in neutropenia or 'possible' IFI only. To date, two treatment strategies are used for patients with fever in neutropenia and suspected IFI: empirical or preemptive antifungal therapy. Both regimens are discussed controversially as there is no clear evidence as to which strategy is superior. Empirical treatment bears the danger of 'overtreatment' with potentially toxic and expensive drugs, whereas preemptive therapy may sometimes be initiated too late to work efficiently against fungal disease. This article reviews both treatment options and discusses advantages and draw-backs of either strategy.


Studies on subcellular fractions which are involved in myelin assembly: labeling of myelin proteins by a double radioisotope approach indicates developmental relationships.
The question of developmental relationships amongst myelin-related membranes in subfractions of myelinating mouse brain (15 days) was investigated by a time-staggered double isotope protocol using [3H]leucine and [14C]leucine. Preliminary results are interpreted and discussed in the context of a mathematical conceptualization of pulse-labeling kinetic analyses of myelin proteins in subcellular membrane compartments. Differences in ratio of the two leucine labels among proteins of myelin-containing subfractions are interpreted as confirming metabolic differences relating to various stages of development rather than precursor-product relationships. The incorporation into myelin of 14K, 17K, and 18.5K basic proteins (MBPs) occurs with relatively short delay times, following their synthesis (less than 5 min), and seems to occur simultaneously into all compartments. The 21.5K MBP and the proteolipid protein, on the other hand, require 10-14 min and 14-20 min, respectively. A scheme is presented to illustrate the probable assignment of subfractions to various myelin "compartments" during myelination, and to serve as a working hypothesis for studies on precursor-product relationships.


Protocadherin B9 Is Associated with Human Esophageal Squamous Cell Carcinoma Progression.
Esophageal cancer is the sixth leading cause of cancer-related death worldwide. However, molecular targeted therapy and novel therapeutic targets are needed for esophageal squamous cell cancer (ESCC). In a previous study, we reported that protocadherin (PCDH) B9 plays an important role in several cancers. Therefore, in this study, we examined the clinical significance of PCDHB9 expression in ESCC. PCDHB9 expression was examined using immunohistochemistry in 128 cases and using quantitative reverse transcription-polymerase chain reaction in 16 cases of ESCC. PCDHB9 function in ESCC cells was examined using RNA interference. High PCDHB9 expression was identified in 5 of 16 (31.3%). In total, 51 (40%) ESCC cases showed strong PCDHB9 expression, whereas nonneoplastic mucosa rarely showed its expression. High PCDHB9 expression was significantly associated with T classification, N grade, and stage in ESCC. In ESCC cell lines, PCDHB9 knockdown affected cell growth, migration, and adhesion. Further, the expression of integrin (ITG) A3, ITGA4, ITGA5, ITGB1, ITGB6, vimentin, snail family transcriptional repressor 1, and cadherin 2 (NCAD) was significantly reduced and cadherin 1 was significantly increased in PCDHB9 knockdown ESCC cells. These results suggest that PCDHB9 plays a tumor-promoting role and is a potential biomarker and therapeutic target in ESCC.


Changes in rumen bacterial community composition in steers in response to dietary nitrate.
The effect of dietary nitrate supplementation on rumen bacterial community composition was examined in beef steers fed either a nitrate-N diet or urea-N diet. An automated method of ribosomal intergenic spacer analysis was applied to solid and liquid fractions of ruminal contents to allow comparison of bacterial communities. Supplemental N source affected relative population size of four amplicon lengths (ALs) in the liquid fraction and three ALs in the solid fraction. Five ALs were more prevalent after adaptation to nitrate. Correspondence analysis indicated that feeding the steers the nitrate-N diet versus urea-N diet changed the bacterial community composition in the liquid but not in the solid fraction. This led to an investigation of the relative sizes of potential nitrate-reducing populations. Mannheimia succiniciproducens, Veillonella parvula, and Campylobacter fetus were obtained from nitrate enrichment culture and quantified by real-time PCR based on 16S rRNA sequence. Nitrate supplementation increased the percentage of C. fetus in the liquid and solid phases, and in solid phase, the percentage of M. succiniciproducens increased. No change in species prevalence was observed for V. parvula. However, even after adaptation to dietary nitrate, the relative population sizes for all three putative nitrate-reducing species were very low (<0.06 % of 16S rRNA gene copy number). The liquid-associated bacterial community composition changed due to nitrate supplementation, and at least part of this change reflects an increase in the species prevalence of C. fetus, a species which is not typically regarded as a ruminal inhabitant.


Maternal third trimester hyperglycaemic excursions predict large-for-gestational-age infants in type 1 diabetic pregnancy.
To determine which maternal glycaemic parameters in type 1 diabetes better predict large-for-gestational-age (LGA) infants. Maternal glycaemic parameters (mean overall, preprandial, and postprandial glucose; the percentage of glucose readings above and below target and HbA1c levels) of LGA (n=37) and appropriate-for-gestational-age (n=36) infants were compared during preconception and each trimester of pregnancy. Logistic regression was used to select predictive variables. Preconception glycaemic parameters were not different. Mean glucose and the percentage of glucose readings above target were higher in mothers of LGA infants in every trimester of pregnancy. Second and third trimesters mean postprandial glucose, third trimester mean preprandial glucose and third trimester HbA1c were also higher. Only third trimester glycaemic variables were risk indicators of LGA infants: mean glucose (OR: 3.45; 95% CI: 1.52-7.80), mean preprandial glucose (OR: 2.97; 95% CI: 1.34-6.60), mean postprandial glucose (OR: 2.09; 95% CI: 1.19-3.67) and the percentage of glucose readings above target (OR: 1.08; 95% CI: 1.03-1.14). The percentage of glucose readings above target was the best risk indicator. Third trimester glycaemic parameters are more powerful predictors of foetal growth than glycaemic parameters earlier in pregnancy or during preconception. Hyperglycaemic excursions are the strongest predictor of LGA infants.


Segmental inhibition of cutaneous heat sensation and of laser-evoked potentials by experimental muscle pain.
The aim of the study was to evaluate the effect of tonic muscle pain evoked by injection of 5% hypertonic saline in the right brachioradialis muscle on the somatosensory sensation of laser-evoked heat pain and laser-evoked potentials. The heat pain pathways were studied in 9 healthy human subjects by recording the scalp potentials evoked by CO(2) laser stimuli delivered on four sites: the skin above the right brachioradialis muscle (ipsilateral local pain), the wrist area where muscle pain was referred in all subjects (ipsilateral referred pain), and two areas on the left arm symmetrical to both local and referred pain (contralateral local pain and contralateral referred pain). Laser-evoked potentials were obtained from 31 scalp electrodes before saline injection, during saline infusion (bolus injection with 0.3 ml saline infused over 20 s, followed by a steady infusion rate of 30 ml/h for the next 25 min), and 20 min after muscle pain had disappeared. While the early N1/P1 component (around 130 ms and 145 ms of latency after stimulation of the skin over the brachioradialis muscle and the wrist, respectively) was not affected by muscle pain, the amplitudes of the later vertex laser-evoked potentials (N2 latency of around 175 ms and 210 ms after stimulation of the skin over the brachioradialis muscle and the wrist, respectively; P2 latency of around 305 ms and 335 ms after stimulation of the skin over the brachioradialis muscle and the wrist, respectively) evoked from ipsilateral local pain, ipsilateral referred pain, and contralateral local pain sites were significantly decreased during muscle pain compared with the baseline recording, while they recovered after pain had disappeared. At the same stimulation sites, the rating of the laser-evoked pain sensation was reduced significantly during muscle pain as compared with the baseline and it recovered after pain had disappeared. On the contrary, muscle pain did not show any effect on both laser-evoked pain and laser-evoked potential amplitude when the contralateral referred pain site was stimulated. The muscle pain inhibitory effect on both heat pain sensation and laser-evoked potential amplitude is probably mediated by an ipsilateral and contralateral segmental mechanism which acts also on the referred pain area, while more general inhibitory mechanisms, such as a distraction effect or a diffuse noxious inhibitory control, are excluded by the absence of any effect of muscle pain on laser-evoked pain and laser-evoked potentials obtained from a remote site, such as the contralateral referred pain area. Since muscle pain induced by hypertonic saline injection is very similar to clinical pain, our results can be useful in understanding the pathophysiology of the somatosensory modifications which can be observed in patients with musculoskeletal pain syndromes.


Photonic helicoid-like surface states in chiral metamaterials.
We investigate the photonic topological phases in chiral metamaterials characterized by the magnetoelectric tensors with diagonal chirality components. The underlying medium is considered a photonic analogue of the topological semimetal featured with a Weyl cone and a cylindrical surface in the frequency-wave vector space. As the 'spin'-degenerate condition is satisfied, the photonic system can be rearranged as two hybrid modes that are completely decoupled. By introducing the pseudospin states as the basis for the hybrid modes, the photonic system is described by two subsystems in the form of spin-orbit Hamiltonians of spin 1, which result in nonzero spin Chern numbers that determine the topological properties. Surface modes at the interface between vacuum and the chiral metamaterial exist in their common gap in the wave vector space, which are analytically formulated by algebraic equations. In particular, the surface modes form a pair of spiral surface sheets wrapping around the Weyl cone, resembling the helicoid surface states that occur in topological semimetals. At the Weyl frequency, the surface modes contain two Fermi arc-like states that concatenate to yield a straight line segment.


