Contrasting effects of aquatic subsidies on a terrestrial trophic cascade.
Subsidies from adjacent ecosystems can alter recipient food webs and ecosystem functions, such as herbivory. Emerging aquatic insects from streams can be an important prey in the riparian zone. Such aquatic subsidies can enhance predator abundances or cause predators to switch prey, depending on the herbivores. This can lead to an increase or decrease of in situ herbivores and herbivory. We examined the effects of aquatic subsidies on a simplified terrestrial food web consisting of two types of herbivores, plants and predators (spiders). In our six-week experiment, we focused on the prey choice of the spiders by excluding predator immigration and reproduction. In accordance with predator switching, survival of leafhoppers increased in the presence of aquatic subsidies. By contrast, the presence of aquatic subsidies indirectly reduced weevils and herbivory. Our study shows that effects of aquatic subsidies on terrestrial predators can propagate through the food web in contrasting ways. Thereby, the outcome of the trophic cascade is determined by the prey choice of predators.


Oral administration of pentachlorophenol induces interferon signaling mRNAs in C57BL/6 male mouse liver.
Pentachlorophenol (PCP) was monitored for transcriptome responses in adult mouse liver at 2, 4, 8 and 24 hr after a single oral administration at four dose levels, 0, 10, 30 and 100 mg/kg. The expression data obtained using Affymetrix GeneChip MOE430 2.0 were absolutized by the Percellome method and expressed as three dimensional (3D) surface graphs with axes of time, dose and copy numbers of mRNA per cell. We developed the programs RSort, for comprehensive screening of the 3D surface data and PercellomeExploror for cross-referencing and confirmed the significant responses by visual inspection. In the first 8 hr, approximately 100 probe sets (PSs) related to PXR/SXR and Cyp2a4 and other metabolic enzymes were induced whereas Fos and JunB were suppressed. At 24 hr, about 1,200 PSs were strongly induced. We cross-referenced the Percellome database consisting of 111 chemicals on the liver transcriptome and found that about half of the PSs belonged to the metabolic pathways including Nrf2-mediated oxidative stress response networks shared with some of the 111 chemicals. The other half of the induced genes were interferon signaling network genes (ISG) and their induction was unique to PCP. Toll like receptors and other pattern recognition receptors, interferon regulatory factors and interferon alpha itself were included but inflammatory cytokines were not induced. In summary, these data indicated that functional symptoms of PCP treatment, such as hyperthermia and profuse sweating might be mediated by the ISG rather than the previously documented mitochondrial uncoupling mechanism. PCP might become a hint for developing low molecular weight orally available interferon mimetic drugs following imiquimod and RO4948191 as agonists of toll-like receptor and interferon receptor.


Renal failure (chronic).
Continued progression of renal failure will lead to renal function too low to sustain healthy life. In developed countries, such people will be offered renal replacement therapy in the form of dialysis or renal transplantation. Requirement for dialysis or transplantation is termed end-stage renal disease (ESRD). We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments used to reduce progression rate of chronic renal failure? What are the effects of lifestyle changes used to reduce progression rate of chronic renal failure? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 44 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: angiotensin II receptor antagonists, angiotensin-converting enzyme (ACE) inhibitors (with or without angiotensin II receptor antagonists), exercise, erythropoiesis-stimulating agents, fibrates, lowering blood pressure below usual targets, nicotinates, psychoeducational intervention, smoking cessation, sodium (dietary), statins, structured programmes to achieve therapeutic goals, and targeted lowering of albuminuria/proteinuria.


A new use for an old tool: maternity waiting homes to improve equity in rural childbirth care. Results from a cross-sectional hospital and community survey in Tanzania.
Limited quality of childbirth care in sub-Saharan Africa primarily affects the poor. Greater quality is available in facilities providing advanced management of childbirth complications. We aimed to determine whether Maternity Waiting Homes (MWHs) may be a tool to improve access of lower socio-economic women to such facilities. Secondary analysis of a cross-sectional hospital survey from Iringa District, Tanzania was carried out. Women who delivered between October 2011 and May 2012 in the only District facility providing comprehensive Emergency Obstetric Care were interviewed. Their socio-economic profile was obtained by comparison with District representative data. Multivariable logistic regression was used to compare women who had stayed in the MWH before delivery with those who had accessed the hospital directly. Out of 1072 study participants, 31.3% had accessed the MWH. In multivariable analysis, age, education, marital status and obstetric factors were not significantly associated with MWH stay. Adjusted odds ratios for MWH stay increased progressively with distance from the hospital (women living 6-25 km, OR 4.38; 26-50 km, OR 4.90; >50 km, OR 5.12). In adjusted analysis, poorer women were more likely to access the MWH before hospital delivery compared with the wealthiest quintile (OR 1.38). Policy makers should consider MWH as a tool to mitigate inequity in rural childbirth care.


