Exploring running styles in the field through cadence and duty factor modulation.
According to the dual-axis model, running styles can be defined by cadence and duty factor, variables that have been associated with running performance, economy and injury risk. To guide runners in exploring different running styles, effective instructions to modulate cadence and duty factor are needed. Such instructions have been established for treadmill running, but not for overground running, during which speed can be varied. In this study, five participants completed eight field training sessions over a 4-week training period with acoustic instructions to modulate cadence, duty factor, and, in combination, running style. Instructions were provided via audio files. Running data were collected with sports watches. Participants' experiences with guided-exploration training were evaluated with the user experience questionnaire. Data analysis revealed acoustic pacing and verbal instructions to be effective in respectively modulating cadence and duty factor, albeit with co-varying effects on speed and the non-targeted variable (i.e. duty factor or cadence). Combining acoustic pacing and verbal instructions mitigated these co-varying effects considerably, allowing for running-style modulations in intended directions (particularly towards the styles with increased cadence and increased duty factor). User experience of this form of guided-exploration training was overall positive, but could be improved in terms of autonomy (dependability). In conclusion, combining acoustic pacing and verbal instructions for running-style modulation is effective in overground running.


[Gene therapy for breast cancer].
Not only the local treatments like surgery and radiation but also the systemic treatments like chemotherapy and hormone therapy are rather effective on both primary and metastatic breast cancer patients. Nevertheless, the curativity and survival of this disease have been not satisfied yet. The difficulties of the treatment seems the emergence of drug-resistant cells and the low immunity of the host. Gene therapy offers a potentially useful approach for the treatment of breast cancer. The approaches of gene therapy for breast cancer that are now undergoing as clinical protocols in USA can be divided into three strategies: (1) approaches that alter the metabolic or signaling pathways within the breast cancer cell; (2) approaches designed to enhance the immune response to the tumor cells(immuno gene therapy); and (3) approaches that use the drug-resistant gene with chemotherapy. According to the new biology of breast cancer by Fisher, the systemic treatments are more important. Immuno-therapy seems especially promising in this field. Moreover, the immuno gene therapy is hopeful that could overcome the difficulties like heterogeneity and low immunogenicity of breast cancer cell.


Diagnosis of gestational diabetes. What are our objectives?
International agreement is lacking with regard to diagnostic criteria for gestational diabetes and its treatment. Consensus is not possible without agreement on the objectives in making the diagnosis. The most commonly used criteria in North America were validated by their predictive value for the subsequent development of overt diabetes in the years after affected pregnancies. The diagnosis is also deemed by many to be important as a risk factor for adverse perinatal outcome in the present pregnancy. Attempts have been made, in various parts of the world, to derive diagnostic criteria based on pregnancy outcome; unfortunately, these have not been so intensively studied as the standards cited above. There is also a lack of agreement on whether gestational diabetes should be considered a disease or merely a risk factor. In addition, consensus has not been reached on whether population-specific criteria should be used in each location or universally accepted diagnostic thresholds should be applied. Many philosophical questions remain unanswered, and numerous opportunities for investigation present themselves. Many of these are dealt with in this workshop-conference, whereas others remain as goals to be attained.


Effects of Antipsychotics on Arrhythmogenic Parameters in Schizophrenia Patients: Beyond Corrected QT Interval.
Antipsychotic drugs have been implicated as risk factors for QT prolongation, which is a predictor of sudden cardiac death. However, the QT interval is considered an imperfect marker for proarrhythmic risk. Recently, improved methods, namely, QT dispersion (QTD), QTD ratio (QTDR), T wave peak-to-end interval (Tp-e), Tp-e/QT ratio and Tp-e/QTc ratio, have been regarded as proarrhythmic risk markers. We attempted to reevaluate the risk of sudden cardiac death due to antipsychotics use by measuring these improved evaluation methods. We retrospectively evaluated QTc, QTD, QTDR, Tp-e, Tp-e/QT ratio and Tp-e/QTc ratio from the medical records of 410 patients with schizophrenia diagnosed by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision, or 5th Edition. Information on drugs administered was obtained from medical records. We investigated the correlation between each index on ECG and medication, such as antipsychotics, prescribed to participants with linear regression analysis. We also compared each index between 235 healthy controls and 235 patients matched for age and sex. Positive correlations between QTc and levomepromazine and brexpiprazole were identified. Levomepromazine and lithium were positively correlated with QTD. Levomepromazine, quetiapine, asenapine, clozapine and carbamazepine were positively correlated with QTDR. Levomepromazine, olanzapine, brexpiprazole and lithium were positively correlated with Tp-e. Olanzapine, brexpiprazole and lithium were positively correlated with the Tp-e/QT ratio. Olanzapine, brexpiprazole and lithium were positively correlated with Tp-e/QTc ratio. Significant differences in all indexes were noted between the patients and healthy controls. According to our results, the prediction of the risk of sudden cardiac death by each index was inconsistent. We should evaluate the predictive factor of ventricular arrhythmia according to various electrocardiogram indexes because QTc alone could not identify the risk of sudden cardiac death.


Curcumin overcomes the inhibitory effect of nitric oxide on Leishmania.
Upon Leishmania infection, macrophages are activated to produce nitrogen and oxygen radicals simultaneously. It is well established that the infected host cells rely on nitric oxide (NO) as the major weapon against the intracellular parasite. In India where leishmaniasis is endemic, the spice turmeric is used prolifically in food and for insect bites. Curcumin, the active principle of turmeric, is a scavenger of NO. This report shows that curcumin protects promastigotes and amastigotes of the visceral species, Leishmania donovani, and promastigotes of the cutaneous species, L. major, against the actions of S-nitroso-N-acetyl-D,L-penicillamine (SNAP) and DETANONOate, which release NO, 3-morpholino-sydnonimine hydrochloride (SIN-1), which releases NO and superoxide, and peroxynitrite, which is formed from the reaction of NO with superoxide. Thus, curcumin, as an antioxidant, is capable of blocking the action of both NO and NO congeners on the Leishmania parasite.


The epidemic of HIV among young homosexual men.
It has been argued that HIV infection is still a major health problem among homosexual men, in particular among young homosexual men. Epidemiological and behavioural information are presented demonstrating the extent to which young homosexual men are at risk. Furthermore, the design of effective health education interventions is discussed. As many as two or three in 10 homosexual men may become infected with HIV before the age of 30 years. Interventions derived from prevailing theoretical models regarding behavioural determinants were found to be more successful in changing high-risk behaviours and relevant behavioural determinants than regular (informational) interventions. The current HIV epidemic among young homosexual men is a major public health concern. Nevertheless, hardly any specific HIV education interventions have been designed for this population. Such interventions are urgently needed and should be based on relevant theory and empirical data.


What can we do with 1000 plastid genomes?
The plastid genome of plants is the smallest and most gene-rich of the three genomes in each cell and the one generally present in the highest copy number. As a result, obtaining plastid DNA sequence is a particularly cost-effective way of discovering genetic information about a plant. Until recently, the sequence information gathered in this way was generally limited to small portions of the genome amplified by polymerase chain reaction, but recent advances in sequencing technology have stimulated a substantial rate of increase in the sequencing of complete plastid genomes. Within the last year, the number of complete plastid genomes accessible in public sequence repositories has exceeded 1000. This sudden flood of data raises numerous challenges in data analysis and interpretation, but also offers the keys to potential insights across large swathes of plant biology. We examine what has been learnt so far, what more could be learnt if we look at the data in the right way, and what we might gain from the tens of thousands more genome sequences that will surely arrive in the next few years. The most exciting new discoveries are likely to be made at the interdisciplinary interfaces between molecular biology and ecology.


Postpartum body condition score and results from the first test day milk as predictors of disease, fertility, yield, and culling in commercial dairy herds.
The study used field data from a regular herd health service to investigate the relationships between body condition scores or first test day milk data and disease incidence, milk yield, fertility, and culling. Path model analysis with adjustment for time at risk was applied to delineate the time sequence of events. Milk fever occurred more often in fat cows, and endometritis occurred between calving and 20 d of lactation more often in thin cows. Fat cows were less likely to conceive at first service than were cows in normal condition. Fat body condition postpartum, higher first test day milk yield, and a fat to protein ratio of > 1.5 increased body condition loss. Fat or thin condition or condition loss was not related to other lactation diseases, fertility parameters, milk yield, or culling. First test day milk yield was 1.3 kg higher after milk fever and was 7.1 kg lower after displaced abomasum. Higher first test day milk yield directly increased the risk of ovarian cyst and lameness, increased 100-d milk yield, and reduced the risk of culling and indirectly decreased reproductive performance. Cows with a fat to protein ratio of > 1.5 had higher risks for ketosis, displaced abomasum, ovarian cyst, lameness, and mastitis. Those cows produced more milk but showed poor reproductive performance. Given this type of herd health data, we concluded that the first test day milk yield and the fat to protein ratio were more reliable indicators of disease, fertility, and milk yield than was body condition score or loss of body condition score.