Familial occurrence of peripartum cardiomyopathy presages a genetic rather than an environmental cause.
Peripartum cardiomyopathy (PPCM) is an uncommon form of left ventricular dysfunction associated with pregnancy and triggered by a number of obstetric factors including pre-eclampsia, plural gestations and multiparity. PPCM is the most frequent cause of pregnancy-related maternal death. Although the clinical outcome of PPCM has been determined, its patho-etiology has not been elucidated. Two recent studies have demonstrated for the first time in a small proportion of patients, convincing evidence of a genetic predisposition for PPCM, activated by modifier genes responding to biochemical and hemodynamic signals during mid to late pregnancy.


Thrombin receptor levels in platelet concentrates during storage and their impact on platelet functionality.
Quality control of platelet (PLT) concentrates is challenging, due to PLT lesions, which are difficult to detect with routine methods. The search for reliable PLT lesion biomarkers is focused on the role of PLTs in primary hemostasis. PLT transfusions also have a significant impact on secondary hemostasis. In this phase, responsiveness of PLTs to small amounts of thrombin is crucial. PAR1 and PAR4 are protease-activated receptors and are responsible for thrombin reactivity of human PLTs. This study should elucidate if levels of those two receptors are changing in PLT concentrates during storage and if those changes have an impact on PLT aggregation and support of thrombin generation. PLT concentrates from buffy coat preparations were stored in SSP+ solution for 9 days at 22±2°C on a horizontal flatbed agitator, and samples were taken daily for analysis. PAR1 and PAR4 levels were evaluated using Western blot analysis. PLT aggregation was measured using Born aggregometry and specific PAR1 or PAR4 agonists. Thrombin generation was measured using calibrated automated thrombography. Levels of both receptors (PAR1 and PAR4) started to decrease after 5 days of storage. PAR1-mediated PLT aggregation remained constant, whereas PAR4-mediated PLT aggregation decreased with storage time. Rate of thrombin generation was accelerated after 5 days of storage. Decreasing levels of PARs in PLT concentrates after 5 days of storage influenced PAR4-mediated, but not PAR1-mediated, aggregation. Thrombin generation with senescent PLTs was increased, which may be attributed to other mechanisms promoting increased phosphatidylserine exposure.


Cell-surface glycans act as attachment factors for porcine hemagglutinating encephalomyelitis virus.
Porcine hemagglutinating encephalomyelitis virus (PHEV) is a neurotropic coronavirus and highly pathogenic in veterinary clinic. Spike (S) protein of PHEV interplays with host components to cross the plasma membrane of target cells, but characterization of its functional receptors is limited. Here, we discovered that cell-surface glycans, i.e., sialic acid (SA) and heparan sulfate (HS), act as critical interacting factors of PHEV, involving in viral attachment. As shown in glycans depletion assay, removing SA or HS from N2a cells inhibits PHEV infection. Soluble sugar monomers were utilized for competitive binding tests, and we found that both SA and HS could specifically bind to PHEV and affect the viral infectivity. Furthermore, the expression of heparan sulfate proteoglycans (HSPGs), including syndecans and glypicans, and endoglycosidase heparinase which cleaves HS were regulated by PHEV RNA replication. Together, we newly identified specificity recognition of cellular glycans and PHEV during infection, providing novel cellular targets for antiviral therapies and better understanding of pathogenesis.


Nasal absorption enhancement strategies for therapeutic peptides: an in vitro study using cultured human nasal epithelium.
This study examined the potential usefulness of cultured human nasal epithelium as a model to investigate nasal absorption enhancement strategies for therapeutic peptides. The transport of leucine enkephalin (Leu-Enk) in the presence of bestatin and puromycin, respectively and various combinations of these protease inhibitors with absorption enhancers capable of inhibiting proteases or protecting peptides against protease degradation (glycocholate, dimethyl-beta-cyclodextrin (DM beta CD)) was studied. Epithelial membrane perturbation, protein leakage, bestatin/puromycin absorption and rebound aminopeptidase activity were used as toxicological end-points. The combination of puromycin with glycocholate or DM beta CD resulted in a higher absorption enhancement of Leu-Enk (9-14%) than when the absorption enhancers were combined with bestatin (1-3%) or when the inhibitors were used alone (2-4%). The higher absorption enhancement resulting from the combination of protease inhibitors with absorption enhancers caused a significant reduction of epithelial resistance and increased sodium fluorescein transport. Although only puromycin permeated the human nasal epithelium, both protease inhibitors induced a significant rebound aminopeptidase activity (25-61%), which can be associated with protein leakage (21-46%). This study highlighted (i) the potential usefulness of cultured human nasal epithelium as a model to study nasal absorption enhancement of therapeutic peptides; (ii) further studies using in vivo nasal models are required to ascertain whether the membrane perturbation and cytotoxicity observed with various combinations of the protease inhibitors and absorption enhancers really raise safety concerns.


Guidance on take-home naloxone distribution and use by community overdose responders in Canada.
The increasing toxicity of opioids in the unregulated drug market has led to escalating numbers of overdoses in Canada and worldwide; takehome naloxone (THN) is an evidence-based intervention that distributes kits containing naloxone to people in the community who may witness an overdose. The purpose of this guidance is to provide policy recommendations for territorial, provincial and federal THN programs, using evidence from scientific and grey literature and community evidence that reflects 11 years of THN distribution in Canada. The Naloxone Guidance Development Group - a multidisciplinary team including people with lived and living experience and expertise of drug use - used the Appraisal of Guidelines for Research & Evaluation (AGREE II) instrument to inform development of this guidance. We considered published evidence identified through systematic reviews of all literature types, along with community evidence and expertise, to generate recommendations between December 2021 and September 2022. We solicited feedback on preliminary recommendations through an External Review Committee and a public input process. The project was funded by the Canadian Institutes of Health Research through the Canadian Research Initiative in Substance Misuse. We used the Guideline International Network principles for managing competing interests. Existing evidence from the literature on THN was of low quality. We incorporated evidence from scientific and grey literature, and community expertise to develop our recommendations. These were in 3 areas: routes of naloxone administration, THN kit contents and overdose response. Take-home naloxone programs should offer the choice of both intramuscular and intranasal formulations of naloxone in THN kits. Recommended kit contents include naloxone, a naloxone delivery device, personal protective equipment, instructions and a carrying case. Trained community overdose responders should prioritize rescue breathing in the case of respiratory depression, and conventional cardiopulmonary resuscitation in the case of cardiac arrest, among other interventions. This guidance development project provides direction for THN programs in Canada in the context of limited published evidence, with recommendations developed in collaboration with diverse stakeholders.


Presence of cardiomyocytes exhibiting Purkinje-type morphology and prominent connexin45 immunoreactivity in the myocardial sleeves of cardiac veins.
Pulmonary vein (PV) myocardium is a known source of atrial fibrillation. A debated question is whether myocardial extensions into caval veins and coronary sinus (CS) have similar properties. No studies have documented specific pacemaker and/or conducting properties of human extracardiac myocardium. The purpose of this study was to characterize the histology and immunohistochemical features of myocardial sleeves in the wall of cardiac veins. Sections of 32 human hearts were investigated. Specimens of PVs, superior caval vein (SVC), CS, sinoatrial and atrioventricular nodes, and left ventricle were stained with Best's Carmine for selective staining of intracellular glycogen. Anti-connexin45 (Cx45)- and Cx43-specific antibodies were used to determine the conduction properties of extracardiac myocardium. Myocardial sleeve was found in the wall of PVs of 15 of 16 hearts, 21 of 22 SVCs, and 8 of 8 CSs. Bundles of glycogen-positive cardiomyocytes exhibiting pale cytoplasm and peripheral myofibrils were observed in the venous sleeves. Strong Cx45 and weak Cx43 labeling was detected in the extracardiac myocardium. Similar staining pattern was observed for the pacemaker and conduction system, whereas ventricular myocardium exhibited prominent Cx43 and no Cx45 immunoreactivity. Myocardial fibers of PVs, SVC, and CS exhibit morphology similar to that of Purkinje fibers and are enriched in glycogen. We provide data for the first time on prominent positive staining for Cx45 in the extracardiac myocardium, indicating its potential pacemaker and/or conducting nature.


Novel exocrine glands in the foreleg coxae of Discothyrea ants.
Workers, queens and males of all examined Discothyrea species of the 'sauteri group', that have laterally expanded frontal lobes and well-developed antennal scrobes, are characterized by two hairy areas on the outer surface of their procoxae. Histological and ultrastructural examination of Discothyrea sauterirevealed that each of these areas is associated with a novel exocrine gland: the proximal procoxal gland is formed by a cluster of 15 round secretory cells of 34 μm with numerous mitochondria, smooth endoplasmic reticulum and Golgi apparatus.Their ducts have a diameter of 0.5-1 μm.The distal procoxal gland contains 50 secretory cells of 22 μm with numerous vacuoles and lamellar inclusions, and narrow ducts with a diameter of only 0.15-0.2 μm.The differences in ultrastructural appearance and duct diameter indicate that both glands produce a different but probably pheromonal secretion. The function of these novel procoxal glands could not yet be determined, although observation of D.sauteri workers and queens shows that they make frequent and peculiar leg movements, in which the foreleg basitarsus rubs over the coxal hairy areas. The foreleg basitarsus then rubs the ipsilateral hindleg basitarsus and antenna. As a last step of the sequence, the hindleg basitarsus strokes the gaster.In addition to the occurrence of these novel procoxal glands, histological examination of D. sauteri also revealed the presence of yet another novel but smaller procoxal base gland. Ants of the 'testacea group', that have less developed frontal lobes and no antennal scrobes, do not have procoxal hairy areas, although a distinct sculpturation with small pores may occur in the corresponding areas. The related Proceratium japonicum, that has a similar lifestyle as Discothyrea, does not have any of the procoxal glands and does not display the peculiar leg movements as reported for D. sauteri.


