Phase-engineered low-resistance contacts for ultrathin MoS2 transistors.
Ultrathin molybdenum disulphide (MoS2) has emerged as an interesting layered semiconductor because of its finite energy bandgap and the absence of dangling bonds. However, metals deposited on the semiconducting 2H phase usually form high-resistance (0.7 kΩ μm-10 kΩ μm) contacts, leading to Schottky-limited transport. In this study, we demonstrate that the metallic 1T phase of MoS2 can be locally induced on semiconducting 2H phase nanosheets, thus decreasing contact resistances to 200-300 Ω μm at zero gate bias. Field-effect transistors (FETs) with 1T phase electrodes fabricated and tested in air exhibit mobility values of ~50 cm(2) V(-1) s(-1), subthreshold swing values below 100 mV per decade, on/off ratios of >10(7), drive currents approaching ~100 μA μm(-1), and excellent current saturation. The deposition of different metals has limited influence on the FET performance, suggesting that the 1T/2H interface controls carrier injection into the channel. An increased reproducibility of the electrical characteristics is also obtained with our strategy based on phase engineering of MoS2.


Chloride equilibrium potential in salamander cones.
GABAergic inhibition and effects of intracellular chloride ions on calcium channel activity have been proposed to regulate neurotransmission from photoreceptors. To assess the impact of these and other chloride-dependent mechanisms on release from cones, the chloride equilibrium potential (ECl) was determined in red-sensitive, large single cones from the tiger salamander retinal slice. Whole cell recordings were done using gramicidin perforated patch techniques to maintain endogenous Cl- levels. Membrane potentials were corrected for liquid junction potentials. Cone resting potentials were found to average -46 mV. To measure ECl, we applied long depolarizing steps to activate the calcium-activated chloride current (ICl(Ca)) and then determined the reversal potential for the current component that was inhibited by the Cl- channel blocker, niflumic acid. With this method, ECl was found to average -46 mV. In a complementary approach, we used a Cl-sensitive dye, MEQ, to measure the Cl- flux produced by depolarization with elevated concentrations of K+. The membrane potentials produced by the various high K+ solutions were measured in separate current clamp experiments. Consistent with electrophysiological experiments, MEQ fluorescence measurements indicated that ECl was below -36 mV. The results of this study indicate that ECl is close to the dark resting potential. This will minimize the impact of chloride-dependent presynaptic mechanisms in cone terminals involving GABAa receptors, glutamate transporters and ICl(Ca).


Indications for drug therapy in premenstrual syndrome patients.
Women with mild to moderate premenstrual syndrome (PMS) should have their symptoms controlled with conservative therapy, including diet, exercise, education and nutritional supplementation. Those patients with moderate to severe PMS whose condition cannot be controlled in this conservative fashion should undergo pharmacologic trials. Recent studies of progesterone supplementation showed no improvement when it was compared to placebo; the one exception was the use of oral micronized progesterone one therapy at a level of 300 mg/day, but the study remains to be repeated by other investigators. The most logical therapy at present is suppression of ovulation with a short-term trial of danazol, perhaps followed by long-term suppression with estrogen implants or depomedroxyprogesterone acetate. Surgical ovariectomy is warranted in a very small number of cases. Prostaglandin inhibitors are effective for the physical complaints that may be associated with PMS. Some antihypertensive agents, such as clonidine and verapamil, which are also antimania drugs, may have a place in the treatment of PMS.


Members of the GH3 Family of Proteins Conjugate 2,4-D and Dicamba with Aspartate and Glutamate.
Auxin homeostasis is a highly regulated process that must be maintained to allow auxin to exert critical growth and developmental controls. Auxin conjugase and hydrolase family proteins play important roles in auxin homeostasis through means of storage, activation, inactivation, response inhibition and degradation of auxins in plants. We systematically evaluated 60 GRETCHEN HAGEN3 (GH3) proteins from diverse plant species for amino acid conjugation activity with the known substrates jasmonic acid (JA), IAA and 4-hydroxybenzoate (4-HBA). While our results largely confirm that Group II conjugases prefer IAA, we observed no clear substrate preference among Group III proteins, and only three of 11 Group I proteins showed the expected preference for JA, indicating that sequence similarity does not always predict substrate specificity. Such a sequence-substrate relationship held true when sequence similarity at the acyl acid-binding site was used for grouping. Several GH3 proteins could catalyze formation of the potentially degradation-destined aspartate (Asp) and glutamate (Glu) conjugates of IAA and the synthetic auxins 2,4-D and dicamba. We found that 2,4-D-Asp/Glu conjugates, but not dicamba and IAA conjugates, were hydrolyzed in Arabidopsis and soybean by AtILL5- and AtIAR3-like amidohydrolases, releasing free 2,4-D in plant cells when conjugates were exogenously applied to seedlings. Dicamba-Asp or dicamba-Glu conjugates were not hydrolyzed in vivo in infiltrated plants nor in vitro with recombinant amidohydrolases. These findings could open the door for exploration of a dicamba herbicide tolerance strategy through conjugation.


Short-term effects of silage volatile compounds on feed intake and digestion in beef cattle.
Two experiments were conducted to evaluate whether fermentation end products in silage affect intake and digestion in beef cattle. Six rumen-cannulated Nellore steers were randomly assigned to a replicated 3 × 3 Latin square design with 14-d periods. Each period consisted of 9 d for adaptation and 5 d for sample collection. Steers were housed in a tie-stall barn and individually fed once daily at 0800 h. The dietary treatments in Exp. 1 were as follows: 60% corn silage plus 40% concentrate (CON), 60% corn silage with added ethanol (2.8% on a DM basis) and 40% concentrate (ET), and 60% corn silage with added lactic acid (5.4% on a DM basis) and 40% concentrate (LA). The DMI was similar (P = 0.41) across treatments (average 11.7 kg/d); however, the LA treatment increased the ruminal pH (P = 0.01) and decreased the acetate:propionate ratio (P < 0.01). Diet digestibility decreased by 2.2 to 2.5 percentage units when the DM content was determined by oven drying (at 105°C) rather than by toluene distillation. The treatments in Exp. 2 were as follows: 75% sugarcane silage with no volatile fraction (oven dried at 60°C and rehydrated) and 25% concentrate (75D), 75% sugarcane silage (original moisture content) and 25% concentrate (75W), and 40% sugarcane silage and 60% concentrate (40W). Approximately 21% of the DM content of sugarcane silage consisted of volatile compounds. The presence of these compounds did not alter the DMI (P = 0.36) but did increase both the acetate:propionate ratio (P < 0.01) and the fractional absorption rates of valerate (P < 0.01) and ethanol (P = 0.02) in the empty reticulorumen. The 40W diet led to a greater DMI (40W = 9.79 vs. 75W = 6.19 kg/d; P < 0.01), which altered most of the measured variables traditionally associated with high-concentrate diets. As in Exp. 1, diet digestibility decreased by 1.5 to 5.4 units when the DM content was determined by oven drying at 105°C rather than by toluene distillation. In this short-term study, volatile compounds did not inhibit the DMI or the digestion process of the animals. On the contrary, volatile compounds contributed to the energy content of the silage, composing up to 10% of the energy value as determined by digestibility. Due to the short experimental periods, the results from this study should be interpreted with caution.


Deoxyribonucleoside triphosphate pools and growth of glutathione-depleted 3T6 mouse fibroblasts.
Buthionine sulfoximine (BSO) selectively blocks g-glutamylcysteine synthetase and thereby depletes cells of glutathione (GSH). In cultures of exponentially growing 3T6 mouse fibroblasts, 0.1 mM BSO rapidly stopped GSH synthesis after treatment for 12 hours. The GSH-depleted cells grew as well as control 3T6 cells with no decrease in DNA synthesis. Furthermore, the pools of deoxyribonucleoside triphosphates (dNTPs), typically tightly regulated in cultured cells, did not change in size. Ribonucleotide reductase catalyzes the reduction of all four ribonucleotides and occupies a key position in dNTP regulation. Our data suggest that the GSH-glutaredoxin (a GSH-dependent disulfide-oxidoreductase) system is not the sole/major hydrogen carrier from NADPH for the reduction of ribonucleoside diphosphates by ribonucleotide reductase.


Effectiveness, predictive response factors, and safety of anti-tumor necrosis factor (TNF) therapies in anti-TNF-naive rheumatoid arthritis.
To evaluate the effectiveness and safety of anti-tumor necrosis factor (anti-TNF) therapies in rheumatoid arthritis (RA), and to identify the factors involved in this response. Dynamic prospective cohort study of patients with RA treated with anti-TNF under clinical practice conditions. Effectiveness was evaluated using Disease Activity Score (DAS) 28, European League Against Rheumatism (EULAR) response, Health Assessment Questionnaire (HAQ), and time to treatment failure. Prior adherence was evaluated retrospectively and safety was evaluated by adverse events (AE). The analysis was restricted to anti-TNF-naive patients. The study included 161 patients treated for RA during 6 years (60 infliximab, 79 etanercept, and 22 adalimumab). At 6 months, 15% reached a good EULAR response and 38% a moderate response. A mean decrease of -1.5 (p < 0.0001) was observed in the DAS28 and of -0.34 in the HAQ (p < 0.0001); however, women showed poorer progress in terms of DAS and HAQ. In the first year, 64.3% did not experience treatment failure and this figure was 50.5% after 2 years. In one-third, glucocorticoids were withdrawn and in the remainder the dose was reduced by 50%. Adherence to treatment, selection of etanercept, and intensification of infliximab were associated with a lower probability of premature failure in the multivariate model. AE were similar to other those in studies and no outstanding differences in safety were found between the 3 anti-TNF therapies. Anti-TNF treatments are effective and safe, reducing the activity of the disease, disability, and the need for corticosteroids. Patients who displayed good adherence prior to the anti-TNF treatment and were treated with etanercept or with increasing doses of infliximab had the best chance of displaying a response.


Dealing with Zeros: Adolescent Drug Use, Perceived Disapproval, and Perceived Harm.
Because studies examining youth drug use often have data with a high proportion of zeros, they often do not meet the assumptions for univariate or linear regression analyses that are typically used. We demonstrate the use of zero-inflated negative binomial regression models to address excessive zeros in drug use frequency on perceptions of disapproval and perceived harm among middle and high school students (N = 522). We found that perceptions of parent disapproval were a better predictor of marijuana use (p = .01) than peer disapproval. Perceived harm was related to marijuana use (p = .04). Researchers should consider using zero-inflated negative binomial regression models when examining youth drug use.