[The role of carbonic acid in the regulation of nitrogen metabolism in the animal body. 1. Effect of changes in CO2 concentration in tissues on the processes of NH+ metabolism in rabbits].
In two groups of rabbits of 24 animals each the dependence of NH4+-utilisation on the level of carbonic acid in the organism was investigates. The rabbits of the second group received injections into the abdominal cavity of 8 ml/kg body weight of a 5% NaHCO3-solution (enriched with CO2, pH 7.35) for the purpose of increasing the concentration of carbonic acid in the blood (pCO2: HCO3) and for the purpose of decreasing it an amount of NaCl-solution, which, in its content of Na+, was equivalent to the NaHCO3-dose. The difference in the concentration of carbonic acid in the blood between the two groups under the conditions of the experiment was between 30 and 35%, the pH-value was approximately the same. In order to investigate the NH4+-metabolism the animals of both groups received injections of 2 ml/kg body weight of a 1% (NH4)2HPO4-solution, their protein metabolism was studied after the intravenous injection of 2-14C-glycine. Together with the increase or decrease resp. of the level of carbonic acid in the organism, the keto acid concentration increases or decreases simultaneously. Due to the NH4-load the keto acid concentration in all animals decreases. it remains, however, higher in the animals with a higher HCO-3-level than in the control animals. The alpha-ketoglutarate concentration in the liver tissue of the animals with a higher HCO-3-level is, despite the NH4+-load, 87%, p less than 0.05, higher than in the control animals. The intensity of a removal of an NH4+-excess from the animal organism is directly dependent on the concentration of carbonic acid in the tissues. One hour after the NH4+-load the NH4+-concentration in the blood of the rabbits with a higher level of carbonic acid is normal again, whereas it is still 36% (p less than 0.05) higher than the original value in the control animals. In the liver and kidney tissues of the animals with an increased HCO-3-concentration 30 minutes after the (NH4)2HPO4-injection is by 16 and 14.5% (p greater than 0,05) resp. lower than that of the control animals. This is caused by the increased supply with NH4+-fixing substrates which are either formed directly or through intermediate stages by CO2-fixing reactions: oxaloacetate (the pyruvate concentration in the liver and kidney tissues compared to the control group was by 58%, p less than 0.05 lower), alpha-ketoglutarate, aspartate.(ABSTRACT TRUNCATED AT 400 WORDS)


Molecules of Escherichia coli MobB assemble into densely packed hollow cylinders in a crystal lattice with 75% solvent content.
The crystal structure of Escherichia coli MobB, an enzyme involved in the final step of molybdenum-cofactor biosynthesis, forms intertwined dimers. Each molecule consists of two segments and requires the second monomer for stable folding. Dimerization buries a quarter of the solvent-accessible area of the monomer. These dimers assemble into a hexagonal lattice with P6(4)22 symmetry and occupy only approximately 25% of the unit-cell volume. The symmetry-related dimers associate tightly into a helical structure with a diameter of 250 A and a pitch of 98 A. Two such helices are intertwined, shifted by 49 A along the sixfold axis. Within the crystal, these helices form thin-walled cylinders with an external diameter of 250 A and an internal diameter of 190 A. Their center is filled with solvent. These cylinders pack closely together, forming a hexagonal lattice with the highest possible packing density. This arrangement of dimers allows extensive intermolecular contacts with 75% solvent content in the crystal.


Construction strategy for an internal amplification control for real-time diagnostic assays using nucleic Acid sequence-based amplification: development and clinical application.
An important analytical control in molecular amplification-based methods is an internal amplification control (IAC), which should be included in each reaction mixture. An IAC is a nontarget nucleic acid sequence which is coamplified simultaneously with the target sequence. With negative results for the target nucleic acid, the absence of an IAC signal indicates that amplification has failed. A general strategy for the construction of an IAC for inclusion in molecular beacon-based real-time nucleic acid sequence-based amplification (NASBA) assays is presented. Construction proceeds in two phases. In the first phase, a double-stranded DNA molecule that contains nontarget sequences flanked by target sequences complementary to the NASBA primers is produced. At the 5' end of this DNA molecule is a T7 RNA polymerase binding sequence. In the second phase of construction, RNA transcripts are produced from the DNA by T7 RNA polymerase. This RNA is the IAC; it is amplified by the target NASBA primers and is detected by a molecular beacon probe complementary to the internal nontarget sequences. As a practical example, an IAC for use in an assay for the detection of Mycobacterium avium subsp. paratuberculosis is described, its incorporation and optimization within the assay are detailed, and its application to spiked and natural clinical samples is shown to illustrate the correct interpretation of the diagnostic results.


Incidence and Prevalence of Achalasia in Central Chicago, 2004-2014, Since the Widespread Use of High-Resolution Manometry.
Reported global incidence and prevalence values for achalasia vary widely, from 0.03 to 1.63 per 100,000 persons per year and from 1.8 to 12.6 per 100,000 persons per year, respectively. This study aimed to reconcile these low values with findings from a major referral center, in central Chicago (which began using high-resolution manometry in 2004 and used it in all clinical studies since 2005), and has determined the incidence and prevalence of achalasia to be much greater. We collected data from the Northwestern Medicine Enterprise Data Warehouse database (tertiary care setting) of adults residing in Chicago with an encounter diagnosis of achalasia from 2004 through 2014. Patient files were reviewed to confirm diagnosis and residential address. US Census Bureau population data were used as the population denominator. We assumed that we encountered every incident case in the city to calculate incidence and prevalence estimates. Data were analyzed for the city at large and for the 13 zip codes surrounding the Northwestern Memorial Hospital (NMH), the NMH neighborhood. We identified 379 cases (50.9% female) that met the full inclusion criteria; of these, 246 were incident cases. Among these, 132 patients resided in the NMH neighborhood, 89 of which were incident cases. Estimated yearly incidences were stable over the study period, ranging from 0.77 to 1.35 per 100,000 citywide (average, 1.07 per 100,000) and from 1.41 to 4.60 per 100,000 in the NMH neighborhood (average, 2.92 per 100,000). The corresponding prevalence values increased progressively, from 4.68 to 14.42 per 100,000 citywide and from 15.64 to 32.58 per 100,000 in the NMH neighborhood. The incidence and prevalence of achalasia in central Chicago diagnosed using state-of-the-art technology and diagnostic criteria are at least 2- to 3-fold greater than previous estimates. Additional studies are needed to determine the generalizability of these data to other regions.


Chemoselective cyclization of unprotected linear peptides by α-ketoacid-hydroxylamine amide-ligation.
Cyclic peptides are important synthetic targets due to their constrained conformation, enhanced metabolic stability and improved bioavailability, which combine to make them promising lead compounds for drug candidates. They are typically synthesized by a multi-step sequence of carefully orchestrated protecting group manipulations and cyclization of side-chain protected linear precursors. In the present manuscript we disclose an alternative approach to the synthesis of peptide macrocycles by the α-ketoacid-hydroxylamine (KAHA) ligation. This reaction allows readily prepared linear peptides to be cyclized without reagents or side-chain protecting groups and delivers a native backbone amide bond at the ligation site. The precursors are prepared with Fmoc-based solid phase peptide synthesis using reagents that we have previously disclosed. No post-cyclization manipulations or deprotections other than purification are required. This protocol was applied to five different cyclic peptide natural products of varying ring sizes and side chain functionalities.


Prolonged hypercalcemia following acute renal failure.
A case is reported of a twenty-one year old man who developed severe hypercalcemia late in the diuretic phase of acute reversible renal failure secondary to severe trauma. Hypercalcemia persisted for approximately five months. Serum immunoreactive parathyroid hormone levels were undetectable and sub-total parathyroidectomy had no appreciable effect on the serum calcium. The most likely source of this patient's hypercalcemia was resorption of calcium from metastatic deposits in soft tissue and possibly from bone. Failure to incorporate calcium into bone during the period of immobilization may explain the prolonged hypercalcemia.


(-)-Nicotine increases mRNA encoding G3PDH and the vesicular acetylcholine transporter in vivo.
The effects of acute in vivo (-)-nicotine exposure on neuronal expression of mRNA encoding the vesicular acetylcholine transport (VAChT) and the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (G3PDH) were examined. The reverse transcription polymerase chain reaction was used to amplify cDNA derived from brain tissue of adult male rats injected acutely with (-)-nicotine and semi-quantification of cDNA products conducted using anion exchange chromatography. In cerebral cortex, levels of cDNA derived from the VAChT mRNA were increased by > 65% above control levels 1 h after (-)-nicotine (0.8 mg/kg, s.c.) exposure. In hippocampal samples, levels of this cDNA were increased by 15% above control levels. cDNA derived from G3PDH mRNA was increased by 86% and 280% above control levels in the cerebral cortex and hippocampus, respectively. Thus, increased expression and function of proteins associated with these mRNA species are likely consequences of acute (-)-nicotine exposure.


[Incidence of dural puncture headache after intradural anesthesia carried out by residents].
To evaluate dural puncture headache (DPH) after intradural anesthesia (IA) carried out by residents of anesthesiology and reanimation, and its relation with the degree of difficulty of the puncture, a sample of 81 patients with ages ranging between 48 and 88 years was evaluated. The incidence of DPH was 12.35%, and it was not statistically associated with age, sex, anesthetic approach, local anesthetic, or degree of difficulty of lumbar puncture.


Protective Effect of Fucoxanthin Isolated from Laminaria japonica against Visible Light-Induced Retinal Damage Both in Vitro and in Vivo.
With increasingly serious eye exposure to light stresses, such as light-emitting diodes, computers, and widescreen mobile phones, efficient natural compounds for preventing visible light-induced retinal damages are becoming compelling needs in the modern society. Fucoxanthin, as the main light absorption system in marine algae, may possess an outstanding bioactivity in vision protection because of its filtration of blue light and excellent antioxidative activity. In this work, both in vitro and in vivo simulated visible light-induced retinal damage models were employed. The in vitro results revealed that fucoxanthin exhibited better bioactivities than lutein, zeaxanthin, and blueberry anthocyanins in inhibiting overexpression of vascular endothelial growth factor, resisting senescence, improving phagocytic function, and clearing intracellular reactive oxygen species in retinal pigment epithelium cells. The in vivo experiment also confirmed the superiority of fucoxanthin than lutein in protecting retina against photoinduced damage. This excellent bioactivity may be attributed to its unique structural features, including allenic, epoxide, and acetyl groups. Fucoxanthin is expected to be an important ocular nutrient in the future.


Autophagy and Mammalian Viruses: Roles in Immune Response, Viral Replication, and Beyond.
Autophagy is an important cellular catabolic process conserved from yeast to man. Double-membrane vesicles deliver their cargo to the lysosome for degradation. Hence, autophagy is one of the key mechanisms mammalian cells deploy to rid themselves of intracellular pathogens including viruses. However, autophagy serves many more functions during viral infection. First, it regulates the immune response through selective degradation of immune components, thus preventing possibly harmful overactivation and inflammation. Additionally, it delivers virus-derived antigens to antigen-loading compartments for presentation to T lymphocytes. Second, it might take an active part in the viral life cycle by, eg, facilitating its release from cells. Lastly, in the constant arms race between host and virus, autophagy is often hijacked by viruses and manipulated to their own advantage. In this review, we will highlight key steps during viral infection in which autophagy plays a role. We have selected some exemplary viruses and will describe the molecular mechanisms behind their intricate relationship with the autophagic machinery, a result of host-pathogen coevolution.