Individual differences in first-pass fixation duration in reading are related to resting-state functional connectivity.
Although there are considerable individual differences in eye movements during text reading, their neural correlates remain unclear. In this study, we investigated the relationship between the first-pass fixation duration (FPFD) in natural reading and resting-state functional connectivity (RSFC) in the brain. We defined the brain regions associated with early visual processing, word identification, attention shifts, and oculomotor control as seed regions. The results showed that individual FPFDs were positively correlated with individual RSFCs between the early visual network, visual word form area, and eye movement control/dorsal attention network. Our findings provide new evidence on the neural correlates of eye movements in text reading and indicate that individual differences in fixation time may shape the RSFC differences in the brain through the time-on-task effect and the mechanism of Hebbian learning.


Outcomes of pelvic exenteration for recurrent and primary locally advanced rectal cancer.
Pelvic exenteration is the only radical treatment for locally advanced (ARC) or recurrent (RRC) rectal cancers. The long-term results of the procedure are variably reported in the literature, with recent series suggesting similar survival between ARC and RRC. The study aimed to analyze and compare the long-term survival and perioperative outcomes of patients undergoing pelvic exenteration for ARC and RRC in a tertiary center. This was a retrospective analysis of prospectively collected data. Comparison of variables was performed using Chi-square, Fisher's exact or Wilcoxon rank sum test as appropriate. The Kaplan Meier method was used to analyze the disease-free survival (DFS) and the log-rank test to compare the two groups. Since 2002, 46 patients underwent pelvic exenteration for ARC (28, 60.9%) and RRC (18, 39.1%). The groups had comparable characteristics, perioperative results, including postoperative complications, and rate of adjuvant chemotherapy. A R0 resection was obtained in 71.4% and 55.6% (p 0.41) and a T4 stage was diagnosed in 75% and 94.4% (p 0.22) of ARC and RRC patients, respectively. After a median follow-up time of 32.5 and 56.6 months (p 0.01), the 5-year DFS was significantly lower in the RRC group (23.6 vs 46.2%, p 0.006), even after exclusion of R1 cases (30 vs 54.5%, p 0.044). The long-term disease free survival of patients undergoing pelvic exenteration is significantly worse when the procedure is performed for RRC, regardless of the tumor involvement of the resection margins.


Consumption of peptide-included and free tryptophan induced by peroxyl radicals: A kinetic study.
It is well-known that tryptophan residues are efficiently oxidized by peroxyl radicals, generating kynurenine, and N-formyl kynurenine as well as hydroperoxide derivatives as products. In the present work we studied the kinetic of such reaction employing free and peptide-included tryptophan. Two azocompounds were used to produce peroxyl radicals: AAPH (2,2'-Azobis(2-methylpropionamidine) dihydrochloride) and ABCVA (4,4'-Azobis(4-cyanovaleric acid)), which generate cationic and anionic peroxyl radicals, respectively. Tryptophan consumption was assessed by fluorescence spectroscopy and the reactions were carried out in phosphate buffer (75mM, pH 7.4) at 45°C. Only a slight effect of the peroxyl radical charge was evidenced on the consumption of free tryptophan and the dipeptide Gly-Trp. Employing AAPH as peroxyl radical source, at low free tryptophan concentrations (1-10µM) near 0.3 mol of tryptophan were consumed per each mol of peroxyl radicals introduced into the system. However, at high free tryptophan concentrations (100µM-1mM) such stoichiometry increased in a tryptophan concentration-way. At 1mM three moles of tryptophan were consumed per mol of AAPH-derived peroxyl radicals, evidencing the presence of chain reactions. A similar behavior was observed when di and tri-peptides (Gly-Trp, Trp-Gly, Gly-Trp-Gly, Trp-Ala, Ala-Trp-Ala) were studied. Nonetheless, at low initial concentration (5µM), the initial consumption rate of tryptophan included in the peptides was two times higher than free tryptophan. In contrast, at high concentration (1mM) free and peptide-included tryptophan showed similar initial consumption rates. These results could be explained considering a disproportionation process of tryptophanyl radicals at low free tryptophan concentrations, a process that would be inhibited when tryptophan is included in peptides.


What you need to know: updates in penile cancer staging.
We sought to discuss the updates in the 8th edition (8E) of The American Joint Committee on Cancer (AJCC) staging for penile cancer and to provide relevant evidence associated with the major changes that occurred. A comprehensive search of PubMed® and Web of Science® was performed for relevant English language articles from 2004 through 2019. Literature resulting from this search were reviewed and articles pertinent to penile cancer staging changes were included. Modifications were observed in the tumor and nodal staging. In the 8E AJCC, Ta disease indicates noninvasive localized squamous cell carcinoma, which allows for inclusion of other historical variants. T1 is subcategorized into T1a and T1b according to existence of lymphovascular invasion, perineural invasion and high-grade tumor. This subcategorization demonstrates different risks for lymph node (LN) metastases and will affect decision strategy when opting for inguinal lymphadenectomy. Urethral invasion is no longer a differentiator between T2 and T3 disease, as T2 includes invasion of the corpus spongiosum and T3 involves invasion of the corpus cavernosum. For nodal staging, pN1 has been increased from a single LN metastases to two unilateral inguinal LN metastases, while pN2 has been modified to three or more inguinal LN metastases. This change was evidenced by demonstrating no significant difference in disease specific mortality between the previous edition's pN1 and pN2. The 8E penile cancer staging provides several modifications that have relevant clinical implications in the management of penile cancer. Nevertheless, it requires refinements that allow for better staging of penile tumors.


Validity and reliability of body composition analysers in children and adults.
We tested the validity and reliability of the BioSpace InBody 320, Omron and Bod-eComm body composition devices in men and women (n 254; 21-80 years) and boys and girls (n 117; 10-17 years). We analysed percentage body fat (%BF) and compared the results with dual-energy X-ray absorptiometry (DEXA) in adults and compared the results of the InBody with underwater weighing (UW) in children. All body composition devices were correlated (r 0.54-0.97; P< or =0.010) to DEXA except the Bod-eComm in women aged 71-80 years (r 0.54; P=0.106). In girls, the InBody %BF was correlated with UW (r 0.79; P< or =0.010); however, a more moderate correlation (r 0.69; P< or =0.010) existed in boys. Bland-Altman plots indicated that all body composition devices underestimated %BF in adults (1.0-4.8 %) and overestimated %BF in children (0.3-2.3 %). Lastly, independent t tests revealed that the mean %BF assessed by the Bod-eComm in women (aged 51-60 and 71-80 years) and in the Omron (age 18-35 years) were significantly different compared with DEXA (P< or =0.010). In men, the Omron (aged 18-35 years), and the InBody (aged 36-50 years) were significantly different compared with DEXA (P=0.025; P=0.040 respectively). In addition, independent t tests indicated that the InBody mean %BF in girls aged 10-17 years was significantly different from UW (P=0.001). Pearson's correlation analyses demonstrated that the Bod-eComm (men and women) and Omron (women) had significant mean differences compared with the reference criterion; therefore, the %BF output from these two devices should be interpreted with caution. The repeatability of each body composition device was supported by small CV (<3.0 %).


Facilitation of kindling by prior induction of long-term potentiation in the perforant path.
Previous studies have revealed that a form of synaptic potentiation resembling long-term potentiation (LTP) occurs at various sites as a result of stimulation that leads to kindling. The present study evaluates what role this synaptic potentiation plays in the development of kindling following periodic stimulation of the entorhinal cortex of the rat. LTP was repetitively induced in the pathway from the entorhinal cortex (EC) to the dentate gyrus (DG) by daily stimulation with high frequency trains that led to LTP, but did not evoke afterdischarge (AD). Subsequently, animals received stimulation designed to induce kindling (that led to AD), and this stimulation was delivered once per day until kindled seizures were induced. While repetitive induction of LTP was not sufficient to produce kindling, prior induction of LTP significantly increased the rate of subsequent kindling as evidenced by a decrease in the number of kindling stimulations required to induce the kindled state. As a group, animals that had received stimulation designed to induce LTP developed kindled seizures after an average of 10 AD's, whereas a control group that had received non-potentiating stimulation required 25 AD's. These results indicate that LTP at EC-DG synapses cannot represent the mechanism of kindling following EC stimulation. However, synaptic potentiation at this site can facilitate the development of epileptogenesis in response to subsequent activation of the perforant path.


Development of Vang Danh anthracite as a cost-effective anode for sodium-ion batteries through a heat-treatment process.
This study focuses on the effects of the chemical process and heating time at 900 °C on pristine anthracite coal (provided by Vang Danh coal, Quang Ninh province, Vietnam) and explores its structure and electrochemical performance when used as an anode in Na-ion batteries. After chemical treatment with NaOH and H2SO4, the impurity content in the raw material decreased significantly (e.g., ash content dropped from 4.4% to 0.9%, etc.). The interspacing between the graphene layers in the anthracite structure also increased after the heat treatment. Besides, on extending the heating time, the anthracite structure became more disordered than the samples heated for shorter times. Therefore, the intercalation ability of Na+ ions in the anthracite structure increased, and the sample heated at 900 °C for 6 hours exhibited the highest reversible capacity of up to 160 mA h g-1 with adequate capacity retention after 100 cycles at C/10 rate.