Molecularly imprinted photonic hydrogels for fast screening of atropine in biological samples with high sensitivity.
Based on molecularly imprinted photonic hydrogels (MIPHs) that combined the colloidal-crystal with molecular imprinting technique, a novel label-free colorimetric chemosensor for convenient and fast efficient detection of atropine with high sensitivity and specificity was developed. Due to the special inverse opal arrays with a thin polymer wall in which the imprinted nanocavities of atropine moleculars distributed, the proposed MIPHs designed as water-compatible exhibited high sensitive (as low as 1 pg/mL), rapid responsive (less than 30 s) and specific detection of atropine in complex matrix. The unique three-dimensional, highly-ordered photonic hydrogels would be obviously swelling in response to the specific atropine molecular recognition process and the response would be directly transferred into visually perceptible optical signal (change in color) that could be detected by the naked eye through Bragg diffractive shifts of ordered macroporous arrays. With a broad concentration range varying from 1 pg/mL to 1 μg/mL of atropine, the distinct color changes of MIPHs almost covered the whole visible-light wavelength range from blue to red for semi-quantitative analysis. The smart chemosensor was successfully employed to determine the trace level atropine in human urine samples, providing a fast and effective alternative for semi-quantitative detection of atropine for clinical analysis and forensic investigations.


What Do Different Modes of AFM-IR Mean for Measuring Soft Matter Surfaces?
In the past decade, rapidly emerging atomic force microscopy-based photothermal infrared microscopy (AFM-IR) techniques have routinely delivered surface chemical imaging with tens of nanometers spatial resolution. The commercial availability of AFM-IR instruments has accelerated their popularity among soft matter and surface science communities. Various AFM-IR modes exist with different characteristics. In this Perspective, we discuss the challenges and opportunities associated with many AFM-IR modes, clarifying the possible confusion arising from terminologies and describing the possible benefits of using multiple AFM-IR modes for a better understanding of the nanoscale composition organization of the interface.


Endobronchial metastasis.
An attempt was made to define the incidence of tumor metastasis to central bronchi that could clinically mimic primary bronchogenic carcinoma. In a retrospective review of 1,359 consecutive autopsies at Walter Reed General Hospital, metastatic involvement of a major airway was present in only 2% of patients who died with solid tumors. The most common extrathoracic tumors associated with metastatic involvement of a central airway are renal and colorectal carcinomas. The clinical and roentogenographic features of endobronchial metastasis and bronchogenic carcinoma were found to be indistinguishable. However, in the majority of cases the primary tumor site is clinically apparent before symptoms of endobronchial metastasis. In most cases of endobronchial metastasis, the histologic appearance of the bronchoscopic biopsy suggests the correct diagnosis. A central bronchogenic carcinoma should rarely be confused with a metastasis to a major airway from an extrathoracic source.


Methylomic Signatures of High Grade Serous Ovarian Cancer.
High-grade serous ovarian cancer (HGSOC) harbours aberrant epigenetic features, including DNA methylation. In this study we delineate pathways and networks altered by DNA methylation and associated with HGSOC initiation and progression to a platinum-resistant state. By including tumours from patients who had been treated with the hypomethylating agent (HMA) guadecitabine, we also addressed the role of HMAs in treatment of HGSOC. Tumours from patients with primary (platinum-naïve) HGSOC (n = 20) were compared to patients with recurrent platinum-resistant HGSOC and enrolled in a recently completed clinical trial (NCT01696032). Human ovarian surface epithelial cells (HOSE; n = 5 samples) served as normal controls. Genome-wide methylation profiles were determined. DNA methyltransferase (DNMT) expression levels were examined by immunohistochemistry and correlated with clinical outcomes. Cancer-related and tumorigenesis networks were enriched among differentially methylated genes (DMGs) in primary OC vs. HOSE. When comparing platinum-resistant and primary tumours, 452 CpG island (CGI)-containing gene promoters acquired DNA methylation; of those loci, decreased (P < 0.01) methylation after HMA treatment was observed in 42% (n = 189 CGI). Stem cell pluripotency and cytokine networks were enriched in recurrent platinum-resistant OC tumours, while drug metabolism and transport-related networks were downregulated in tumours from HMA-treated patients compared to HOSE. Lower DNMT1 and 3B protein levels in pre-treatment tumours were associated with improved progression-free survival. The findings provide important insight into the DNA methylation landscape of HGSOC tumorigenesis, platinum resistance and epigenetic resensitization. Epigenetic reprogramming plays an important role in HGSOC aetiology and contributes to clinical outcomes.


Identification of the role of TRPM8 in glioblastoma and its effect on proliferation, apoptosis and invasion of the U251 human glioblastoma cell line.
Glioblastoma multiforme (GBM) is the most commonly occurring brain cancer, and is characterized by its poor patient outcomes. The present study examined the mRNA expression levels of the transient receptor potential melastatin (TRPM) family in various types of cancer using the ONCOMINE database, along with their corresponding expression profiles in an array of cancer cell lines based on the Cancer Cell Line Encyclopedia (CCLE) datasets. Kaplan‑Meier plotter survival analysis via the Chinese Glioma Genome Atlas (CGGA) database was also used to evaluate the prognostic value of transient receptor potential melastatin 8 (TRPM8). For the activity test on the TRPM8 channel, patch‑clamp recordings and Ca2+ measurements by fluorescence imaging of Fluo‑4am were performed. Short hairpin RNA (shRNA) targeting TRPM8 was designed, synthesized and then transfected into the U251 cells via Lipofectamine 2000. The expression of extracellular singnal‑regulated kinase (ERK), cyclin D1 and Bcl‑2 were detected by performing western blotting and immunofluorescence. The apoptosis, proliferation and invasion of glioma cells were detected by using flow cytometry, and CCK‑8 and Transwell invasion assays. In the present study, TRPM8 was distinctively upregulated in GBM cell lines. TRPM8 is functional and has the characteristic of outward rectification, which was verified via electrophysiology and Ca2+ fluorescence imaging in U251 cells. The western blot and immunofluorescence results revealed that the expression of ERK, cyclin D1 and Bcl‑2 were decreased in the shRNA interference group. The CCK‑8 assay demonstrated that the proliferation ability of U251 cells in the U251/TRPM8 group was higher than that in the U251 group and U251/Con group (P<0.05). The result of the Transwell invasion assay indicated that the invasion of human glioblastoma U251 cells was positively correlated with the expression level of TRPM8. Collectively, the results of the present study indicated that Ca2+‑permeable TRPM8 nonselective cation channels contribute to survival, proliferation, apoptosis, and local tumor invasion of glioblastoma. Therefore, TRPM8 is a promising biomarker for aggressiveness of GBM, and a potential target in future anti‑glioblastoma therapies.


Mismatch Repair Deficiency as a Predictive Biomarker for Immunotherapy Efficacy.
Immunotherapy has revolutionized cancer treatment. Immune-checkpoint inhibitors, on balance, showed a favorable efficacy/toxicity profile with durable response in different cancer types. No predictive biomarker has been validated thus far to select patients who would benefit from therapy. Among the candidate predictive biomarkers, mismatch repair status of the tumor is currently one of the most promising. Indeed, tumors displaying mismatch repair deficiency or microsatellite instability showed remarkable response to immunotherapy in clinical trials. This correlation has been first reported in colorectal cancers, but similar results have been observed also in other cancer types. The possible mechanism behind this correlation may be the higher mutational load observed in mismatch repair deficient tumors, leading to neoantigens formation, recruitment of immune cells, and release of proinflammatory factors in the microenvironment. These results support an approach to treatment based on assessment of the genomic stability of the tumor besides its biologic characteristics and may change our therapeutic decision making process. However, due to the small percentage of patients with tumors displaying mismatch repair deficiency, data from clinical trials should not be considered definitive and need further confirmation.


Lack of resistance to macrolides in Mycoplasma genitalium detected in South African pregnant women.
Azithromycin regimens have been considered first-line treatment for Mycoplasma genitalium (M. genitalium), a sexually transmitted infection (STI) associated with adverse pregnancy outcomes. However, recent years have seen rapid emergence of macrolide resistance in M. genitalium as a result of widespread administration of azithromycin. Currently, there are limited data on macrolide resistance in pregnant women from KwaZulu-Natal (KZN), South Africa. This study investigated the prevalence of M. genitalium and emerging patterns of macrolide resistance in pregnant women from KZN. This was a sub-study of a larger study which involved laboratory-based detection of STIs in pregnant women. In the main study, pregnant women provided urine samples for detection of STIs. For this study, deoxyribose nucleic acid (DNA) extracted from stored urine was used to determine emerging macrolide resistance by amplification of the 23S ribosomal ribonucleic acid (rRNA) gene of M. genitalium by polymerase chain reaction (PCR) and sequencing of amplicons to identify mutations associated with resistance. The Allplex™ MG & AziR assay was used as a confirmatory assay. The prevalence of M. genitalium in pregnant women was 5.9% (13 out of 221). Sequencing of PCR amplicons did not reveal the presence of the A2059G and A2058G mutations associated with macrolide resistance. These findings were confirmed by the Allplex™ MG & AziR assay. Despite the lack of resistance to macrolides in this study population, continued antimicrobial resistance surveillance for M. genitalium in pregnant women is important because azithromycin is now part of the South African national STI syndromic management guidelines for vaginal discharge syndrome.


Introgression between two cutthroat trout subspecies with substantial karyotypic, nuclear and mitochondrial genomic divergence.
The authors used allozymes encoded by nuclear genes and restriction enzyme analysis of mitochondrial DNA (mtDNA) to study secondary contact between westslope (Salmo clarki lewisi) and Yellowstone cutthroat trout (Salmo clarki bouvieri) in Forest Lake, Montana. Eleven diagnostic allozyme loci identified this as a random-mating hybrid swarm. No parental, first-generation hybrid or backcross genotypes were detected in the sample (N = 33), and genotype distributions at all the variable loci conform to binomial expectations. There is little linkage disequilibrium between the diagnostic loci, indicating that the nuclear genomes of the two subspecies are largely randomly associated. The allozymes and mtDNA give identical estimates of the proportional genetic contribution of each subspecies. Thus, males and females from both subspecies have contributed equally to this hybrid swarm. Although these subspecies have accumulated substantial genetic divergence between their nuclear (Nei's D = 0.34) and mitochondrial (2% sequence divergence) genomes, this has not resulted in a genetic barrier to exchange between them.