Dissociation of psychomotor sensitization from compulsive cocaine consumption.
The transition from drug use to drug addiction is associated with a process of escalation, whereby drug use becomes excessive and difficult to control. Several mechanisms have been advanced to explain escalating patterns of drug use as opposed to nonescalating patterns. Although current evidence favors hedonic tolerance, there remains some dispute about the contribution of behavioral sensitization to cocaine intake escalation. Here, we concurrently assessed the ability of cocaine to induce psychomotor sensitization and drug-seeking behavior in animals with 1-h (short access or ShA) vs 6-h (long access or LgA) access to intravenous (i.v.) cocaine self-administration. As expected, cocaine intake by LgA rats escalated over time and became excessive compared to cocaine intake by ShA rats, which remained low and stable. Despite escalated levels of cocaine consumption, however, LgA rats were not more sensitized to cocaine than ShA rats. The dose-effect function for cocaine-induced locomotion (0.125-1 mg, i.v.) was shifted to the left in LgA rats by the same amount as in ShA rats after cocaine self-administration. In contrast, LgA rats were much more responsive than ShA rats to the motivational effects of cocaine, as measured by the ability of i.v. cocaine to reinstate extinguished drug-seeking behavior. This study demonstrates a dissociation of psychomotor sensitization from the change in motivation underlying the transition to compulsive cocaine consumption, and therefore suggests that responsiveness to the motivational effects of the drug, not psychomotor sensitization, would represent a specific behavioral marker of the transition to and maintenance of compulsive cocaine use.


Confirmation of amphetamine, methamphetamine, MDA and MDMA in urine samples using disk solid-phase extraction and gas chromatography-mass spectrometry after immunoassay screening.
A method using mixed phase disk solid-phase extraction (SPE) and gas chromatography-mass spectrometry (GC-MS) was developed for confirmation of amphetamine (AMP), methamphetamine (MET), 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA) in urine samples after immunoassay screening. Disk SPE provided hydrophobic (C(18)) and strong cation-exchange (SCX) interactions. The analytes were retained on SCX functional groups in the disk and eluted with ammoniated ethyl acetate after washed with methanol. Confirmation and quantitation was exercised by selected ion monitoring using nikethamide as chromatographic standard. Recoveries of the amphetamines were between 73.0 and 104.6% with RSDs in range of 2.1-6.4% (n=3). The limits of detection were 2 ng/ml for AMP, MET and MDMA, and 4 ng/ml for MDA. Five real urine samples were tested with the method after immunoassay screening, and the results were comparable to those of traditional liquid-liquid extraction (LLE). The method was solvent-saved, simple, rapid and reliable, and the extract was cleaner than that of LLE.


Monoamine Oxidase Inhibition by Kavalactones from Kava (Piper Methysticum).
Monoamine oxidases (MAOs) are key metabolic enzymes for neurotransmitter and dietary amines and are targets for the treatment of neuropsychiatric and neurodegenerative disorders. This study examined the MAO inhibition potential of kavain and other kavalactones from the roots of kava (Piper methysticum), a plant that has been used for its anxiolytic properties. (±)-Kavain was found to be a good potency in vitro inhibitor of human MAO-B with an IC50 of 5.34 µM. (±)-Kavain is a weaker MAO-A inhibitor with an IC50 of 19.0 µM. Under the same experimental conditions, the reference MAO inhibitor, curcumin, displays IC50 values of 5.01 µM and 2.55 µM for the inhibition of MAO-A and MAO-B, respectively. It was further established that (±)-kavain interacts reversibly and competitively with MAO-A and MAO-B with enzyme-inhibitor dissociation constants (Ki) of 7.72 and 5.10 µM, respectively. Curcumin in turn, displays a Ki value of 3.08 µM for the inhibition of MAO-A. Based on these findings, other kavalactones (dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin) were also evaluated as MAO inhibitors in this study. Yangonin proved to be the most potent MAO inhibitor with IC50 values of 1.29 and 0.085 µM for MAO-A and MAO-B, respectively. It may be concluded that some of the central effects (e.g., anxiolytic) of kava may be mediated by MAO inhibition.


Effects of Piperazine Derivative on Paclitaxel Pharmacokinetics.
Paclitaxel (PTX) is an anticancer agent that is used to treat many cancers but it has a very low oral bioavailability due, at least in part, to the drug efflux transporter, P-glycoprotein (P-gp). Therefore, this study was performed to enhance oral bioavailability of PTX. In this study, we investigated the effects of several piperazine derivatives on P-gp function in vitro. Compound 4 was selected as the most potent P-gp inhibitor from the in vitro results for examining the pharmacokinetic (PK) changes of PTX in rats. Compound 4 increased the AUCinf of PTX without alterations in the Cmax value. The elimination half-life was extended and the oral clearance decreased. Additionally, the Tmax was delayed or widened in the treatment groups. Therefore, the bioavailability (BA) of PTX was improved 2.1-fold following the co-administration of 5 mg/kg of the derivative. A piperazine derivative, compound 4, which was confirmed as a substantial P-gp inhibitor in vitro increased the BA of PTX up to 2-fold by a lingering absorption, in part due to inhibition of intestinal P-gp and a low oral clearance of PTX. These results suggest that co-administering compound 4 may change the PK profile of PTX by inhibiting P-gp activity in the body.


Management of encapsulating peritoneal sclerosis: a guideline on optimal and uniform treatment.
Encapsulating peritoneal sclerosis (EPS) represents a rare complication of long-term peritoneal dialysis (PD). It is characterised by diffuse peritoneal membrane fibrosis, progressive intestinal encapsulation and the clinical spectrum of intestinal obstruction. The pathogenesis is as yet not well understood but includes inflammation, angiogenesis and fibrosis. The current diagnosis of EPS lacks specificity and relies on clinical, radiographic or macroscopic evaluation. There is no general agreement on managing EPS although accumulating clinical data suggest drug treatment (steroids, tamoxifen), surgery (enterolysis) or a combination of both. Here, we provide a short overview on the current knowledge of EPS, with a focus on treatment. Moreover, we present a diagnostic and a therapeutic algorithm for EPS based on the best available published data and our combined experience.


Routine using pattern and performance of diagnostic tests for tuberculosis on a university hospital.
Nucleic acid amplification tests to detect Mycobacterium tuberculosis in clinical specimens are used increasingly as a laboratory tool. We aimed to investigate the routine using pattern and the effects on therapeutic decision of diagnostic tests for tuberculosis in our hospital. In this descriptive study, we investigated retrospectively the routine using pattern and the effects on therapeutic decision of diagnostic tests for tuberculosis. Patients with discordant results were clinically evaluated retrospectively by a chest physician. Samples were tested for the presence of M. tuberculosis by a smear technique, M. tuberculosis culture growth technique (Löwenstein-Jensen and/or BACTEC-960), and IS6110 polymerase chain reaction (PCR). Culture positivity was 7.2% (83 of 1159 patients). In total, 198 (62.4%) were tested with PCR, acid-fast bacilli, and culture. On the basis of culture results as a gold standard, sensitivity, specificity, positive predictive value, and negative predictive value of PCR were 46%, 89%, 23%, and 93.5%, respectively. Selection of appropriate patients for further testing and exclusion of low-risk patients from microbiologic testing by experienced clinicians may help to optimize the positive predictive value of PCR.


Utility of Drinking Water in Hepatobiliary Scintigraphy When Possible Acute Cholecystitis Was Considered.
A 15-year-old boy underwent hepatobiliary scintigraphy for suspected acute cholecystitis. The initial images revealed an activity in the neighborhood of normal gallbladder fossa, suggestive of possible activity in the gallbladder, which would be inconsistent with a diagnosis of acute cholecystitis. However, after drinking 6 oz of water, the activity was no longer seen. Acute cholecystitis was confirmed pathologically after cholecystectomy.


Novel Synthesis and Antiviral Evaluation of New Benzothiazole-Bearing N-Sulfonamide 2-Pyridone Derivatives as USP7 Enzyme Inhibitors.
In this article, a series of benzothiazole-bearing N-sulfonamide 2-pyridone derivatives were synthesized via the reaction of benzothiazole sulfonylhydrazide with sodium salts of both (hydroxymethylene) cycloalkanones and unsaturated ketones, as well as ethoxymethylene derivatives. The structures of the resultant compounds were confirmed using IR, 1H NMR, 13C NMR, 1H-1H correlation spectroscopy (COSY), 1H-13C heteronuclear multiple bond coherence (HMBC), and 1H-13C heteronuclear multiple quantum coherence (HSQC) spectral analysis and elemental analysis. The newly synthesized compounds were evaluated in vitro for their antiviral activities against the HSV-1, HAV HM175, HCVcc genotype 4, CBV4, and HAdV7 viruses. Additionally, the compounds were examined for their cytotoxic effect on five normal cell lines. It was observed that five compounds were found to possess viral reduction of 50% or more against CBV4 with significant IC50, CC50, and SI values. In the case of HSV-1 and HAV HM175 viruses, three compounds have shown more than 50% reduction, while in the case of HCVcc genotype 4 and HAdV7 viruses, only two compounds demonstrated more than 50% reduction. Furthermore, the physicochemical properties of the most active compounds were evaluated. The two most potent compounds against HSV-1 virus, 7e and 13a, were evaluated for their inhibitory activity against USP7. Docking studies using Molecular Operating Environment (MOE) were used to identify the interactions between 7e and 13a compounds and the active site of the USP7 enzyme.


Citalopram augmentation for subsyndromal symptoms of depression in middle-aged and older outpatients with schizophrenia and schizoaffective disorder: a randomized controlled trial.
Subsyndromal symptoms of depression (SSD) in older outpatients with schizophrenia are common and clinically important. While many physicians prescribe antidepressants to patients with schizophrenia and schizoaffective disorder who have SSD, evidence for their effectiveness and safety has been meager. We describe a randomized placebo-controlled trial of citalopram in 198 patients. Participants in this 2-site study, conducted from September 1, 2001, to August 31, 2007, were men and women with DSM-IV schizophrenia or schizoaffective disorder who were 40 years of age or older and who met study criteria for SSD. Patients were randomly assigned to flexible-dose treatment with citalopram or placebo augmentation of their current antipsychotic medication. Analysis of covariance was used to compare improvement in scores on the Hamilton Rating Scale for Depression and Calgary Depression Rating Scale between treatment groups; secondary efficacy analyses compared improvement in several other dimensions of schizophrenia. Augmentation with citalopram was significantly more effective than with placebo in improving depressive (p = .002) and negative (p = .049) symptoms, mental functioning (p = .000), and quality of life (p = .046). There were no significant differences between citalopram and placebo in suicidal ideation, positive symptoms, cognition, general medical health, physical functioning, or symptoms of movement disorders. No adverse events were more frequent in participants receiving citalopram than in those receiving placebo, and only 4 participants from each treatment group terminated early because of side effects. Subsyndromal symptoms of depression in middle aged and older patients with schizophrenia responded to treatment with citalopram with lessening of depressive symptoms and improved functioning and quality of life. It may be important for clinicians to identify and treat SSD in middle-aged and older patients with chronic schizophrenia. clinicaltrials.gov Identifier: NCT00047450.