Relationship between predictors of the risk of clinical progression of benign prostatic hyperplasia and metabolic syndrome in men with moderate to severe lower urinary tract symptoms.
To investigate the association between the metabolic syndrome (MetS) and the predictors of the progression of benign prostatic hyperplasia (BPH). A total of 778 male police officers in their 50s with moderate to severe lower urinary tract symptoms (International Prostate Symptom Score > 7) were included in the present study. We defined the predictors of the risk of clinical progression of BPH as the total prostate volume ≥31 cm(3), prostate-specific antigen level ≥1.6 ng/mL, maximal flow rate <10.6 mL/s, and postvoid residual urine volume of ≥39 mL. The MetS was defined using the National Cholesterol Education Program-Adult Treatment Panel III guidelines. We used the Mantel-Haenszel extension test and logistic regression analyses to statistically examine their relationship. The percentage of participants with ≥1 predictor for the progression of BPH, the percentage of participants with a total prostate volume of ≥31 cm(3), and the percentage of participants with a postvoid residual urine volume of ≥39 mL increased significantly with the increase in the number of components of the MetS (P = .003, P = .001, and P = .007, respectively). After adjusting for age and serum testosterone levels, the MetS was shown to be significantly associated with the presence ≥1 predictor for the progression of BPH (odds ratio 1.423, 95% confidence interval 1.020-1.986). Our data have shown that the MetS is associated with the predictors of the risk of clinical progression of BPH in men in their 50s with moderate to severe lower urinary tract symptoms.


N-[(E)-4-Bromo-benzyl-idene]-3,4-di-methyl-aniline.
In the title compound, C15H14BrN, the dihedral angle between the benzene rings is 6.4 (2)° and the mol-ecule has an E conformation about the C=N bond. In the crystal, mol-ecules are linked by C-H⋯π inter-actions, forming two-dimensional networks lying parallel to (001).


Cross-reactivity of mouse monoclonal antibodies produced by in vitro or in vivo immunization.
The effect of different immunization schemes on the resulting antibody specificity was investigated. The cross-reactivity of monoclonal antibodies produced by in vitro vs. in vivo immunization was tested, using a solid phase enzyme immunoassay. Ten different monoclonal antibodies were tested against 15 different antigens. There was no difference in cross-reactivity between the two types of antibodies when tested against antigens coated onto the plastic wells in a buffer solution. When the antigens were dried onto the plastic wells the IgM monoclonal antibodies produced by in vitro immunization exhibited a somewhat different reactivity pattern. However, the assay design was shown to be of more importance than the immunization procedure when determining antibody specificities.


Circadian rhythms of lipid and apolipoprotein pattern in adult fasted rats.
Data on circadian rhythms of serum lipids and apolipoproteins in animals and in human subjects are scarce. The goal of this study was to investigate the existence of circadian rhythms in the lipids and apolipoproteins of fasted rats. We showed that in fasted rats well-defined circadian rhythms were present in total serum triglycerides and in cholesterol and triglycerides of very low density lipoprotein (VLDL), intermediate density lipoprotein-low density lipoprotein (IDL-LDL) and high density lipoprotein (HDL). Moreover, our data clearly show that the circadian rhythm of lipoproteins is accompanied by a well defined circadian rhythm of B apoprotein, in all lipoprotein classes examined.


Modulation in growth, biochemical attributes and proteome profile of rice cultivars under salt stress.
One of the major abiotic stresses that affect productivity of rice is salinity. Rice cultivars showed significant genetic variation in response to salt stress. In the present investigation, differential growth pattern and physio-chemical traits-based screening of high yielding rice cultivars of various salt affected areas of India was carried out, and salt-sensitive and salt-tolerant cultivars were identified. Differential responses of antioxidant enzyme activity and tolerance index at maximum level of salt treatment depicted that Jhelum and Vytilla-4 cultivars of rice were sensitive and tolerant to salt stress, respectively. Analysis of growth, morpho-physiological, and biochemical parameters also confirmed the salt-tolerant and salt-sensitive characters of cv. Vytilla-4 and cv. Jhelum, respectively. Nano-LCMS/MS-based proteome profile of these two cultivars was carried out to find out the mechanism lying behind the salt tolerance. A total number of 514 and 770 protein spots were reported in the most salt-tolerant (cv. Vytilla-4) and salt-sensitive (cv. Jhelum) cultivars, respectively. The differentially expressed proteins (DEPs) were found associated with major metabolic pathways including photosynthesis, energy metabolism, amino acid metabolism, nitrogen assimilation and stress and signalling pathways. The changes in the major proteins like Ribulose bisphosphate carboxylase small chain, chlorophyll a-b binding protein, phosphoglycerate kinase, cytochrome c oxidase subunit 5C, glutamine synthetase, glutathione S-transferase, peroxidase, and thioredoxin elucidated the mechanism activated by salt-tolerant cv. Vytilla-4. The transcriptional validation of some of the differentially expressed proteins through real-time quantitative PCR analysis further validated the proteomic results. Outcomes of this work could help in finding out the potential cross-links of different pathways involved in salt-tolerance mechanisms operating in the studied here rice cultivars under salt stress.


Left ventricular flow propagation velocity measurement: Is it cast in stone?
This study aims to investigate the measurement of left ventricular flow propagation velocity, V p, using phase contrast magnetic resonance imaging and to assess the discrepancies resulting from inflow jet direction and individual left ventricular size. Three V p measuring techniques, namely non-adaptive (NA), adaptive positions (AP) and adaptive vectors (AV) method, were suggested and compared. We performed the comparison on nine healthy volunteers and nine post-infarct patients at four measurement positions, respectively, at one-third, one-half, two-thirds and the conventional 4 cm distances from the mitral valve leaflet into the left ventricle. We found that the V p measurement was affected by both the inflow jet direction and measurement positions. Both NA and AP methods overestimated V p, especially in dilated left ventricles, while the AV method showed the strongest correlation with the isovolumic relaxation myocardial strain rate (r = 0.53, p < 0.05). Using the AV method, notable difference in mean V p was also observed between healthy volunteers and post-infarct patients at positions of: one-half (81 ± 31 vs. 58 ± 25 cm/s), two-thirds (89 ± 32 vs. 45 ± 15 cm/s) and 4 cm (98 ± 23 vs. 47 ± 13 cm/s) distances. The use of AV method and measurement position at one-half distance was found to be the most suitable method for assessing diastolic dysfunction given varying left ventricular sizes and inflow jet directions.


Outcomes following balloon tibioplasty versus conventional osteosynthesis techniques for Schatzker type III tibial plateau fractures: a systematic review.
Schatzker type III fractures of the tibial plateau require elevation of the depressed portions to regain articular congruity. Balloon tibioplasty has been used as an alternative to conventional metal instruments for elevation of the lateral tibial plateau. This study compared functional outcomes following balloon tibioplasty or conventional osteosynthesis techniques in patients with type III fractures of the tibial plateau. A systematic literature search was performed using PubMed, EMBASE, and Cochrane Library to identify studies published through March 29, 2021, pertaining to balloon tibioplasty or conventional osteosynthesis techniques for type III fractures. Non-human studies, opinion or editorial pieces, systematic reviews, case series (< 5 patients), and articles published in a non-English language were excluded. Primary outcomes were Rasmussen clinical score, range of motion, and Knee Society Score (KSS). A Joanna Briggs Institute (JBI) risk of bias assessment was performed for all studies. A total of 95 studies were identified, with 10 studies (and 132 total patients) meeting inclusion criteria: 1 study focused on balloon tibioplasty, 8 studies reported outcomes following conventional osteosynthesis, and 1 study compared outcomes of the two techniques. Mean follow-up times varied widely, from 4 to 76.3 months. Where reported, balloon tibioplasty resulted in good to excellent functional outcomes as indicated by Rasmussen clinical scores (mean 28.3 in a case series; mean 28.9 in a randomized controlled trial) and range of motion (≥ 140° in both studies) 1-2 years following surgery. KSS was not reported consistently enough for comparison. Studies ranged from low to high risk of bias according to the JBI assessment. Balloon tibioplasty can lead to excellent functional outcomes in patients with depression fractures of the lateral tibial plateau. More research is needed to directly compare outcomes following treatment with balloon tibioplasty or conventional osteosynthesis techniques.


Cardiovascular manifestations in idiopathic inflammatory myopathies.
Cardiovascular involvement in idiopathic inflammatory myopathies (IIM) is an understudied area which is gaining increasing recognition in recent times. Recent advances in imaging modalities and biomarkers have allowed the detection of subclinical cardiovascular manifestations in IIM. However, despite the availability of these tools, the diagnostic challenges and underestimated prevalence of cardiovascular involvement in these patients remain significant. Notably, cardiovascular involvement remains one of the leading causes of mortality in patients with IIM. In this narrative literature review, we outline the prevalence and characteristics of cardiovascular involvement in IIM. Additionally, we explore investigational modalities for early detection of cardiovascular involvement, as well as newer approaches in screening to facilitate timely management. Key points • Cardiac involvement in IIM in majority cases is subclinical and a major cause of mortality. • Cardiac magnetic resonance imaging is sensitive for detection of subclinical cardiac involvement.