Erratum.
Figure 1 in the report "Ice nucleation by, alcohols arranged in monolayers at the surface of water drops" by M. Gavish et al. (16 Nov., p. 973) should have been credited to B. Kamb [in Structural Chemistry and Molecular Biology, A. Rich, Ed. (Freeman, New York, 1968), pp. 507-542, figure 3a].


A Strategy against the Osteonecrosis of the Jaw Associated with Nitrogen-Containing Bisphosphonates (N-BPs): Attempts to Replace N-BPs with the Non-N-BP Etidronate.
Bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) can occur when enhanced bone-resorptive diseases are treated with nitrogen-containing BPs (N-BPs). Having previously found, in mice, that the non-N-BP etidronate can (i) reduce the inflammatory/necrotic effects of N-BPs by inhibiting their intracellular entry and (ii) antagonize the binding of N-BPs to bone hydroxyapatite, we hypothesized that etidronate-replacement therapy (Eti-RT) might be useful for patients with, or at risk of, BRONJ. In the present study we examined this hypothesis. In each of 25 patients receiving N-BP treatment, the N-BP was discontinued when BRONJ was suspected and/or diagnosed. After consultation with the physician-in-charge and with the patient's informed consent, Eti-RT was instituted in one group according to its standard oral prescription. We retrospectively compared this Eti-RT group (11 patients) with a non-Eti-RT group (14 patients). The Eti-RT group (6 oral N-BP patients and 5 intravenous N-BP patients) and the non-Eti-RT group (5 oral N-BP patients and 9 intravenous N-BP patients) were all stage 2-3 BRONJ. Both in oral and intravenous N-BP patients (particularly in the former patients), Eti-RT promoted or tended to promote the separation and removal of sequestra and thereby promoted the recovery of soft-tissues, allowing them to cover the exposed jawbone. These results suggest that Eti-RT may be an effective choice for BRONJ caused by either oral or intravenous N-BPs and for BRONJ prevention, while retaining a level of anti-bone-resorption. Eti-RT may also be effective at preventing BRONJ in N-BP-treated patients at risk of BRONJ. However, prospective trials are still required.


CT colonography at different radiation dose levels: feasibility of dose reduction.
To investigate the sensitivity and specificity of polyp detection and the image quality of computed tomographic (CT) colonography at different radiation dose levels and to study effective doses reported in literature on CT colonography. CT colonography and colonoscopy were performed with 100 mAs in 50 consecutive patients at high risk for colorectal cancer; 50- and 30-mAs CT colonographic examinations were simulated with controlled addition of noise to raw transmission measurements. One radiologist randomly evaluated all original and simulated images for the presence of polyps and scored image quality. Differences in image quality were assessed with the Wilcoxon rank test. Scan protocols from the literature and recent (unpublished) updates were collected. In nine of 10 patients with polyps 5 mm in diameter or larger (sensitivity, 90%) and in seven of 17 patients with polyps smaller than 5 mm, polyps were correctly identified with CT colonography at all dose levels. Specificity for patients without polyps 5 mm or larger was 53%-60% at all dose levels and for patients without any polyps was 26% (at 100 and 50 mAs) and 48% (at 30 mAs). Image quality decreased significantly as the dose level decreased. The median effective doses (supine and prone positions) calculated from protocols reported in the literature and updates were 7.8 and 8.8 mSv, respectively. Although image quality decreases significantly at 30 mAs (3.6 mSv), polyp detection remains unimpaired. The median dose for CT colonography at institutions that perform CT colonographic research is currently 8.8 mSv.


