Prenatal MAM treatment altered fear conditioning following social isolation: Relevance to schizophrenia.
Adolescent social isolation (SI) might change the trajectory of brain development. In the present study, we investigated the effect of short-term adolescent SI on fear memory, anxiety and protein levels in the adult medial prefrontal cortex of rats prenatally treated with methylazoxymethanol, MAM-E17 model of schizophrenia. The animals were maintained in standard housing (SH) or social isolation (P30-P40, SI) conditions. Behavioural tests (trace or delay fear conditioning, light/dark box) were performed in late adolescence and early adulthood. The results showed that MAM treatment did not alter fear memory, which was investigated with the use of either trace or delay fear conditioning, at any age, and SI decreased the fear response in adult control animals only under trace conditioning. Neither MAM nor SI influenced anxiety-related behaviour measured in the light/dark box. A proteomics study showed that both MAM and SI changed the protein levels related to synapse maturation and cytoskeletal organization, energy transfer and metabolic processes. Prenatal or adolescent environmental factors are able to change the expression of proteins that are correlated with behavioural impairments. Moreover, SI reversed some alterations in proteins induced by MAM. Thus, normally developing brains showed different responses to adolescent SI than those with altering courses of MAM administration.


Effects of emergency medical services times on traffic injury severity: A random effects ordered probit approach.
Emergency medical services (EMS) play a vital role in the postcrash effort to reduce fatalities by providing first aid treatment and transportation to medical facilities. This study aims to analyze the time required for crash reporting and EMS arrival in fatal traffic crashes and to explore the effects of EMS time on the traffic injury severity. The time required for EMS reporting, arrival, and transport to hospital was calculated by location type and roadway functional classification using 2016 Fatality Analysis Reporting System (FARS) data. Subsequently, an ordered probit model was developed to identify factors contributing to injury severity considering EMS time. The average time for the crash-reporting duration is 5.38 min, the reporting-scene arrival interval is 10.52 min, and the scene-hospital interval is 34.72 min. The average crash reporting and reporting-scene arrival intervals were the longest on conventional roads in rural areas and the shortest on conventional roads in urban areas. The average scene-hospital interval was longest in conventional rural areas and the shortest on freeways/expressways in urban areas. The developed random effects ordered probit model shows that prolonged reporting-scene arrival and scene-hospital intervals result in more severe injuries. The result also presents that crash type, violation, age, location, lighting condition, and alcohol/drug involvement have significant effects on injury severity. The key findings from this study indicate that EMS times differ according to urban/rural location and road functional classification and that reporting-scene arrival and scene-hospital intervals have significant effects on injury severity along with various factors. It is expected that the findings from this study can be used to develop effective and practical strategic plans to minimize EMS reporting, arrival time, and transport to hospital and therefore decrease the traffic injury severity.


Molecular identification of Cryptosporidium parvum and Giardia duodenalis in the Italian water buffalo (Bubalus bubalis).
Livestock are commonly infected with protozoan parasites of the genera Cryptosporidium and Giardia, and some of the species and genotypes found in these animals have zoonotic significance. We characterized isolates of both parasites recovered from the Italian water buffalo (Bubalus bubalis), an economically important species whose milk is used for the production of "buffalo mozzarella" fresh cheese. Molecular analysis of the Cryptosporidium small subunit ribosomal DNA gene and of the Giardia beta-giardin gene shows the presence of both zoonotic parasites (Cryptosporidium parvum and Giardia duodenalis assemblage A) and host-specific parasites (G. duodenalis assemblage E), suggesting that water buffaloes can contribute to environmental contamination with oocysts and cysts potentially infectious to humans if their faeces are improperly disposed of. On the other hand, mozzarella cheese is probably a safe product, given that its production involves the treatment of cheese curd at 85-95 degrees C, which is likely to kill or inactivate the parasites.


Pulmonary blood supply by a branch from the distal ascending aorta in pulmonary atresia with ventricular septal defect: differential diagnosis of fifth aortic arch.
A patient with pulmonary atresia and a ventricular septal defect is described in whom an arterial branch from the distal ascending aorta supplied segments of both lungs. The branch is considered to represent a persistent fifth aortic arch. The possible morphogenesis and differential diagnosis of a communication between the ascending aorta and the pulmonary artery in pulmonary atresia with ventricular septal defect are discussed.


Short research article: COVID-19 and its impact on child and youth mental health service demand in the community and emergency department.
To explore changes in child and youth mental health service (CYMHS) demand in Brisbane, Australia, following the COVID pandemic. The number of monthly presentations and referrals to respectively the emergency department (ED) and community CYMHS were compared among 2018, 2019 and 2020. The study shows a marked increase in referrals to ED starting from July and in the community from May 2020. In the population referred to as community teams, the proportions of Indigenous children and those from lower socio-economic areas decreased. The COVID-19 pandemic has aggravated the supply and demand disparity in CYMHS, with the largest effect on the most vulnerable families.


Development of ion pairing LC-MS/MS method for itaconate and cis-aconitate in cell extract and cell media.
Accumulation of Immune Responsive Gene 1(IRG1) in macrophage induced by lipopolysaccharide (LPS) and interferon gamma (IFN-γ) leads to production of itaconate by decarboxylation of cis-aconitate. The biology associated with IRG1 and itaconate is not fully understood. A rapid and sensitive method for measurement of itaconate will benefit the study of IRG1 biology. Multiple HPLC and derivatization methods were tested. An ion pairing LC-MS/MS method using tributylamine/formic acid as ion pairing agents and a HypercarbTM guard column we proposed demonstrated better peak shape and better sensitivity for itaconate. The current protocol allows baseline separation of itaconate, citraconate, and cis-aconitate without derivatization and direct analysis of analytes in 80% methanol/water solution to avoid the dry-down step. It provides the limit of quantitation (LOQ) of 30 pg itaconate on column with a 4.5-minute run time. This method is validated for measurement of itaconate and cis-aconitate in RAW264.7 cell extract and cell media in a 96-well plate format. We applied this method to successfully measure the increase of itaconate and the decrease of cis-aconitate in RAW cell extract and cell media after LPS/IFN-γ treatment.


Adenosine kinase inhibition enhances microvascular dilator function and improves left ventricle diastolic dysfunction.
Inhibition of adenosine kinase (ADK), via augmenting endogenous adenosine levels exerts cardiovascular protection. We tested the hypothesis that ADK inhibition improves microvascular dilator and left ventricle (LV) contractile function under metabolic or hemodynamic stress. In Obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid rats, treatment with the selective ADK inhibitor, ABT-702 (1.5 mg/kg, intraperitoneal injections for 8-week) restored acetylcholine-, sodium nitroprusside-, and adenosine-induced dilations in isolated coronary arterioles, an effect that was accompanied by normalized end-diastolic pressure (in mm Hg, Lean: 3.4 ± 0.6, Obese: 17.6 ± 4.2, Obese + ABT: 6.6 ± 1.4) and LV relaxation constant, Tau (in ms, Lean: 6.9 ± 1.5, Obese: 13.9 ± 1.7, Obese + ABT: 6.0 ± 1.1). Mice with vascular endothelium selective ADK deletion (ADKVEC KO) exhibited an enhanced dilation to acetylcholine in isolated gracilis muscle (lgEC50 WT: -8.2 ± 0.1, ADKVEC KO: -8.8 ± 0.1, P < .05) and mesenteric arterioles (lgEC50 WT: -7.4 ± 0.2, ADKVEC KO: -8.1 ± 1.2, P < .05) when compared to wild-type (WT) mice, whereas relaxation of the femoral artery and aorta (lgEC50 WT: -7.03 ± 0.6, ADKVEC KO: -7.05 ± 0.8) was similar in the two groups. Wild-type mice progressively developed LV systolic and diastolic dysfunction when they underwent transverse aortic constriction surgery, whereas ADKVEC -KO mice displayed a lesser degree in decline of LV function. Our results indicate that ADK inhibition selectively enhances microvascular vasodilator function, whereby it improves LV perfusion and LV contractile function under metabolic and hemodynamic stress.


Actinomyces viscosus cell-free synthesis of extracellular slime polysaccharide.
A cell-free extract of Actinomyces viscosus T14Av catalyzed the synthesis of extracellular N-acetylglucosamine-rich slime polysaccharide. The activity was localized in the cytoplasmic membrane fraction and required the presence of ADP-glucose and UDP-N-acetylglucosamine. Maximal activity was demonstrated at pH 7.5 and also required the presence of divalent cations such as Mg2+ or Mn2+. Extracellular slime appeared to serve as a primer for slime biosynthesis. The antibiotic tunicamycin acted as an inhibitor of slime formation. However, another glucosamine analogue, amphomycin, as well as the antibiotic bacitracin produced moderate stimulatory effects on slime biosynthesis.


sRNATargetDigger: A bioinformatics software for bidirectional identification of sRNA-target pairs with co-regulatory sRNAs information.
Identification of the target genes of microRNAs (miRNAs), trans-acting small interfering RNAs (ta-siRNAs), and small interfering RNAs (siRNAs) is an important step for understanding their regulatory roles in plants. In recent years, many bioinformatics software packages based on small RNA (sRNA) high-throughput sequencing (HTS) and degradome sequencing data analysis have provided strong technical support for large-scale mining of sRNA-target pairs. However, sRNA-target regulation is achieved using a complex network of interactions since one transcript might be co-regulated by multiple sRNAs and one sRNA may also affect multiple targets. Currently used mining software can realize the mining of multiple unknown targets using known sRNA, but it cannot rule out the possibility of co-regulation of the same target by other unknown sRNAs. Hence, the obtained regulatory network may be incomplete. We have developed a new mining software, sRNATargetDigger, that includes two function modules, "Forward Digger" and "Reverse Digger", which can identify regulatory sRNA-target pairs bidirectionally. Moreover, it has the ability to identify unknown sRNAs co-regulating the same target, in order to obtain a more authentic and reliable sRNA-target regulatory network. Upon re-examination of the published sRNA-target pairs in Arabidopsis thaliana, sRNATargetDigger found 170 novel co-regulatory sRNA-target pairs. This software can be downloaded from http://www.bioinfolab.cn/sRNATD.html.


The epidemic of nonmelanoma skin cancer and the widespread use of statins: Is there a connection?
We hypothesize that some of the mechanisms involved in the "epidemic" of nonmelanoma skin cancer might also be due to widespread use of cholesterol lowering statin drugs.