Integration of Triboluminescent EuD4TEA Crystals to Transparent Polymers: Impact Sensor Application.
Lanthanide-based organometallic materials are well-known candidate triboluminescent (TL) materials that can show bright emission when a mechanical force is applied. These materials are usually in the form of crystalline powders, and it is often useful to integrate these samples into a polymer matrix in order to achieve processability, enabling coating from a solution/molten state or fabrication as a complex-shaped matrix. In this work, micrometer-sized europium tetrakis (dibenzoylmethide) triethylammonium (EuD4TEA) crystals were synthesized and integrated with various transparent polymers (PMMA, PS, PVDF, and PU) using two approaches: (i) blending and (ii) surface impregnation. In the former method, the crystalline particles were molecularly dissolved; therefore, a TL response cannot be achieved. More than 10 wt % TL crystals in the composite is needed to obtain TL signals. However, TL signal was achieved at 2.5 wt % when a composite was prepared by the latter approach. TL intensity shows exponential decay with consecutive mechanical action. The TL emission of PU-based surface impregnated composite expires with long-lived emission, and maximum TL response with respect to applied force was measured between 2.45 and 42.0 N.


Adrenocorticotropic hormone and cortisol in calves after corticotropin-releasing hormone.
The aim for this study was to analyze responsiveness of the hypothalamo-pituitary-adrenocortical axis to exogenous bovine corticotropin-releasing hormone (bCRH) in calves. Two dose-response studies were carried out, using either bCRH alone (dose rates of 0, .01, .03, and .1 microg bCRH/kg live weight) or in combination with arginine-vasopressin (bCRH:AVP, 0:0, .1:.05, .5:.25, and 1:.5 microg kg live weight). The bCRH was administered i.v. to calves (n = 5 to 7 per dose) housed individually or in groups. Serial blood samples were obtained from before to 300 min after injection and analyzed for plasma ACTH and cortisol concentrations. The lowest bCRH dose that produced a response in all calves was .1 microg/kg. In the experiment using bCRH with AVP, increasing the bCRH dose from .1 to 1 microg/kg resulted in an increase in peak ACTH concentration (321 vs. 2,003 pg/mL) but did not significantly affect the peak cortisol concentration (37 vs. 40 ng/mL). The time to reach the peak cortisol concentration increased with the dose of bCRH with AVP (from 38 to 111 min). The ACTH and cortisol concentrations determined at any time between 20 and 90 min after bCRH injection were correlated to the integrated responses calculated as areas under the ACTH and the cortisol curves (r between .61 and .99, P<.05). In comparison with results from studies in humans, pigs, and sheep, our data showed that the pituitary of calves seems less sensitive to CRH than that of other mammals, despite a greater capacity to produce ACTH. Moreover, the calf's adrenals seem to have a lower capacity to produce cortisol than adrenals of other mammals. As in other species, it seems that AVP enhances the release of ACTH and cortisol. For CRH challenge to be used in calves, we suggest injecting at least .1 microg of bCRH/kg live weight either with or without AVP and taking several blood samples before injection and between 20 and 90 min after injection.


Permeability characteristics of bile duct in the rat.
To determine the permeability of the bile duct epithelium of the rat to several hydrophilic nonelectrolytes, isolated segments of rat bile duct (1-2 cm) were perfused with Ringer solution in situ. [14C]urea, [14C]erythritol, [14C]sucrose, or [3H]inulin was administered intravenously, and drops of duct perfusate were collected. Perfusate-to-plasma ratios for each solute were inversely related to their molecular weight (MW): inulin [0.13 +/- 0.06 (SD)], sucrose (0.20 +/- 0.08), erythritol (0.32 +/- 0.11), and urea (0.34 +/- 0.13). Permeability coefficients (P) expressed in cm.s-1 X 10(5) were determined for inulin (4.5 +/- 1.5), sucrose (8.5 +/- 2.6), erythritol (12.6 +/- 3.9), and urea (15.8 +/- 1.6). These values vary directly with their respective nonaqueous-aqueous partition coefficients (K) and inversely with their MW. Although P is directly related to K in both olive oil and isobutanol systems, the bile duct behaves as if its permeability barrier is more hydrophilic than isobutanol. These results indicate that the inert solutes urea, erythritol, sucrose, and inulin cross the epithelium of the rat bile duct by a polar route, possibly via intercellular junctions, and that erythritol may not be an ideal marker of canalicular bile flow.


Isolation and characterization of a phospholipid transfer protein (LTP-II) from human plasma.
In this report we have described the purification of a human plasma phospholipid transfer protein, designated LTP-II, which displayed the following characteristics: i) facilitated both the exchange and net mass transfer of lipoprotein phospholipids; ii) did not facilitate the transfer of lipoprotein cholesteryl esters (CE) or triglycerides (TG); iii) was not recognized by antibody to the human cholesteryl ester transfer protein (LTP-I); iv) showed no amino acid sequence homology to the cholesteryl ester transfer protein (LTP-I); v) has an apparent molecular weight (Mr) of 70,000 off Sephacryl S200, and 69,000 off sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE); vi) has an apparent isoelectric point of 5.0 by chromatofocusing; and vii) when added to an incubation mixture of VLDL, HDL3, and the human plasma cholesteryl ester transfer protein (LTP-I), enhanced the observed transfer of cholesteryl esters from HDL3 to VLDL, even though LTP-II has no intrinsic cholesteryl ester transfer activity of its own. These results show that this phospholipid transfer protein is unique from the human plasma cholesteryl ester transfer protein, and may play an important role in human lipoprotein lipid metabolism.


Extra-virgin olive oil increases the resistance of LDL to oxidation more than refined olive oil in free-living men with peripheral vascular disease.
Patients with peripheral vascular disease (Fontaine stage II) are characterized by ischemia of the lower extremities, atherosclerosis and alteration of blood coagulation and fibrinolysis. A randomized, two-period, crossover design was used to compare the effects of extra-virgin (VO) and refined olive (RO) oils on plasma lipids and lipoprotein composition and LDL oxidation susceptibility in free-living men with peripheral vascular disease. The oils differed in their antioxidant profile (alpha-tocopherol: 300 vs. 200 mg/kg; phenolic compounds 800 vs. 60) and concentration but not in their fatty acid composition. Subjects were randomly assigned to two groups. The first group (n = 12) received VO with which to freely cook all meals for 3 mo, followed by a 3-mo wash-out period; they then received RO for the final 3 mo. The second group (n = 12) consumed the oils in the opposite order. Energy, fat, polyunsaturated fatty acids (PUFA) and alpha-tocopherol intakes were not different when patients consumed the two oils. Profiles of the major fatty acids in plasma and LDL were not different after consumption of VO and RO. The slope of the line for LDL oxidation vs. the line for copper concentration was significantly higher after the intake of RO than after the intake of VO. Total LDL taken up by macrophages was significantly greater when the men consumed RO rather than VO. We suggest that antioxidants present in VO may protect LDL against oxidation more than does RO in men with peripheral vascular disease.


Heat shock response and autophagy--cooperation and control.
Protein quality control (proteostasis) depends on constant protein degradation and resynthesis, and is essential for proper homeostasis in systems from single cells to whole organisms. Cells possess several mechanisms and processes to maintain proteostasis. At one end of the spectrum, the heat shock proteins modulate protein folding and repair. At the other end, the proteasome and autophagy as well as other lysosome-dependent systems, function in the degradation of dysfunctional proteins. In this review, we examine how these systems interact to maintain proteostasis. Both the direct cellular data on heat shock control over autophagy and the time course of exercise-associated changes in humans support the model that heat shock response and autophagy are tightly linked. Studying the links between exercise stress and molecular control of proteostasis provides evidence that the heat shock response and autophagy coordinate and undergo sequential activation and downregulation, and that this is essential for proper proteostasis in eukaryotic systems.


G-quadruplex-induced instability during leading-strand replication.
G-quadruplexes are four-stranded nucleic acid structures whose biological functions remain poorly understood. In the yeast S. cerevisiae, we report that G-quadruplexes form and, if not properly processed, pose a specific challenge to replication. We show that the G-quadruplex-prone CEB1 tandem array is tolerated when inserted near ARS305 replication origin in wild-type cells but is very frequently destabilized upon treatment with the potent Phen-DC(3) G-quadruplex ligand, or in the absence of the G-quadruplex-unwinding Pif1 helicase, only when the G-rich strand is the template of leading-strand replication. The orientation-dependent instability is associated with the formation of Rad51-Rad52-dependent X-shaped intermediates during replication detected by two-dimensional (2D) gels, and relies on the presence of intact G-quadruplex motifs in CEB1 and on the activity of ARS305. The asymmetrical behaviour of G-quadruplex prone sequences during replication has implications for their evolutionary dynamics within genomes, including the maintenance of G-rich telomeres.


Patient demographics and cardiovascular risk factors differentially influence geometric remodeling of the aorta compared with the peripheral arteries.
Detailed knowledge of the dimensions and shape of the main arteries of the body and how they change with age and disease is important for understanding arterial pathophysiology and improving minimally invasive devices to treat arterial diseases. Our goal was to describe and compare geometric remodeling of the aorta and peripheral arteries in the context of patient demographics and cardiovascular risk factors. Three-dimensional reconstructions of computed tomography angiography scans were performed in 122 subjects 5-93 years of age (mean 47 ± 24 years, 64 M/58 F). Best-fit arterial diameters, lengths, and tortuosity for the principle named arteries in the chest, abdomen, pelvis, and upper thigh were measured, and multiple linear regression analysis was performed to examine how these morphologic parameters associate with patient demographics and risk factors. Large elastic arteries increased their diameter, length, and tortuosity with age, whereas muscular arteries primarily became more tortuous. Demographics and risk factors explained >70% of the variation in diameters of the abdominal aorta, paravisceral aorta, and the aortic arch; and >75% of variation in tortuosity from the profunda femoris to the brachiocephalic artery. Male sex, larger body mass index, and hypertension contributed to larger diameters, whereas the presence of diabetes was associated with somewhat-straighter arteries. Overall, the effects of cardiovascular risk factors on geometric remodeling were small compared with those of demographics. The geometry of the vascular tree is greatly affected by aging, demographics, and some risk factors. Elastic and muscular arteries remodel differently, possibly as the result of differences in their microstructure.


fac-Re(CO)3-based neutral heteroleptic tetrahedrons.
Four new flexible ditopic nitrogen donors possessing a xylene spacer and 2-phenylbenzimidazolyl or its derivatives as a coordinating unit and one rigid bis-chelating ligand consisting of two 2-hydroxyphenylbenzimidazolyl motifs and a central phenylene spacer were synthesized and further used with Re2(CO)10 for making a new family of neutral, heteroleptic tetrahedral-shaped supramolecular coordination complexes via a one-pot approach. The new ligands and the complexes were characterized using various analytical and spectroscopic methods. The molecular structures of the complexes were determined using single crystal X-ray diffraction analysis, which reveal that four rhenium cores are arranged in the vertices, and four ligands are at the edges of the tetrahedron.