Occurrence ofFusarium toxins in the 1999's harvest.
Continuing the monitoring ofFusarium toxins in cereals, we investigated 245 samples of wheat, barley, triticale and oats in 1999. 84 samples out of 100 analysed forFusarium could be found to be infected. The most prominentFusarium species detected whereF. avenaceum, F. poae, F. detected whereF. avenaceum, F. poae, F. graminearum, andF. sporotrichoides. The level of mycotoxin contamination of the samples varied depending on their origins and was in general very low in comparison with the result obtained in samples of the previous year. There where only some wheat samples with deoxynivalenol (DON) concentrations beyond existing advisory levels. The average DON concentration of all samples was 0.35 mg/kg with a median of 0.007 mg/kg. 3-Acetyldeoxynivalenol and zearalenone (ZEA) could only be detected at minor concentrations (below 0.1 and 0.05 mg/kg, respectively) in less than 10% of the samples. The analysis of commercial cereal flour reflects this situation. Flour bought in the first quarter of 1999, which was suspected to contain a high portion of the 1998 harvest, was contaminated by DON to a higher extent than those purchased in 2000. The average DON concentration in the flour samples of 1999 and 2000 was 0.35 mg/kg and 0.23 mg/kg, respectively. Although the general mycotoxin level in the 1999 harvest was lower as in 1998 there were some highly contaminated samples that had mainly been grown in fields with either maize or other cereals as previous crop and reduced tillage. The combination of maize as previous crop and non-tillage could be stated as most unsuitable, which promotes enhanced mycotoxin contamination, and should therefore be avoided.


[Philosophical and ethics aspects of the composite tissues allotransplantations (CTA)].
The first successes of total hand and partial face transplants raise several philosophical and ethical questions. This paper examines the perspective of the recipient, the donor and the social aspect. The question of the identity remains unsolved. Philosophical point of view shows an historical continuity in the desire of the human being for improving his condition.


Biohythane production from food waste in a two-stage process: assessing the energy recovery potential.
ABSTRACTBiohythane (hydrogen + methane) production in a two stage dark fermentation (DF) and anaerobic digestion (AD) process from food waste (FW) has been studied. This paper investigated the effect of operation temperature, i.e. mesophilic (34 °C) and thermophilic (55 °C) , on biohythane yield and total energy recovery carried out at the initial culture pH 5.5 and pH 7, respectively for DF and AD batch tests. The mesophilic DF tests gave a higher hydrogen yield of 53.5 (±4) mL H2/g VS added compared to thermophilic DF tests, i.e. 37.6 (±1) mL H2/g VS added. However, higher methane yields, i.e. 307.5 (± 10) mL CH4/g VS, were obtained at thermophilic AD tests compared to mesophilic AD, i.e. 276.5 (±4.3) mL CH4/g VS. The total energy recovery from thermophilic DF + AD was higher (11.4 MJ/kg VS) than the mesophilic (10.4 MJ/kg VS) combined process. Interestingly, the analysis of kinetic parameters of mesophilic tests, determined from the Modified Gompertz equation, showed that mesophilic DF had faster H2 production kinetics, which can be attributed to a faster adaptation of the heat-shocked inoculum used in the tests to the incubation temperature. However, thermophilic AD tests exhibited faster kinetics for methane production.


Quantitative aspects of a unified model of diffusion mediated receptor--cyclase coupling.
A quantitative model is presented of diffusion mediated coupling of adenylate cyclase to multivalent plasma membrane receptors which accounts for a wide range of phenomena including non linear occupation-activation plots with either positive or negative second derivatives, spare receptors, silent receptors, and negative and positive binding cooperativity. A non linear least square fit of the predicted equation for cyclase activation to available data predicts translational diffusion coefficients in the range of (10(-10) - 10(-11))cm2/s.


Chilled, starved or frozen: insect mitochondrial adaptations to overcome the cold.
Physiological adaptations to tackle cold exposure are crucial for insects living in temperate and arctic environments and here we review how cold adaptation is manifested in terms of mitochondrial function. Cold challenges are diverse, and different insect species have evolved metabolic and mitochondrial adaptations to i) energize homeostatic regulation at low temperatures ii) stretch energy reserves during prolonged cold exposure, and iii) preserve the structural organization of organelles following extracellular freezing. While the literature is still sparse, our review suggests that cold-adapted insects preserve ATP production at low temperatures by maintaining preferred mitochondrial substrate oxidation, which is otherwise challenged in cold-sensitive species. Chronic cold exposure and metabolic depression during dormancy are linked to reduced mitochondrial metabolism and may involve mitochondrial degradation. Finally, adaptation to extracellular freezing could be associated with the superior structural integrity of the mitochondrial inner membrane following freezing which is linked to cellular and organismal survival.


Effect of high pressure ammoniation procedure on the detoxification of aflatoxins.
Ammoniation represents the best technique to detoxify aflatoxin-contaminated grain and it is considered as economically practicable for commercial applications. In the present studyAspergillus parasiticus was used to contaminate yellow corn to produce the final concentration reached 4000 μg/kg corn total aflatoxin. Two procedures of ammoniation (in aqueous ammonia concentrations, 0.25, 0.5, 1, 1.5 and 2% ) were adopted for aflatoxin destruction. The first procedure was under atmospheric pressure at ambient temperature (AP/AT) for 24 hrs, and the second procedure was under high pressure (2 bar) at high temperature (121°C) (HP/HT ) for 15 min. Aflatoxin concentrations were determined by HPLC using fluorescence detection. The effect of HP/HT procedure was compared with the ammoniation procedure under AP/AT. The detoxification pattern of the two ammoniation procedures as well as the detoxification pattern of the different types of aflatoxins under the two procedures was studied.


Decreased surface and bottom salinity and elevated bottom temperature in the Northern Baltic Sea over the past six decades.
Temperature and salinity are key factors in controlling marine habitats and gas fluxes. Finnish and Swedish temperature and salinity monitoring data from the northern Baltic Sea since the 1960s, and Argo buoy data from the eastern Gotland Basin and the Bothnian Sea from 2012 to 2021 were examined using linear trend analysis. Since the 1960's near-bottom temperature has increased by 0.75-2.9 °C (0.013-0.115 °C/a) and surface salinity declined by 0.31-1.14 units (0.005-0.019/a). Surface temperature trends at monitoring stations were negative (16 cases out of 33) but deemed unreliable. Near-bottom salinity has declined by 0.35-1.45 units (0.007-0.025/a), except in the northern Baltic Proper and the central-eastern Gulf of Finland. Most rapid increases in near-bottom temperature have occurred after 1993, especially in the northern Baltic Proper and the Gulf of Finland. Argo data corroborated declining surface salinity in the eastern Gotland Basin, increasing deep-water temperature in the eastern Gotland Basin and the Bothnian Sea and increasing deep-water salinity in the eastern Gotland Basin. Argo data from 2013 to 2021 indicated deep-water temperature increase in the Gotland basin was more rapid than the concomitant salinity increase and is probably related to global change.


Penicamedine A, a Highly Oxygenated Hexacyclic Indole Alkaloid from Penicillium camemberti.
A highly oxygenated hexacyclic indole alkaloid, penicamedine A (1), bearing a rare furan ring, was isolated from the culture broth of Penicillium camemberti, together with two known analogs, iso-α-cyclopiazonic acid (2) and cyclopiazonic acid (3). The structure of 1 was elucidated by comprehensive spectroscopic analyses including NMR and HR-ESI-MS. Its absolute configuration was further confirmed unambiguously by single-crystal X-ray diffraction analysis. Compound 1 was evaluated for anti-HIV activity with p24 assays and tested for cytotoxic activities against five human cancer cell lines, including HL-60, SMMC-7721, A-549, MCF-7, SW480, and the immortalized non-cancerous human pulmonary epithelial cell line BEAS-2B by MTS method.


The evolutionary origin of jaw yaw in mammals.
Theria comprises all but three living mammalian genera and is one of the most ecologically pervasive clades on Earth. Yet, the origin and early history of therians and their close relatives (i.e., cladotherians) remains surprisingly enigmatic. A critical biological function that can be compared among early mammal groups is mastication. Morphometrics and modeling analyses of the jaws of Mesozoic mammals indicate that cladotherians evolved musculoskeletal anatomies that increase mechanical advantage during jaw rotation around a dorsoventrally-oriented axis (i.e., yaw) while decreasing the mechanical advantage of jaw rotation around a mediolaterally-oriented axis (i.e., pitch). These changes parallel molar transformations in early cladotherians that indicate their chewing cycles included significant transverse movement, likely produced via yaw rotation. Thus, I hypothesize that cladotherian molar morphologies and musculoskeletal jaw anatomies evolved concurrently with increased yaw rotation of the jaw during chewing cycles. The increased transverse movement resulting from yaw rotation may have been a crucial evolutionary prerequisite for the functionally versatile tribosphenic molar morphology, which underlies the molars of all therians and is retained by many extant clades.