Significant difference in the efficacies of silicon application regimes on cadmium species and environmental risks in rice rhizosphere.
Silicon (Si) is commonly applied as base-fertilizer or foliar-topdressing to palliate the uptake-translocation-accumulation of cadmium (Cd) in rice through Si-Cd antagonism. However, little is known about the fate of Cd in rice rhizosphere soil and its eco-environmental effects under different Si treatments. Here, systematic works had been carried out to elucidate the Cd species, soil properties, and environmental risks in rice rhizosphere driven by different Si soil-fertilization regimes including CK (without Si-addition), TSi (added before transplanting stage), JSi (added at jointing stage), and TJSi (split into two equal parts, added half before transplanting and another half at jointing stage). Results showed that TJSi outperformed the rest of fertilization regimes. The solid-phase-Cd concentrations treated with TSi, TJSi and JSi were increased by 4.18%, 5.73% and 3.41%, respectively, when compared to CK. The labile Cd (F1+F2) proportion of TJSi was reduced by 16.30%, 9.30% and 6.78%, respectively, when compared to CK, TSi, and JSi. Simultaneously, the liquid-phase-Cd concentration was appreciably suppressed by TJSi throughout the rice lifecycle, while TSi mainly abated Cd dissociation during the vegetative period, and JSi attenuated it during the grain-filling stage. The mobility factor of Cd treated with TJSi was the lowest, which was significantly lower than that of TSi (9.30%) and JSi (6.78%), respectively. Similarly, the oral exposure risk of TJSi was reduced by 4.43% and 32.53%; and the food-chain exposure risk of TJSi was decreased by 13.03% and 42.78%. Additionally, TJSi was the most effective in promoting enzyme activities and nutrient content in rhizosphere soil. Overall, TJSi is more positive and sustainable than TSi and JSi in reconstructing Cd-contaminated rhizosphere environments and abating the environmental risks of Cd. Agronomic practices in Cd-contaminated paddy soils can be informed by applying Si-fertilizer separately before transplanting and at jointing stage to achieve soil welfare and food security.


A new antigen SUMI carried on glycophorin A encoded by the GYPA*M with c.91A>C (p.Thr31Pro) belongs to the MNS blood group system.
MNS is one of the highly polymorphic blood groups comprising many antigens generated by genomic recombination among the GYPA, GYPB, and GYPE genes as well as by single-nucleotide changes. We report a patient with red blood cell (RBC) antibody against an unknown low-frequency antigen, tentatively named SUMI, and investigated its carrier molecule and causal gene. Standard serologic tests, including enzyme tests, were performed. Monoclonal anti-SUMI-producing cells (HIRO-305) were established by transformation and hybridization methods using lymphocytes from a donor having anti-SUMI. SUMI+ RBCs were examined by immunocomplex capture fluorescence analysis (ICFA) using HIRO-305 and murine monoclonal antibodies against RBC membrane proteins carrying blood group antigens. Genomic DNA was extracted from whole blood, and the GYPA gene was analyzed by polymerase chain reactions and Sanger sequencing. Serologic screening revealed that 23 of the 541,522 individuals (0.0042%) were SUMI+, whereas 1351 of the 10,392 individuals (13.0%) had alloanti-SUMI. SUMI antigen was sensitive to ficin, trypsin, pronase, and neuraminidase, but resistant to α-chymotrypsin and sulfydryl-reducing agents. ICFA revealed that the SUMI antigen was carried on glycophorin A (GPA). According to Sanger sequencing and cloning, the SUMI+ individuals had a GYPA*M allele with c.91A>C (p.Thr31Pro), which may abolish the O-glycan attachment site. The new low-frequency antigen SUMI is carried on GPA encoded by the GYPA*M allele with c.91A>C (p.Thr31Pro). Neuraminidase sensitivity suggests that glycophorin around Pro31 are involved in the SUMI determinant.


Acute urinary retention secondary to urethral inflammation from a vaginal contraceptive suppository in a 17-year-old boy.
We report the case of a 17-year-old boy who developed acute urinary retention following unprotected intercourse. His partner employed for the first time a nonoxynol-9-based commercial vaginal contraceptive insert. During intercourse the patient felt severe burning pain in the urethra. He was subsequently unable to void. Flexible cystourethroscopy revealed gross mucosal erythema and inflammation in the distal urethra and navicular fossa. We discuss the clinical management and review relevant literature.


Adherence to Canadian C-Spine Rule in a regional hospital: a retrospective study of 406 cases.
Cervical spine radiography may be over-utilised in an emergency department setting. The Canadian C-Spine Rule has been developed to reduce unnecessary radiography. Our aim was to retrospectively determine the proportion of cervical spine radiographs requested through the emergency department for trauma patients that were clinically indicated, according to the Canadian C-Spine Rule. This was a cross-sectional survey conducted at a regional centre in Northern Queensland, Australia. All cervical spine radiographs for trauma, performed at the Mackay Base Hospital from 1 January 2009 to the 31 December 2009, were reviewed. The relevant patient charts were audited for evidence of indications for radiography. Of 406 patients in the study, 155 patients (38%) (95% confidence interval 33.3%, 42.7%) had cervical spine imaging performed that was not indicated according to the Canadian C-Spine Rule. None of these patients had a significant cervical spine injury on radiography. Applying the Canadian C-Spine Rule would have safely reduced the incidence of cervical spine radiography by 38%. This would also reduce costs, patient morbidity and radiation exposure.


The POLR2E rs3787016 polymorphism is associated with susceptibility to and prognosis of gastric cancer.
Long non-coding RNAs (lncRNAs) have been proposed as promising diagnostic and prognostic biomarkers for cancer. We investigated the associations of RNA polymerase II subunit E (POLR2E) rs3787016 polymorphism with the risk and prognosis of gastric cancer (GC). The study subjects included 368 GC patients who underwent surgical resection and 294 healthy volunteers, adjusted for age, gender, smoking status, alcohol status, and Helicobacter pylori infection status. The data was subjected to logistic regression analyses and revealed that the subjects carrying AA genotype of rs3787016 in POLR2E had a significant 1.85-1.98-fold increased risk of GC when compared with those carrying GG genotype (adjusted OR=1.979, 95% CI=1.198-3.267; p=0.008) or those carrying AG/GG genotypes (adjusted OR=1.847, 95% CI=1.222-2.793; p=0.004). For the GC patients, the AA genotype of rs3787016 was significantly correlated with poorly differentiated GC (p=0.018), advanced TNM stage (p=0.023), higher depth of invasion (p=0.022), positive lymph node metastasis (p=0.01), and worse overall survival (OS; p=0.004). Multivariate analysis confirmed that the POLR2E rs3787016 polymorphism is an independent prognostic factor for GC (HR=1.668, 95% CI=1.058-2.631; p=0.028). Our cumulative results thus suggest that the presence of POLR2E rs3787016 polymorphism could serve as a genetic factor that affects the susceptibility to and the prognosis of GC.


Prevention of meticillin-resistant Staphylococcus aureus bloodstream infections in European hospitals: moving beyond policies.
There is evidence that meticillin-resistant Staphylococcus aureus (MRSA) bacteraemia can be reduced with improved infection control and antibiotic stewardship. To survey infection control and antibiotic stewardship practices within European hospitals and to identify initiatives that correlate with reduced MRSA prevalence. Online questionnaires were sent to European hospitals about their surveillance, hand hygiene, intravenous device management, admission screening, isolation, antibiotic prescribing, hospital demographics and MRSA blood culture isolates during 2010. In all, 269 replies were received from hospitals in 29 European countries. Lower MRSA prevalence showed significant association with presence of incidence surveillance, performance of root cause analysis, mandatory training requirements for hand hygiene, accountability measures for persistent non-compliance, and multi-stakeholder teamwork in antibiotic prescribing. Presence of policies on intravenous catheter insertion and management showed no variation between different MRSA prevalence groups. However, low-prevalence hospitals reported more competency assessment programmes in insertion and maintenance of peripheral and central venous catheters. Hospitals from the UK and Ireland reported the highest uptake of infection control and antibiotic stewardship practices that were significantly associated with low MRSA prevalence, whereas Southern European hospitals exhibited the lowest. In multiple regression analysis, isolation of high-risk patients, performance of root cause analysis, obligatory training for nurses in hand hygiene, and undertaking joint ward rounds including microbiologists and infectious disease physicians remained significantly associated with lower MRSA prevalence. Proactive infection control and antibiotic stewardship initiatives that instilled accountability, ownership, teamwork, and validated competence among healthcare workers were associated with improved MRSA outcomes.


Tumor Growth Rate as a Predictive Marker for Recurrence and Survival After Liver Resection in Patients with Liver Metastases of Uveal Melanoma.
Surgical management of liver metastases of uveal melanoma (LMUM) is associated with the best survival rates, especially for patients with a low tumor burden in the liver. The aim was to determine whether the tumor growth rate (TGR0) before liver resection helps predict survival in patients with resectable LMUM. This retrospective study included 99 patients with LMUM treated with liver resection between November 2007 and November 2020. TGR0 was expressed as the percentage change in tumor volume over 1 month according to two pretreatment imaging scans. Multivariate Cox analyses identified independent predictors of disease-free survival (DFS) and overall survival (OS). DFS and OS had a statistically significant positive linear relationship (Spearman correlation r = 0.68, p < 0.001). A disease-free interval (DFI) > 24 months and a TGR0 ≤ 50%/month were independent factors associated with better DFS and OS. The 2-component model including TGR0 and DFI had a mean time-dependent area under the curve (AUC) of 0.81 (95% CI, 0.75-0.86) and 0.77 (95% CI, 0.67-0.87), respectively, for predicting DFS and OS. DFI with TGR0 defined three kinetic risk groups that had distinct DFS and OS outcomes (p < 0.001). Cytogenetic alterations at baseline were partially predictive factors of the kinetic risk score based on TGR0 and DFI. The assessment of TGR0 improves prognostic stratification by identifying patients at high risk of recurrence and poor survival after liver resection. TGR0 and DFI, reflecting tumor aggressivity, have the potential to be important markers for systemic adjuvant decisions.


Prediction of single-cell mechanisms for disease progression in hypertrophic remodelling by a trans-omics approach.
Heart failure is a heterogeneous disease with multiple risk factors and various pathophysiological types, which makes it difficult to understand the molecular mechanisms involved. In this study, we proposed a trans-omics approach for predicting molecular pathological mechanisms of heart failure and identifying marker genes to distinguish heterogeneous phenotypes, by integrating multiple omics data including single-cell RNA-seq, ChIP-seq, and gene interactome data. We detected a significant increase in the expression level of natriuretic peptide A (Nppa), after stress loading with transverse aortic constriction (TAC), and showed that cardiomyocytes with high Nppa expression displayed specific gene expression patterns. Multiple NADH ubiquinone complex family, which are associated with the mitochondrial electron transport system, were negatively correlated with Nppa expression during the early stages of cardiac hypertrophy. Large-scale ChIP-seq data analysis showed that Nkx2-5 and Gtf2b were transcription factors characteristic of high-Nppa-expressing cardiomyocytes. Nppa expression levels may, therefore, represent a useful diagnostic marker for heart failure.


Detection and potential early warning of catastrophic flow events with regional seismic networks.
Early warning is a critical potential tool for mitigating the impacts of large mass wasting and flood events, a major hazard in the Himalaya. We used data from a dense seismic network in Uttarakhand, India, to detect and track a fatal rockslide to mass flow to flood cascade and examine the potential for regional networks to provide early warning for extreme flow events. Detection limits of the 7 February 2021 event depend on the nature of the active process and on the anthropogenic and environmental seismic noise levels at each station. With the existing network, a seismic monitoring system could have detected all event phases from up to 100 kilometers and provided downstream warnings within minutes of event initiation.