Antibacterial & antitoxic effects of the cardiovascular drug lacidipine in an animal model.
Vibrio cholerae produces acute infection by liberating potent enterotoxin, called cholera toxin in human intestine. Cardiovascular drug lacidipine possessing powerful in vitro action against V. cholerae was tested to determine its possible activity against a toxigenic V. cholerae strain in an established animal model. In the rabbit intestine four loops were constructed, 3 of which were injected with over night grown V. cholerae 569B culture. Of these, two loops were simultaneously given graded doses (100, 200 μg) of lacidipine, one was left as such for a positive control. The first loop received sterile medium (negative control). After 18 h, contents of all the loops were examined for accumulation of fluid and number of viable cells. Lacidipine when administrated with live V. cholerae 569B, caused a reduction in the number of viable bacteria along with amount of fluid in the loops. The amount of fluid and number of viable cells were much reduced in the loop that had 200 μg of lacidipine than the loop that received 100 μg of the drug. Lacidipine has distinct inhibitory action against V. cholerae 569B with respect to both viability and production of cholera toxin in the rabbit ileum. Structural modifications of this compound may possibly lead to procurement of new potent antimicrobial drugs.


Defining Diagnostic Error: A Scoping Review to Assess the Impact of the National Academies' Report Improving Diagnosis in Health Care.
Standards for accurate and timely diagnosis are ill-defined. In 2015, the National Academies of Science, Engineering, and Medicine (NASEM) committee published a landmark report, Improving Diagnosis in Health Care , and proposed a new definition of diagnostic error, "the failure to ( a ) establish an accurate and timely explanation of the patient's health problem(s) or ( b ) communicate that explanation to the patient." This study aimed to explore how researchers operationalize the NASEM's definition of diagnostic error with relevance to accuracy, timeliness, and/or communication in peer-reviewed published literature. Using the Arskey and O'Malley's framework framework, we identified published literature from October 2015 to February 2021 using Medline and Google Scholar. We also conducted subject matter expert interviews with researchers. Of 34 studies identified, 16 were analyzed and abstracted to determine how diagnostic error was operationalized and measured. Studies were grouped by theme: epidemiology, patient focus, measurement/surveillance, and clinician focus. Nine studies indicated using the NASEM definition. Of those, 5 studies also operationalized with existing definitions proposed before the NASEM report. Four studies operationalized the components of the NASEM definition and did not cite existing definitions. Three studies operationalized error using existing definitions only. Subject matter experts indicated that the NASEM definition functions as foundation for researchers to conceptualize diagnostic error. The NASEM report produced a common understanding of diagnostic error that includes accuracy, timeliness, and communication. In recent peer-reviewed literature, most researchers continue to use pre-NASEM report definitions to operationalize accuracy and timeliness. The report catalyzed the use of patient-centered concepts in the definition, resulting in emerging studies focused on examining errors related to communicating diagnosis to patients.


Polycyclic aromatic hydrocarbons in soil of the Canadian river floodplain in Oklahoma.
The accumulation of polycyclic aromatic hydrocarbons (PAH) in soil, plants, and water may impart negative effects on ecosystem and human health. We quantified the concentration and distribution of 41 PAH (n = 32), organic C, total N, and S (n = 140) and investigated PAH sources using a chronosequence of floodplain soils under a natural vegetation succession. Soil samples were collected between 0- and 260-cm depth in bare land (the control), wetland, forest, and grassland areas near a closed municipal landfill and an active asphalt plant (the contaminant sources) in the north bank of the Canadian River near Norman, OK. Principal component, cluster, and correlation analyses were used to investigate the spatial distribution of PAH, in combination with diagnostic ratios to distinguish pyrogenic vs. petrogenic PAH suites. Total PAH concentration (SigmaPAH) had a mean of 1300 ng g(-1), minimum of 16 ng g(-1), and maximum of 12,000 ng g(-1). At 0- to 20-cm depth, SigmaPAH was 3500 +/- 1600 ng g(-1) (mean +/- 1 SE) near the contaminant sources. The most common compounds were nonalkylated, high molecular weight PAH of pyrogenic origin, i.e., fluoranthene (17%), pyrene (14%), phenanthrene (9%), benzo(b)fluoranthene (7%), chrysene (6%), and benzo(a)anthracene (5%). SigmaPAH in the control (130 +/- 23 ng g(-1)) was comparable to reported concentrations for the rural Great Plains. Perylene had a unique distribution pattern suggesting biological inputs. The main PAH contamination mechanisms were likely atmospheric deposition due to asphalt production at the 0- to 20-cm depth and past landfill operations at deeper depths.


[Evaluation of the management of inhalers by the nursing personnel in a reference hospital].
To evaluate the knowledge and skills of nurses on the management of inhaled therapy in different hospitalization wards. We carried out a cross-sectional study, in which nurses were asked to perform a practical demonstration of the management of a pressurized canister with an inhalation chamber, without previous theoretical instruction about the technique. The inhalation technique was evaluated step by step following the recommendations of the Spanish Society of Pneumologists and Chest Surgeons (SEPAR). We could obtain the participation of 144 of the 177 nurses working in different wards (29 males, 115 females, mean age 42.5 + 7 years). Previous knowledge of the management of inhalers was declared by 85.4%. We found that 70.8% of the nurses did not correctly perform all the steps: 24.5% made only one mistake, while the rest had mistakes in two or more steps. The most common mistakes were: not to perform a slow and deep exhalation before using the inhaler (27.3%), not to hold the breath after the inhalation (24.4%), and not to wait 30 seconds between inhalation manoeuvres (21.5%). When evaluating different wards, we found that 44.4% of the nurses in the Short Stay Unit performed the technique correctly in contrast to 31.3% of the nurses in the Pneumology Ward. The percentage of mistakes in the inhalation technique by the nursing personnel was high. The health personnel must have an adequate level of training in order to correctly instruct the patient, because the efficacy of inhaled treatment greatly depends on the adequacy of the technique.


Saturation of hemoglobin in intracranial arteries is similar in patients with hemodynamically relevant and irrelevant stenosis of the internal carotid artery.
The aim of this study was to establish if patients with hemodynamically relevant or irrelevant stenoses of the extracranial internal carotid artery have different intracranial arterial oxygen saturation as measured by transcranial pulse oximetry using near infrared spectroscopy. Patients with unilateral stenosis > 70% according to North American Symptomatic Carotid Endarterectomy Trial (NASCET) were included. Hemodynamic relevance was assessed using ultrasound criteria. Transcranial spectroscopy recordings were taken before and after surgical or interventional treatment of the stenosis. Optodes were placed bilaterally on the intact frontoparietal aspect of the skull. Oxygen saturation and diversion angle alpha from the hemoglobin plane were measured. There were no significant differences regarding arterial oxygen saturation between the two groups. Oxygen saturation ranged from 0.910 +/- 0.08 to 0.957 +/- 0.028 in the subgroups (all values as mean +/- S.E.). These values are consistent with previous studies and theoretical values. In smokers we found a significantly shifted diversion angle from the hemoglobin plane to the negative side. This indicates the presence of an absorber other than oxy- and desoxyhemoglobin in the optical field. We conclude that transcranial pulse oximetry cannot distinguish between patients with hemodynamically relevant and irrelevant stenosis of the internal carotid artery. However it seems to be capable of distinguishing smokers from non-smokers.


Electrocardiographic Findings in Brazilian Adults without Heart Disease: ELSA-Brasil.
The electrocardiogram (ECG) is widely used in population-based studies. However, there are few studies on electrocardiographic findings in Latin America and in Brazil. The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) comprised 15,105 participants (35-74 years) from six Brazilian capitals. To describe electrocardiographic findings in Brazilian adults without heart disease, stratified by sex, age and race/skin color. Cross-sectional study with baseline data of 11,094 adults (44.5% men) without heart disease from ELSA-Brasil. The ECGs were recorded with the Burdick Atria 6100 machine and stored at the Pyramis System. ECG analysis was automatically performed using the Glasgow University software. A descriptive analysis of heart rate (HR), P, QRS and T waves' duration, PR and QT intervals, and P, R and T axes was performed. After stratification by sex, race/color and age, the groups were compared by the Wilcoxon and Kruskal-Wallis test at a significance level of 5%. Linear regression models were used to evaluate the behavior of electrocardiographic parameters over age. Major electrocardiographic abnormalities defined by the Minnesota code were manually revised. Medians values of the electrocardiographic parameters were different between men and women: HR 63 vs. 66 bpm, PR 164 vs.158 ms, QT corrected 410 vs. 421 ms, QRS duration 92 vs. 86 ms, P-wave duration 112 vs. 108 ms, P-wave axis 54 vs. 57 degrees, R-wave axis 35 vs. 39 degrees, T-wave axis 39 vs. 45 degrees (p < 0.001 for all). The 2nd and the 98th percentiles of each variable were also obtained, and graphs were constructed to illustrate the behavior of the electrocardiographic findings over age of participants stratified by sex and race/skin color. The values for the electrocardiographic measurements herein described can be used as reference for Brazilian adults free of heart disease, stratified by sex. Our results suggest that self-reported race/skin color have no significant influence on electrocardiographic parameters.


Detection of quantitative trait loci for growth and beef carcass fatness traits in a cross between Bos taurus (Angus) and Bos indicus (Brahman) cattle.
This study was conducted to detect quantitative trait loci (QTL) affecting growth and beef carcass fatness traits in an experimental population of Angus and Brahman crossbreds. The three-generation mapping population was generated with 602 progeny from 29 reciprocal backcross and three F2 full-sib families, and 417 genetic markers were used to produce a sex-averaged map of the 29 autosomes spanning 2,642.5 Kosambi cM. Alternative interval-mapping approaches were applied under line-cross (LC) and random infinite alleles (RA) models to detect QTL segregating between and within breeds. A total of 35 QTL (five with genomewide significant and 30 with suggestive evidence for linkage) were found on 19 chromosomes. One QTL affecting yearling weight was found with genomewide significant evidence for linkage in the interstitial region of bovine autosome (BTA) 1, and an additional 19 QTL were detected with suggestive evidence for linkage under the LC model. Many of these QTL had a dominant (complete or overdominant) mode of gene action, and only a few of the QTL were primarily additive, which reflects the fact that heterosis for growth is known to be appreciable in crosses among Brahman and British breeds. Four QTL affecting growth were detected with genomewide significant evidence for linkage under the RA model on BTA 2 and BTA 6 for birth weight, BTA 5 for yearling weight, and BTA 23 for hot carcass weight. An additional 11 QTL were detected with suggestive evidence for linkage under the RA model. None of the QTL (except for yearling weight on BTA 5) detected under the RA model were found by the LC analyses, suggesting the segregation of alternate alleles within one or both of the parental breeds. Our results reveal the utility of implementing both the LC and RA models to detect dominant QTL and also QTL with similar allele frequency distributions within parental breeds.