Effect of Metformin Added to Insulin on Glycemic Control Among Overweight/Obese Adolescents With Type 1 Diabetes: A Randomized Clinical Trial.
Previous studies assessing the effect of metformin on glycemic control in adolescents with type 1 diabetes have produced inconclusive results. To assess the efficacy and safety of metformin as an adjunct to insulin in treating overweight adolescents with type 1 diabetes. Multicenter (26 pediatric endocrinology clinics), double-blind, placebo-controlled randomized clinical trial involving 140 adolescents aged 12.1 to 19.6 years (mean [SD] 15.3 [1.7] years) with mean type 1 diabetes duration 7.0 (3.3) years, mean body mass index (BMI) 94th (4) percentile, mean total daily insulin 1.1 (0.2) U/kg, and mean HbA1c 8.8% (0.7%). Randomization to receive metformin (n = 71) (≤2000 mg/d) or placebo (n = 69). Primary outcome was change in HbA1c from baseline to 26 weeks adjusted for baseline HbA1c. Secondary outcomes included change in blinded continuous glucose monitor indices, total daily insulin, BMI, waist circumference, body composition, blood pressure, and lipids. Between October 2013 and February 2014, 140 participants were enrolled. Baseline HbA1c was 8.8% in each group. At 13-week follow-up, reduction in HbA1c was greater with metformin (-0.2%) than placebo (0.1%; mean difference, -0.3% [95% CI, -0.6% to 0.0%]; P = .02). However, this differential effect was not sustained at 26-week follow up when mean change in HbA1c from baseline was 0.2% in each group (mean difference, 0% [95% CI, -0.3% to 0.3%]; P = .92). At 26-week follow-up, total daily insulin per kg of body weight was reduced by at least 25% from baseline among 23% (16) of participants in the metformin group vs 1% (1) of participants in the placebo group (mean difference, 21% [95% CI, 11% to 32%]; P = .003), and 24% (17) of participants in the metformin group and 7% (5) of participants in the placebo group had a reduction in BMI z score of 10% or greater from baseline to 26 weeks (mean difference, 17% [95% CI, 5% to 29%]; P = .01). Gastrointestinal adverse events were reported by more participants in the metformin group than in the placebo group (mean difference, 36% [95% CI, 19% to 51%]; P < .001). Among overweight adolescents with type 1 diabetes, the addition of metformin to insulin did not improve glycemic control after 6 months. Of multiple secondary end points, findings favored metformin only for insulin dose and measures of adiposity; conversely, use of metformin resulted in an increased risk for gastrointestinal adverse events. These results do not support prescribing metformin to overweight adolescents with type 1 diabetes to improve glycemic control. clinicaltrials.org Identifier: NCT01881828.


Screening for visual and ocular disorders in children, evaluation of the system in Sweden.
The aim of this study was to evaluate the visual screening system in Sweden. We have made a retrospective investigation of the results of screening for ocular disease and visual impairment of all children born in 1982 in three Swedish communities. The records from screening examinations from 0 to 10 y and from diagnostic follow-up at the departments of ophthalmology that the children were referred to were inspected. The data were used to evaluate the efficiency of the Swedish visual screening system. The study included 3126 children. The attendance rate at the 4-y examination was better than 99%. The sensitivity of the 4- and 5.5-y screening examinations was on the average 92% and the specificity was 97%. The average number of false negative cases at 4 y was 5.6 in 1000 (0.56%). With this screening and subsequent diagnosis and treatment, the prevalence of amblyopia at different levels of visual acuity at the age of 10 y was: 0.06% with visual acuity < or = 0.1, 0.9% with visual acuity < or = 0.5 and 1.7% with visual acuity < or = 0.7. In spite of largely unchanged pressure of amblyogenic factors in the population, the prevalence of deep and moderate amblyopia has been markedly reduced by screening and early treatment.


Endoscopic stapling for pharyngeal pouch: does it make the cut?
Endoscopic stapling to treat pharyngeal pouch is a relatively new technique with the potential to reduce the morbidity associated with the open approach for pharyngeal pouch. Despite enthusiasm for the endoscopic approach there have been no series reported in Australia, and descriptions of outcomes and benefits are currently anecdotal. The aim of the present study was to determine the outcome associated with endoscopic stapling of pharyngeal pouch in an Australian setting. All patients admitted for endoscopic stapling for a pharyngeal pouch between 1998 and 2002 by surgeons from the Adelaide and Flinders Universities were identified, and their medical records were reviewed for clinical and operative details. All patients were interviewed by telephone using a structured questionnaire to determine symptom resolution and patient satisfaction. The Likert scale was used to assess the impact of preoperative and postoperative symptoms upon quality of life. A total of 31 patients were identified. The mean age of the group was 75 years (range: 35-91 years) and half the patients had an American Society of Anesthesiologists physical status score of 3 or greater. In four patients the procedure was abandoned; (for three because of inability to pass the diverticuloscope and for one because the pouch was too small). Standard open surgery was undertaken in these patients. Of the 27 procedures completed endoscopically, interview follow up was obtained in 23, at a mean follow up of 17 months (range: 2-68 months). Outcome was very good or excellent in 21 (91%), with significant symptom resolution, reduction in Likert scores and high patient satisfaction. Three patients had previously had pouch surgery and endoscopic stapling was straightforward in these patients. Recurrence of a symptomatic pouch occurred in three patients. There was no significant morbidity related to the procedure. The early experience of endoscopic stapling for pharyngeal pouch in Adelaide is encouraging. The procedure achieves excellent control of symptoms and can be undertaken with minimal morbidity. Recurrence may be a problem, although repeat endoscopic stapling can be undertaken without difficulty.


Active control of lateral balance in human walking.
We measured variability of foot placement during gait to test whether lateral balance must be actively controlled against dynamic instability. The hypothesis was developed using a simple dynamical model that can walk down a slight incline with a periodic gait resembling that of humans. This gait is entirely passive except that it requires active control for a single unstable mode, confined mainly to lateral motion. An especially efficient means of controlling this instability is to adjust lateral foot placement. We hypothesized that similar active feedback control is performed by humans, with fore-aft dynamics stabilized either passively or by very low-level control. The model predicts that uncertainty within the active feedback loop should result in variability in foot placement that is larger laterally than fore-aft. In addition, loss of sensory information such as by closing the eyes should result in larger increases in lateral variability. The control model also predicts a slight coupling between step width and length. We tested 15 young normal human subjects and found that lateral variability was 79% larger than fore-aft variability with eyes open, and a larger increase in lateral variability (53% vs. 21%) with eyes closed, consistent with the model's predictions. We also found that the coupling between lateral and fore-aft foot placements was consistent with a value of 0.13 predicted by the control model. Our results imply that humans may harness passive dynamic properties of the limbs in the sagittal plane, but must provide significant active control in order to stabilize lateral motion.


Synthesis of herpes simplex virus DNA in preparations of chromatin from infected cell nuclei.
Chromatin prepared from cells infected with Herpes simplex virus type 1 or type 2 can synthesize both virus and cell DNA in vitro. The rate of synthesis is comparable to that of isolated whole nuclei. Incorporation is limited, and both cell and virus DNA synthesis are sensitive to the presence of virus-specific antiserum and phosphonoacetate. In chromatin from cells infected with a phosphonoacetate resistant virus mutant, both types of DNA synthesis are resistant to the presence of the inhibitor.


Herbal preparations for the treatment of hair loss.
Though hair does not serve any crucial physiological function in modern humans, it plays an important role in our self-esteem. Androgenic baldness (androgenic alopecia) and circular/spot baldness (alopecia areata) are the most common forms of hair loss. Many active ingredients of synthetic origin are available for treatment; however, they have a number of limitations. Their effectiveness and safety are questionable and the amount of time needed to achieve the effect is both long and unclear. This has increased interest in finding an alternative approach against hair loss using preparations containing plants and/or their isolated active ingredients. A number of studies (mostly randomized, placebo-controlled) of plants and preparations made of plants have been performed to confirm their effectiveness in treating hair loss. The plants with the most evidence-based effect against alopecia are Curcuma aeruginosa (pink and blue ginger), Serenoa repens (palmetto), Cucurbita pepo (pumpkin), Trifolium pratense (red clover), and Panax ginseng (Chinese red ginseng). The assumed mechanism of action is predominately inhibition of 5α-reductase, with enhanced nutritional support and scalp blood circulation playing a role as well.


Strategical isolation of efficient chicken feather-degrading bacterial strains from tea plantation soil sample.
Chicken feather waste is generally insufficiently utilized despite its high content of protein, constituting an environmental issue. Biodegradation of the waste with enabling microbes provides an advantageous option among the available solutions. In this study, an efficient whole feather-degrading strain was strategically isolated from a soil sample taken from a local tea plantation that has little or nothing to do with feathers. The strain was identified as Bacillus thuringiensis (designated as FDB-10) according to the cloned complete 16S rRNA sequence. The FDB-10 could efficiently degrade briefly heat-treated whole feather (102 °C, 5 min; up to 90% of a maximum concentration of 30 g/L) in a salt medium supplemented with 0.1 g/L yeast extract within 24 h (37 °C, 150 rpm). Addition of carbon sources (glycerol, glucose, starch, Tween 20, Tween 80, 1.25 g/L as glycerol) to the fermentation medium could improve the degradation. However, significant inhibition could be observed when the added carbon source reached the amount usually adopted in the investigation of carbon source preference (1%). Nitrogen source (NH4Cl, (NH4)2SO4, peptone) adversely influenced the performance of the strain. When the molar concentrations of NH4+ were equal for the two salt, the inhibitory effect on degradation of whole feathers was similar. Entirely different from other reported feather-degrading strains showing a preference to melanin-free feather substrates, the strain isolated in this study could degrade melanin-containing feather equally efficiently, and higher protease activity could be detected in the digest mix. As a plus, the strain could degrade feathers in rice wash produced in daily cooking, indicating its potential use in the simultaneous treatment of rice cooker wastewater produced by a rice processing plant. All these results imply that the FDB-10 is a strain with great potential in the biodegradation of feather waste.