Consistent determination of the heating rate of light-absorbing aerosol using wavelength- and time-dependent Aethalometer multiple-scattering correction.
Accurate and temporally consistent measurements of light absorbing aerosol (LAA) heating rate (HR) and of its source apportionment (fossil-fuel, FF; biomass-burning, BB) and speciation (black and brown Carbon; BC, BrC) are needed to evaluate LAA short-term climate forcing. For this purpose, wavelength- and time-dependent accurate LAA absorption coefficients are required. HR was experimentally determined and apportioned (sources/species) in the EMEP/ACTRIS/COLOSSAL-2018 winter campaign in Milan (urban-background site). Two Aethalometers (AE31/AE33) were installed together with a MAAP, CPC, OPC, a low volume sampler (PM2.5) and radiation instruments. AE31/AE33 multiple-scattering correction factors (C) were determined using two reference systems for the absorption coefficient: 1) 5-wavelength PP_UniMI with low time resolution (12 h, applied to PM2.5 samples); 2) timely-resolved MAAP data at a single wavelength. Using wavelength- and time-independent C values for the AE31 and AE33 obtained with the same reference device, the total HR showed a consistency (i.e. reproducibility) with average values comparable at 95% probability. However, if different reference devices/approaches are used, i.e. MAAP is chosen as reference instead of a PP_UniMI, the HR can be overestimated by 23-30% factor (by both AE31/AE33). This became more evident focusing on HR apportionment: AE33 data (corrected by a wavelength- and time-independent C) showed higher HRFF (+24 ± 1%) and higher HRBC (+10 ± 1%) than that of AE31. Conversely, HRBB and HRBrC were -28 ± 1% and -29 ± 1% lower for AE33 compared to AE31. These inconsistencies were overcome by introducing a wavelength-dependent Cλ for both AE31 and AE33, or using multi-wavelength apportionment methods, highlighting the need for further studies on the influence of wavelength corrections for HR determination. Finally, the temporally-resolved determination of C resulted in a diurnal cycle of the HR not statistically different whatever the source- speciation- apportionment used.


Bay 12-8039, a new 8-methoxy-quinolone: comparative in-vitro activity with nine other antimicrobials against anaerobic bacteria.
The in-vitro activity of a new 8-methoxy-quinolone, Bay 12-8039, was assessed against 218 anaerobic bacteria. Ninety-eight per cent of strains belonging to the Bacteroides fragilis group (n = 65) were inhibited by < or = 2 mg/L of Bay 12-8039 whereas 97%, 94%, 94% and 100%, respectively, of Gram-negative bacilli (n = 93), non-sporing Gram-positive bacilli (n = 36), endospore-forming Gram-positive bacilli (n = 34) and Gram-positive cocci (n = 45) were also inhibited by < or = 2 mg/L. Eighty-three per cent of all anaerobes tested were inhibited by < or = 1 mg/L Bay 12-8039 and 99.5% by < or = 4 mg/L. When compared with ciprofloxacin, clinafloxacin, ofloxacin and trovafloxacin, Bay 12-8039 was more active than ciprofloxacin and ofloxacin, equipotent to trovafloxacin but not as active as clinafloxacin.


Empathic Accuracy and Cognitive and Affective Empathy in Young Adults With and Without Autism Spectrum Disorder.
This study investigated whether young adults with ASD (n = 29) had impairments in Cognitive Empathy (CE), Affective Empathy (AE) or Empathic Accuracy (EA; the ability to track changes in others' thoughts and feelings) compared to typically-developing individuals (n = 31) using the Empathic Accuracy Task (EAT), which involves watching narrators recollecting emotionally-charged autobiographical events. Participants provided continuous ratings of the narrators' emotional intensity (indexing EA), labelled the emotions displayed (CE) and reported whether they shared the depicted emotions (AE). The ASD group showed deficits in EA for anger but did not differ from typically-developing participants in CE or AE on the EAT. The ASD group also reported lower CE (Perspective Taking) and AE (Empathic Concern) on the Interpersonal Reactivity Index, a self-report questionnaire.


Economic burden of pediatric prescription opioid poisonings in the United States.
BACKGROUND: Among the different drugs involved in pediatric exposures and poisonings, opioids are the most important, given their rise in nonmedical use. Opioid poisonings in children can result in serious symptoms or complications, including respiratory disorders such as apnea, respiratory failure, and respiratory depression; psychiatric or nervous system disorders such as agitation, seizures, and coma; and cardiac disorders such as tachycardia, bradycardia, and cardiac arrest. Opioid poisonings in children can have delayed onset of symptoms as well as severe and prolonged toxic effects. Many studies have examined the economic burden of opioid poisoning in the general population, but very little is known about the pediatric population. OBJECTIVE: To estimate the economic burden associated with pediatric prescription opioid poisonings. METHODS: This study examined opioid poisonings in pediatric patients, defined as patients aged less than 18 years, for the 2012 base year. Costs were estimated using the 2012 Nationwide Emergency Department Sample (NEDS), Kids' Inpatient Database (KID), Multiple Cause-of-Death (MCOD) file, and other published sources, while applying a societal perspective. The Bottom Up approach was used to estimate the total cost of pediatric prescription opioid poisonings. Direct costs included costs associated with emergency department (ED) visits, hospitalizations, and ambulance transports. Indirect costs were estimated using the human capital method and included productivity costs due to caregivers' absenteeism and premature mortality among children. Descriptive statistics were employed in calculating costs. RESULTS: The total costs of pediatric prescription opioid poisonings and exposure in the United States were $230.8 million in 2012. Total direct costs were estimated to be over $21.1 million, the majority resulting from prescription opioid poisoning-related inpatient stays. Total indirect (productivity) costs were calculated at $209.7 million, and 98.6% of these costs were attributed to opioid poisoning-related mortality. Pediatric prescription opioid poisoning-related ED visits, inpatient stays, and deaths were most common in patients aged 13-17 years and those in mid to large urban areas. Most were unintentional. CONCLUSIONS: Pediatric prescription opioid poisonings resulted in direct and indirect costs of $230.8 million in 2012. While these costs are low in comparison with the costs of prescription opioid poisoning in the general population, the number of pediatric poisonings represents only a small fraction of total poisonings. Quantified costs associated with pediatric prescription opioid poisonings can help decision makers to understand the economic trade-offs in planning interventions. DISCLOSURES: This research had no external funding but was funded by an unrestricted research grant made to the Department of Pharmacotherapy & Outcomes Science by kaléo Pharma, maker of a naloxone product. The authors declare no conflicts of interest or financial interests. Portions of this study were presented as an abstract at the 22nd Annual ISPOR Meeting; May 22, 2017; Boston, MA.


Crystal structure of 4-amino-benzoic acid-4-methyl-pyridine (1/1).
In the title 1:1 adduct, C6H7N·C7H7NO2, the carb-oxy-lic acid group is twisted at an angle of 4.32 (18)° with respect to the attached benzene ring. In the crystal, the carb-oxy-lic acid group is linked to the pyridine ring by an O-H⋯N hydrogen bond, forming a dimer. The dimers are linked by N-H⋯O hydrogen bonds, generating (010) sheets.


Recombinant heteromeric phenylalanine monooxygenase and the oxygenation of carbon and sulfur substrates.
The aim of this investigation was to provide in-vitro enzyme kinetic data to support the hypothesis that the in-vivo heterozygous dominant phenotype for phenylalanine monooxygenase (hPAH) was responsible for the S-oxidation polymorphism in the metabolism of S-carboxymethyl-l-cysteine reported in humans. Using a dual-vector expression strategy for the co-production of wild-type and mutant human hPAH subunits we report for the first time the kinetic parameters (K(m) , V(max) , CL(E) ) for the C-oxidation of l-phenylalanine and the S-oxidation of S-carboxymethyl-l-cysteine in homomeric wild-type, heteromeric mutant and homomeric mutant hPAH proteins in vitro. A PRO(TM) dual-vector bacterial expression system was used to produce the required hPAH proteins. Enzyme activity was determined by HPLC with fluorescence detection. The heteromeric hPAH proteins (I65T, R68S, R158Q, I174T, R261Q, V338M, R408W and Y414C) all showed significantly decreased V(max) and CL(E) values when compared to the homomeric wild-type hPAH enzyme. For both substrates, all calculated K(m) values were significantly higher than homomeric wild-type hPAH enzyme, with the exception of I65T, R68S and Y414C heteromeric hPAH proteins employing l-phenylalanine as substrate. The net outcome for the heteromeric mutant hPAH proteins was a decrease significantly more dramatic for S-carboxymethyl-l-cysteine S-oxidation (1.0-18.8% of homomeric wild-type hPAH activity) when compared to l-phenylalanine C-oxidation (25.9-52.9% of homomeric wild-type hPAH activity) as a substrate. Heteromeric hPAH enzyme may be related to the variation in S-carboxymethyl-l-cysteine S-oxidation capacity observed in humans.


Analysis of the rpoD gene encoding the principal sigma factor of Pseudomonas putida.
The gene (rpoD) encoding the principal sigma factor of Pseudomonas putida (Pp) was cloned and sequenced. The amino-acid sequence deduced from the nucleotide sequence of rpoD contained sequences with significant similarity to the conserved region of the principal sigma factors. In vivo transcriptional analyses revealed that the Pp rpoD is transcribed as a monocistronic mRNA of 2.1 kb and that the transcription of rpoD is under control of the heat-shock (HS) response. The transcription start point (tsp) of the gene was determined and found to be different depending on either normal growth (at 30 degrees C) or HS (at 42 degrees C) conditions. The possible promoter sequences for the principal (sigma 70) and the HS RNA polymerase of Pseudomonas were located in the upstream region of the tsp.


Surf4 facilitates reprogramming by activating the cellular response to endoplasmic reticulum stress.
Maternal factors that are enriched in oocytes have attracted great interest as possible key factors in somatic cell reprogramming. We found that surfeit locus protein 4 (Surf4), a maternal factor, can facilitate the generation of induced pluripotent stem cells (iPSCs) previously, but the mechanism remains elusive. In this study, we investigated the function and mechanism of Surf4 in somatic cell reprogramming using a secondary reprogramming system. Alkaline phosphatase (AP) staining, qPCR and immunofluorescence (IF) staining of expression of related markers were used to evaluate efficiency of iPSCs derived from mouse embryonic fibroblasts. Embryoid body and teratoma formation assays were performed to evaluate the differentiation ability of the iPSC lines. RNA-seq, qPCR and western blot analysis were applied to validate the downstream targets of Surf4. Surf4 can significantly facilitate the generation of iPSCs in a proliferation-independent manner. When co-expressed with Oct4, Sox2, Klf4 and c-Myc (OSKM), Surf4 can activate the response to endoplasmic reticulum (ER) stress at the early stage of reprogramming. We further demonstrated that Hspa5, a major ER chaperone, and the active spliced form of Xbp1 (sXbp1), a major mediator of ER stress, can mimic the effects of Surf4 on somatic cell reprogramming. Concordantly, blocking the unfolded protein response compromises the effect of Surf4 on reprogramming. Surf4 promotes somatic cell reprogramming by activating the response to ER stress.