Prediction of an U2S3-type polymorph of Al2O3 at 3.7 Mbar.
We predict by first principles a phase transition in alumina at approximately 3.7 Mbar and room temperature from the CaIrO(3)-type polymorph to another with the U(2)S(3)-type structure. Because alumina is used as window material in shock-wave experiments, this transformation should be important for the analysis of shock data in this pressure range. Comparison of our results on all high-pressure phases of alumina with shock data suggests the presence of two phase transitions in shock experiments: the corundum to Rh(2)O(3)(II)-type structure and the Rh(2)O(3)(II)-type to CaIrO(3)-type structure. The transformation to the U(2)S(3)-type polymorph is in the pressure range reached in the mantle of recently discovered terrestrial exoplanets and suggests that the multi-megabar crystal chemistry of planet-forming minerals might be related to that of the rare-earth sulfides.


Localization of MGSA/GRO protein in cutaneous lesions.
Melanoma growth stimulatory activity (MGSA/GRO), a cytokine originally characterized as an autocrine growth factor for melanoma cells, is highly chemotactic for neutrophils and releases neutrophil elastase as well as other matrix-degrading enzymes. Previous work has demonstrated the presence of MGSA/GRO in melanocytic lesions and in the epidermal keratinocytes of non-lesional skin and psoriatic scale. Herein, MGSA/GRO localization was examined in a variety of human skin lesions exhibiting proliferative and/or differentiative disorders using immunohistochemical methods. Most lesions showed greater MGSA/GRO immunoreactivity in the more differentiated suprabasal keratinocytes of the stratum spinosum and stratum granulosum than in the stratum basalis, where the dividing basal cells are found. Hair follicles, sebaceous glands, and sweat glands were also frequently positive for MGSA/GRO. The highest level of immunoreactive MGSA/GRO in diseased epidermis was detected in verruca vulgaris, followed by psoriasis, keratoacanthoma, and squamous cell carcinoma. Detection of MGSA/GRO in basal cell carcinoma was variable, being present in the sclerosing variant and absent in the more common nodular variant. Melanocytic lesions stained less intensely for MGSA/GRO than keratinocytic lesions, where the levels of MGSA/GRO expression correlated with the inflammatory response and degree of keratinocyte differentiation.


Retirement and death in office of U.S. Supreme Court justices.
We construct demographic models of retirement and death in office of U.S. Supreme Court justices, a group that has gained demographic notice, evaded demographic analysis, and is said to diverge from expected retirement patterns. Models build on prior multistate labor force status studies, and data permit an unusually clear distinction between voluntary and "induced" retirement. Using data on every justice from 1789 through 2006, with robust, cluster-corrected, discrete-time, censored, event-history methods, we (1) estimate retirement effects of pension eligibility, age, health, and tenure on the timing of justices' retirements and deaths in office, (2) resolve decades of debate over the politicized departure hypothesis that justices tend to alter the timing of their retirements for the political benefit or detriment of the incumbent president, (3) reconsider the nature of rationality in retirement decisions, and (4) consider the relevance of organizational conditions as well as personal circumstances to retirement decisions. Methodological issues are addressed.


Phytochemical Profile, Mineral Content, and Bioactive Compounds in Leaves of Seed-Propagated Artichoke Hybrid Cultivars.
The globe artichoke (Cynara cardunculus L. subsp. Scolymus (L.) Hegi) is a multi-year species rich in various classes of phytochemicals with known nutritional and pharmacological properties, such as polyphenols, sesquiterpene lactones, and terpenoids. Over the last decade, hybrids cultivars are transforming the artichoke market for their higher uniformity and stability over the traditional landraces, further increasing the potential of the artichoke as a source of commercial extracts and bioactive molecules. Our aim was to investigate the mineral and phytochemical profiles of leaves from seven seed-propagated hybrids by using an untargeted metabolomic approach based on ultra-high-pressure liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry. Metabolomics identified several compounds in the tested varieties, namely 98 polyphenols, 123 sesquiterpene lactones, and 221 other metabolites. The phenolic content ranged from 3.01 mg Eq./g fw (for 'Opera') to 4.71 mg Eq./g fw (for 'Opal'). Sesquiterpene lactones were, on average, 2.11 mg Eq./g fw. Multivariate statistics (HCA, PCA and OPLS-DA) highlighted the main metabolomics differences among cultivars, which weakly correlated with their agronomic classification. The seven cultivars showed distinctive metabolomics profiles, with 'Opal' and 'Istar' being the most valuable hybrids. The 3-hydroxyphenyl-valeric acid (a medium-chain fatty acid) and the 6-Gingesulfonic acid (a methoxyphenol) were the most discriminant markers. Our findings illustrated the quantitative and qualitative variation of several classes of phytochemicals in seed-propagated artichoke cultivars and allowed identifying distinctive metabolic signatures for both phenolic compounds and sesquiterpene lactones. This work supports the exploitation of the artichoke leaves from hybrid cultivars as a rich source of bioactive phytochemicals.


Bactericidal cationic peptides involved in bacterial antagonism and host defence.
There are numerous reports in the literature on small, strongly cationic peptides displaying marked antimicrobial activity. These peptides are produced by bacteria as well as higher organisms, and are thought to be involved in bacterial antagonism or host defence mechanisms.


Methods for applying accurate digital PCR analysis on low copy DNA samples.
Digital PCR (dPCR) is a highly accurate molecular approach, capable of precise measurements, offering a number of unique opportunities. However, in its current format dPCR can be limited by the amount of sample that can be analysed and consequently additional considerations such as performing multiplex reactions or pre-amplification can be considered. This study investigated the impact of duplexing and pre-amplification on dPCR analysis by using three different assays targeting a model template (a portion of the Arabidopsis thaliana alcohol dehydrogenase gene). We also investigated the impact of different template types (linearised plasmid clone and more complex genomic DNA) on measurement precision using dPCR. We were able to demonstrate that duplex dPCR can provide a more precise measurement than uniplex dPCR, while applying pre-amplification or varying template type can significantly decrease the precision of dPCR. Furthermore, we also demonstrate that the pre-amplification step can introduce measurement bias that is not consistent between experiments for a sample or assay and so could not be compensated for during the analysis of this data set. We also describe a model for estimating the prevalence of molecular dropout and identify this as a source of dPCR imprecision. Our data have demonstrated that the precision afforded by dPCR at low sample concentration can exceed that of the same template post pre-amplification thereby negating the need for this additional step. Our findings also highlight the technical differences between different templates types containing the same sequence that must be considered if plasmid DNA is to be used to assess or control for more complex templates like genomic DNA.


On-Particle Hyperbranched Rolling Circle Amplification-Scaffolded Magnetic Nanoactuator Assembly for Ferromagnetic Resonance Detection of MicroRNA.
Inspired by natural molecular machines, scientists are devoted to designing nanomachines that can navigate in aqueous solutions, sense their microenvironment, actuate, and respond. Among different strategies, magnetically driven nanoactuators can easily be operated remotely in liquids and thus are valuable in biosensing. Here we report a magnetic nanoactuator swarm with rotating-magnetic-field-controlled conformational changes for reaction acceleration and target quantification. By grafting nucleic acid amplification primers, magnetic nanoparticle (MNP) actuators can assemble and be fixed with a flexible DNA scaffold generated by surface-localized hyperbranched rolling circle amplification in response to the presence of a target microRNA, osa-miR156. Net magnetic anisotropy changes of the system induced by the MNP assembly can be measured by ferromagnetic resonance spectroscopy as shifts in the resonance field. With a total assay time of ca. 120 min, the proposed biosensor offers a limit of detection of 6 fM with a dynamic detection range spanning 5 orders of magnitude. The specificity of the system is validated by testing different microRNAs and salmon sperm DNA. Endogenous microRNAs extracted from Oryza sativa leaves are tested with both quantitative reverse transcription-PCR and our approach, showing comparable performances with a Pearson correlation coefficient >0.9 (n = 20).


Strain-specific genome evolution in Trypanosoma cruzi, the agent of Chagas disease.
The protozoan Trypanosoma cruzi almost invariably establishes life-long infections in humans and other mammals, despite the development of potent host immune responses that constrain parasite numbers. The consistent, decades-long persistence of T. cruzi in human hosts arises at least in part from the remarkable level of genetic diversity in multiple families of genes encoding the primary target antigens of anti-parasite immune responses. However, the highly repetitive nature of the genome-largely a result of these same extensive families of genes-have prevented a full understanding of the extent of gene diversity and its maintenance in T. cruzi. In this study, we have combined long-read sequencing and proximity ligation mapping to generate very high-quality assemblies of two T. cruzi strains representing the apparent ancestral lineages of the species. These assemblies reveal not only the full repertoire of the members of large gene families in the two strains, demonstrating extreme diversity within and between isolates, but also provide evidence of the processes that generate and maintain that diversity, including extensive gene amplification, dispersion of copies throughout the genome and diversification via recombination and in situ mutations. Gene amplification events also yield significant copy number variations in a substantial number of genes presumably not required for or involved in immune evasion, thus forming a second level of strain-dependent variation in this species. The extreme genome flexibility evident in T. cruzi also appears to create unique challenges with respect to preserving core genome functions and gene expression that sets this species apart from related kinetoplastids.


Platelet-activating factor: a paracrine factor in preimplantation stages of reproduction?
Platelet-activating factor (PAF) exerts its actions through activation of specific membrane binding sites found in a variety of tissues, including hypothalamus and endometrium. PAF has been identified in several reproductive tissues (i.e. embryo, ovary, uterus, and spermatozoon). In the uterus, PAF levels are hormonally controlled, being elevated by progesterone and prostaglandin E2 (PGE2). Antagonists of PAF interfere with sperm function, ovulation, and implantation. The available evidence suggests that PAF may be an important physiological regulator in reproduction.