Biochemical evidence for an alternate pathway in N-linked glycoprotein biosynthesis.
Asparagine-linked glycosylation is a complex protein modification conserved among all three domains of life. Herein we report the in vitro analysis of N-linked glycosylation from the methanogenic archaeon Methanococcus voltae. Using a suite of synthetic and semisynthetic substrates, we show that AglK initiates N-linked glycosylation in M. voltae through the formation of α-linked dolichyl monophosphate N-acetylglucosamine, which contrasts with the polyprenyl diphosphate intermediates that feature in both eukaryotes and bacteria. Notably, AglK has high sequence homology to dolichyl phosphate β-glucosyltransferases, including Alg5 in eukaryotes, suggesting a common evolutionary origin. The combined action of the first two enzymes, AglK and AglC, afforded an α-linked dolichyl monophosphate glycan that serves as a competent substrate for the archaeal oligosaccharyl transferase AglB. These studies provide what is to our knowledge the first biochemical evidence revealing that, despite the apparent similarity of the overall pathways, there are actually two general strategies to achieve N-linked glycoproteins across the domains of life.


Association of statin use with a pathologic complete response to neoadjuvant chemoradiation for rectal cancer.
To assess whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, might enhance the efficacy of neoadjuvant chemoradiation in rectal cancer. Between 1996 and 2001, 358 patients with clinically resectable, nonmetastatic rectal cancer underwent surgery at Memorial Sloan-Kettering Cancer Center after neoadjuvant chemoradiation for either locally advanced tumors or low-lying tumors that would require abdominoperineal resection. We excluded 9 patients for radiation therapy dose <45 Gy or if statin use was unknown, leaving 349 evaluable patients. Median radiation therapy dose was 50.4 Gy (range, 45-55.8 Gy), and 308 patients (88%) received 5-fluorouracil-based chemotherapy. Medication use, comorbid illnesses, clinical stage as assessed by digital rectal examination and ultrasound, and type of chemotherapy were analyzed for associations with pathologic complete response (pCR), defined as no microscopic evidence of tumor. Fisher's exact test was used for categoric variables, Mantel-Haenszel test for ordered categoric variables, and logistic regression for multivariate analysis. Thirty-three patients (9%) used a statin, with no differences in clinical stage according to digital rectal examination or ultrasound compared with the other 324 patients. At the time of surgery, 23 nonstatin patients (7%) were found to have metastatic disease, compared with 0% for statin patients. The unadjusted pCR rates with and without statin use were 30% and 17%, respectively (p = 0.10). Variables significant univariately at the p = 0.15 level were entered into a multivariate model, as were nonsteroidal anti-inflammatory drugs (NSAIDs), which were strongly associated with statin use. The odds ratio for statin use on pCR was 4.2 (95% confidence interval, 1.7-12.1; p = 0.003) after adjusting for NSAID use, clinical stage, and type of chemotherapy. In multivariate analysis, statin use is associated with an improved pCR rate after neoadjuvant chemoradiation for rectal cancer. The low prevalence of statin use limits the power to detect a significant difference at a type I error threshold of p = 0.05 in this analysis. Although no definitive conclusions can be drawn on the basis of this retrospective study, the unusually high incidence of pCR after chemoradiation suggests that the use of statins in the treatment of rectal cancer warrants further evaluation.


Second hyperpolarizability of delta shaped disubstituted acetylene complexes of beryllium, magnesium, and calcium.
Present theoretical study involves the delta shape complexes of beryllium, magnesium, and calcium where the metal atom interacts perpendicularly with disubstituted acetylene. Most of the complexes are found to be fairly stable. The dependence of second-hyperpolarizability on the basis set with increasing polarization and diffuse functions has been examined which showed the importance of 'f-type' type polarization function for heavy metal (Mg, Ca) and 'd-type' polarization function for beryllium. Larger second hyperpolarizability has been predicted for complexes having significant ground state polarization and low lying excited states favoring strong electronic coupling. Transition energy plays the most significant role in modulating the second hyperpolarizability.


[Behavior of plutonium in the body of rats following its intragastric administration in a complex with tributyl phosphate].
A study was made of the distribution of plutonium-239 within the rat body after single intragastric administration thereof (1.85 MBq) in a mixture with tributyl phosphate (TBP) and as Pu(IV) nitrate at a time interval from 4 min to 512 days. It was shown that the distribution of the radionuclide was virtually the same but its absorption from the gastrointestinal tract with Pu-TBP was higher by one order of magnitude and exceeded the value recommended by ICRP for soluble plutonium compounds.


Activation of thiamine diphosphate in pyruvate decarboxylase from Zymomonas mobilis.
Replacement of tryptophan 392 located in the active site cavity of pyruvate decarboxylase (PDC; EC 22.214.171.124) from Zymomonas mobilis by methionine or glutamine yields enzymes with smaller catalytic constants of 8.5 s(-1) and 3.6 s(-1) at 4 degrees C, compared to that of the wild-type enzyme (17 s(-1)). The rate constants of the H/D exchange at the C2 of the coenzyme thiamine diphosphate have been determined to be 130 s(-1) for the wild-type enzyme, 56 s(-1) for the methionine and 30 s(-1) for the glutamine mutant, respectively. A group with a pKa of about 5 has been identified to be essential for C2 deprotonation of the enzyme-bound thiamine diphosphate from the pH dependence of the H/D exchange.


Catastrophic brain injury after nicotine insecticide ingestion.
Much attention has been paid to the long-term toxic and carcinogenic effects of nicotine-containing substances, particularly tobacco. Although rare, acute ingestions of large amounts of nicotine can produce rapid and dramatic toxicity. We present a case of an ingestion of a nicotine sulfate solution by a 15-year-old boy resulting in hypoxia and irreversible encephalopathy. The diagnosis of acute nicotine toxicity potentially could be delayed due to the fact that nicotine and cotinine are so commonly found on drug screens that they are considered "normal variants."


Radiotherapy in oncological emergencies: fast-track treatment planning.
To report on our clinical experience with a newly implemented workflow for radiotherapy (RT) emergency treatments, which allows for a fast treatment application outside the regular working-hours, and its clinical applicability. Treatment planning of 18 emergency RT patients was carried out using diagnostic computed tomography (CT) without a dedicated RT simulation CT. The cone-beam CT (CBCT) deviations of the first RT treatment were analyzed regarding setup accuracy. Furthermore, feasibility of the "fast-track" workflow was evaluated with respect to dose deviations caused by different Hounsfield unit (HU) to relative electron density (rED) calibrations and RT treatment couch surface shapes via 3D gamma index analysis of exemplary treatment plans. The dosimetric uncertainty introduced by different CT calibrations was quantified. Mean patient setup vs. CBCT isocenter deviations were (0.49 ± 0.44) cm (x), (2.68 ± 1.63) cm (y) and (1.80 ± 1.06) cm (z) for lateral, longitudinal and vertical directions, respectively. Three out of four dose comparisons between the emergency RT plan calculated on the diagnostic CT and the same plan calculated on the treatment planning CT showed clinically acceptable gamma passing rates, when correcting for surface artifacts. The maximum difference of rED was 0.054, while most parts of the CT calibration curves coincided well. In an emergency RT setting, the use of diagnostic CT data for treatment planning might be time-saving and was shown to be suitable for many cases, considering reproducibility of patient setup, accuracy of initial patient setup and accuracy of dose-calculation.


Generating alternatives: a key component in human reasoning?
According to mental models theory, a key aspect of deductive reasoning is the production of alternative models that can falsify provisional conclusions. In the present paper, the possibility is investigated that there are individual differences in the ability to produce alternative models. The results indicate that some people do not proceed beyond the first model when they reason with syllogisms but that others do. Furthermore, the ability to generate alternatives can be independently measured by asking participants to generate different representations of pairs of premises. These findings support the predictions of mental models theory and also indicate the potential importance of alternatives generation as a measure of individual differences in processing style.


Characteristics of worker accidents on NYSDOT construction projects.
This paper aims at providing cost-effective safety measures to protect construction workers in highway work zones, based on real data. Two types of accidents that occur in work zones were: (a) construction work area accidents, and (b) traffic accidents involving construction worker(s). A detailed analysis of work zone accidents involving 36 fatalities and 3,055 severe injuries to construction workers on New York State Department of Transportation (NYSDOT) construction projects from 1990 to 2001 established that five accident types: (a) Struck/Pinned by Large Equipment, (b) Trip or Fall (elevated), (c) Contact w/Electrical or Gas Utility, (d) Struck-by Moving/Falling Load, and (e) Crane/Lift Device Failure accounted for nearly 96% of the fatal accidents, nearly 63% of the hospital-level injury accidents, and nearly 91% of the total costs. These construction work area accidents had a total cost of $133.8 million. Traffic accidents that involve contractors' employees were also examined. Statistical analyses of the traffic accidents established that five traffic accident types: (a) Work Space Intrusion, (b) Worker Struck-by Vehicle Inside Work Space, (c) Flagger Struck-by Vehicle, (d) Worker Struck-by Vehicle Entering/Exiting Work Space, and (e) Construction Equipment Struck-by Vehicle Inside Work Space accounted for nearly 86% of the fatal, nearly 70% of the hospital-level injury and minor injury traffic accidents, and $45.4 million (79.4%) of the total traffic accident costs. The results of this paper provide real statistics on construction worker related accidents reported on construction work zones. Potential preventions based on real statistics have also been suggested. The ranking of accident types, both within the work area as well as in traffic, will guide the heavy highway contractor and owner agencies in identifying the most cost effective safety preventions.