Expression of cyclin D1 and cyclin E significantly associates with human papillomavirus subtypes in Bowenoid papulosis.
Human papillomavirus (HPV) incorporates high-risk HPV (hrHPV) and low-risk HPV (lrHPV) subtypes according to its contribution to oncogenesis. Different HPV subtypes could regulate the cell cycle of infected cells at different levels. To date, the expression of cyclin D1 and cyclin E in Bowenoid papulosis (BP) tissues and its association with HPV infection still remains elusive. In the present study, genotyping was performed to identify the HPV subtypes in 44 BP specimens. In addition, immunohistochemistry was performed to detect the expression of cell cycle related proteins cyclin D1 and cyclin E in BP tissues as well as normal tissues. We found that there were 20 patients with hrHPV subtypes, 6 patients with lrHPV subtypes, and 18 patients with combined high and low (hr/lr) HPV subtypes. Cyclin D1 expression in patients with hrHPV subtypes (P=0.0408), in patients with lrHPV subtypes (P=0.0002) and in patients with hr/lr HPV subtypes (P=0.0047) was significantly higher than that in normal controls, respectively. Cyclin D1 expression in patients with hr/lr HPV subtypes (P<0.0001) and in patients with lrHPV subtypes (P=0.0244) was significantly higher than that in patients with hrHPV subtypes, respectively. Cyclin E expression in patients with hrHPV subtypes (P<0.0001), in patients with lrHPV subtypes (P=0.0005), and in patients with hr/lr HPV subtypes (P<0.0001) was significantly higher than that in normal controls, respectively. Cyclin E expression in patients with hrHPV subtypes was significantly higher than that in patients with lrHPV subtypes (P=0.0032). Our data suggest that HPV infection is strongly associated with the pathogenesis of BP, and further support the notion that HPV may be involved in the regulation of the expression of cell cycle related proteins, cyclin D1 and cyclin E, in the pathogenesis of BP.


Spin-lattice relaxation of 13CH3 groups in 13C-enriched aspirin after proton saturation.
We studied the spin-lattice relaxation of the 13C magnetisation, M(C), in 13C-enriched single crystal of aspirin (only methyl carbons enriched to 99%) at the carbon resonance frequency of 54.5 MHz. After the carbon saturation the recovery appears exponential except below 30K, where it is biexponential due to the presence of the level crossing omega(t)=omega(C)+omega(H) (the symbols refer, respectively, to the tunnel frequency and the carbon and proton resonance frequencies in angular units). After the saturation of the proton magnetisation, M(H), the description of the M(C) recovery needs three exponentials. The evaluation of the time constants is easiest from the data in this case, since M(C) varies with time in an initial growth-subsequent decrease (or an initial decrease-subsequent growth depending on temperature) manner, instead of the monotonous growth after the carbon saturation. Experimental data agree semiquantitatively with the predictions of our recent model. According to the model the relaxation of M(C) is coupled to M(H) and the tunnel energy TE at temperatures below the minimum of the 13C relaxation time. Sufficiently above this minimum M(C) is coupled to M(H) and the rotational polarization (but not to TE) in agreement with experiment. Also the effect of torsional oscillations of a methyl group on the magnitude of various 13C-related transition rates was considered in detail. In aspirin the rates are reduced roughly by 10% and the reduction should become larger in samples with a larger tunnel splitting. The reduction also changes somewhat the angular dependence of these rates.


The foramen of Huschke: age and gender specific features after childhood.
The foramen of Huschke (FH) is an aperture that is formed in the tympanic plate of the temporal bone at the age of about 1 year. The FH usually closes before the age of 5 years; but it occasionally persists throughout life. A persistent FH may result in complications such as temporomandibular joint (TMJ) herniation and salivary fistula formation, and facilitate ear injury during TMJ arthroscopy. In this study, the authors examined 1994 temporal bones from 997 Japanese dry skulls, in order to define age and gender specific features of the persistent FH after childhood. A persistent FH was found in 12% of men and in 20% of women, representing a female predominance (P<0.0001). The incidence of a persistent FH decreased with age in both genders, suggesting that a persistent FH can close over time.


Survival outcomes of patients with stage III colorectal cancer aged ≥ 80 years who underwent curative resection: the HiSCO-04 prospective cohort study.
The efficacy of adjuvant chemotherapy in elderly patients aged ≥ 80 years with stage III colorectal cancer remains unclear. In parallel with a multicenter prospective phase II trial evaluating the efficacy of uracil-tegafur and leucovorin as adjuvant chemotherapy (HiSCO-03), we conducted a prospective observational study of these patients to assess survival outcomes, including those ineligible for chemotherapy. This multi-institutional prospective cohort study included 17 institutions in Hiroshima, Japan. Patients aged ≥ 80 years with stage III colorectal cancer who underwent curative resection were enrolled. The primary endpoint was 3-year disease-free survival, and the secondary endpoints were 3-year overall and relapse-free survival. Propensity score matching was used to assess the effects of adjuvant chemotherapy on survival outcomes. A total of 214 patients were analyzed between 2013 and 2018, including 99 males and 115 females with a median age of 84 years (range 80-101 years). Recurrence occurred in 58 patients and secondary cancers were observed in 17. The 3-year disease-free, overall, and relapse-free survival rates were 63.3%, 76.9%, and 62.9%, respectively. Adjuvant chemotherapy was administered to 65 patients with a completion rate of 52%. In a study of 80 patients that adjusted for background factors using propensity score matching, patients who completed the planned treatment showed improved disease-free survival (3-year disease-free survival: completed, 80.0%; not received, 65.5%; and discontinued, 56.3%; p = 0.029). Completion of adjuvant chemotherapy may improve the prognosis of patients with colorectal cancer aged ≥ 80 years, although the number of patients who would benefit from it is limited.


Free from Dysphagia? A Test Battery to Differentiate Between Mild and No Dysphagia.
Assessing mild oropharyngeal dysphagia (OD) raises the question where to draw the line between normal and pathological swallowing. There is a lack of clinical test methods appropriate in the subacute phase of recovery from dysphagia following stroke and other brain injuries. The aim of this pilot study was to investigate the diagnostic accuracy of a new test battery, called the Swallow Battery (SwaB), in relation to Fiberoptic Endoscopic Evaluation of Swallowing (FEES). SwaB consists of the validated tests Repetitive Saliva Swallowing Test (RSST), Timed Water Swallowing Test (TWST) and parts of the Test of Masticating and Swallowing Solids (ToMaSS). Nineteen adult patients with acquired brain injury who were enrolled in a rehabilitation programme underwent the SwaB and a FEES, both resulting in a pass or fail outcome. The pass or fail results were based on RSST's and TWST's suggested cutoffs, normative values of ToMaSS and on established rating scales used for FEES. The SwaB's ability to predict FEES results was 74% according to a binary logistic regression analysis, with a 92% correct prediction of fail results and 33% correct prediction of pass results. The ToMaSS was sensitive to small changes in eating ability, failing 13 out of 19 patients using 95% CI normative values as cutoff, including patients with a passed FEES. Alternative cutoffs were therefore suggested, depending on purpose of dysphagia assessment. The results of this study indicate that the SwaB may be a useful tool when assessing mild dysphagia following brain injury. Further studies of SwaB's validity and clinical utility are suggested.


Prevalence and pattern of multiple sclerosis in Benghazi, north-eastern Libya.
A search for Libyan patients with multiple sclerosis (MS) was made in Benghazi, located on the southern Mediterranean coast at a latitude of 32 degrees N. Twenty-one clinically definite and probable cases were detected during the period July 1982-June 1984. On the basis of 2 probable incidental cases, the incidence for 1983 was 0.8 per 100 000 of the population at risk (10-50 years). On July 1st, 1984, the rough prevalence rate for the total population was 4 per 100 000 and the age-adjusted prevalence rate was 5.9 per 100 000. This study suggests that Benghazi falls within the medium frequency band for MS. High prevalence of brainstem involvement and cerebellar dysfunction and infrequent occurrence of the severe optic-spinal form and sphincter disturbance indicates that the present group of patients resembles Western pattern of MS as opposed to Asian MS.


Fluorine-19 or phosphorus-31 NMR spectroscopy: a suitable analytical technique for quantitative in vitro metabolic studies of fluorinated or phosphorylated drugs.
Fluorine-19 or phosphorus-31 NMR (19F NMR or 31P NMR) spectroscopy provides a highly specific tool for identification of fluorine- or phosphorus-containing drugs and their metabolites in biological media as well as a suitable analytical technique for their absolute quantification. This article focuses on the application of in vitro 19F or 31P NMR to the quantitative metabolic studies of some fluoropyrimidine or oxazaphosphorine drugs in clinical use. The first part presents an overview of the advantages (non-destructive and non-selective direct quantitative study of the biological matrices) and limitations (expensive cost of the spectrometers, limited mass or concentration sensitivity) of NMR spectroscopy. The second part deals with the criteria to be considered for successful quantification by NMR (uniform excitation over the entire spectral width of the spectrum, resonance signals properly characterised by taking into account T1 values and avoiding NOE enhancements, optimisation of the data processing, choice of a suitable standard reference). The third and fourth parts report some examples of quantification of 5-fluorouracil, its prodrug capecitabine, 5-fluorocytosine and their metabolites in bulk solutions (biofluids, tissue extracts, perfusates and culture media) and heterogeneous media (excised tissues and packed intact cells) as well as cyclophosphamide and ifosfamide in biofluids. These two parts emphasise the high potential of in vitro 19F or 31P NMR for absolute quantification, in a single run, of all the fluorine- or phosphorus-containing species in the matrices analysed. The limit of quantification in bulk solutions is 1-3 microM for 19F NMR and approximately 10 microM for 31P NMR. In heterogeneous media analysed with 19F NMR, it is 2-5 nmol in excised tissues and cell pellets.


Hypothalmic lesions and sexual behavior in the female rat.
This study reports selective effects on the mating pattern of the female rat of partial destruction of the hypothalamus. Independent neural control of the ovarian cycle and of the mating response are demonstrated. Both depressed and augmented female sexual activity are reported.


SpliceAid: a database of experimental RNA target motifs bound by splicing proteins in humans.
The correct post-transcriptional RNA processing is finely regulated by RNA-binding proteins. Unfortunately, there is little experimental information on target RNA sequences of RNA-binding proteins and moreover such experimentally derived target sequences are annotated in a compact form by the score matrices that overestimate the number of possible recognized sequences. We carried out an exhaustive hand curated literature search to create a database, SpliceAid, collecting all the experimentally assessed target RNA sequences that are bound by splicing proteins in humans. We built a web resource, database driven, to easy query SpliceAid and give back the results by an accurate and dynamic graphic representation. SpliceAid database is freely accessible at http://www.introni.it/splicing.html.