Oxidized-LDL enhances coronary vasoconstriction by increasing the activity of protein kinase C isoforms alpha and epsilon.
Oxidized low-density lipoprotein (ox-LDL) plays a critical role in the development of atherosclerotic coronary vasospasm; however, the cellular mechanisms involved are not fully understood. We tested the hypothesis that ox-LDL enhances coronary vasoconstriction by increasing the activity of specific protein kinase C (PKC) isoforms in coronary smooth muscle. Active stress was measured in de-endothelialized porcine coronary artery strips; cell contraction and [Ca(2+)](i) were monitored in single coronary smooth muscle cells loaded with fura-2; and the cytosolic and particulate fractions were examined for PKC activity and reactivity with isoform-specific anti-PKC antibodies with Western blots. Ox-LDL (100 microgram/mL) caused slow but significant increases in active stress to 1.3+/-0.4x10(3) N/m(2) and cell contraction (10%) that were completely inhibited by GF109203X (10(-6) mol/L), an inhibitor of Ca(2+)-dependent and -independent PKC isoforms, with no significant change in [Ca(2+)](i). 5-Hydroxytryptamine (5-HT; 10(-7) mol/L) and KCl (24 mmol/L) caused increases in cell contraction and [Ca(2+)](i) that were inhibited by the Ca(2+) channel blocker verapamil (10(-6) mol/L). Ox-LDL enhanced coronary contraction to 5-HT and KCl with no additional increases in [Ca(2+)](i). Direct activation of PKC by phorbol 12-myristate13-acetate (PMA; 10(-7) mol/L) caused a contraction similar in magnitude and time course to ox-LDL-induced contraction and enhanced 5-HT- and KCl-induced contraction with no additional increases in [Ca(2+)](i). The ox-LDL-induced enhancement of 5-HT and KCl contraction was inhibited by Gö6976 (10(-6) mol/L), an inhibitor of Ca(2+)-dependent PKC isoforms. Both ox-LDL and PMA caused an increase in PKC activity in the particulate fraction, a decrease in the cytosolic fraction, and an increase in the particulate/cytosolic PKC activity ratio. Western blots revealed the Ca(2+)-dependent PKC-alpha and the Ca(2+)-independent PKC-delta, -epsilon, and -zeta isoforms. In unstimulated tissues, PKC-alpha- and -epsilon were mainly cytosolic, PKC-delta was mainly in the particulate fraction, and PKC-zeta was equally distributed in the cytosolic and particulate fractions. Ox-LDL alone or PMA alone caused translocation of PKC-epsilon from the cytosolic to particulate fraction, whereas the distribution pattern of PKC-alpha, -delta, and -zeta remained unchanged. 5-HT (10(-7) mol/L) alone and KCl alone did not change PKC activity. In tissues pretreated with ox-LDL or PMA, 5-HT and KCl caused additional increases in PKC-alpha activity. Native LDL did not significantly affect coronary contraction, [Ca(2+)](i), or PKC activity. These results suggest that ox-LDL causes coronary contraction via activation of the Ca(2+)-independent PKC-epsilon and enhances the contraction to [Ca(2+)](i)-increasing agonists by activating the Ca(2+)-dependent PKC-alpha. Activation of PKC-alpha and -epsilon may represent a possible cellular mechanism by which ox-LDL could enhance coronary vasospasm.


Telomere and telomerase in chronic liver disease and hepatocarcinoma.
The pathogenesis of liver cirrhosis is not completely elucidated. Although in the majority of patients, the risk factors may be identified in B and C viral hepatitis, alcohol intake, drugs or fatty liver disease, there is a small percentage of patients with no apparent risk factors. In addition, the evolution of chronic liver disease is highly heterogeneous from one patient to another. Among patient with identical risk factors, some rapidly progress to cirrhosis and hepatocellular carcinoma (HCC) whereas others have a benign course. Therefore, a genetic predisposition may contribute to the development of cirrhosis and HCC. Evidence supporting the role of genetic factors as a risk for cirrhosis has been accumulating during the past years. In addition to the results from epidemiological studies, polymorphisms studies and data on twins, the concept of telomere shortening as a genetic risk factor for chronic liver disease and HCC has been proposed. Here we review the literature on telomerase mutations, telomere shortening and liver disease including hepatocellular carcinoma.


Azithromycin, cardiovascular risks, QTc interval prolongation, torsade de pointes, and regulatory issues: A narrative review based on the study of case reports.
Over the past year, three articles have appeared in the New England Journal of Medicine describing conflicting findings about azithromycin and cardiac safety, particular azithromycin-induced QTc interval prolongation and torsade de pointes. The FDA wants healthcare providers to consider azithromycin-induced fatal cardiac arrhythmias for patients already at risk for cardiac death and other potentially arrhythmogenic cardiovascular conditions. In a systematic review of case reports we sought to determine factors that link to azithromycin-induced/associated QTc interval prolongation and torsade de pointes. We found 12 cases: seven female and five male. Of the nine adults with reported azithromycin doses, concurrent QTc interval measurement, and without congenital long QT syndrome, we found no significant relationship between dose and QTc interval duration. Additional risk factors were female sex, older age, heart disease, QTc interval prolonging drugs and metabolic inhibitors, hypokalemia, and bradycardia. All 12 subjects had at least two additional risk factors. Elderly women with heart disease appear to be at particularly risk for drug-related QTc interval prolongation and torsade de pointes.


Estimating the impacts of conservation on ecosystem services and poverty by integrating modeling and evaluation.
Scholars have made great advances in modeling and mapping ecosystem services, and in assigning economic values to these services. This modeling and valuation scholarship is often disconnected from evidence about how actual conservation programs have affected ecosystem services, however. Without a stronger evidence base, decision makers find it difficult to use the insights from modeling and valuation to design effective policies and programs. To strengthen the evidence base, scholars have advanced our understanding of the causal pathways between conservation actions and environmental outcomes, but their studies measure impacts on imperfect proxies for ecosystem services (e.g., avoidance of deforestation). To be useful to decision makers, these impacts must be translated into changes in ecosystem services and values. To illustrate how this translation can be done, we estimated the impacts of protected areas in Brazil, Costa Rica, Indonesia, and Thailand on carbon storage in forests. We found that protected areas in these conservation hotspots have stored at least an additional 1,000 Mt of CO2 in forests and have delivered ecosystem services worth at least $5 billion. This aggregate impact masks important spatial heterogeneity, however. Moreover, the spatial variability of impacts on carbon storage is the not the same as the spatial variability of impacts on avoided deforestation. These findings lead us to describe a research program that extends our framework to study other ecosystem services, to uncover the mechanisms by which ecosystem protection benefits humans, and to tie cost-benefit analyses to conservation planning so that we can obtain the greatest return on scarce conservation funds.