Generation of flat-top picosecond pulses by coherent pulse stacking in a multicrystal birefringent filter.
This paper deals with the pulse-shaping properties of birefringent filters that feature an optical layout similar to a Solc fan filter. A simple computational model is given that explains the pulse-shaping process in the fan filter in two steps: First, the input pulse is split into several mutually delayed replicas due to the birefringence of the crystals. Second, these replicas interfere at the output polarizer of the filter and form the shaped output pulse. Fine-tuning of the phases of the replicas of the input pulse is permitted by tuning the temperature of the crystals. A birefringent pulse shaper containing ten birefringent crystals was investigated experimentally. The shape of the output pulses was measured by means of a special cross-correlation technique. Although a variety of pulse shapes can be generated with the described filter, it is particularly well suited for generation of flattop pulses featuring a 20-ps-long plateau and rising and falling edges shorter than 2 ps.


Oncologic mechanical emergencies.
Prevalence of cancer and its various related complications continues to rise. Increasingly these life-threatening complications are initially managed in the emergency department, making a prompt and accurate diagnosis crucial to effectively institute the proper treatment and establish goals of care. The following oncologic emergencies are reviewed in this article: pericardial tamponade, superior vena cava syndrome, brain metastasis, malignant spinal cord compression, and hyperviscosity syndrome.


The intranasal dexmedetomidine plus ketamine for procedural sedation in children, adaptive randomized controlled non-inferiority multicenter trial (Ketodex): a statistical analysis plan.
Procedural sedation and analgesia (PSA) is frequently required to perform closed reductions for fractures and dislocations in children. Intravenous (IV) ketamine is the most commonly used sedative agent for closed reductions. However, as children find IV insertion a distressing and painful procedure, there is need to identify a feasible alternative route of administration. There is evidence that a combination of dexmedetomidine and ketamine (ketodex), administered intranasally (IN), could provide adequate sedation for closed reductions while avoiding the need for IV insertion. However, there is uncertainty about the optimal combination dose for the two agents and whether it can provide adequate sedation for closed reductions. The Intranasal Dexmedetomidine Plus Ketamine for Procedural Sedation (Ketodex) study is a Bayesian phase II/III, non-inferiority trial in children undergoing PSA for closed reductions that aims to address both these research questions. This article presents in detail the statistical analysis plan for the Ketodex trial and was submitted before the outcomes of the trial were available for analysis. The Ketodex trial is a multicenter, four-armed, randomized, double-dummy controlled, Bayesian response adaptive dose finding, non-inferiority, phase II/III trial designed to determine (i) whether IN ketodex is non-inferior to IV ketamine for adequate sedation in children undergoing a closed reduction of a fracture or dislocation in a pediatric emergency department and (ii) the combination dose for IN ketodex that provides optimal sedation. Adequate sedation will be primarily measured using the Pediatric Sedation State Scale. As secondary outcomes, the Ketodex trial will compare the length of stay in the emergency department, time to wakening, and adverse events between study arms. The Ketodex trial will provide evidence on the optimal dose for, and effectiveness of, IN ketodex as an alternative to IV ketamine providing sedation for patients undergoing a closed reduction. The data from the Ketodex trial will be analyzed from a Bayesian perspective according to this statistical analysis plan. This will reduce the risk of producing data-driven results introducing bias in our reported outcomes. ClinicalTrials.gov NCT04195256 . Registered on December 11, 2019.


Production of colony-stimulating factor by leukemic leukocytes.
The production of colony-stimulating factor (CSF) by the peripheral blood cells of untreated patients with acute myeloid leukemia (AML) was measured in the agar culture system using normal human bone marrow as the source of colony-forming units (CFUc). CSF production was found to be variable and was related to the morphologic subtype of AML--cells from patients with monocytic leukemia produced normal or large quantities of CSF, while (with one exception) those from patients with myeloblastic leukemia produced little or no CSF. There was a general relationship between CSF production and serum lysozyme levels. Attempts to demonstrate a consistent inhibitory effect exerted by leukemic peripheral blood cells on normal leukopoiesis in vitro were negative. Results instead suggested that the addition to the feeder layer of cells from patients with monocytic leukemia could raise CSF levels above those obtained with normal peripheral blood leukocytes alone, possibly by recruiting additional CFUc from normal marrow.


Avian metapneumovirus subgroup C induces autophagy through the ATF6 UPR pathway.
An increasing number of studies have demonstrated that macroautophagy/autophagy plays an important role in the infectious processes of diverse pathogens. However, it remains unknown whether autophagy is induced in avian metapneumovirus (aMPV)-infected host cells, and, if so, how this occurs. Here, we report that aMPV subgroup C (aMPV/C) induces autophagy in cultured cells. We demonstrated this relationship by detecting classical autophagic features, including the formation of autophagsomes, the presence of GFP-LC3 puncta and the conversation of LC3-I into LC3-II. Also, we used pharmacological regulators and siRNAs targeting ATG7 or LC3 to examine the role of autophagy in aMPV/C replication. The results showed that autophagy is required for efficient replication of aMPV/C. Moreover, infection with aMPV/C promotes autophagosome maturation and induces a complete autophagic process. Finally, the ATF6 pathway, of which one component is the unfolded protein response (UPR), becomes activated in aMPV/C-infected cells. Knockdown of ATF6 inhibited aMPV/C-induced autophagy and viral replication. Collectively, these results not only show that autophagy promotes aMPV/C replication in the cultured cells, but also reveal that the molecular mechanisms underlying aMPV/C-induced autophagy depends on regulation of the ER stress-related UPR pathway.


Methylphenidate v. placebo--a randomised double-blind crossover study in children with the attention deficit disorder.
Fourteen pupils of the New Hope School in Pretoria who were considered to be responsive to methylphenidate were randomised to receive either the active drug or placebo in a double-blind trial for each of 4 weeks. Their behaviour was monitored by parents and teachers, who were required to complete a questionnaire (Conner's Abbreviated Teachers' Rating Scale) three times per week. After analysis of the data, only 2 children were identified as methylphenidate responders and 1 as a probable responder. One child showed significant deterioration on the drug while another showed deterioration that approached significance. The remaining 9 exhibited no significant response to methylphenidate.


Childhood Trauma Questionnaire: factor structure, measurement invariance, and validity across emotional disorders.
To study the psychometric properties of the Childhood Trauma Questionnaire-Short Form (CTQ-SF), we determined its dimensional structure, measurement invariance across presence of emotional disorders, the association of the CTQ-SF with an analogous interview-based measure (CTI) across presence of emotional disorders, and the incremental value of combining both instruments in determining associations with severity of psychopathology. The sample included 2,308 adults, ages 18-65, consisting of unaffected controls and chronically affected and intermittently affected persons with an emotional disorder at Time 0 (T0) or 4 years later at T4. Childhood maltreatment was measured at T0 with an interview and at T4 with the CTQ-SF. At each wave, patients were assessed for Diagnostic and Statistical Manual of Mental Disorders (4th ed., or DSM-IV; American Psychiatric Association, 1994)-based emotional disorders (Composite Interview Diagnostic Instrument) and symptom severity (Inventory of Depressive Symptomatology, Beck Anxiety Inventory, Fear Questionnaire). Besides the correlated original 5-factor solution, an indirect higher order and direct bifactorial model also showed a good fit to the data. The 5-factor solution proved to be invariant across disordered-control comparison groups. The CTQ-SF was moderately associated with the CTI, and this association was not attenuated by disorder status. The CTQ-SF was more sensitive in detecting emotional abuse and emotional neglect than the CTI. Combined CTQ-SF/CTI factor scores showed a higher association with severity of psychopathology. We conclude that although the original 5-factor model fits the data well, results of the hierarchical analyses suggest that the total CTQ scale adequately captures a broad dimension of childhood maltreatment. A 2-step measurement approach in the assessment of childhood trauma is recommended in which screening by a self-report questionnaire is followed by a (semi-)structured diagnostic interview.


An updated gene atlas for maize reveals organ-specific and stress-induced genes.
Maize (Zea mays L.), a model species for genetic studies, is one of the two most important crop species worldwide. The genome sequence of the reference genotype, B73, representative of the stiff stalk heterotic group was recently updated (AGPv4) using long-read sequencing and optical mapping technology. To facilitate the use of AGPv4 and to enable functional genomic studies and association of genotype with phenotype, we determined expression abundances for replicated mRNA-sequencing datasets from 79 tissues and five abiotic/biotic stress treatments revealing 36 207 expressed genes. Characterization of the B73 transcriptome across six organs revealed 4154 organ-specific and 7704 differentially expressed (DE) genes following stress treatment. Gene co-expression network analyses revealed 12 modules associated with distinct biological processes containing 13 590 genes providing a resource for further association of gene function based on co-expression patterns. Presence-absence variants (PAVs) previously identified using whole genome resequencing data from 61 additional inbred lines were enriched in organ-specific and stress-induced DE genes suggesting that PAVs may function in phenological variation and adaptation to environment. Relative to core genes conserved across the 62 profiled inbreds, PAVs have lower expression abundances which are correlated with their frequency of dispersion across inbreds and on average have significantly fewer co-expression network connections suggesting that a subset of PAVs may be on an evolutionary path to pseudogenization. To facilitate use by the community, we developed the Maize Genomics Resource website (maize.plantbiology.msu.edu) for viewing and data-mining these resources and deployed two new views on the maize electronic Fluorescent Pictograph Browser (bar.utoronto.ca/efp_maize).