Antibiotic Resistance and Azithromycin Resistance Mechanism of Legionella pneumophila Serogroup 1 in China.
Legionnaires' disease, caused by Legionella pneumophila, has been treated primarily with antibiotics. However, few reports have been published on antibiotic-resistant Legionella in China. Our aim was to determine the azithromycin resistance mechanism of L. pneumophila serogroup 1 in China. The sensitivities of 149 L. pneumophila serogroup 1 strains, isolated from clinical cases or environmental water in China from 2002 to 2016, to five antibiotics, including erythromycin, azithromycin, levofloxacin, moxifloxacin, and rifampin, were evaluated. The mechanisms of the resistance of L. pneumophila serogroup 1 to azithromycin were studied. The expression levels of efflux pump gene lpeAB and the MIC of azithromycin-resistant strains in the presence and absence of the efflux pump inhibitor carbonyl cyanide-chlorophenylhydrazone (CCCP) were determined. All 149 strains were sensitive to erythromycin, levofloxacin, moxifloxacin, and rifampin, among which 25 of the strains exhibited azithromycin resistance. These 25 strains, including strains of sequence type 1 (ST1), ST144, ST150, ST154, and ST629, were screened. Expression of lpeAB was responsible for the reduced azithromycin susceptibility in all 25 of these strains. The phenotypes of 25 strains with virulence were linked by evaluating the intracellular growth ability in mouse macrophage J774 cells. Among the 25 strains, 60% were more virulent than the ATCC 33152 reference strain. The results determined in our study represent data supporting the further study of the antibiotic sensitivity of L. pneumophila strains in China.


[Ion-regulating renal function during oral and parenteral potassium loading].
Ion-regulating renal function and influence of vasopressin and its analogues on the rate and selectiveness of the urinary potassium excretion were investigated after short-term parenteral and oral potassium loading. In experiments with Wistar rats it was shown that increase in volume of orally administrated 1.25% KCl solution from 1 to 5 ml per 100 g body weight led to the proportional rise in potassium excretion. Hyperkalemia was already observed at 5 min after parenteral potassium loading, potassium excretion reached the maximum after administration of 2 ml of KCl solution per 100 g body weight. Kaliuresis induced by oral potassium load was higher and faster than after parenteral load and was followed by increase in diuresis, urinary sodium and magnesium excretion. Desmopressin and 1-deamino-Arg4-vasotocin prevented rise of diuresis, natriuresis and magniuresis under these conditions; 1-deamino-Arg4-vasotocin and vasopressin stimulated urinary potassium excretion during first 30 min after loading. After parenteral potassium load vasopressin analogues did not affect urinary potassium and sodium excretion. The data obtained suggest the participation of the gut in regulatory signal transduction to the kidney after potassium entering and prevention of significant changes in the internal environment.


Multiple pheromone system controlling mating in Drosophila melanogaster.
The signals essential to Drosophila melanogaster courtship include pheromones emitted by the female which stimulate the male to court and pheromones emitted by the courting male which stimulate the female to accept. Genetic variation among these phermones is a common (if not universal) requirement for stimulation of either sex. The signal from the courting male to the female involves both a volatile and a nonvolatile component. The volatile component is associated with loci on the second and/or third chromosomes, while the monvolatile component is associated with the X and/or fourth chromosomes. This widespread distribution in the genome of loci controlling various components in the communication network inevitably results in linkage associations with other loci. The genetic array of gametes was limited. When combined with the negative assortitative mating pattern produced by the stimulation by dissimilar pheromones, linkage disequilibrium creates a strong counterforce to inbreeding during population bottlenecks.


Personality is of central concern to understand health: towards a theoretical model for health psychology.
This paper sets out the case that personality traits are central to health psychology. To achieve this, three aims need to be addressed. First, it is necessary to show that personality influences a broad range of health outcomes and mechanisms. Second, the simple descriptive account of Aim 1 is not sufficient, and a theoretical specification needs to be developed to explain the personality-health link and allow for future hypothesis generation. Third, once Aims 1 and 2 are met, it is necessary to demonstrate the clinical utility of personality. In this review I make the case that all three Aims are met. I develop a theoretical framework to understand the links between personality and health drawing on current theorising in the biology, evolution, and neuroscience of personality. I identify traits (i.e., alexithymia, Type D, hypochondriasis, and empathy) that are of particular concern to health psychology and set these within evolutionary cost-benefit analysis. The literature is reviewed within a three-level hierarchical model (individual, group, and organisational) and it is argued that health psychology needs to move from its traditional focus on the individual level to engage group and organisational levels.


Genetic effects of chronic habitat fragmentation on tree species: the case of Sorbus aucuparia in a deforested Scottish landscape.
Sustainable forest restoration and management practices require a thorough understanding of the influence that habitat fragmentation has on the processes shaping genetic variation and its distribution in tree populations. We quantified genetic variation at isozyme markers and chloroplast DNA (cpDNA), analysed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in severely fragmented populations of Sorbus aucuparia (Rosaceae) in a single catchment (Moffat) in southern Scotland. Remnants maintain surprisingly high levels of gene diversity (HE) for isozymes (HE = 0.195) and cpDNA markers (HE = 0.490). Estimates are very similar to those from non-fragmented populations in continental Europe, even though the latter were sampled over a much larger spatial scale. Overall, no genetic bottleneck or departures from random mating were detected in the Moffat fragments. However, genetic differentiation among remnants was detected for both types of marker (isozymes Theta n = 0.043, cpDNA Theta c = 0.131; G-test, P-value < 0.001). In this self-incompatible, insect-pollinated, bird-dispersed tree species, the estimated ratio of pollen flow to seed flow between fragments is close to 1 (r = 1.36). Reduced pollen-mediated gene flow is a likely consequence of habitat fragmentation, but effective seed dispersal by birds is probably helping to maintain high levels of genetic diversity within remnants and reduce genetic differentiation between them.


Advance decisions to refuse treatment and suicidal behaviour in emergency care: 'it's very much a step into the unknown'.
Complex challenges may arise when patients present to emergency services with an advance decision to refuse life-saving treatment following suicidal behaviour. To investigate the use of advance decisions to refuse treatment in the context of suicidal behaviour from the perspective of clinicians and people with lived experience of self-harm and/or psychiatric services. Forty-one participants aged 18 or over from hospital services (emergency departments, liaison psychiatry and ambulance services) and groups of individuals with experience of psychiatric services and/or self-harm were recruited to six focus groups in a multisite study in England. Data were collected in 2016 using a structured topic guide and included a fictional vignette. They were analysed using thematic framework analysis. Advance decisions to refuse treatment for suicidal behaviour were contentious across groups. Three main themes emerged from the data: (a) they may enhance patient autonomy and aid clarity in acute emergencies, but also create legal and ethical uncertainty over treatment following self-harm; (b) they are anxiety provoking for clinicians; and (c) in practice, there are challenges in validation (for example, validating the patient's mental capacity at the time of writing), time constraints and significant legal/ethical complexities. The potential for patients to refuse life-saving treatment following suicidal behaviour in a legal document was challenging and anxiety provoking for participants. Clinicians should act with caution given the potential for recovery and fluctuations in suicidal ideation. Currently, advance decisions to refuse treatment have questionable use in the context of suicidal behaviour given the challenges in validation. Discussion and further patient research are needed in this area. D.G., K.H. and N.K. are members of the Department of Health's (England) National Suicide Prevention Advisory Group. N.K. chaired the National Institute for Health and Care Excellence (NICE) guideline development group for the longer-term management of self-harm and the NICE Topic Expert Group (which developed the quality standards for self-harm services). He is currently chair of the updated NICE guideline for Depression. K.H. and D.G. are NIHR Senior Investigators. K.H. is also supported by the Oxford Health NHS Foundation Trust and N.K. by the Greater Manchester Mental Health NHS Foundation Trust.


[Occurrence of Staphylococcus aureus enterotoxigenic strains isolated from pregnant women with pathology].
137 S. aureus strains, isolated from the larynx of pregnant women in cases of pathology, were studied for the formation of staphylococcal enterotoxins of types A and B (SEA and SEB) by the indirect hemagglutination test. The study revealed that SEA was produced by 35.0% and SEB, by 56.6% of the strains under study. The proportion of SEA and SEB producers among staphylococci isolated from mothers and children was, respectively, 18.4% and 20.0%, 89.41% and 67.5%. The number of enterotoxigenic staphylococci in the upper respiratory tract of newborn infants and mothers practically coincided with that in mothers. The occurrence of SEA- and SEB-producing enterotoxigenic strains in the medical personnel was 25.5% and 62.7% respectively.


Colonic Pseudo-obstruction With Transition Zone: A Peculiar Eastern Severe Dysmotility.
Previous studies from Korea have described chronic intestinal pseudo-obstruction (CIPO) patients with transition zone (TZ) in the colon. In this study, we evaluated the pathological characteristics and their association with long-term outcomes in Korean colonic pseudo-obstruction (CPO) patients with TZ. We enrolled 39 CPO patients who were refractory to medical treatment and underwent colectomy between November 1989 and April 2016 (median age at symptoms onset: 45 [interquartile range, 29-57] years, males 46.2%). The TZ was defined as a colonic segment connecting a proximally dilated and distally non-dilated segment. Detailed pathologic analysis was performed. Among the 39 patients, 37 (94.9%) presented with TZ and 2 (5.1%) showed no definitive TZ. Median ganglion cell density in the TZ adjusted for the colonic circumference was significantly decreased compared to that in proximal dilated and distal non-dilated segments in TZ (+) patients (9.2 vs 254.3 and 150.5, P < 0.001). Among the TZ (+) patients, 6 showed additional pathologic findings including eosinophilic ganglionitis (n = 2), ulcers with combined cytomegalovirus infection (n = 2), diffuse ischemic changes (n = 1), and heterotropic myenteric plexus (n = 1). During follow-up (median, 61 months), 32 (82.1%) TZ (+) patients recovered without symptom recurrence after surgery. The presence of pathological features other than hypoganglionosis was an independent predictor of symptom recurrence after surgery (P = 0.046). Hypoganglionosis can be identified in the TZ of most Korean CPO patients. Detection of other pathological features in addition to TZ-associated hypoganglionosis was associated with poor post-operative outcomes.


Some of the Factors Involved in Male Infertility: A Prospective Review.
Infertility is defined as the inability of couples to have a baby after one year of regular unprotected intercourse, affecting 10 to 15% of couples. According to the latest WHO statistics, approximately 50-80 million people worldwide sufer from infertility, and male factors are responsible for approximately 20-30% of all infertility cases. The diagnosis of infertility in men is mainly based on semen analysis. The main parameters of semen include: concentration, appearance and motility of sperm. Causes of infertility in men include a variety of things including hormonal disorders, physical problems, lifestyle problems, psychological issues, sex problems, chromosomal abnormalities and single-gene defects. Despite numerous efforts by researchers to identify the underlying causes of male infertility, about 70% of cases remain unknown. These statistics show a lack of understanding of the mechanisms involved in male infertility. This article focuses on the histology of testicular tissue samples, the male reproductive structure, factors affecting male infertility, strategies available to find genes involved in infertility, existing therapeutic methods for male infertility, and sperm recovery in infertile men.