Multibeat echocardiographic phase detection using deep neural networks.
Accurate identification of end-diastolic and end-systolic frames in echocardiographic cine loops is important, yet challenging, for human experts. Manual frame selection is subject to uncertainty, affecting crucial clinical measurements, such as myocardial strain. Therefore, the ability to automatically detect frames of interest is highly desirable. We have developed deep neural networks, trained and tested on multi-centre patient data, for the accurate identification of end-diastolic and end-systolic frames in apical four-chamber 2D multibeat cine loop recordings of arbitrary length. Seven experienced cardiologist experts independently labelled the frames of interest, thereby providing infallible annotations, allowing for observer variability measurements. When compared with the ground-truth, our model shows an average frame difference of -0.09 ± 1.10 and 0.11 ± 1.29 frames for end-diastolic and end-systolic frames, respectively. When applied to patient datasets from a different clinical site, to which the model was blind during its development, average frame differences of -1.34 ± 3.27 and -0.31 ± 3.37 frames were obtained for both frames of interest. All detection errors fall within the range of inter-observer variability: [-0.87, -5.51]±[2.29, 4.26] and [-0.97, -3.46]±[3.67, 4.68] for ED and ES events, respectively. The proposed automated model can identify multiple end-systolic and end-diastolic frames in echocardiographic videos of arbitrary length with performance indistinguishable from that of human experts, but with significantly shorter processing time.


The lowest effective dose of tissue plasminogen activator for fibrinolysis of postvitrectomy fibrin.
Tissue plasminogen activator (tPA) has been shown to be effective at a dose of 25 micrograms in the treatment of severe postvitrectomy fibrin. However, a recent report based on an animal model indicates that retinal toxicity may occur at doses as low as 25 micrograms. This study uses a low dose (1.5 micrograms to 3 micrograms) of tPA for 34 injections in 26 eyes, and determines the lowest effective dose to be between 1.5 and 3 micrograms. Complete fibrinolysis was achieved in all 28 eyes in which 3 micrograms of tPA was administered within 10 days of vitrectomy, whereas partial fibrinolysis was achieved in eyes treated with 3 micrograms of tPA 27 days and 82 days after vitrectomy. Complete fibrinolysis occurred in only 1 of 4 eyes that receive 1.5 micrograms of tPA. A dose of 3 micrograms of tPA is recommended for treatment of severe fibrin after vitrectomy, as it has a wider margin of safety than do higher doses.


Treatment re-entry and outcomes of opioid addicts during a four-year follow-up after drug abuse treatment in the United States.
Post-treatment outcome measures during a four-year follow-up period were examined in relation to readmissions to drug abuse treatment. The sample included 1,174 opioid addicts admitted during 1972-1973 to 26 different treatment programmes throughout the United States that participated in the Drug Abuse Reporting Program (DARP). Admissions to methadone maintenance programmes, therapeutic communities, outpatient drug-free treatments, and outpatient detoxification programmes were studied, as well as a comparison group which completed admission procedures but did not return for treatment at the DARP agency. The examination of temporal patterns of treatment and outcome indicators presenting drug use, criminality, and productive activities during the four-year follow-up period showed that there were beneficial effects associated with treatment.


The hidden truth about gene expression in Tregs: is it what you don't see that counts?
A population of IL-10 secreting regulatory T cells (PI-Tregs) can be induced in a mouse TCR transgenic model of experimental autoimmune encephalomyelitis (EAE) by intranasal administration of the N-terminal peptide of myelin basic protein. A paper in this issue of the European Journal of Immunology identifies patterns of gene expression that distinguish PI-Treg from naïve T cells after activation in vivo. PI-Tregs are anergic and the expression of egr2 may be involved in regulation of the cell cycle. The surprising expression of the Th1 determining gene T-bet in PI-Tregs may be functionally relevant as transfection of T-bet into a hybridoma induced some genes associated with regulatory T cells, such as tlr2 and gzmb. In this commentary, PI-Tregs are considered in comparison to other Tregs, such as the natural CD4(+)CD25(+) and Tr1 cells, and there seems to be considerable overlap in gene expression between all three Treg populations, but also with both Th1 and Th2 cells. It is suggested that regulatory activity may be a common feature of all activated T cells and that a defining principle of a Treg is the lack of effector functions due to a partial or incomplete differentiation to either Th1 or Th2.


A Water-Soluble Schiff Base Turn-on Fluorescent Chemosensor for the Detection of Al3+ and Zn2+ Ions at the Nanomolar Level: Application in Live-Cell Imaging.
A water-soluble Schiff base, 2,3-bis((E)-(2-hydroxy-3-methoxybenzylidene)amino) propanoic acid (ODA) prepared by condensing o-vanillin and DL-2,3-diaminopropionic acid was evaluated as an efficient "turn on" fluorescent chemosensor for the selective recognition of Al3+ and Zn2+ ions in presence of several interfering metal ions (detection limit; for Al3+ = 1.82 nM, Zn2+ = 7.06 nM). The probe also shows a selective chromogenic behavior towards Al3+ and Zn2+ ions that the naked eye can view. The binding stoichiometry was determined using 1H-NMR titration and ESI-MS spectrometry. The sensing mechanism is due to the inhibition of ESIPT and isomerization of -C=N of ODA on complexation with Al3+/Zn2+. The intramolecular hydrogen bonding energy and the critical bond energy in ODA-Al3+/Zn2+ were calculated using QTAIM analysis. The Thin Layer Chromatography (TLC) plates and strip papers loaded with ODA were used to test the practical applications for sensing Al3+ and Zn2+ ions. Moreover, the probe has been used for live-cell imaging to detect Al3+ and Zn2+ ions in hepatoma C3A and human glioblastoma U87 cells.


Resistance status and evolution trends of Klebsiella pneumoniae isolates in a university hospital in Greece: ineffectiveness of carbapenems and increasing resistance to colistin.
Due to its increased non-susceptibility rates, Klebsiella pneumoniae has emerged as one of the most problematic pathogens. The level of resistance to 25 antimicrobials of K. pneumoniae isolates from a teaching hospital in Greece and the evolution trends during 2 decades were examined. A statistically significant increase in non-susceptibility rates was found for almost all antimicrobials examined. During 2008, the isolates presented non-susceptibility rates to aminoglycosides >50% and to quinolones >60%. Nowadays, 1 out of 10 isolates is non-susceptible to colistin. Moreover, the isolates non-susceptible to imipenem were almost doubled between 2007 (29%) and 2008 (50%). Among the imipenem-resistant isolates, 1 out of 4 was also resistant to colistin. The effectiveness of carbapenems has been compromised and the increase in resistance to colistin is rapid and steep.


The conservative coronary angioplasty strategy after thrombolysis for acute myocardial infarction: immediate and short-term results.
The in-hospital and short-term follow-up results of a conservative coronary angioplasty approach in 354 consecutive patients treated after thrombolysis for acute myocardial infarction were compared with results obtained in 408 control noninfarcted patients treated for the classical indication of myocardial ischemia. Only 20% of the study patients underwent angioplasty during the initial hospitalization period and the clinical success rate was 93% versus 95% in the control group (p = NS). No significant differences in the total number of in-hospital untoward events were observed (10.2% and 7.6%, respectively). During a 7.4 +/- 1.5 month follow-up period, the total number of adverse events was only 16.9% in the study patients but it was 27.8% in the control group (p < 0.001). There were no significant differences in death, myocardial infarction, or coronary surgery as individual events, but repeat angioplasty was less frequent in the study group (14.0% versus 21.5%, p < 0.01). Thus in-hospital results in patients undergoing angioplasty on a deferred basis after thrombolysis for myocardial infarction were largely comparable with those results obtained in noninfarcted patients. Moreover, short-term clinical follow-up events were reduced when compared with the control group, an observation apparently largely related to the subgroup without clinical evidence of residual ischemia.


Peptidylarginine Deiminases 2 Mediates Caspase-1-Associated Lethality in Pseudomonas aeruginosa Pneumonia-Induced Sepsis.
Pseudomonas aeruginosa (PA) is a pathogenic bacterium that causes severe pneumonia in critically ill and immunocompromised patients. Peptidylarginine deiminase (PAD) 2, PAD4, and caspase-1 are important enzymes in mediating host response to infection. The goal of this study was to determine the interplay between PAD2, PAD4, and caspase-1 in PA pneumonia-induced sepsis. Pneumonia was produced in wild-type, Pad2-/-, and Pad4-/- mice by intranasal inoculation of PA (2.5 × 106 colony-forming units per mouse), and survival (n = 15/group) was monitored for 10 days. Bone marrow-derived macrophages (BMDMs) were isolated for in vitro studies. Samples were collected at specific timepoints for Western blot, bacterial load determination, and flow cytometry analysis. Caspase-1-dependent inflammation was diminished in PA-inoculated Pad2-/- mice, contributing to reduced macrophage death and enhanced bacterial clearance. In addition, Pad2-/- mice exhibited improved survival and attenuated acute lung injury after PA infection. In contrast, Pad4-/- mice did not display diminished caspase-1 activation, altered bacterial loads, or improved survival. Peptidylarginine deiminase 2 plays an essential role in the pathogenesis of pulmonary sepsis by mediating caspase-1 activation. This goes against previous findings of PAD4 in sepsis. Our study suggests that PAD2 is a potential therapeutic target of PA pneumonia-induced sepsis.


Anaerobic digestion of animal waste: effect of mode of mixing.
Laboratory-scale digesters were operated to study the effect of mixing (via biogas recirculation, impeller mixing, and slurry recirculation) on biogas production. Three sets of experiments were performed using cow manure slurry feed with either 50, 100, or 150 g/L total solids (TS) concentrations (referred in the text as 5%, 10%, and 15% manure slurry). The experiments were conducted at a controlled temperature of 35 degrees C and a hydraulic retention time of 16.2 days, resulting in TS loadings of 3.1, 6.2, and 9.3g/Ld for 5%, 10%, and 15% manure slurry feeds, respectively. Results showed that the unmixed and mixed digesters performed quite similarly when fed with 5% manure slurry and produced biogas at a rate of 0.84-0.94 L/Ld. The methane yield was found to be 0.26-0.28 L CH4/g volatile solids loaded. However, the effect of mixing and the mode of mixing became important when the digesters were fed thick manure slurry feeds (10% and 15%). Digesters fed with 10% and 15% manure slurry and equipped with external mixing produced about 10-30% more biogas than the unmixed digester. While the mixed digesters produced more biogas than unmixed digesters, digester mixing during start-up was not beneficial, as it resulted in lower pH, performance instability and prolonged start-up time. Mixing using biogas recirculation system was found not to be effective in the case of 15% manure slurry feed under the experimental conditions studied.