Novel quinolines carrying pyridine, thienopyridine, isoquinoline, thiazolidine, thiazole and thiophene moieties as potential anticancer agents.
As a part of ongoing studies in developing new anticancer agents, novel 1,2-dihydropyridine 4, thienopyridine 5, isoquinolines 6-20, acrylamide 21, thiazolidine 22, thiazoles 23-29 and thiophenes 33-35 bearing a biologically active quinoline nucleus were synthesized. The structure of newly synthesized compounds was confirmed on the basis of elemental analyses and spectral data. All the newly synthesized compounds were evaluated for their cytotoxic activity against the breast cancer cell line MCF7. 2,3-Dihydrothiazole-5-carboxamides 27, 25, 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (34), 1,2-dihydroisoquinoline-7-carbonitrile (7), 5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide (35), 1,2-dihydroisoquinoline-7-carbonitrile (6), 2-cyano-3-(dimethylamino)-N-(quinolin-3-yl)acrylamide (21), 1,2-dihydroisoquinoline-7-carbonitriles (11) and (8) exhibited higher activity (IC50 values of 27-45 μmol L-1) compared to doxorubicin (IC50 47.9 μmol L-1). LQ quinolin-3-yl)-1,2-dihydroisoquinoline-7-carbonitrile (12), 2-thioxo-2,3-dihydrothiazole-5-carboxamide (28) and quinolin-3-yl)-1,2-dihydroisoquinoline-7-carbonitrile (15) show activity comparable to doxorubicin, while (quinolin-3-yl)-1,2-dihydroisoquinoline-7-carbonitrile (9), 2,3-dihydrothiazole-5-carboxamide (24), thieno [3,4-c] pyridine-4(5H)-one (5), cyclopenta[b]thiophene-3-carboxamide (33) and (quinolin-3-yl)-6-stryl-1,2-dihydroisoquinoline-7-carbonitrile (10) exhibited moderate activity, lower than doxorubicin.


A randomized clinical trial comparing nelfinavir and ritonavir in patients with advanced HIV disease (CPCRA 042/CTN 102).
To compare the long-term clinical efficacy and toxicity of initial strategies of nelfinavir (NFV) or ritonavir (RTV) in patients with CD4+ cells below 200/mm3. This was an open-label randomized multicenter trial (CPCRA, CTN). Patients were naïve to protease inhibitor use except for hard gel saquinavir. Patients who were intolerant to their assigned therapy were allowed to switch arms (later RTV-intolerant patients could switch to indinavir). The primary objective was to compare the regimens for AIDS-defining conditions and death (AIDS/death) using intent-to-treat analysis. Hazard ratios (HR) for NFV and RTV were estimated using Cox's proportional hazards models. Kaplan-Meier life table summaries were also used to compare the two groups. There were 775 patients who were randomized beginning in January 1997 and followed through December 2001. At entry, mean CD4+ cell count was 58 cells/mm3 and HIV RNA level averaged 4.9 log copies/mL. After a median follow-up of 52 months, rates of AIDS/death were 12.7 and 11.0 per 100 person years for the NFV and RTV groups, respectively (HR=1.16; 95% CI, 0.92-1.46; p=.21). Discontinuations occurred earlier in the RTV group (p=.0001). There are moderate differences in efficacy and large differences in tolerability between a strategy of initial NFV or RTV in patients with advanced disease. Finding the right balance between potency and tolerability remains a challenge.


Anti-dormant mycobacterial activity and target analysis of nybomycin produced by a marine-derived Streptomyces sp.
In the course of our search for anti-dormant Mycobacterial substances, nybomycin (1) was re-discovered from the culture broth of a marine-derived Streptomyces sp. on the bioassay-guided separation. Compound 1 showed anti-microbial activity against Mycobacterium smegmatis and Mycobacterium bovis BCG with the MIC of 1.0μg/mL under both actively growing aerobic conditions and dormancy inducing hypoxic conditions. Compound 1 is also effective to Mycobacterium tuberculosis including the clinically isolated strains. The mechanistic analysis indicated that 1 bound to DNA and induces a unique morphological change to mycobacterial bacilli leading the bacterial cell death.


Proinflammatory cytokines found in amniotic fluid induce collagen remodeling, apoptosis, and biophysical weakening of cultured human fetal membranes.
The mechanisms by which fetal membranes (FM) rupture during the birth process are unknown. We have recently reported that FM weaken, at least in part, because of a developmental process of extracellular matrix remodeling and apoptosis. We now hypothesize that cytokines that normally increase in amniotic fluid at term induce FM collagen remodeling and apoptosis with concomitant weakening. Full-thickness FM fragments were cultured with (0-100 ng/ml) or without tumor necrosis factor (TNF) or interleukin 1, beta (IL1B). Physical properties were then examined with specially adapted industrial rupture strength testing equipment. Cultured FM were also evaluated for evidence of collagen remodeling and apoptosis. Cytokine-treated FM exhibited a dose-dependent decrease in strength and work to rupture. Compared with controls, the highest TNF dose caused maximal decrease in FM rupture strength (13.2 +/- 1.2 N versus 3.8 +/- 1.5 N; P = 0.0003) and work to rupture (0.035 +/- 0.005 J versus 0.005 +/- 0.002 J; P < 0.0001). The highest IL1B dose also decreased rupture strength (12.9 +/- 3.2 versus 4.6 +/- 1.1 N; P = 0.0027) and work to rupture (0.018 +/- 0.005 J versus 0.005 +/- 0.002 J; P < 0.01). Matrix metalloproteinase 9 (MMP9) protein increased, tissue inhibitor of matrix metalloproteinase 3 (TIMP3) protein decreased, and poly (ADP-ribose) polymerase (PARP1) cleavage increased with increasing TNF or IL1B doses (all P < 0.05), suggesting collagen remodeling and apoptosis. TNF and IL1B cause significant weakening of cultured FM. Both cytokines induce biochemical markers in the FM in a manner characteristic of the weak zone of FM overlying the cervix. TNF and or IL1B may be involved in the development of the weak zone of the FM.


The binding of spin-labeled derivatives of NAD+ and its structural components to pig skeletal muscle lactate dehydrogenase.
The binding of spin-labeled derivatives of NAD+ and its structural components to pig skeletal muscle lactate dehydrogenase (L-lactate:NAD+ oxidoreductase, EC 184.108.40.206) is described. In contrast to results previously obtained with the heart muscle isozyme (Wenzel, H.R., Pfleiderer, G., Trommer, W.E., Paschenda, K. and Redhardt, A. (1976) Biochim. Biophys. Acta 452,292--301), no significant increase is observed in the binding constant of N6-SL-ADP as compared N6-SL-AMP. This different behavior can be explained by the substitution of glutamine-31 for alanine in the muscle isozyme, which has been proposed to account for the the tighter binding of NADH to the heart type. In both isozymes the binding of the binding of the spin-labeled coenzyme itself is weaker than found for its structural components.


Switching of platelet P2Y12 receptor inhibitors in patients with acute coronary syndromes undergoing percutaneous coronary intervention: Review of the literature and practical considerations.
The combination of aspirin and a P2Y12 receptor inhibitor is the cornerstone of treatment in patients with acute coronary syndromes (ACSs) and in those undergoing percutaneous coronary intervention (PCI). At the present time, 3 different oral P2Y12 receptor inhibitors are available on the market; 2 have obtained the indication for ACS (clopidogrel and ticagrelor) and 1 for ACS with planned PCI (prasugrel). An intravenous direct acting P2Y12 inhibitor, cangrelor, has also been recently approved by US and European regulatory agencies for patients undergoing PCI. Although the correct timing and modality of transition from intravenous cangrelor to oral P2Y12 inhibitors is still controversial and needs further evidence, switching between oral P2Y12 receptor inhibitors frequently occurs in clinical practice for several reasons. This practice raises the question of the relative safety of this strategy and of which switching approaches are preferable. In this article, we review the data on switching antiplatelet treatment strategies with P2Y12 receptor inhibitors and discuss practical considerations for switching therapies in patients with ACS undergoing PCI.


Induction of rat liver angiotensinogen mRNA following acute inflammation.
Inflammatory responses of the angiotensinogen mRNA in rat liver and brain were examined by RNA blot-hybridization analysis with use of a cDNA probe specific for rat angiotensinogen. The angiotensinogen mRNA in the liver increased rapidly during the first 5 h following the administration of Escherichia coli lipopolysaccharide, and at maximum level of induction, the mRNA increased approximately 5-fold over its normal level. The levels of the mRNA increased with increasing doses of lipopolysaccharide, the half-maximal dose being approximately 1 microgram/100 g body weight. In contrast, no such increase was observed in the brain angiotensinogen mRNA. Thus, the expression of the rat angiotensinogen mRNA is regulated in a tissue-specific manner in response to induction of acute inflammation.