Cortical and Subcortical Contributions to Long-Term Memory-Guided Visuospatial Attention.
Long-term memory (LTM) helps to efficiently direct and deploy the scarce resources of the attentional system; however, the neural substrates that support LTM-guidance of visual attention are not well understood. Here, we present results from fMRI experiments that demonstrate that cortical and subcortical regions of a network defined by resting-state functional connectivity are selectively recruited for LTM-guided attention, relative to a similarly demanding stimulus-guided attention paradigm that lacks memory retrieval and relative to a memory retrieval paradigm that lacks covert deployment of attention. Memory-guided visuospatial attention recruited posterior callosal sulcus, posterior precuneus, and lateral intraparietal sulcus bilaterally. Additionally, 3 subcortical regions defined by intrinsic functional connectivity were recruited: the caudate head, mediodorsal thalamus, and cerebellar lobule VI/Crus I. Although the broad resting-state network to which these nodes belong has been referred to as a cognitive control network, the posterior cortical regions activated in the present study are not typically identified with supporting standard cognitive control tasks. We propose that these regions form a Memory-Attention Network that is recruited for processes that integrate mnemonic and stimulus-based representations to guide attention. These findings may have important implications for understanding the mechanisms by which memory retrieval influences attentional deployment.


Information loss in an optimal maximum likelihood decoding.
The mutual information between a set of stimuli and the elicited neural responses is compared to the corresponding decoded information. The decoding procedure is presented as an artificial distortion of the joint probabilities between stimuli and responses. The information loss is quantified. Whenever the probabilities are only slightly distorted, the information loss is shown to be quadratic in the distortion.


Receptor dimerization--rationale for the design of bivalent ligands.
Accumulating evidence has confirmed the existence and functional significance of GPCR and other types of receptor homodimers and heterodimers. However, many aspects of the biology and pharmacology of the dimerization process remain unclear. Several crystal structures of the dimerized proteins or protein-ligand complex have provided useful insights to the understanding of such process. As a common phenomenon of most receptors, homodimerization and heterodimerization have added a new dimension to characterize the receptor different from the traditional way, and open a new avenue to rational drug design and discovery.


Partner age difference and prevalence of chlamydial infection among young adult women.
Sexual partner mixing by age is common among adolescents and adults. Although adolescent girls with older male partners are at increased risk of sexually transmitted infection, the importance of this association in young adults is unclear. To assess the association between partner age difference and prevalence of chlamydial infection among young women. Using Wave III of the National Longitudinal Study of Adolescent Health (April 2, 2001-May 9, 2002), the authors examined the relation between the prevalence of chlamydial infection and the partner age among women aged 18 to 26 years. Among women with most recent partners 2 to 8 years younger, the odds of chlamydial infection were approximately 2 times greater [adjusted odds ratio (OR), 1.8; 95% confidence interval (CI), 0.9, 3.5] than among women with partners within 1-year age difference, adjusting for number of partners in the past year. Prevalence of chlamydial infection was only slightly greater for women with partners 2 to 5 years older (adjusted OR, 1.4; 95% CI, 0.9, 2.3) and partners 6 or more years older (adjusted OR, 1.6; 95% CI, 0.9, 2.8), when compared with women with partners within 1-year age difference. The relation between most discordant partner age difference and chlamydial infection seems to vary by women's race/ethnicity, although these stratified estimates are imprecise. These findings suggest that among young adult women, in contrast to adolescents, older male partners are only moderately associated with the prevalence of chlamydial infection. Young adult women have the lowest odds of infection with partners within 1 year of age difference.


Antimicrobial stewardship program implementation in a medical intensive care unit at a tertiary care hospital in Saudi Arabia.
Antimicrobial stewardship programs (ASPs) have shown to prevent the emergence of antimicrobial resistance associated with an inappropriate antimicrobial use. The primary objective of this study was to compare the prescribing appropriateness rate of the empirical antibiotic therapy before and after the ASP implementation in a tertiary care hospital. Secondary objectives include the rate of Clostridium difficile-associated diarrhea (CDAD), physicians' acceptance rate, patient's intensive care unit (ICU) course, total utilization using defined daily dose, and total direct cost of antibiotics. This is a comparative, historically controlled study. Adult medical ICU patients were enrolled in a prospective fashion under the active ASP arm and compared with historical patients who were admitted to the same unit before the ASP implementation. This study was approved by the institutional review board, and the need for informed consent was waived because the interventions and recommendations were evidence based and considered the standard of care. The study was conducted at KFSHRC, Riyadh. Adult medical ICU patients were enrolled under the active ASP arm if they were on any of the 5 targeted antibiotics (piperacillin/tazobactam, imipenem/cilastatin, meropenem, vancomycin, tigecycline), and had no official infectious disease consultation. The interventions were conducted via prospective audit and feedback. A total of 73 subjects were recruited, 49 in historical control and 24 in the active arm. The appropriateness of empirical antibiotics was improved from 30.6% (15/49) in the historical control arm to 100% (24/24) in the proactive ASP arm (P value < .05). For the ASP group, initially 79.1% (19/24) of the antibiotic uses were inappropriate and diminished by ASPs to 0% on the recommendations implementation. A total of 27 interventions were made with an acceptance rate of 96.3%. The rate of CDAD did not differ between the groups. A reduction in antibiotics utilization and direct cost were also noticed in the ASP arm. A proactive ASP is a vital approach in optimizing the appropriate empirical antibiotics utilization in an ICU setting in tertiary care hospitals. This study highlights the importance of such a program and may serve as a foundation for further ASP initiatives particularly in our region.


Reconstruction of complex oncologic chest wall defects: a 10-year experience.
The repair of complex chest wall defects presents a challenging problem for the reconstructive surgeon. Although the majority of such defects could be repaired with the use of local and regional musculocutaneous flaps, more complicated cases require increasingly sophisticated reconstructive techniques. This study reviews the experience at a single cancer center with chest wall reconstruction over a decade. A retrospective review was undertaken for each patient who underwent chest wall reconstruction from 1992 to 2002. Patient demographics and variables, including pathologic diagnosis, extent of resection, size of defect, method of reconstruction, and outcome were evaluated. There was a total of 113 patients, 88 females and 25 males. The average age was 58 years (range, 19-88 years). The most common diagnoses were breast cancer and sarcoma. The average area of the chest wall defect after resection was 266 cm. One hundred fifty-seven musculocutaneous or muscle flaps were performed for reconstruction of the chest wall. Eleven percent of patients underwent reconstruction with autologous free tissue transfer. One hundred six patients underwent a single operation. Seven patients required a second operation for salvage of a complication. In 19 cases (15%), more than 1 flap was used simultaneously to complete the reconstruction. Eighty-four percent of the patients achieved stable chest wall reconstruction with no complications. Seven patients (4%) had partial (>10%) flap loss. The most common remaining postoperative complications were delayed wound healing (3% of patients), infection (2.5%), and hematoma (2.5%). Immediate chest wall reconstruction is safe, reliable, and can most often be accomplished with 1 operation. A variety of flaps, both single and in combination, could be used to achieve definitive coverage of the chest wall after extirpative surgery. The reconstructive choice is dependent on factors such as size of the defect, location on the chest wall, arc of rotation of the flap, and availability of recipient vessels. Based on this single institutional experience over a decade, an algorithm to chest wall reconstruction is provided.


Coping with large litters: the management of neonatal piglets and sow reproduction.
As a result of intensive breeding, litter size has considerably increased in pig production over the last three decades. This has resulted in an increase in farrowing complications. Prolonged farrowing will shorten the window for suckling colostrum and reduce the chances for high-quality colostrum intake. Studies also agree that increasing litter sizes concomitantly resulted in decreased piglet birth weight and increased within-litter birth weight variations. Birth weight, however, is one of the critical factors affecting the prognosis of colostrum intake, and piglet growth, welfare, and survival. Litters of uneven birth weight distribution will suffer and lead to increased piglet mortality before weaning. The proper management is key to handle the situation. Feeding strategies before farrowing, management routines during parturition (e.g., drying and moving piglets to the udder and cross-fostering) and feeding an energy source to piglets after birth may be beneficial management tools with large litters. Insulin-like growth factor 1 (IGF-1)-driven recovery from energy losses during lactation appears critical for supporting follicle development, the viability of oocytes and embryos, and, eventually, litter uniformity. This paper explores certain management routines for neonatal piglets that can lead to the optimization of their colostrum intake and thereby their survival in large litters. In addition, this paper reviews the evidence concerning nutritional factors, particularly lactation feeding that may reduce the loss of sow body reserves, affecting the growth of the next oocyte generation. In conclusion, decreasing birth weight and compromised immunity are subjects warranting investigation in the search for novel management tools. Furthermore, to increase litter uniformity, more focus should be placed on nutritional factors that affect IGF-1-driven follicle development before ovulation.


Emerging strategies to strengthen the anti-tumour activity of type I interferons: overcoming survival pathways.
Interferon-a (IFN-a) is currently the most used cytokine in the treatment of cancer. However, the potential anti-tumour activity of IFN-a is limited by the activation of tumour resistance mechanisms. In this regard, we have shown that IFN-a, at growth inhibitory concentrations, enhances the EGF-dependent Ras-->Erk signalling and decreases the adenylate cyclase/cAMP pathway activity in cancer cells; both effects represent escape mechanisms to the growth inhibition and apoptosis induced by IFN-a. The selective targeting of these survival pathways might enhance the antitumor activity of IFN-ain cancer cells, as shown by: i) the combination of selective EGF receptor tyrosine kinase inhibitor (gefitinib) and IFN-a having cooperative anti-tumour effects; ii) the farnesyl-transferase inhibitor R115777 strongly potentiating the anti-tumour activity of IFN-a both in vitro and in vivo through the inhibition of different escape mechanisms that are dependent on isoprenylation of intracellular proteins such as ras; iii) the cAMP reconstituting agent (8-Br-cAMP) enhancing the pro-apoptotic activity of IFN-alpha. IFN-beta is a multifunctional cytokine binding the same receptor of IFN-alpha, but with higher affinity (10-fold) and differential structural interactions. We recently showed that IFN-beta is considerably more potent than IFN-alpha in its anti-tumour effect through the induction of apoptosis and/or cell cycle arrest in S-phase. The emergence of long-acting pegylated forms of IFN-beta makes this agent a promising anti-cancer drug. These observations open a new scenario of anticancer intervention able to strengthen the antitumor activity of IFN-alpha or to use more potent type I IFNs.