Prognosis of metal concentrations in sediments and water of Paraopeba River following the collapse of B1 tailings dam in Brumadinho (Minas Gerais, Brazil).
In January 25, 2019, the B1 dam of Córrego do Feijão mine located in Brumadinho municipality (Minas Gerais, Brazil) collapsed and injected nearly 2.8 Mm3 of iron (Fe)- and manganese (Mn)-rich tailings in the Paraopeba River. This study assessed the contribution of tailings to the contamination of sediments and water by those metals. The dataset was built through daily to weekly samplings executed in the two years following the event, at 27 sites located along the Paraopeba plus 9 sites located at the confluence of main tributaries. The results evidenced a distinct contribution in the sectors "Anomalous" (8.6-63.3 km downstream from the dam) and "Natural" (115.8-341.6 km). The "Anomalous" sector presented large Fe/Al (12.2 ± 6.4) and Mn/Al (0.33 ± 0.19) ratios in sediments, thus being rich in tailings, while the "Natural" sector presented small ratios (2.4 ± 1.0; 0.06 ± 0.03) comparable to the natural sediments. A 500-700 m3/s stream flow discharge in the Paraopeba caused pronounced drops to the Fe/Al and Mn/Al ratios in the "Anomalous" sector, attributed to the mixture of contaminated sediments from the main water course with uncontaminated sediments injected by the tributaries during the event. Non-linear regressions showed Fe/Al and Mn/Al declines in the "Anomalous" sector, related with tailings mobilization downstream. The concentrations of Fe and Al in the sediments correlated positively with the corresponding concentrations in the Paraopeba water, conditioned by raising discharge rates and variations in the water pH. The contribution of tailings to the Fe correlation was demonstrated. No direct relation was established between the Mn concentrations in water and stream discharge, because manganese is associated with fine particles in the tailings that are mobilized to the water column even under low flows. The preliminary results of Seasonal Autoregressive Integrated Moving Average models predicted the return of Paraopeba to a pre-collapse condition in 7-11 years.


Role of Fas/FasL in regulation of inflammation in vaginal tissue during HSV-2 infection.
To assess the role of Fas in lesion development during genital HSV-2 infection, we used a well-established HSV-2 murine model applied to MRL-Fas(lpr)/J (Fas-/-) and C3-Fasl(gld)/J (FasL-/-) C57BL6 mice. In vitro infection of murine keratinocytes and epithelial cells was used to clarify molecular details of HSV-2 infection. Despite upregulation of Fas and FasL, HSV-2-infected keratinocytes and epithelial cells showed a moderate level of apoptosis due to upregulated expression of the anti-apoptotic factors Bcl-2, Akt kinase and NF-κB. Inflammatory lesions within the HSV-2-infected epithelium of C57BL6 mice consisted of infected cells upregulating Fas, FasL and Bcl-2, uninfected cells upregulating Fas and neutrophils expressing both Fas and FasL. Apoptosis was detected in HSV-2-infected cells and to even higher extent in non-infected cells surrounding HSV-2 infection sites. HSV-2 infection of Fas- and FasL-deficient mice led to increased apoptosis and stronger recruitment of neutrophils within the infection sites. We conclude that the Fas pathway participates in regulation of inflammatory response in the vaginal epithelium at the initial stage of HSV-2 infection.


Mu opioid receptor expression is increased in inflammatory bowel diseases: implications for homeostatic intestinal inflammation.
Recent studies with mu opioid receptor (MOR) deficient mice support a physiological anti-inflammatory effect of MOR at the colon interface. To better understand the potential pharmacological effect of certain opiates in inflammatory bowel diseases (IBD), we (1) evaluated the regulation in vivo and in vitro of human MOR expression by inflammation; and (2) tested the potential anti-inflammatory function of a specific opiate (DALDA) in inflamed and resting human mucosa. Expression of MOR mRNA and protein was evaluated in healthy and inflamed small bowel and colonic tissues, isolated peripheral blood mononuclear cells and purified monocytes, and CD4+ and CD8+ T cells from healthy donors and IBD patients. The effect of cytokines and nuclear factor kappaB (NFkappaB) activation on MOR expression in lymphocyte T and monocytic human cell lines was assessed. Finally, DALDA induced anti-inflammatory effect was investigated in mucosal explants from controls and IBD patients. MOR was expressed in ileal and colonic enteric neurones as well as in immunocytes such as myeloid cells and CD4+ and CD8+ T cells. Overexpressed in active IBD mucosa, MOR was significantly enhanced by cytokines and repressed by NFkappaB inhibitor in myeloid and lymphocytic cell lines. Furthermore, ex vivo DALDA treatment dampened tumour necrosis factor alpha mRNA expression in the colon of active IBD patients. Given the increased expression of MOR and the ex vivo beneficial effect of DALDA in active IBD, natural and/or synthetic opioid agonists could help to prevent overt pathological intestinal inflammation.


Caspase inhibition attenuates contractile dysfunction following cardioplegic arrest and rewarming in the setting of left ventricular failure.
Hyperkalemic cardioplegic arrest (HCA) and rewarming evokes postoperative myocyte contractile dysfunction, a phenomenon of particular importance in settings of preexisting left ventricular (LV) failure. Caspases are intracellular proteolytic enzymes recently demonstrated to degrade myocardial contractile proteins. This study tested the hypothesis that myocyte contractile dysfunction induced by HCA could be ameliorated with caspase inhibition in the setting of compromised myocardial function. LV myocytes were isolated from control pigs (n = 9, 30 kg) or pigs with LV failure induced by rapid pacing (n = 6, 240 bpm for 21 days) and were randomized to the following: (1) normothermia (2003 myocytes), incubation in cell culture medium for 2 hours at 37 degrees C; (2) HCA only (506 myocytes), incubation for 2 hours in hypothermic HCA solution (4 degrees C, 24 mEq K); or (3) HCA + z-VAD, incubation in hypothermic HCA solution supplemented with 10 microM of the caspase inhibitor z-VAD (z-Val-Ala-Asp-fluoromethyl-ketone, 415 myocytes). Inotropic responsiveness was examined using beta-adrenergic stimulation (25 nM isoproterenol). Ambient normothermic myocyte shortening velocity (microm/s) was reduced with LV failure compared with control values (54 +/- 2 versus 75 +/- 2, respectively, P < 0.05). Following HCA, shortening velocity decreased in the LV failure and control groups (27 +/- 5 and 45 +/- 3, P < 0.05). Institution of z-VAD increased myocyte shortening velocity following HCA in both the LV failure and control groups (49 +/- 5 and 65 +/- 5, P < 0.05). Moreover, HCA supplementation with z-VAD increased beta-adrenergic responsiveness in both groups compared with HCA-only values. This study provides proof of concept that caspase activity contributes to myocyte contractile dysfunction following simulated HCA. Pharmacologic caspase inhibition may hold particular relevance in the execution of cardiac surgical procedures requiring HCA in the context of preexisting LV failure.


Randomized Trial to Reduce Risky Sexual Behavior Among Justice-Involved Adolescents.
Justice-involved adolescents are at high risk for sexually transmitted infections; one primary reason is co-occurring substance use. This study investigates the additive benefit of including alcohol and cannabis use content in a theory-based sexual risk reduction intervention, delivered using group-based motivational enhancement therapy. This study had a cluster randomized design, with randomization of single-sex clusters to 1 of 3 interventions. Participants were male and female justice-involved adolescents (N=460) residing in youth detention facilities. Data were collected from 2010 to 2014; analyses were completed in 2018-2019. Adolescents were randomized to 1 of 3 motivational enhancement therapy interventions: sexual risk reduction intervention, sexual risk reduction intervention with alcohol content, or sexual risk reduction intervention with alcohol and cannabis content. The primary outcome was risky sexual behavior (aggregation of condom use and frequency of intercourse), measured every 3 months for 1 year. Secondary outcomes were theoretical mechanisms on which the intervention was based (condom use attitudes, self-efficacy, peer norms, and behavioral intentions), collected at baseline and post-test. Risky sexual behavior significantly decreased from baseline to 3-month follow-up (t=10.59, p<0.001) and this decrease was maintained 1 year later (t=9.04, p<0.001). Intervention was associated with improved values on all theoretical mechanisms. Although all outcomes improved over time, changes did not differ by intervention condition (p>0.29 for all). Comparisons to a historical, information-only, sexual risk reduction control arm conducted with a similar juvenile justice sample confirm the effectiveness of all 3 motivational enhancement therapy-based interventions. All 3 interventions were associated with decreased sexual risk up to 1 year later, suggesting that the intervention modality (motivational enhancement therapy) may resonate with this population beyond the specific substance use content. This single-session manualized intervention can be readily disseminated to juvenile justice settings. This study is registered at www.clinicaltrials.gov NCT01170260.


Fulminant myocarditis associated with novel H1N1 influenza A.
Myocarditis secondary to H1N1 influenza has been described in children, but only very rarely in adults. We describe a 36-year-old man with no significant medical history who presented with flu-like symptoms of 3-week duration. When he sought medical attention, he was already manifesting heart failure secondary to fulminant myocarditis, along with multiorgan failure. Despite aggressive management, including circulatory support with a catheter-based mechanical cardiac assist device (Impella 2.5 Cardiac Assist Device, Abiomed, Danvers, MA) as a bridge to cardiac transplant, and aggressive antiviral and antibacterial therapy, the patient died of cardiac arrest. An H1N1 polymerase chain reaction postmortem assay produced positive results, and a diagnosis of fulminant viral myocarditis and multiorgan system failure was established.


Influence of denture plaque biofilm on oral mucosal membrane in patients with chronic obstructive pulmonary disease.
Patients with chronic obstructive pulmonary disease (COPD) have the lower airways colonized with pathogenic bacteria in a stable period of the disease and during exacerbations. The etiology of bacterial exacerbations of COPD depends on the underlying disease, the frequency of exacerbations and antibiotic therapy. Microorganisms can be aspirated off the denture plaque biofilm into the lower respiratory tract and could reduce the patient's immunity and cause pneumonia. COPD patients, who are using acrylic dentures in oral cavity, are exposed to denture stomatitis and oral candidiasis. The aim of this study was to establish the composition of denture plaque biofilm and its impact on the oral mucosa in COPD patients. The study included patients in a stable phase of COPD using removable denture and the control group included healthy wearer's appliances. Examinations concerned the oral mucosal membrane and the hygienic condition of prosthetic restorations. Microbiological examinations were performed by taking a direct swab from the surface of acrylic dentures. Seventeen bacterial and fungal strains were isolated from denture plaque of COPD patients, which could be a reservoir of pathogens in the upper and lower airways. The results showed a greater frequency of prosthetic stomatitis complicated by mucosal infections among COPD patients compared to healthy subjects.