Genetic analysis of temperature-sensitive mutants which define the gene for the major herpes simplex virus type 1 DNA-binding protein.
We have assigned eight temperature-sensitive mutants of herpes simplex virus type 1 to complementation group 1-1. Members of this group fail to complement mutants in herpes simplex virus type 2 complementation group 2-2. The mutation of one member of group 1-1, tsHA1 of strain mP, has been shown to map in or near the sequence which encodes the major herpes simplex virus type 1 DNA-binding protein (Conley et al., J. Virol. 37:191-206, 1981). The mutations of five other members of group 1-1 map in or near the sequence in which the tsHA1 mutation maps, a sequence which lies near the center of UL between the genes for the viral DNA polymerase and viral glycoprotein gAgB. These mutants can be divided into two groups; the mutations of one group map between coordinates 0.385 and 0.398, and the mutations of the other group map between coordinates 0.398 and 0.413. At the nonpermissive temperature mutants in group 1-1 are viral DNA negative, and mutant-infected cells fail to react with monoclonal antibody to the 130,000-dalton DNA-binding protein. Taken together, these data indicate that mutants in complementation groups 1-1 and 2-2 define the gene for the major herpes simplex virus DNA-binding protein, an early gene product required for viral DNA synthesis.


Oral teicoplanin administration suppresses recurrence of Clostridioides difficile infection: Proof of concept.
Teicoplanin is a potential antimicrobial candidate for Clostridioides difficile infection (CDI) treatment. However, the therapeutic potential of teicoplanin against severe CDI has not been clinically proven. In the present study, we investigated the efficacy of oral teicoplanin administration against severe CDI and the recurrence of severe CDI after teicoplanin treatment in a mouse model. A lethal CDI mouse model was established by colonizing the mice with C. difficile ATCC® 43255; they were orally administered teicoplanin (128 mg/kg/d) or vancomycin (160 mg/kg/d) for 10 d, 24 h after C. difficile spore challenge, and physiological and biological responses were monitored for 20 d after the initial antibiotic treatment. We also performed the in vitro time-kill assay and determined minimum inhibitory concentration (MIC), post-antibiotic effect, and toxin production with antibiotic exposure. The therapeutic response (survival rates, body weight change, clinical sickness score grading, C. difficile load, and toxin titer in feces) of oral teicoplanin administration was comparable to that of oral vancomycin administration in the lethal CDI mouse model. Moreover, teicoplanin treatment suppressed the re-onset of diarrhea and re-increase in toxin titer 10 d after treatment compared with that by vancomycin treatment. In in vitro experiments, teicoplanin exhibited time-dependent antibacterial activity and possessed lower MIC and longer post-antibiotic effect than vancomycin against C. difficile. C. difficile toxin production was numerically lower with teicoplanin exposure than with vancomycin exposure. The results obtained from the present basic experiments could suggest that teicoplanin is a potential antibiotic for the treatment of severe CDI with recurrence-prevention activity.


Imprinted gene dysregulation in a Tet1 null mouse model is stochastic and variable in the germline and offspring.
Imprinted genes are expressed from one parental allele and regulated by differential DNA methylation at imprinting control regions (ICRs). ICRs are reprogrammed in the germline through erasure and re-establishment of DNA methylation. Although much is known about DNA methylation establishment, DNA demethylation is less well understood. Recently, the Ten-Eleven Translocation proteins (TET1-3) have been shown to initiate DNA demethylation, with Tet1-/- mice exhibiting aberrant levels of imprinted gene expression and ICR methylation. Nevertheless, the role of TET1 in demethylating ICRs in the female germline and in controlling allele-specific expression remains unknown. Here, we examined ICR-specific DNA methylation in Tet1-/- germ cells and ascertained whether abnormal ICR methylation impacted imprinted gene expression in F1 hybrid somatic tissues derived from Tet1-/- eggs or sperm. We show that Tet1 deficiency is associated with hypermethylation of a subset of ICRs in germ cells. Moreover, ICRs with defective germline reprogramming exhibit aberrant DNA methylation and biallelic expression of linked imprinted genes in somatic tissues. Thus, we define a discrete set of genomic regions that require TET1 for germline reprogramming and discuss mechanisms for stochastic imprinting defects.


Cellular and molecular basis of cerebellar development.
Historically, the molecular and cellular mechanisms of cerebellar development were investigated through structural descriptions and studying spontaneous mutations in animal models and humans. Advances in experimental embryology, genetic engineering, and neuroimaging techniques render today the possibility to approach the analysis of molecular mechanisms underlying histogenesis and morphogenesis of the cerebellum by experimental designs. Several genes and molecules were identified to be involved in the cerebellar plate regionalization, specification, and differentiation of cerebellar neurons, as well as the establishment of cellular migratory routes and the subsequent neuronal connectivity. Indeed, pattern formation of the cerebellum requires the adequate orchestration of both key morphogenetic signals, arising from distinct brain regions, and local expression of specific transcription factors. Thus, the present review wants to revisit and discuss these morphogenetic and molecular mechanisms taking place during cerebellar development in order to understand causal processes regulating cerebellar cytoarchitecture, its highly topographically ordered circuitry and its role in brain function.


Biosynthesis and characterization of ¹⁵N₆-labeled phomopsin A, a lupin associated mycotoxin produced by Diaporthe toxica.
The hepatotoxin phomopsin A (PHO-A), a secondary metabolite mainly produced by the fungus Diaporthe toxica, occurs predominantly on sweet lupins. Along with the growing interest in sweet lupins for food and feed commodities, concerns have been raised about fungal infestations, and consequently, about the determination of PHO-A. High performance liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) represents the most suitable analytical technique for sensitive and selective detection of mycotoxins including PHO-A. However, isotopic labeled substances are needed as internal standards for a reliable and convenient quantification. As no isotope standard for PHO-A is currently available, a biosynthesis of fully (15)N6-labeled PHO-A was established by cultivation of D. toxica on defined media containing Na(15)NO3 and (15)N-labeled yeast extract as the only nitrogen sources. The identity of (15)N6-PHO-A was confirmed by high resolution mass spectrometry. The new (15)N6-labeled standard will facilitate the method development for PHO-A including a more accurate quantification by LC-MS/MS.


Temporal chunking as a mechanism for unsupervised learning of task-sets.
Depending on environmental demands, humans can learn and exploit multiple concurrent sets of stimulus-response associations. Mechanisms underlying the learning of such task-sets remain unknown. Here we investigate the hypothesis that task-set learning relies on unsupervised chunking of stimulus-response associations that occur in temporal proximity. We examine behavioral and neural data from a task-set learning experiment using a network model. We first show that task-set learning can be achieved provided the timescale of chunking is slower than the timescale of stimulus-response learning. Fitting the model to behavioral data on a subject-by-subject basis confirmed this expectation and led to specific predictions linking chunking and task-set retrieval that were borne out by behavioral performance and reaction times. Comparing the model activity with BOLD signal allowed us to identify neural correlates of task-set retrieval in a functional network involving ventral and dorsal prefrontal cortex, with the dorsal system preferentially engaged when retrievals are used to improve performance.


Scalable Characterization of 2D Gallium-Intercalated Epitaxial Graphene.
Scalable synthesis of two-dimensional gallium (2D-Ga) covered by graphene layers was recently realized through confinement heteroepitaxy using silicon carbide substrates. However, the thickness, uniformity, and area coverage of the 2D-Ga heterostructures have not previously been studied with high-spatial resolution techniques. In this work, we resolve and measure the 2D-Ga heterostructure thicknesses using scanning electron microscopy (SEM). Utilizing multiple correlative methods, we find that SEM image contrast is directly related to the presence of uniform bilayer Ga at the interface and a variation of the number of graphene layers. We also investigate the origin of SEM contrast using both experimental measurements and theoretical calculations of the surface potentials. We find that a carbon buffer layer is detached due to the gallium intercalation, which increases the surface potential as an indication of the 2D-Ga presence. We then scale up the heterostructure characterization over a few-square millimeter area by segmenting SEM images, each acquired with nanometer-scale in-plane resolution. This work leverages the spectroscopic imaging capabilities of SEM that allows high-spatial resolution imaging for tracking intercalants, identifying relative surface potentials, determining the number of 2D layers, and further characterizing scalability and uniformity of low-dimensional materials.


Primate trace amine receptor 1 modulation by the dopamine transporter.
Recently identified trace amine receptors are potential direct targets for drugs of abuse, including amphetamine and 3,4-methylenedioxymethamphetamine (MDMA). We cloned full-length rhesus monkey trace amine receptor 1 (rhTA(1)) that was 96% homologous to human TA(1). The trace amines tyramine and beta-phenylethylamine (PEA) and the monoamine transporter substrates (+/-)-amphetamine and (+/-)-MDMA stimulated cAMP accumulation in rhTA(1)-expressing cell lines, as measured by a cAMP response element-luciferase assay. Cocaine did not stimulate cAMP accumulation in rhTA(1) cells, but it blocked [(3)H]PEA transport mediated by the dopamine transporter. Cotransfection with the human dopamine transporter enhanced PEA-, amphetamine-, and MDMA-mediated rhTA(1) receptor activation, but it diminished tyramine activation of rhTA(1). Because TA(1) (EGFP-rhTA(1) chimera) was largely intracellular, conceivably the dopamine transporter can facilitate access of specific agonists to intracellular TA(1). rhTA(1) mRNA expression was detected in rhesus monkey substantia nigra, implying that TA(1) may be colocalized with the dopamine transporter in dopamine neurons. In summary, primate TA(1) receptors are direct targets of trace amines, amphetamine, and MDMA. These receptors could also be indirect targets of amphetamine, MDMA, and cocaine through modification of monoamine transporter function. Conceivably, rhTA(1) receptors may be located on pre- or postsynaptic membranes. Interference with the carrier function of monoamine transporters with a consequent rise of extracellular levels of trace amines could activate these receptors. The cloning of a highly homologous TA(1) from rhesus monkey and demonstration that rhTA(1) receptors are activated by drugs of abuse, indicate that nonhuman primates may serve to model physiological and pharmacological TA(1)-mediated responses in humans.


Smooth muscle cell and arterial aging: basic and clinical aspects.
Arterial aging engages a plethora of key signalling pathways that act in concert to induce vascular smooth muscle cell (VSMC) phenotypic changes leading to vascular degeneration and extracellular matrix degradation responsible for alterations of the mechanical properties of the vascular wall. This review highlights proof-of-concept examples of components of the extracellular matrix, VSMC receptors which connect extracellular and intracellular structures, and signalling pathways regulating changes in mechanotransduction and vascular homeostasis in aging. Furthermore, it provides a new framework for understanding how VSMC stiffness and adhesion to extracellular matrix contribute to arterial stiffness and how interactions with endothelial cells, platelets, and immune cells can regulate vascular aging. The identification of the key players of VSMC changes operating in large and small-sized arteries in response to increased mechanical load may be useful to better elucidate the causes and consequences of vascular aging and associated progression of hypertension, arteriosclerosis, and atherosclerosis.