Efficacy of human leucocyte alpha-interferon treatment for chronic hepatitis C virus infection.
A total of 42 Swedish patients with biopsy-proven chronic hepatitis C virus (HCV) infection were treated with a natural human leucocyte alpha-interferon (HuIFN-alpha-Le), Alfanative (BioNative AB, Umeå, Sweden) in an open uncontrolled study. Two patients were withdrawn from treatment within 2 weeks due to non-compliance and were omitted from further analysis, and 40 patients (17 females), mean age 39 years (range 24-71) completed the study. All patients were HCV RNA-positive in serum prior to treatment, with raised alanine aminotransferase (ALT) levels > 1.5 times the upper normal limit known for more than 6 months. Interferon was given at a dose of 3 MU t.i.w. for an intended 24 weeks and follow-up was a further 24 weeks after treatment. Biochemical non-responders were withdrawn from treatment within 12-16 weeks but continued follow-up. Overall 21/40 (52.5%) patients had a complete biochemical response with normal ALT levels at the end of treatment. Sustained response during follow-up was seen in 8 (20%) whereas 13 (32.5%) had a non-sustained response. At the end of treatment 23 (58%) patients had undetectable serum HCV RNA and 9 (23%) at follow-up. Patients with sustained, non-sustained and non-response had a mean pretreatment HCV RNA level of 3.2 x 10(5), 2.5 x 10(6) and 3.2 x 10(6) genomes/ml, respectively, differences that did not reach statistical significance. Of the patients 3, 9, 10 and 14 had genotype 1b, 3a, 1a, and 2b, respectively, and 4 had mixed genotypes. Of the 23 patients with genotype 2b or 3a, 7 had a sustained response vs. none of the 13 patients with genotype 1a or 1b (p = 0.03). No patients with cirrhosis had a sustained response whereas 4/18 with chronic persistent and 4/18 with chronic active hepatitis had such a response. It is concluded that some 50% of patients treated with HuIFN-alpha-Le responded with normalisation of ALT levels but that only 20% had a durable response 24 weeks post-treatment, and that patients with genotypes 3a or 2b seem to respond better than patients with other genotypes.


Nardilysin regulates axonal maturation and myelination in the central and peripheral nervous system.
Axonal maturation and myelination are essential processes for establishing an efficient neuronal signaling network. We found that nardilysin (N-arginine dibasic convertase, also known as Nrd1 and NRDc), a metalloendopeptidase enhancer of protein ectodomain shedding, is a critical regulator of these processes. Nrd1-/- mice had smaller brains and a thin cerebral cortex, in which there were less myelinated fibers with thinner myelin sheaths and smaller axon diameters. We also found hypomyelination in the peripheral nervous system (PNS) of Nrd1-/- mice. Neuron-specific overexpression of NRDc induced hypermyelination, indicating that the level of neuronal NRDc regulates myelin thickness. Consistent with these findings, Nrd1-/- mice had impaired motor activities and cognitive deficits. Furthermore, NRDc enhanced ectodomain shedding of neuregulin1 (NRG1), which is a master regulator of myelination in the PNS. On the basis of these data, we propose that NRDc regulates axonal maturation and myelination in the CNS and PNS, in part, through the modulation of NRG1 shedding.


Analysis of microRNA signatures using size-coded ligation-mediated PCR.
The expression pattern and regulatory functions of microRNAs (miRNAs) are intensively investigated in various tissues, cell types and disorders. Differential miRNA expression signatures have been revealed in healthy and unhealthy tissues using high-throughput profiling methods. For further analyses of miRNA signatures in biological samples, we describe here a simple and efficient method to detect multiple miRNAs simultaneously in total RNA. The size-coded ligation-mediated polymerase chain reaction (SL-PCR) method is based on size-coded DNA probe hybridization in solution, followed-by ligation, PCR amplification and gel fractionation. The new method shows quantitative and specific detection of miRNAs. We profiled miRNAs of the let-7 family in a number of organisms, tissues and cell types and the results correspond with their incidence in the genome and reported expression levels. Finally, SL-PCR detected let-7 expression changes in human embryonic stem cells as they differentiate to neuron and also in young and aged mice brain and bone marrow. We conclude that the method can efficiently reveal miRNA signatures in a range of biological samples.


Bioactive Sr2+/Fe3+co-substituted hydroxyapatite in cryogenically 3D printed porous scaffolds for bone tissue engineering.
Developing multi-doped bioceramics that possess biological multifunctionality is becoming increasingly attractive and promising for bone tissue engineering. In this view innovative Sr2+/Fe3+co-substituted nano-hydroxyapatite with gradient doping concentrations fixed at 10 mol% has been deliberately designed previously. Herein, to evaluate their therapeutic potentials for bone healing, novel gradient SrFeHA/PCL scaffolds are fabricated by extrusion cryogenic 3D printing technology with subsequent lyophilization. The obtained scaffolds exhibit desired 3D interconnected porous structure and rough microsurface, along with appreciable release of bioactive Sr2+/Fe3+from SrFeHA components. These favorable physicochemical properties render printed scaffolds realizing effective biological applications bothin vitroandin vivo, particularly the moderate co-substituted Sr7.5Fe2.5HA and Sr5Fe5HA groups exhibit remarkably enhanced bioactivity that not only promotes the functions of MC3T3 osteoblasts and HUVECs directly, but also energetically manipulates favorable macrophages activation to concurrently facilitate osteogenesis/angiogenesis. Moreover,in vivosubcutaneous implantation and cranial defects repair outcomes further confirm their superior capacity to dictate immune reaction, implants vascularization andin situbone regeneration, mainly dependent on the synergetic effects of released Sr2+/Fe3+. Accordingly, for the first time, present study highlights the great potential of Sr7.5Fe2.5HA and Sr5Fe5HA for ameliorating bone regeneration process by coupling of immunomodulation with enhanced angio- and osteogenesis and hence may provide a new promising alternative for future bone tissue engineering.


Localized vasculitis of the gastrointestinal tract: a case report and literature review.
Localized gastrointestinal vasculitis is a rare condition. It may be observed as an incidental unexpected pathologic finding at the time of biopsy of an abdominal mass or may present as unexplained abdominal pain with or without unexplained lower gastrointestinal bleeding. In this report we describe a new case of localized polyarteritis nodosa with involvement of peripancreatic middle-sized blood vessels. A literature review of cases of localized gastrointestinal vasculitis was also conducted. A major point of concern is whether a single organ vasculitis of the gastrointestinal tract is actually a localized gastrointestinal vasculitis or simply an initial manifestation of a more severe systemic vasculitis. Due to this, in cases of localized gastrointestinal vasculitis a complete evaluation of the patient to exclude the presence of a systemic a potentially threatening systemic vasculitis is required.


Differentiation of Shewanella putrefaciens and Shewanella alga on the basis of whole-cell protein profiles, ribotyping, phenotypic characterization, and 16S rRNA gene sequence analysis.
Seventy-six presumed Shewanella putrefaciens isolates from fish, oil drillings, and clinical specimens, the type strain of Shewanella putrefaciens (ATCC 8071), the type strain of Shewanella alga (IAM 14159), and the type strain of Shewanella hanedai (ATCC 33224) were compared by several typing methods. Numerical analysis of sodium dodecyl sulfate-polyacrylamide gel electrophoresis of whole-cell protein and ribotyping patterns showed that the strains were separated into two distinct clusters with 56% +/- 10% and 40% +/- 14% similarity for whole-cell protein profiling and ribotyping, respectively. One cluster consisted of 26 isolates with 52 to 55 mol% G + C and included 15 human isolates, mostly clinical specimens, 8 isolates from marine waters, and the type strain of S. alga. This homogeneous cluster of mesophilic, halotolerant strains was by all analyses identical to the recently defined species S. alga (U. Simidu et al., Int. J. Syst. Bacteriol, 40:331-336, 1990). Fifty-two typically psychrotolerant strains formed the other, more heterogeneous major cluster, with 43 to 47 mol% G + C. The type strain of S. putrefaciens was included in this group. The two groups were confirmed by 16S rRNA gene sequence analysis. It is concluded that the isolates must be considered two different species, S. alga and S. putrefaciens, and that most mesophilic isolates formerly identified as S. putrefaciens belong to S. alga. The ecological role and potential pathogenicity of S. alga can be evaluated only if the organism is correctly identified.


Gerontome: a web-based database server for aging-related genes and analysis pipelines.
Aging is a complex and challenging phenomenon that requires interdisciplinary efforts to unravel its mystery. Insight into genes relevant to the aging process would offer the chance to delay and avoid some of deteriorative aspects of aging through the use of preventive methods. To assist basic research on aging, a comprehensive database and analysis platform for aging-related genes is required. We developed a web-based database server, called Gerontome that contains aging-related gene information and user-friendly analysis pipelines. To construct the Gerontome database, we integrated aging-related genes and their annotation data. The aging-related genes were categorized by a set of structural terms from Gene Ontology (GO). Analysis pipelines for promoter analysis and protein-ligand docking were developed. The promoter analysis pipeline allows users to investigate the age-dependent regulation of gene expression. The protein-ligand docking pipeline provides information on the position and orientation of a ligand in an age-related protein surface. Gerontome can be accessed through web interfaces for querying and browsing. The server provides comprehensive age-related gene information and analysis pipelines. Gerontome is available free at http://gerontome.kobic.re.kr.


[Treatment of neutropenic enterocolitis].
Neutropenic enterocolitis is a life-threatening complication that usually occurs in connection with chemotherapy for acute leukemias. Our experience with diagnosis and treatment of these patients is presented. Medical records from patients treated for neutropenic enterocolitis at Ullevaal University Hospital in the period 2000-2008 were retrospectively reviewed. 16 patients with median age 33 years were treated for neutropenic enterocolitis. Induction chemotherapy was given for acute myelogenic (n = 9) or lymphatic (n = 4) leukemia, myelomatosis (n = 2) or lymphoma (n = 1). The patients developed aplasia five days (median) after start of chemotherapy. All patients were first treated conservatively with broad-spectrum antibiotics, fluids and electrolyte supplementation; nine of them recovered without complications. Four underwent surgery for perforation or ileus and these had the longest period with aplasia (median 31 days). Surgery for perforation is mainly limited resection and construction of ileostomy reservoirs (one or two). Three patients died. These were only treated conservatively; aplasia occurred quicker in these patients (after median two days) and they had the largest number of affected bowel segments (median nine). Neutropenic enterocolitis is a heterogeneous condition and the treatment is mainly conservative. Surgical intervention is mandatory in patients with free intraabdominal air, ileus and intractable intestinal bleeding. The prognosis seems to worsen when aplasia develops after a short time and when there is a large number of affected bowel segments.