The cost-effectiveness of a long-acting reversible contraceptive (Implanon) relative to oral contraception in a community setting.
Within the setting of a UK community sexual health service, the cost-effectiveness of Implanon and oral contraception provision over a 36-month period was compared. A case-controlled retrospective cost-effectiveness study was done on a cohort of 493 Implanon users and 493 oral contraceptive users. The actual cost of provision of both methods was calculated. Cost-effectiveness was calculated based on provision of method and pregnancy costs of each cohort. Implanon provision is more cost-effective than oral contraception at all time points. After 12 months of use, Implanon is half the cost of oral contraception. Oral contraception reached similar annual cost to Implanon at 36 months of use. Long-acting reversible contraception is perceived to be expensive. It is reassuring to contraception providers that Implanon is, in fact, highly cost-effective when compared to oral contraception with typical use.


DiapixUK: task materials for the elicitation of multiple spontaneous speech dialogs.
The renewed focus of attention on investigating spontaneous speech samples in speech and language research has increased the need for recordings of speech in interactive settings. The DiapixUK task is a new and extended set of picture materials based on the Diapix task by Van Engen et al. (Language and Speech, 53, 510-540, 2010), where two people are recorded while conversing to solve a 'spot the difference' task. The new task materials allow for multiple recordings of the same speaker pairs due to a larger set of picture pairs that have a number of tested features: equal difficulty across all 12 picture pairs, no learning effect of completing more than one picture task and balanced contributions from both speakers. The new materials also provide extra flexibility, making them useful in a wide range of research projects; they are multi-layered electronic images that can be adapted to suit different research needs. This article presents details of the development of the DiapixUK materials, along with data taken from a large corpus of spontaneous speech that are used to demonstrate its new features. Current and potential applications of the task are also discussed.


Coexpression of neuropeptide Y and vasoactive intestinal polypeptide in pelvic plexus neurones innervating the uterus and cervix in the rat.
The present study investigates the distribution and coexpression of neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP) in neurones of the accessory ganglion (AG), hypogastric plexus (HP) and paracervical ganglion (PCG), which compose the pelvic plexus in the female rat. Nerve cell bodies immunoreactive for NPY and VIP represent 84% and 46% of the neurone population in the PCG, respectively, while immunoreactivity for each peptide is observed in about 90% of the AG and HP neurones. Adjacent sections immunostained for NPY and VIP, as well as the use of immunocytochemistry combined with in situ hybridization show that 92% of the VIP-containing neurones in the pelvic plexus also contain NPY. In addition, a retrograde tracing study performed in combination with immunocytochemistry demonstrates that pelvic plexus neurones project preferentially to the lower part of the uterus and to the cervix, and that about 95% of these projecting neurones contain VIP. Taken together, our findings indicate that in the female rat, neurones of the pelvic plexus projecting to the lower genital tract mainly coexpress VIP and NPY, and supply nerve fibres to the vascular and nonvascular smooth muscle in the uterocervical region. Since NPY and VIP exert distinct effects according to the target tissue, our results suggest that neurones coexpressing these peptides play important roles in the local regulation of the vascular bed and motor activity of the lower genital tract.


A Potent and Selective Kallikrein-5 Inhibitor Delivers High Pharmacological Activity in Skin from Patients with Netherton Syndrome.
Regulation of proteolytic activity in the skin plays a pivotal role in epidermal homeostasis. This is best exemplified in Netherton syndrome, a severe genetic skin condition caused by loss-of-function mutations in the gene serine protease inhibitor Kazal-type 5 encoding lympho-epithelial Kazal-type-related inhibitor, a serine protease inhibitor that regulates kallikrein (KLK)-related peptidase 5, 7, and 14 activities. KLK5 plays a central role in stratum corneum shedding and inflammatory cell signaling, activates KLK7 and KLK14, and is therefore an optimal therapeutic target. We aimed to identify a potent and selective small-molecule inhibitor of KLK5 amenable to epidermal delivery. GSK951 was identified using a structure-based design strategy and showed a half maximal inhibitory concentration of 250 pM for KLK5 and greater than 100-fold selectivity over KLK7 and KLK14. Cocrystal structure analysis identified the critical catalytic site interactions to a surrogate for KLK5. Topical application of GSK951-containing cream inhibited KLK5 activity in TgKLK5 mouse skin, reduced transepidermal water loss, and decreased proinflammatory cytokine expression. GSK951 achieved high concentrations in healthy human epidermis following topical application in a cream formulation. Finally, KLK5 protease activity was increased in stratum corneum of patients with Netherton syndrome and significantly inhibited by GSK951. These findings unveil a KLK5-specific small-molecule inhibitor with a high therapeutic potential for patients with Netherton syndrome.


Older age, kidney concordant diseases and the dilemma of adherence to guidelines: A narrative review.
Evidence-based medicine is pivotal to contemporary clinical practice, and the excellence of a healthcare institution is measured by the adherence of its clinical staff to the clinical practice guidelines (CPGs) among other standards and policies. Following the recommendations of CPGs in older adults poses different challenges to prescribers. In this narrative review we explore research studies that assessed clinicians' adherence to CPGs when prescribing to older adults with chronic kidney disease and its concordant disorders, and to discuss the potential barriers and facilitators to better adherence to CPGs. Our review of the literature found that the adherence level to CPGs differed according to country, disease condition and healthcare setting. Clinicians' attitudes toward older adults and the CPGs, the unfamiliarity with the CPGs, and the lack of time, were commonly cited barriers. Interventions suggested to improve adherence to CPGs include direct mentoring, educational activities, and the integration of CPGs recommendations within hospital protocols and policies.


Water permeation through gramicidin A: desformylation and the double helix: a molecular dynamics study.
Multinanosecond molecular dynamics simulations of gramicidin A embedded in a dimyristoylphosphatidylcholine bilayer show a remarkable structural stability for both experimentally determined conformations: the head-to-head helical dimer and the double helix. Water permeability was found to be much higher in the double helical conformation, which is explained by lower hydrogen bond-mediated enthalpic barriers at the channel entrance and its larger pore size. Free-energy perturbation calculations show that the double helical structure is stabilized by the positive charges at the N termini introduced by the desformylation, whereas the helical dimer is destabilized. Together with the recent experimental observation that desformyl gramicidin conducts water hundredfold better than gramicidin, this suggests that desformyl gramicidin A predominantly occurs in the double helical conformation.


Intra-hippocampal microinjection of oxytocin produced antiepileptic effect on the pentylenetetrazol-induced epilepsy in rats.
In addition to its role as a circulating hormone, oxytocin can also act as a neurotransmitter and a neuromodulator within the brain. In this study, we investigated the intra-hippocampal effect of oxytocin on an experimental seizure model induced by pentylenetetrazole (PTZ) in rats. We also used atosiban (oxytocin antagonist), diazepam and flumazenil (gamma-aminobutyric acid or GABA-benzodiazepine receptor agonist and antagonist, respectively) to clarify the involved mechanism. In ketamine-xylazine anesthetized rats, the right and left sides of the dorsal hippocampus (CA1) were implanted with two guide cannulas. Epileptic behaviors were induced by intraperitoneal (ip) injection of PTZ (60mg/kg), and the latency time to onset of first myoclonic jerk, and the duration of epileptic seizures were determined for 30min. Intra-hippocampal microinjections of oxytocin at doses of 10 and 20ng/site, diazepam (100 and 200ng/site) and co-administration of their ineffective doses significantly (p<0.01) increased the onset of first myoclonic jerk and decreased duration of epileptic seizure. Antiepileptic effects of oxytocin (20ng/site) were inhibited by atosiban (20 and 40ng/site) and flumazenil (100 and 200ng/site) pretreatments. On the other hand, prior administration of flumazenil (100 and 200ng/site) and atosiban (20 and 40ng/site) prevented the antiepileptic effects induced by diazepam (100 and 200ng/site). The results of the present study showed that at the level of the hippocampus oxytocin suppressed the severity of epileptic behaviors. A hippocampal GABA-benzodiazepine receptor mechanism may be involved in antiepileptic effect of oxytocin.


Does pro-sociality or trust better predict staying home behavior during the Covid-19?
Voluntary compliance of preventive and mitigation measures due to social concerns can play a crucial role in slowing down the spread of the Covid-19. The existing economic models for disease spread however do not direct a lot of focus on the possible role of pro-social behavior and general trust in predicting preventive behaviors amid the Covid-19. Therefore, this study analyzes whether pro-sociality and general trust measured in the short run (2020 and 2019) and in the long run (2015 and 2010) predict attitudes towards the stay home behavior and the intended stay home behavior in case the government mandates it due to the Covid-19 in the Netherlands. The results suggest that these preferences positively influence attitudes towards staying home behavior. However, trust in comparison to pro-sociality is a stable and robust predictor of stay home attitudes both in the short as well as long run. On the other hand, neither trust nor pro-sociality influences the intended stay home behavior in case the government mandates the lockdown, and it is most likely due to the timing of the survey coinciding with a significant drop in the Covid-19 infections and easing out of the lockdown restrictions by the Dutch government.


Chronic exposure to sub-lethal beta-amyloid (Abeta) inhibits the import of nuclear-encoded proteins to mitochondria in differentiated PC12 cells.
Studies on amyloid beta (Abeta|), the peptide thought to play a crucial role in the pathogenesis of Alzheimer's disease, have implicated mitochondria in Abeta-mediated neurotoxicity. We used differentiated PC12 cells stably transfected with an inducible green fluorescent protein (GFP) fusion protein containing an N'-terminal mitochondrial targeting sequence (mtGFP), to examine the effects of sub-lethal Abeta on the import of nuclear-encoded proteins to mitochondria. Exposure to sub-lethal Abeta(25-35) (10 mumol/L) for 48 h inhibited mtGFP import to mitochondria; average rates decreased by 20 +/- 4%. Concomitant with the decline in mtGFP, cytoplasmic mtGFP increased significantly while mtGFP expression and intramitochondrial mtGFP turnover were unchanged. Sub-lethal Abeta(1-42) inhibited mtGFP import and increased cytoplasmic mtGFP but only after 96 h. The import of two endogenous nuclear-encoded mitochondrial proteins, mortalin/mtHsp70 and Tom20 also declined. Prior to the decline in import, mitochondrial membrane potential (mmp), and reactive oxygen species levels were unchanged in Abeta-treated cells versus reverse phase controls. Sustained periods of decreased import were associated with decreased mmp, increased reactive oxygen species, increased vulnerability to oxygen-glucose deprivation and altered mitochondrial morphology. These findings suggest that an Abeta-mediated inhibition of mitochondrial protein import, and the consequent mitochondrial impairment, may contribute to Alzheimer's disease.


The p53 tumour suppressor inhibits glucocorticoid-induced proliferation of erythroid progenitors.
Hypoxia encountered at high altitude, blood loss and erythroleukemia instigate stress erythropoiesis, which involves glucocorticoid-induced proliferation of erythroid progenitors (ebls). The tumour suppressor p53 stimulates hematopoietic cell maturation and antagonizes glucocorticoid receptor (GR) activity in hypoxia, suggesting that it may inhibit stress erythropoiesis. We report that mouse fetal liver ebls that lack p53 proliferate better than wild-type cells in the presence of the GR agonist dexamethasone. An important mediator of GR-induced ebl self-renewal, the c-myb gene, is induced to higher levels in p53(-/-) ebls by dexamethasone. The stress response to anemia is faster in the spleens of p53(-/-) mice, as shown by the higher levels of colony forming units erythroids and the increase in the CD34/c-kit double positive population. Our results show that p53 antagonizes GR-mediated ebl expansion and demonstrate for the first time that p53-GR cross-talk is important in a physiological process in vivo: stress erythropoiesis.