Statins and Risk of Intracerebral Hemorrhage in Individuals With a History of Stroke.
Background and Purpose- It has been suggested that statins increase the risk of intracerebral hemorrhage in individuals with a history of stroke, which has led to a precautionary principle of avoiding statins in patients with prior intracerebral hemorrhage. However, such prescribing reticence may be unfounded and potentially harmful when considering the well-established benefits of statins. This study is so far the largest to explore the statin-associated risk of intracerebral hemorrhage in individuals with prior stroke. Methods- We conducted a population-based, propensity score-matched cohort study using information from Danish national registers. We included all individuals initiating statin treatment after a first-time stroke diagnosis (intracerebral hemorrhage, N=2728 or ischemic stroke, N=52 964) during 2002 to 2016. For up to 10 years of follow-up, they were compared with a 1:5 propensity score-matched group of statin nonusers with the same type of first-time stroke. The difference between groups was measured by adjusted hazard ratios for intracerebral hemorrhage calculated by type of first-time stroke as a function of time since statin initiation. Results- Within the study period, 118 new intracerebral hemorrhages occurred among statin users with prior intracerebral hemorrhage and 319 new intracerebral hemorrhages in users with prior ischemic stroke. The risk of intracerebral hemorrhage was similar for statin users and nonusers when evaluated among those with prior intracerebral hemorrhage, and it was reduced by half in those with prior ischemic stroke. These findings were consistent over time since statin initiation and could not be explained by concomitant initiation of other medications, by dilution of treatment effect (due to changes in exposure status over time), or by healthy initiator bias. Conclusions- This large study found no evidence that statins increase the risk of intracerebral hemorrhage in individuals with prior stroke; perhaps the risk is even lower in the subgroup of individuals with prior ischemic stroke.


The effects of Gilbert's syndrome on the mean platelet volume and other hematological parameters.
The protective effect of increased levels of indirect bilirubin on atherosclerotic heart disease in patients of Gilbert's syndrome is well known. The aim of the study was to investigate the effects of increased levels of bilirubin on the mean platelet volume (MPV) and other hematological parameters. Thirty-two men and 36 women (a total of 68 Gilbert's syndrome patients) and a similar age group of 68 healthy individuals (32 men and 36 women) were included in the study. Hematologic tests, C-reactive protein (CRP) and biochemical values of the two groups were checked. MPV level of Gilbert's syndrome group was 7.8±1.0fl and CRP 0.2±0.27mg/dl. In the control group MPV was 8.6±1.0fl and CRP 0.3±0.38mg/dl. MPV of patients group (P<0.001) and CRP (P=0.037) were significantly lower than the control group. When dividing Gilbert's syndrome and control groups according to sex into subgroups the level of indirect bilirubin in men with Gilbert's syndrome (1.8±0.8mg/dl) was found to be higher than other groups. Healthy men had higher levels of MPV (8.8±0.9fl) whereas Gilbert's syndrome male patients had lower levels (7.7±1.1fl), (P<0.001). The elevated levels of bilirubin and decreasing levels of MPV and CRP in Gilbert's syndrome patients may have an effect on the slowing down of the atherosclerotic process.


Comparing fatal occupational accidents in Denmark and Sweden 1993-2012.
Denmark and Sweden are in many respects two very similar countries with similar welfare state systems and work environment authorities. Nevertheless, marked differences in the incidence of fatal occupational accidents have been found in earlier comparisons of the two countries. To investigate differences in the incidence of fatal occupational accidents in the period from 1993 to 2012 to establish to what extent characteristics of the deceased can explain some of the difference between the two countries. Analyses of the accident registers of the two countries' national work environment authorities with supplemental linkages to official registers on employment status are used to determine the incidence of fatal occupational accidents for different groups. The analysis is based on 2375 accidents (1068 in Denmark and 1307 in Sweden) over the period of 20 years. Poisson regression is used to derive incidence rates over time for specific groups. In the study period, the incidence of fatal occupational accidents decreased in both countries (incidence rate ratio [IRR]: 0.95), although the incidence was on average higher in Denmark (IRR: 1.20) and grew larger over time. This difference did not disappear after adjusting for age, sex and industry among the deceased (IRR: 1.12). The incidence of fatal occupational accidents was slightly higher in Denmark in the entire period. The difference could not be explained completely by sociodemographic differences or differences related to the labour market structure in the two countries, i.e. other factors (e.g. cultural) may play a role in producing the difference.


Smad2 transduces common signals from receptor serine-threonine and tyrosine kinases.
SMAD proteins mediate signals from receptor serine-threonine kinases (RSKs) of the TGF-beta superfamily. We demonstrate here that HGF and EGF, which signal through RTKs, can also mediate SMAD-dependent reporter gene activation and induce rapid phosphorylation of endogenous SMAD proteins by kinase(s) downstream of MEK1. HGF induces phosphorylation and nuclear translocation of epitope-tagged Smad2 and a mutation that blocks TGF-beta signaling also blocks HGF signal transduction. Smad2 may thus act as a common positive effector of TGF-beta- and HGF-induced signals and serve to modulate cross talk between RTK and RSK signaling pathways.


Jump into the void? Factors related to a preferred retirement age: gender, social interests, and leisure activities.
Using the frameworks of the life course perspective and continuity theory, this study focuses on the association among working people between gender and specific leisure activities, social interests and individuals' preferred retirement age. The study is based on the first wave of the Norwegian Life Course, Aging and Generation (NorLAG) study, concentrating on workers 40-61 years old, thinking about retirement (n=2339). Results indicate that some leisure activities and interests are associated with preferences for early retirement, while other activities and interests are associated with preferences for later retirement. Different leisure activities and interests are related to men's and women's retirement preferences. Single women prefer to retire later than married women. Findings suggest that leisure activities and social interests have different relevance for men's and women's preferences for leaving the labor force. Women active in voluntary work prefer later retirement, while men engaged in fishing and hunting prefer early retirement.


Identification and genetic characterization of Haemophilus influenzae genetic island 1.
The type b capsule of pathogenic Haemophilus influenzae is a critical factor for H. influenzae survival in the blood and the establishment of invasive infections. Other pathogenic factors associated with type b strains may also play a role in invasion and sustained bacteremia, leading to the seeding of deep tissues. The gene encoding haemocin is the only noncapsular gene found to be specific to type b strains until now. Here we report the discovery of an approximately 16-kb genetic locus, HiGI1, that is present primarily in type b strains. Pulsed-field gel electrophoresis and Southern hybridization were used to map this new locus between secG (HI0445) and fruA (HI0446), which are contiguous in Rd, a nonpathogenic derivative of a serotype d strain. It is inserted at the 3' end of tRNA(4)(Leu) and has regions whose G+C content differs from the average genomic G+C content of H. influenzae. An integrase gene, which encodes a CP4-57 like integrase, is located downstream of tRNA(4)(Leu). Hybridization probes based on the sequences within the HiGI1 locus have been used to screen 61 H. influenzae strains (2 type a, 22 type b, 2 type c, 1 type d, 3 type e, 7 type f, and 21 nontypeable H. influenzae [NTHi]) from our collection. This HiGI1 locus exists in all 22 type b strains and two NTHi strains and is likely to have been acquired by an ancestral type b strain.


TGF β 3 immunoassay standardization: comparison of NIBSC reference preparation code 98/608 with avotermin lot 205-0505-005.
Juvista™ drug product contains human recombinant active transforming growth factor beta 3 (TGFβ3; avotermin). Juvista is being developed for the prevention and reduction of human scarring. Phase II and III clinical and development batches of Juvista were assayed for content by an immunoenzymometric assay (IEMA) using a National Institute for Biological Standards and Control (NIBSC) TGFβ3 reference material (98/608) and avotermin standard (Lot 205-0505-005). Paired Juvista TGFβ3 data were compared directly, pooled, and processed using the statistical analysis described by Bland and Altman. A direct comparison of the two standards was also made. The Bland-Altman result was 1.958, the best estimate of the relationship between Lot 205-0505-005 and reference material 98/608. By IEMA, reference material 98/608 has approximately 50% of the immunoreactivity of Lot 205-0505-005. During clinical development, no change in Juvista TGFβ3 dosage was made, but the standard used for Juvista TGFβ3 assay was changed from 98/608 to 205-0505-005. The stated amount of Juvista TGFβ3 in phase III trials was approximately one-half of that in phase II trials. This article highlights the importance of early adoption of an appropriate and representative standard to achieve accurate quantification of protein drug during clinical development.


Efficacy of zinc supplementation for neonatal sepsis: a systematic review and meta-analysis.
Background: Zinc supplementation has some potential in treating neonatal sepsis. We conduct a systematic review and meta-analysis to explore the efficacy of zinc supplementation for neonatal sepsis. Methods: PubMed, Embase, Web of science, EBSCO, and Cochrane Library databases are systematically searched. Randomized controlled trials (RCTs) assessing the efficacy of zinc supplementation in neonatal sepsis are included. Two investigators independently search articles, extract the data, and assessed the quality of included studies. Meta-analysis is performed using the random-effect model. Results: Four RCTs involving 986 patients are included in the meta-analysis. Overall, compared with control intervention in neonatal sepsis, zinc supplementation is able to significantly reduce mortality rate (risk ratio (RR) = 0.48; 95% confidence intervals (CIs) = 0.25-0.94; p = .03) and improve serum zinc (mean difference (MD) = 81.97; 95% CI = 34.57-129.37; p = .0007), but has no remarkable influence on hospital stay (MD = -4.51; 95% CI = -15.08 to 6.05; p = .40) and the number of expired patients (RR = 0.63; 95% CI = 0.24-1.65; p = .35). Conclusions: Zinc supplementation may significantly reduce mortality rate and improve serum zinc in neonatal sepsis, but has no substantial influence on hospital stay and the number of expired patients.