COMplot, A Graphical Presentation of Complication Profiles and Adverse Effects for the Curative Treatment of Gastric Cancer: A Systematic Review and Meta-Analysis.
Background: For the curative treatment of gastric cancer, several neoadjuvant, and adjuvant treatment-regimens are available which have shown to improve overall survival. No overview is available regarding toxicity and surgery related outcomes. Our aim was to construct a novel graphical method concerning adverse events (AEs) associated with multimodality treatment and perform a meta-analysis to compare different clinically relevant cytotoxic regimens with each other. Methods: The PubMed, EMBASE, CENTRAL, and ASCO/ESMO databases were searched up to May 2019 for randomized controlled trials investigating curative treatment regimens for gastric cancer. To construct single and bidirectional bar-charts (COMplots), grade 1-2 and grade 3-5 AEs were extracted per cytotoxic regimen. For surgery-related outcomes a pre-specified set of complications was used. Thereafter, treatment-arms comparing the same regimens were combined in a single-arm random-effects meta-analysis and pooled-proportions were calculated with 95% confidence-intervals. Comparative meta-analyses were performed based on clinical relevance and compound similarity. Results: In total 16 RCTs (n = 4,526 patients) were included investigating pre-operative-therapy and 39 RCTs investigating adjuvant-therapy (n = 13,732 patients). Pre-operative COMplots were created for among others; 5-fluorouracil/leucovorin-oxaliplatin-docetaxel (FLOT), epirubicin-cisplatin-fluoropyrimidine (ECF), cisplatin-fluoropyrimidine (CF), and oxaliplatin-fluoropyrimidine (FOx). Pre-operative FLOT showed a minor increase in grade 1-2 and grade 3-4 AEs compared to pre-operative ECF, CF, and FOx. A pooled analysis of patients who had received pre-operative therapy compared to patients who underwent direct surgery did not reveal any significant difference in surgery related morbidity/mortality. When we compared three commonly used adjuvant regimens; S-1 had the lowest amount of grade 3-4 AEs compared to capecitabine with oxaliplatin (CAPOX) and 5-FU with radiotherapy (5-FU+RT). Conclusion: COMplot provides a novel tool to visualize and compare treatment related AEs for gastric cancer. Based on our comparisons, pre-operative FLOT had a manageable toxicity profile compared to other pre-operative doublet or triplet regimens. We found no evidence indicating surgical outcomes might be hampered by pre-operative therapy. Adjuvant S-1 had a more favorable toxicity profile compared to CAPOX and 5-FU+RT.


Insights from deconvolution of cell subtype proportions enhance the interpretation of functional genomic data.
Cell subtype proportion variability between samples contributes significantly to the variation of functional genomic properties such as gene expression or DNA methylation. Although the impact of the variation of cell subtype composition on measured genomic quantities is recognized, and some innovative tools have been developed for the analysis of heterogeneous samples, most functional genomics studies using samples with mixed cell types still ignore the influence of cell subtype proportion variation, or just deal with it as a nuisance variable to be eliminated. Here we demonstrate how harvesting information about cell subtype proportions from functional genomics data can provide insights into cellular changes associated with phenotypes. We focused on two types of mixed cell populations, human blood and mouse kidney. Cell type prediction is well developed in the former, but not currently in the latter. Estimating the cellular repertoire is easier when a reference dataset from purified samples of all cell types in the tissue is available, as is the case for blood. However, reference datasets are not available for most other tissues, such as the kidney. In this study, we showed that the proportion of alterations attributable to changes in the cellular composition varies strikingly in the two disorders (asthma and systemic lupus erythematosus), suggesting that the contribution of cell subtype proportion changes to functional genomic properties can be disease-specific. We also showed that a reference dataset from a single-cell RNA-seq study successfully estimated the cell subtype proportions in mouse kidney and allowed us to distinguish altered cell subtype differences between two different knock-out mouse models, both of which had reported a reduced number of glomeruli compared to their wild-type counterparts. These findings demonstrate that testing for changes in cell subtype proportions between conditions can yield important insights in functional genomics studies.


Outcomes After Primary Repair of Insertional Ruptures of the Achilles Tendon.
Achilles tendon insertional sleeve avulsions occur when the Achilles distal tendon sleeve ruptures off of its insertion into the calcaneal tuberosity, sometimes with a small bony fragment from calcific tendinosis. Little evidence exists describing the outcomes and rerupture rate after operative management of Achilles tendon sleeve avulsions. A retrospective chart review was performed to identify patients who sustained an Achilles sleeve avulsion injury treated with operative repair between October 2005 and July 2014. A cohort of 16 patients from the general population and 12 professional athletes were included in the study. The primary outcome variable was rerupture of the Achilles tendon or need for revision surgery. Secondary outcome variables included the Coughlin Satisfaction Scale, visual VR-12, and Foot and Ankle Ability Measure (FAAM). In the general population cohort, median follow-up was 8.1 years (range, 3.2-11.1 years). The median FAAM Activities of Daily Living score was 100 (range, 42.9-106), and the median FAAM Sports score was 100 (range, 7.1-103.6). The median VR-12 Mental Component Score was 66.9 (range, 45.6-71.8), and the median VR-12 Physical Component Score was 53 (range, 30.8-57.5). In the cohort of professional athletes, preceding insertional Achilles symptoms were present in 91.7% (11/12) of athletes for more than 9 months prior to rupture. All athletes returned to play with an average time of 13.4 months. No patients sustained a rerupture in the follow-up period. Operative repair of Achilles tendon sleeve avulsions was safe and effective with high patient satisfaction and good clinical outcomes in patients from the general population. Level IV, retrospective case series.


A Selection for Assembly Reveals That a Single Amino Acid Mutant of the Bacteriophage MS2 Coat Protein Forms a Smaller Virus-like Particle.
Virus-like particles are used to encapsulate drugs, imaging agents, enzymes, and other biologically active molecules in order to enhance their function. However, the size of most virus-like particles is inflexible, precluding the design of appropriately sized containers for different applications. Here, we describe a chromatographic selection for virus-like particle assembly. Using this selection, we identified a single amino acid substitution to the coat protein of bacteriophage MS2 that mediates a uniform switch in particle geometry from T = 3 to T = 1 icosahedral symmetry. The resulting smaller particle retains the ability to be disassembled and reassembled in vitro and to be chemically modified to load cargo into its interior cavity. The pair of 27 and 17 nm MS2 particles will allow direct examination of the effect of size on function in established applications of virus-like particles, including drug delivery and imaging.


[Vagotomy in the treatment of bleeding reflux-esophagitis and gastroduodenal bleedings].
Fifteen-year experience in the treatment of 588 patients with esophageal and gastroduodenal bleedings is analyzed. Surgery was performed in 286 patients, 302 patients were treated conservatively including 71 patients who underwent endoscopic procedures. Principles of differentiated treatment policy are developed. Selective proximal vagotomy in combination with fundoplication (if indicated, with surgeries draining the stomach) is surgery of choice in bleeding reflux-esophagitis and gastroduodenal ulcerous bleedings. These methods eliminate pathogenetic factors of bleeding gastro-esophageal reflux, lower acidity of gastric juice.


The association between knee breadth and body mass: The Northern Finland Birth Cohort 1966 case study.
Body mass estimation from skeletal dimensions is a useful tool when studying archeological human samples. Bony articular surface dimensions of the lower limb have frequently been utilized to estimate body size. In the present study, we investigated the association between knee breadth and body mass in a Northern European population. Our study aimed to confirm both methodology and results presented in earlier studies. The study sample consists of 1,290 subjects belonging to the Northern Finland Birth Cohort 1966. Three knee breadth dimensions-femoral biepicondylar breadth, mediolateral breadth of femoral condyles, and mediolateral breadth of the tibial plateau-were measured from subjects' knee PA-radiographs. Measurements and their association with body weight at 31 years were utilized for creating body mass estimation equations using linear regression and reduced major axis regression. Correlations between knee measurements and body weight at three different ages (18, 31, and 46) were also analyzed. Positive associations were detected between each knee breadth variable and weight in the total sample and both genders separately. Body mass estimation equations were created for the total sample, for males and for females. R values of the models ranged from 0.38 to 0.74. Median absolute percent prediction errors ranged from 6.89 to 9.72%. The highest correlations were obtained between knee breadth and body weight in early adulthood. Our large sample confirmed that equations derived from knee breadth dimensions are accurate when estimating body mass of modern humans. Knee breadth measurements clearly have a positive association with body weight in early maturity.


Direct observation of intramolecular vibrational energy redistribution under white light excitation. II. Fluorescence spectra of fluorobenzene derivatives by controlled electron impact.
The low-resolution (resolution: 0.6 nm) fluorescence spectra of fluorobenzene derivatives, o-, m- and p-fluorotoluene (o-, m- and p-FT) were observed to investigate intramolecular vibrational energy redistribution (IVR) under controlled electron impact. The o- and m-FT spectra mainly consisted of unstructured emission from optically inactive states (bath modes) populated through IVR. The p-FT spectrum consisted of structured emission from optically active states and unstructured emission. The high-resolution (resolution: 0.15 nm) fluorescence spectrum of p-FT was measured to estimate the fraction of the structured emission intensity to the total emission intensity. The IVR rate of p-FT under electron impact excitation was faster than that under laser excitation. The fraction did not depend on the incident energy of electrons from 20 to 200 eV, and thus the IVR acceleration is not attributable to breakdown of the Born approximation.


Structural and functional brain changes beyond visual system in patients with advanced glaucoma.
In order to test the hypothesis that in primary open angle glaucoma (POAG), an important cause of irreversible blindness, a spreading of neurodegeneration occurs through the brain, we performed multimodal MRI and subsequent whole-brain explorative voxelwise analyses in 13 advanced POAG patients and 12 age-matched normal controls (NC). Altered integrity (decreased fractional anisotropy or increased diffusivities) of white matter (WM) tracts was found not only along the visual pathway of POAG but also in nonvisual WM tracts (superior longitudinal fascicle, anterior thalamic radiation, corticospinal tract, middle cerebellar peduncle). POAG patients also showed brain atrophy in both visual cortex and other distant grey matter (GM) regions (frontoparietal cortex, hippocampi and cerebellar cortex), decreased functional connectivity (FC) in visual, working memory and dorsal attention networks and increased FC in visual and executive networks. In POAG, abnormalities in structure and FC within and outside visual system correlated with visual field parameters in the poorer performing eyes, thus emphasizing their clinical relevance. Altogether, this represents evidence that a vision disorder such as POAG can be considered a widespread neurodegenerative condition.