Nestin expression during differentiation of fetal endothelial progenitor cells and hypoxic culture of human umbilical vein endothelial cells.
The aim of this study was to assess whether nestin is expressed during differentiation of endothelial progenitor cells (EPCs) obtained from human umbilical cord blood (HUCB), and nestin expression is changed in hypoxia-conditioned culture of human umbilical vein endothelial cells (HUVECs). Among deliveries at our institute, 20 normal pregnant women who delivered by cesarean section at 37-40 weeks' gestation were selected. HUCB mononuclear cells (MNCs) from HUCB were isolated and cultivated. After characterization of CXCR4/KDR/CD34 positive cells (EPCs) by flow cytometry and fluorescent chemical staining, EPC culture was continued through day 10 for differentiation to outgrowth endothelial cell (OEC). For identification of EPC and OEC, RT-PCR was performed for each specific cell markers, such as AC133, CD45, CXCR4, CDH5, vWF, eNOs, CD34, and Flt 1. HUVECs were isolated from human umbilical cord veins by collagenase treatment. Culture of HUVEC in hypoxic and normoxic conditions was performed for 24 h. Nestin expression in EPCs, OECs and HUVECs was detected by RT-PCR and Western blotting. Western blot analysis and RT-PCR revealed that nestin was not expressed in EPC, but well expressed in OECs and HUVECs. During 24 h of HUVEC culture, time course gene expression of VEGF was significantly increased, but nestin was not changed. Our results showed that nestin could be used as a new differentiation marker of EPCs, and hypoxic stimuli did not directly affect nestin gene expression.


DDT: interaction with nerve membrane conductance changes.
The falling phase of action potentials of lobster giant axons is prolonged by DDT; finally a plateau phase is produced like cardiac action potentials. In axons poisoned with DDT, peak transient (sodium) currents associated with step depolarizations are turned off very slowly, and steady-state (potassium) currents are markedly suppressed. These two changes would cause the prolongation of action potentials and are considered the major ionic mechanisms of DDT action.


Influence of manual therapy on functional mobility after joint injury in a rat model.
Animal models can be used to investigate manual therapy mechanisms, but testing manipulation in animal models is problematic because animals cannot directly report their pain. To develop a rat model of inflammatory joint injury to test the efficacy of manual therapy in reducing nociception and restoring function. The authors induced acute inflammatory joint injury in rats by injecting carrageenan into the ankle and then measured voluntary running wheel activity in treated and untreated rats. Treatments included manual therapy applied to the ankle and knee of the injured limb and several analgesic medications (eg, morphine, ketorolac, prednisone). Intra-articular injection of carrageenan to the ankle produced significant swelling (diameter of the ankle increased by 64% after injection; P=.004) and a robust reduction in voluntary running wheel activity (running distance reduced by 91% compared with controls; P<.001). Injured rats gradually returned to running levels equal to controls over 10 days. Neither manual therapy nor analgesic medications increased running wheel activity relative to untreated rats. Voluntary running wheel activity appears to be an appropriate functional measure to evaluate the impact of an acute inflammatory joint injury. However, efforts to treat the injury did not restore running relative to untreated rats.


Epoetin alfa offers clinically significant improvements in the quality of life of anaemic cancer patients.
Anaemia is a common problem for cancer patients and often causes fatigue and reduces quality of life (QoL). Although randomised trials have repeatedly shown that treatment with epoetin alfa raises haemoglobin levels, reduces fatigue and improves overall QoL, such findings may be hard to put into a clinical context and, as a result, cancer-related fatigue remains undertreated. This study gathered data using the FACT-An QoL scale from 1400 people on an internet survey panel. The 1400 were randomly selected and chosen to be representative of the total US population. Survey results were then compared with the findings from a large placebo-controlled study involving 375 anaemic cancer patients. FACT-An showed good psychometric properties in the survey population and was able to distinguish respondents with histories of anaemia and cancer from those without. Comparing the population norm values for FACT-An with the trial data showed that treatment with epoetin alfa led to clinically meaningful improvements in cancer patients' QoL.