Magnetic resonance separation imaging using a divided inversion recovery technique (DIRT).
The divided inversion recovery technique is an MRI separation method based on tissue T(1) relaxation differences. When tissue T(1) relaxation times are longer than the time between inversion pulses in a segmented inversion recovery pulse sequence, longitudinal magnetization does not pass through the null point. Prior to additional inversion pulses, longitudinal magnetization may have an opposite polarity. Spatial displacement of tissues in inversion recovery balanced steady-state free-precession imaging has been shown to be due to this magnetization phase change resulting from incomplete magnetization recovery. In this paper, it is shown how this phase change can be used to provide image separation. A pulse sequence parameter, the time between inversion pulses (T180), can be adjusted to provide water-fat or fluid separation. Example water-fat and fluid separation images of the head, heart, and abdomen are presented. The water-fat separation performance was investigated by comparing image intensities in short-axis divided inversion recovery technique images of the heart. Fat, blood, and fluid signal was suppressed to the background noise level. Additionally, the separation performance was not affected by main magnetic field inhomogeneities.


Ortner's syndrome: a centenary review of unilateral recurrent laryngeal nerve palsy secondary to cardiothoracic disease.
Ortner's Syndrome (described 100 years ago in 1897) is a clinical entity with hoarseness due to a left recurrent laryngeal nerve (LRLN) palsy caused by cardiac disease. A 35-year-old woman presented with a LRLN palsy due to a huge thoracic aneurysm. The anatomy of the LRLN and the cardiothoracic complaints which may cause the palsy are discussed.


Titanium (IV) oxide anatase nanoparticles as vectors for diclofenac: assessing the antioxidative responses to single and combined exposures in the aquatic macrophyte Egeria densa.
Titanium dioxide, frequently used in commonplace products, is now regularly detected in aquatic environments. Understanding its toxic effects on native biota is essential. However, combined toxicity with commonly occurring pollutants, such as the pharmaceutical diclofenac, may provide more insight into environmental situations. Therefore, the present study aimed to evaluate the effects of titanium dioxide and diclofenac, individually and combined, on the macrophyte Egeria densa. Diclofenac uptake and removal by the macrophyte were assessed. Diclofenac and titanium dioxide were mixed prior to exposure to allow binding, which was assessed. Toxicity of the individual compounds and the combination was evaluated by assaying enzymes as bioindicators of biotransformation and the antioxidative system. Cytosolic glutathione S-transferase and glutathione reductase activities were increased by diclofenac, titanium dioxide, and the combination. Both enzymes' activities were more significantly elevated by diclofenac and the combination than nanoparticles alone. Microsomal glutathione S-transferase was unaffected by diclofenac exposure but inhibited with titanium dioxide and the mixture. Diclofenac elicited the most significant response. Based on the data, the cytosolic enzymes effectively prevented damage.


Individuals with dyslexia use a different visual sampling strategy to read text.
Individuals with dyslexia present with reading-related deficits including inaccurate and/or less fluent word recognition and poor decoding abilities. Slow reading speed and worse text comprehension can occur as secondary consequences of these deficits. Reports of visual symptoms such as atypical eye movements during reading gave rise to a search for these deficits' underlying mechanisms. This study sought to replicate established behavioral deficits in reading and cognitive processing speed while investigating their underlying mechanisms in more detail by developing a comprehensive profile of eye movements specific to reading in adult dyslexia. Using a validated standardized reading assessment, our findings confirm a reading speed deficit among adults with dyslexia. We observed different eye movements in readers with dyslexia across numerous eye movement metrics including the duration of a stop (i.e., fixation), the length of jumps (i.e., saccades), and the number of times a reader's eyes expressed a jump atypical for reading. We conclude that individuals with dyslexia visually sample written information in a laborious and more effortful manner that is fundamentally different from those without dyslexia. Our findings suggest a mix of aberrant cognitive linguistic and oculomotor processes being present in adults with dyslexia.


Genz-644282, a novel non-camptothecin topoisomerase I inhibitor for cancer treatment.
Genz-644282 [8,9-dimethoxy-5-(2-N-methylaminoethyl)-2,3-methylenedioxy-5H-dibenzo[c,h][1,6]naphthyridin-6-one] has emerged as a promising candidate for antitumor agents. This report describes the bone marrow colony-forming unit, granulocyte macrophage (CFU-GM) and tumor cell CFU activity of topoisomerase I (Top1) inhibitors, such as Genz-644282, topotecan, irinotecan/SN-38, and ARC-111, and examines their activity in several human tumor xenograft models. Colony-forming assays were conducted with mouse and human bone marrow and eight human tumor cell lines. In addition, 29 human tumor cell lines representing a range of histology and potential resistance mechanisms were assayed for sensitivity to Genz-644282 in a 72-hour exposure assay. The efficacy of Genz-644282 was compared with standard anticancer drugs (i.e., irinotecan, docetaxel, and dacarbazine) in human tumor xenografts of colon cancer, renal cell carcinoma, non-small cell lung cancer, and melanoma. Human bone marrow CFU-GM was more sensitive to the Top1 inhibitors than was mouse bone marrow CFU-GM. The ratio of mouse to human IC(90) values was more than 10 for the camptothecins and less than 10 for Genz-644282, which had more potency as a cytotoxic agent toward human tumor cells in culture than the camptothecins in the colony-forming and 72-hour proliferation assays. Genz-644282 has superior or equal antitumor activity in the human tumor xenografts than the standard drug comparators. On the basis of preclinical activity and safety, Genz-644282 was selected for development and is currently undergoing phase 1 clinical trial.


IL-33 and HMGB1 alarmins: sensors of cellular death and their involvement in liver pathology.
'Alarmins' are a group of proteins or molecules that are released from cells during cellular demise to alert the host immune system. Two of them, Interleukin-33 (IL-33) and high-mobility group box-1 (HMGB1), share many similarities of cellular localization, functions and involvement in various inflammatory pathologies including hepatitis. The expressions of IL-33 and HMGB1, and their receptors ST2 and receptor for advanced glycation end products (RAGE), are substantially up-regulated during acute and chronic hepatitis. Recent data evidence a possible protective role of IL-33/ST2 axis during liver injury. A contrast in expression of IL-33 and HMGB1 alarmins were associated with type of hepatocellular death mediated by immune cells or hepato-toxic agents. The massive release of active form of IL-33 from hepatocytes may affect the recruitment and activation of its ST2-positive target immune cells in the liver to confer its alarmin functions. This review highlights the emerging roles of alarmin proteins in various liver pathologies, by focusing on classical HMGB1 and a newly discovered alarmin, the IL-33.


Confining redox-active metal sites in acidic porous scaffolds for the catalytic transformation of lignin-derived phenols to naphthenes.
The hydrodeoxygenation transformation of lignin-derived phenols provides an attractive pathway for the production of renewable biofuels; however, harsh process conditions strongly hinder its practical application. Herein, we report a porous metal silicate (PMS) material, PMS-36, which consists of metallic nickel and Lewis acid AlIII sites inside the pores, demonstrating high efficiency in catalyzing the hydrodeoxygenation transformation of guaiacol under mild conditions. PMS-36 also exhibits robust stability, which can be attributed to the strong interaction and charge transfer between metallic Ni and AlIII Lewis acid sites inside the confined pores. This study shows the importance of synergistic and confinement effects in developing high-performance and stable heterogeneous catalysts for the chemical transformation of biomass and its derivatives.


Neurologic manifestations in familial Mediterranean fever.
Neurologic involvement in children with familial Mediterranean fever is relatively uncommon and rarely described in the pediatric literature. Although headaches occur frequently, meningitis and convulsions are rare. Thirteen of 101 children with familial Mediterranean fever developed neurologic manifestations. Of these 13 patients, 10 had headaches during acute episodes of the fever. Two patients had convulsions with fever before the age of 5 years; the convulsions and acute episodes recurred at ages 9 and 10 years. Another patient had two episodes of aseptic meningitis followed by convulsive disorder before the diagnosis of familial Mediterranean fever was made; his convulsions were resistant to antiepileptic drugs alone and subsided only when colchicine was added. The possibility of neurologic involvement should be considered in patients with familial Mediterranean fever.


Effects of recurrent otitis media in infancy on auditory perception and speech.
Recurrent otitis media is commonly encountered in children before 3 years of age. Conductive hearing loss up to 40 dB is frequently associated with suppurative otitis media. Good hearing is believed to be critical to the development of normal language. This study was undertaken to evaluate the effect of recurrent otitis media on auditory perception and speech. The experimental group consisted of 33 children with a history of at least three episodes of acute otitis media before 2 years of age. A control group of 29 children experienced one or fewer episodes of otitis media in the first 2 years of age. At the time of investigation, all children were 8 to 10 years of age and had attended similar pre-school, kindergarten, and elementary school programs. None showed evidence of mental retardation nor behavioral or emotional disorders. Speech ability was assessed by a battery of tests specific for Slovene language. Subtests of the Wechsler Intelligence Scale for Children were used as well as the Reading and Writing Test. Auditory perception disorders were evident in 88% of children investigated who had a history of at least three episodes of otitis media by 2 years of age. Decreased auditory stimulation during the time of auditory maturation could prevent the development of these functions completely. No statistically significant differences were observed in the development of articulation. These observations underscore the importance of early management of recurrent otitis media during the first 2 years of age.


Effective adsorption and in-situ SERS detection of multi-target pesticides on fruits and vegetables using bead-string like Ag NWs@ZIF-8 core-shell nanochains.
In-situ, real-time and sensitive detection of multiple pesticide residues in food is always an important issue in food safety. Herein, a novel multifunctional bead-string like Ag nanowires@zeolitic imidazolate framework-8 (Ag NW@ZIF-8) core-shell nanochains was successfully synthesized and utilized as surface-enhanced Raman scattering (SERS) substrate for in-situ and simultaneous detection of pesticide residues. Due to the microporous framework structure of ZIF-8 shell and the plasmon property of Ag NWs core, the Ag NWs@ZIF-8 composite was demonstrated to have strong adsorption performance and high SERS activity (enhancement factor: 4.6 × 107). The Ag NWs@ZIF-8 based SERS strategy achieved sensitive detection of two water-insoluble pesticides methylparathion and carbaryl with detection limits as low as 7.6 × 10-9 M and 5.7 × 10-9 M, as well as the in-situ detection of multi-pesticide residues on fruits and vegetables with acceptable recovery ranged from 77.4 % to 117.5 %, demonstrating its great potential for in-situ and rapid detection of food contaminants.