Tree recruitment in an empty forest.
To assess how the decimation of large vertebrates by hunting alters recruitment processes in a tropical forest, we compared the sapling cohorts of two structurally and compositionally similar forests in the Rio Manu floodplain in southeastern Peru. Large vertebrates were severely depleted at one site, Boca Manu (BM), whereas the other, Cocha Cashu Biological Station (CC), supported an intact fauna. At both sites we sampled small (> or =1 m tall, <1 cm dbh) and large (> or =1 cm and <10 cm dbh) saplings in the central portion of 4-ha plots within which all trees > or =10 cm dbh were mapped and identified. This design ensured that all conspecific adults within at least 50 m (BM) or 55 m (CC) of any sapling would have known locations. We used the Janzen-Connell model to make five predictions about the sapling cohorts at BM with respect to CC: (1) reduced overall sapling recruitment, (2) increased recruitment of species dispersed by abiotic means, (3) altered relative abundances of species, (4) prominence of large-seeded species among those showing depressed recruitment, and (5) little or no tendency for saplings to cluster closer to adults at BM. Our results affirmed each of these predictions. Interpreted at face value, the evidence suggests that few species are demographically stable at BM and that up to 28% are increasing and 72% decreasing. Loss of dispersal function allows species dispersed abiotically and by small birds and mammals to substitute for those dispersed by large birds and mammals. Although we regard these conclusions as preliminary, over the long run, the observed type of directional change in tree composition is likely to result in biodiversity loss and negative feedbacks on both the animal and plant communities. Our results suggest that the best, and perhaps only, way to prevent compositional change and probable loss of diversity in tropical tree communities is to prohibit hunting.


Time to Take Sleeping Pills and Subjective Satisfaction among Cancer Patients.
We investigated the influence of the time to take hypnotics and daytime activity on patient satisfaction with sleeping pills. Ninety-six cancer patients who were currently taking benzodiazepine or z-drug as hypnotics were grouped into satisfied and dissatisfied groups. The subjects' symptoms, time to take sleeping pills, bedtime, sleep onset time, wake up time, and time in bed within 24 hours (TIB/d) were obtained. The satisfied group had significantly late sleeping pill ingestion time (p=0.04); significantly early wake up time (p=0.01); and significantly shorter sleep latency, TIB/d, duration from the administration of pills to sleep onset, and duration from the administration of pills to wake up time (PTW). Logistic regression analysis revealed that the significant predictors of patient satisfaction to hypnotics were less severity of insomnia [odds ratio (OR)=0.91] and the time variables, including late sleeping pill administration time (OR=1.53) and early wake up time (OR=0.57). Among the duration variables, short PTW (OR=0.30) and short TIB/d (OR=0.64) were significantly related with the satisfaction to hypnotics. Reducing the duration from the administration of hypnotics to wake up time and TIB/d can influence the satisfaction to sleeping pills.


A biodegradable CO2-based polymeric antitumor nanodrug via a one-pot surfactant- and solvent-free miniemulsion preparation.
In the present study, low molecular weight poly(propylene carbonate) (PPC, Mn = 3500), a biodegradable liquid polymer easily prepared from carbon dioxide (CO2), was modified into poly(propylene carbonate)diacrylate (PPC-DA) by acylation, and methoxy poly(ethylene glycol) (mPEG) was modified into methoxy poly(ethylene glycol) acrylate (mPEG-A). Using PPC-DA as the dispersant to dissolve hydrophobic doxorubicin (DOX) and the initiator, and with mPEG-A as the co-monomer and polymerisable surfactant, a biodegradable nanodrug with excellent biocompatibility was prepared by shear emulsification polymerization without surfactants or organic solvent residues. The nanodrug can be efficiently endocytosed by tumor cells and can rapidly release doxorubicin triggered by the acidic endosomal pH. As evidenced by experiments in tumor-bearing mice, such a nanodrug is stealthy during blood circulation, and targets tumor sites with high efficiency. Moreover, this nanodrug is more effective and less toxic than free doxorubicin. This study provides a green and versatile approach for preparing biodegradable nanodrugs via a simple and efficient process. Moreover, this study extends the applications of CO2 based polymers in the biomedical field, promoting the development of CO2 polymerization fixation.


Recent advances in the modelling and simulation of electrokinetic effects: bridging the gap between atomistic and macroscopic descriptions.
Electrokinetic phenomena are of great practical importance in fields as diverse as micro-fluidics, colloid science and oil exploration. However, the quantitative prediction of electrokinetic effects was until recently limited to relatively simple geometries that allowed the use of analytical theories. In the past decade, there has been a rapid development in the use of numerical methods that can be used to model electrokinetic phenomena in complex geometries or, more generally, under conditions where the existing analytical approaches fail. The present paper discusses these recent developments, with special emphasis on the advent of coarse-grained models that make it possible to bridge the gap between a purely atomistic and macroscopic descriptions.


Neuronal activity in the primate premotor, supplementary, and precentral motor cortex during visually guided and internally determined sequential movements.
1. Single-cell activity was recorded from three different motor areas in the cerebral cortex: the primary motor cortex (MI), supplementary motor area (SMA), and premotor cortex (PM). 2. Three monkeys (Macaca fuscata) were trained to perform a sequential motor task in two different conditions. In one condition (visually triggered task, VT), they reached to and touched three pads placed in a front panel by following lights illuminated individually from behind the pads. In the other condition (internally guided task, IT), they had to remember a predetermined sequence and press the three pads without visual guidance. In a transitional phase between the two conditions, the animals learned to memorize the correct sequence. Auditory instruction signals (tones of different frequencies) told the animal which mode it was in. After the instruction signals, the animals waited for a visual signal that triggered the first movement. 3. Neuronal activity was analyzed during three defined periods: delay period, premovement period, and movement period. Statistical comparisons were made to detect differences between the two behavioral modes with respect to the activity in each period. 4. Most, if not all, of MI neurons exhibited similar activity during the delay, premovement, and movement periods, regardless of whether the sequential motor task was visually guided or internally determined. 5. More than one-half of the SMA neurons were preferentially or exclusively active in relation to IT during both the premovement (55%) and movement (65%) periods. In contrast, PM neurons were more active (55% and 64% during the premovement and movement periods) in VT. 6. During the instructed-delay period, a majority of SMA neurons exhibited preferential or exclusive relation to IT whereas the activity in PM neurons was observed equally in different modes. 7. Two types of neurons exhibiting properties of special interest were observed. Sequence-specific neurons (active in a particular sequence only) were more common in SMA, whereas transition-specific neurons (active only at the transitional phase) were more common in PM. 8. Although a strict functional dichotomy is not acceptable, these observations support a hypothesis that the SMA is more related to IT, whereas PM is more involved in VT. 9. Some indications pointing to a functional subdivision of PM are obtained.


[X-ray changes in the region of long-bone fractures in early post-traumatic period].
Described are the results of computer-based X-ray interpretation of images of long-bone fractures made immediately after trauma. The difference between roentgenograms made on the day of trauma and on the next day is demonstrated. A new soft, which was used by the author for X-ray interpretations, is depicted.


Latino Physicians in the United States, 1980-2010: A Thirty-Year Overview From the Censuses.
To update and extend a 2000 study on the California Latino physician workforce, the authors examined the Latino physician workforce in the 30-year time frame spanning 1980 to 2010, comparing changes in the rates of physicians per 100,000 population for the Latino and non-Hispanic white (NHW) populations in the United States as a whole and in the five states with (in 2010) the largest Latino populations. The authors used detailed data from the U.S. Census (Public Use Microdata Samples for 1980-2010) to identify total population, total number of physicians, and Spanish-language ability for both the Latino and NHW populations. They examined nativity for only Latinos. At the national level, the NHW physician rate per 100,000 of the NHW population increased from 211 in 1980 to 315 in 2010 while the Latino physician rate per 100,000 of the Latino population dropped over the same period from 135 to 105. With small variations, the same trend occurred in all five of the states examined. At the national and state levels, Latino physicians were far more likely to speak Spanish than NHW physicians. Over the 30-year period, the Latino physician population has evolved from being primarily foreign born to being about evenly split between foreign born and U.S. born. The Latino physician shortage has worsened over the past 30 years. The authors recommend immediate action on the national and local level to increase the supply of Latino physicians.


The mediating effects of working hours, sleep duration, and depressive mood on the association between shift work and the risk of suicidal ideation in Korean workers.
This study aimed to investigate the mediating effects of working hours, sleep duration, and depressive mood on the association between shift work and the risk of suicidal ideation in Korean workers. Data from 33,047 workers were obtained from the nationwide cross-sectional Korea National Health and Nutrition Examination Surveys conducted in 2007-2018. Healthy workers without depressive disorders and chronic medical illnesses were included in the current study. Shift work patterns, sleep duration, working hours, depressive mood, and suicidal ideation were assessed using self-reported questionnaires. Multivariate logistic regressions were used to examine the association between shift work and the risk of suicidal ideation. Additionally, mediating studies were conducted to identify the roles of working hours and sleep durations on the association. Compared with daytime workers, shift workers had 1.33 times greater risk of suicidal ideation (OR = 1.33, 95% Cl = 1.17-1.52, p < 0.001). Specifically, among shift work patterns, fixed-night shift, 24-h rotating shift and irregular rotating shift were associated with the risk of suicidal ideation when compared with daytime workers (irregular rotating shift: OR = 1.92, 95% Cl = 1.29-2.86, p = 0.001; fixed-night shift: OR = 1.75, 95% Cl = 1.32-2.31, p < 0.001; 24-h rotating shift: OR = 1.58, 95% Cl = 1.06-2.36, p = 0.024). In the mediating study, working hours, sleep duration and depressive mood significantly mediated the relationship between shift work and suicidal ideation (direct effect: β = 0.019, p = 0.001; indirect effect: β = 0.004, p = 0.031; total effect: β = 0.023, p < 0.001). This study revealed that shift workers had a greater risk of suicidal ideation. The patterns significantly associated with suicidal ideation were irregular rotating, fixed-night, and 24-h rotating shifts. The pathway analysis revealed serial mediating effects of working hours, sleep duration, and depressive mood on the association between shift work and suicidal ideation.


Heteronormativity, school climates, and perceived safety for gender nonconforming peers.
Students' perceptions of their school climates are associated with psychosocial and academic adjustment. The present study examined the role of school strategies to promote safety in predicting students' perceptions of safety for gender nonconforming peers among 1415 students in 28 high schools. Using multilevel modeling techniques, we examined student- and school-level effects on students' perceptions of safety for gender nonconforming peers. We found that older students, bisexual youth, Latino youth, and youth who experienced school violence perceived their gender nonconforming male peers to be less safe. Similarly, we found that older students and students who experienced school violence and harassment due to gender nonconformity perceived their gender nonconforming female peers to be less safe. At the school-level, we found that when schools included lesbian, gay, bisexual, transgender, and queer (LGBTQ) issues in the curriculum and had a Gay-Straight Alliance, students perceived their schools as safer for gender nonconforming male peers.