Implications of optical properties of ocean, lake, and ice for ultrahigh-energy neutrino detection.
The collecting power and imaging ability of planned ultrahigh-energy neutrino observatories depend on wavelength-dependent absorption and scattering coefficients for the detector medium. Published data are compiled for deep ice at the South Pole, for deep fresh water at Lake Baikal, and for deep seawater. The effective scattering coefficient is smallest for the clearest deep ocean sites, whereas the absorption coefficient is an order of magnitude smaller for deep ice than for the ocean and lake sites. The effective volume per detector element as a function of energy is calculated for electromagnetic cascades produced by electron neutrinos interacting at the various sites. It is largest for deep bubble-free ice, smallest for shallow bubbly ice, and intermediate for lake and seawater. The effective volume per element is calculated for detection of positrons resulting from the capture of a few megaelectron volt supernova neutrinos by protons in the medium. This volume is proportional to the absorption length and independent of the scattering length; it is larger for ice than for seawater or lake water.


Risk factors for development of nontyphoid Salmonella bacteremia.
The objective of this paper was to identify risk factors for nontyphoid Salmonella bacteremia by making a retrospective chart review of 39 patients with nontyphoid Salmonella bacteremia. The control group included 30 patients with positive Salmonella stool culture (gastroenteritis group). Demographic factors, presenting signs and symptoms, antimicrobial treatment before admission, and microbiologic results were recorded. Nine patients (23%) were excluded owing to recognized risk factors for development of extraintestinal disease. Seventeen cases (57%) occurred during summer time, whereas the gastroenteritis group had a less seasonal tendency. Eighty percent of the patients with Salmonella bacteremia had a previous history of diarrhea. At admission more patients in the bacteremia group were febrile and had leukocytosis (73% vs 33% and 37% vs 20%, respectively). More patients in the bacteremia group had previous antibiotic treatment (57% vs 20%, p<0.01). The Salmonella types were mainly C and D in the bacteremia group (40% each), and B and C in the gastroenteritis group (26% and 52%, respectively). The risk factors for Salmonella bacteremia in previously healthy children include warm season, previous gastrointestinal illness, and preexposure to antibiotics.


Leiomyosarcoma of bone. A clinicopathologic, immunohistochemical, and ultrastructural study of five cases.
The authors identified five leiomyosarcomas (LMS) in a review of 13 nonmatrix-producing spindle cell sarcomas of bone. Only two were initially recognized as LMS; the others had been diagnosed as malignant fibrous histiocytoma (two) and fibrosarcoma (one). The patients, four of whom were women, ranged in age from 32 to 70 years. Sites included proximal humerus (two), distal femur (two), and rib (one). All tumors presented with clinical and radiographic features consistent with a diagnosis of primary bone neoplasms, although one probably represented a solitary metastasis from a primary uterine LMS. Radiographs showed lytic bone destruction with a moth-eaten appearance, and three cases had soft tissue extension. Histologically, all tumors showed broad, interlacing fascicles of spindle cells with pleomorphic nuclei, frequent mitoses, and necrosis. Two cases had a focal storiform pattern and bizarre multinucleated cells, and two other cases had focally prominent osteoclast-like giant cells. Extensive immunoreactivity for muscle actin was seen in all cases and for desmin in three. In each case, electron microscopy showed definite smooth muscle differentiation including cytoplasmic filaments with densities. At this writing, two patients are free of disease (including the patient with a presumed metastasis), one is alive with locally recurrent disease, and two are dead of disease. Experience suggests that LMS of bone is a distinct clinicopathologic entity that may be more common than previously recognized. Application of immunohistochemistry and electron microscopy to nonmatrix-producing bone sarcomas should facilitate diagnosis of additional cases.


The psychological harms of screening: the evidence we have versus the evidence we need.
Systematic reviews for the US Preventive Services Task Force have found less high-quality evidence on psychological than physical harms of screening. To understand the extent of evidence on psychological harms, we developed an evidence map that quantifies the distribution of evidence on psychological harms for five adult screening services. We also note gaps in the literature and make recommendations for future research. We systematically searched PubMed, PsycInfo, and CINAHL from 2002 to 2012 for studies of any research design that assessed the burden or frequency of psychological harm associated with screening for: prostate and lung cancers, osteoporosis, abdominal aortic aneurysm (AAA) and carotid artery stenosis (CAS). We also searched for studies that estimated rates of overdiagnosis (a marker for unnecessary labeling). We included studies published in English and used dual independent review to determine study inclusion and to abstract information on design, types of measures, and outcomes assessed. Sixty-eight studies assessing psychological harms met our criteria; 62 % concerned prostate cancer and 16 % concerned lung cancer. Evidence was scant for the other three screening services. Overall, only about one-third of the studies used both longitudinal designs and condition-specific measures (ranging from 0 % for AAA and CAS to 78 % for lung cancer), which can provide the best evidence on harms. An additional 20 studies that met our criteria estimated rates of overdiagnosis in lung or prostate cancer. No studies estimated overdiagnosis for the non-cancer screening services. Evidence on psychological harms varied markedly across screening services in number and potential usefulness. We found important evidence gaps for all five screening services. The evidence that we have on psychological harms is inadequate in number of studies and in research design and measures. Future research should focus more clearly on the evidence that we need for decision making about screening.


Design and characterization of a multimeric DNA binding protein using Sac7d and GCN4 as templates.
The protein Sac7d belongs to a class of small chromosomal proteins from the hyperthermophilic archaeon Sulfolobus acidocaldarius. Sac7d is extremely stable to heat, acid, and chemical agents. This protein is a monomer and it binds DNA without any particular sequence preference, while inducing a sharp kink in the DNA. By appending a leucine-zipper-like helical peptide derived from the yeast transcriptional activator GCN4 to the C-terminal end of Sac7d, the modified monomers (denoted S7dLZ) are expected to interact with each other via hydrophobic force to form a parallel dimer. The recombinant S7dLZ was expressed in Escherichia coli and purified by heating and ion-exchange chromatography. The formation of dimer was detected by gel-filtration chromatography and chemical cross-link. The results of surface plasmon resonance and circular dichroism experiments showed that the DNA-binding capacity was retained. Furthermore, X-ray diffraction analysis of single crystals of S7dLZ in complex with DNA decamer CCTATATAGG showed that the leucine-zipper segments of S7dLZ were associated into an antiparallel four-helix bundle. There are two DNA fragments bound to each S7dLZ tetramer in the crystal. This model works as a successful template that endows protein a new function without losing original properties.


Daycase trauma list: a safe and cost-effective service delivery.
Daycase trauma surgery is an evolving and a novel approach. The aim of our study was to report our experience of daycase trauma surgery with a focus on safety, patient experience, complications and limitations. Patients scheduled and operated on a daycase trauma list from January 2013 to December 2016 were included in the study. Age, sex, case mix, readmissions within 48 hours, complications, patient satisfaction, reasons for overnight stay and cost effectiveness were evaluated. A total of 229 procedures were carried out. The mean age of the patients was 44.3 years (range 16-85 years) . There were 128 men and 101 women, 178 upper-limb and 51 lower-limb cases. Only 2.6% of the patients had stayed overnight for pain control, physiotherapy and neurological observations; 94.5% of the patients were satisfied. The mean visual analogue scale score for satisfaction was 8.7. There were no admissions within 48 hours of discharge and one complication with failure of ankle fixation. The estimated cost saving was £65,562. We conclude that a daycase trauma service is safe, cost effective, and yields high patient satisfaction. It reduces the burden on hospital beds and a wide range of upper- and lower-limb cases can be performed as daycase trauma surgery with adequate planning and teamwork.


The multiple origins of aluminium resistance in hexaploid wheat include Aegilops tauschii and more recent cis mutations to TaALMT1.
Acid soils limit plant production worldwide because their high concentrations of soluble aluminium cations (Al(3+) ) inhibit root growth. Major food crops such as wheat (Triticum aestivum L.) have evolved mechanisms to resist Al(3+) toxicity, thus enabling wider distribution. The origins of Al(3+) resistance in wheat are perplexing because all progenitors of this hexaploid species are reportedly sensitive to Al(3+) stress. The large genotypic variation for Al(3+) resistance in wheat is largely controlled by expression of an anion channel, TaALMT1, which releases malate anions from the root apices. A current hypothesis proposes that the malate anions protect this sensitive growth zone by binding to Al(3+) in the apoplasm. We investigated the evolution of this trait in wheat, and demonstrated that it has multiple independent origins that enhance Al(3+) resistance by increasing TaALMT1 expression. One origin is likely to be Aegilops tauschii while other origins occurred more recently from a series of cis mutations that have generated tandemly repeated elements in the TaALMT1 promoter. We generated transgenic plants to directly compare these promoter alleles and demonstrate that the tandemly repeated elements act to enhance gene expression. This study provides an example from higher eukaryotes in which perfect tandem repeats are linked with transcriptional regulation and phenotypic change in the context of evolutionary adaptation to a major abiotic stress.


In-Hospital Mortality in Cirrhotic Patients with End-Stage Renal Disease Treated with Hemodialysis Versus Peritoneal Dialysis: A Nationwide Study.
Cirrhotic patients often develop end-stage renal disease (ESRD) requiring renal replacement therapy in the form of hemodialysis (HD) or peritoneal dialysis (PD). Studies comparing the outcomes and difference in in-hospital mortality between these 2 groups, particularly among those with ascites, are sparse. We set our objective to determine the dialysis modality with a better in-hospital survival rate among cirrhotic patients with ESRD (ESRD-cirrhosis). Data was extracted from the 2005 to 2012 Nationwide Inpatient Sample (NIS). Using propensity score matching, ESRD-cirrhosis patients on PD were matched with patients on HD at a 1:1 ratio. Another subgroup analysis of ESRD-cirrhosis patients with ascites was performed using the same matching algorithm. Analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC, USA). Among 26,135 cirrhotic patients with incident ESRD, 25,686 (98.3%) and 449 (1.7%) were initiated on HD and PD, respectively, during the hospitalization. There was a nonsignificant mortality difference between the ESRD-cirrhosis patients treated with PD and those treated with HD. In a subgroup analysis of these patients with ascites, 18 patients underwent PD while 1,878 patients required HD. Also, PD had a significantly lower in-hospital mortality compared with HD in this subgroup (0% vs 26.67%, p = 0.03). Mean length of stay for those who received HD was 8.34 days compared with 7.06 days for the PD group (p < 0.0001). Similarly, mean hospital charges were greater for those who had HD compared with PD ($74,501 vs $57,460; p < 0.001). Cirrhotic patients with ESRD and ascites who undergo PD have a significantly lower mortality than those who are started on HD. However PD is rarely initiated for ESRD in cirrhotic patients with ascites during hospitalization in the United States. Due to the potential advantages of PD, nephrologists should encourage PD when selecting dialysis modality in this subgroup of patients whenever possible.


Management of Complications after Levator Resection for Ptosis.
To analyse the complications after external levator resection (ELR) for ptosis, and their management. Observational Study. Place and Duration of the Study: Mughal Eye Hospital Trust, Lahore, from June 2018 to December 2022. A total of 256 eyes were operated for ptosis cases having good levator function who were treated by ELR. The exclusion criteria was any history of operation of lids or orbits or poor levator function, Marcus Gunn jaw-winking phenomenon, and neurogenic ptosis. The frequency of complications and their management was documented. Age ranged from 6 to 65 years. The follow-up ranged from 8 weeks to 3 years. Eleven (4.3%) cases developed complications. Two cases had mild undercorrection and did not require any treatment. In moderate overcorrection encountered in one eye, pulling the lid down for a few times daily improved lid level in four weeks. Four eyes had severe overcorrection, 2 patients required one operation and the other two patients required two operations each. These included hang-back sutures in two eyes (with 5/O Ethibond in one eye and 6/O Vicryl sutures in another eye) and simple incision in the levator (disinserting it partially from the tarsal plate) in two eyes. Lagophthalmos in two eyes improved with conservative treatment. Notching in two eyes improved with partial disinsertion of levator by cutting one Vicryl suture attaching levator to the tarsal plate and leaving 2 Vicryl sutures connecting levator to the tarsal plate. Ptosis correction by ELR is a low-complication procedure with good corrective results. Ptosis, Good levator function, Overcorrection after ptosis operation, Hang-back sutures, Partial levator disinsertion.


Painful sex (dyspareunia) in women: prevalence and associated factors in a British population probability survey.
To estimate the prevalence of painful sex among women in Britain, and to explore associated sexual, relationship and health factors that should be considered in assessment. Multi-stage, clustered and stratified population probability sample survey, using computer-assisted self-interview. Sample frame was the British Postcode Address File. Participants interviewed at home between 2010 and 2012. A total of 15 162 adults aged 16-74 years (8869 women). Data reported from 6669 sexually active women. Age-adjusted logistic regressions to examine associations between painful sex and indicators of sexual, relational, mental and physical health. Physical pain as a result of sex for ≥3 months in the past year, plus measures of symptom severity. Painful sex was reported by 7.5% (95% CI 6.7-8.3) of sexually active women, of whom one-quarter experienced symptoms very often or always, for ≥6 months, and causing distress. Reporting painful sex was strongly associated with other sexual function problems, notably vaginal dryness (age adjusted odds ratio 7.9; 6.17-10.12), anxiety about sex (6.34; 4.76-8.46) and lacking enjoyment in sex (6.12; 4.81-7.79). It was associated with sexual relationship factors [such as not sharing same level of interest in sex (2.56; 1.97-3.33)], as well as with adverse experiences such as non-volitional sex (2.17; 1.68-2.80). Associations were also found with measures of psychological and physical health, including depressive symptoms (1.68; 1.28-2.21). Painful sex is reported by a sizeable minority of women in Britain. Health professionals should be supported to undertake holistic assessment and treatment which takes account of the sexual, relationship and health context of symptoms. Painful sex-reported by 7.5% of women in Britain-is linked to poorer sexual, physical, relational and mental health.


UPLC-QTOF-MS identification of metabolites in rat biosamples after oral administration of Dioscorea saponins: a comparative study.
Among the 49 species of the genus Dioscorea distributed in China, Dioscorea nipponica Makino (DN), Dioscorea panthaica Prain et Burkill (DP), and Dioscorea zingiberensis C. H. Wright (DZ) possess more or less similar traditional therapeutic actions, such as activating blood, relieving pain, and dispersing swelling; they have been used as folk medicine in China since 1950s. The modern pharmaceutical industry has developed these three species as herbal medicines that have been used for decades for treating cardiovascular diseases. However, there is no available information in the literature explaining how their chemical components are converted and interrelated in vivo to support their efficacies. The present study aimed to a) compare the metabolic profiles of saponins from DN, DP and DZ, which are considered to be their bioactive components, and b) to compare the changes in sustained levels of metabolites from rat biosamples. Total saponins (TS) from each of the three species, and four individual saponins, namely protodioscin (PD), pseudoprotodioscin (PSD), dioscin (DC) and diosgenin (DG), were given to rats by oral administration. Chemical profiles of the rats' plasma, urine and feces were monitored 1-36 h. A UPLC-QTOF-MS based method was performed to identify the absorbed constituents and their metabolic products in rat biosamples (i.e., blood, urine, and feces); the ratio of peak area of major saponins to that of internal standard was calculated and plotted versus time to characterize the sustained levels of saponins in biosamples. Totally 10 saponin-related compounds were detected in rat plasma, 10 in rat urine and 18 in rat feces. The results indicated that formation of diosgenin by desugarization was the main pathway by which steroidal glycosides were metabolized. Other types of bio-transformation were found among glycosides and aglycones, such as ring cyclization through loss of 26-O-glucosyl, substitution of β-D-glucopyranosyl for α-L-rhamnopyrannosyl, hydrogenation of diosgenin at 5(6)-double bond, and hydration of 20(22)-double bond. Generally, the metabolic profiles of DN and DP were shown to be quite similar, but different from that of DZ. However, some particular similarities and connections were found among these three TS. Diosgenin was one of the main metabolites commonly found in plasma and feces (excluding urine), from all groups receiving different TS, as well as individual saponins; this is likely to be one of the bioactive constituents playing an essential role in cardioprotective efficacy. Furostane-type saponins in TS of DN, DP or DZ, such as PD, protogracillin, parvifloside, protodeltonin and protobioside, showed fast absorption into blood (<1h), but were maintained for a relatively short period (mostly<8h), while the spirostane-type saponin and sapogenin (DC and DG, respectively), were absorbed into circulation more slowly (>1h), but increased gradually and lasted longer (>36h). These two patterns suggest that the therapeutic effect of these Dioscorea saponins is achieved through a complex, multi-step process over time. In addition, it appears that PD, PSD, and DC contained in DN and DP were transformed into certain glycosides originally found in DZ but not in DN or DP (protodeltonin, deltonin, trillin, and progenin II), which might indicate another linkage among these three species. These similarities and connections described above constitute evidence supporting similarity in efficacy of these three herbs from the perspective of metabolism. The UPLC-QTOF-MS based method is accurate and efficient for analyzing metabolic changes in rat biosamples over time.


Multidisciplinary Frontotemporal Orbitozygomatic Craniotomy for Spheno-orbital Meningiomas: Ophthalmic and Orbital Outcomes.
Advances in surgical approaches have improved access for total or near-total resection of spheno-orbital meningiomas (SOM). Herein, the outcomes of multidisciplinary resection and reconstruction of SOM via frontotemporal orbitozygomatic craniotomy at a single institution are evaluated. A retrospective chart review was performed of all patients with SOM who underwent joint neurosurgical and oculofacial plastic resection via frontotemporal orbitozygomatic craniotomy between January 1999 and December 2018. Demographic data, clinical presentation, risk factors for meningioma, radiographic imaging, pathology results, postoperative outcomes, and surgical complications were reviewed. The outcome measures assessed included visual acuity, pupillary function, color vision, ocular motility, visual fields, and proptosis. A total of 48 patients were identified having had multidisciplinary frontotemporal orbitozygomatic craniotomy for SOM of which 43 met inclusion criteria. A mean follow-up period of 23.9 ± 20.4 months (range 1-60) was observed. There were 35 patients who underwent primary resection and 8 patients who had prior surgical resection. The main presenting complaints were proptosis (88%), headache (44%), and reduced vision (12%). Gross total resection was achieved in 15 patients (35%) while near-total or subtotal resection was achieved in the remainder. Histologic analysis revealed World Health Organization grade I meningioma in 72% of tumors, grade II in 23%, and grade III in 5%. Mean visual acuity (Logarithm of the Minimum Angle of Resolution) improved from 0.24 ± 0.46 preoperatively to 0.09 ± 0.13 postoperatively (p = 0.03). Surgery improved proptosis, with a reduction in mean Hertel exophthalmometry from 22.37 ± 3.78 mm to 17.91 ± 3.84 mm (p < 0.001), of which 80% had no residual proptosis or developed subsequent recurrence. Exophthalmic index calculated by radiologic evaluation also improved from a mean preoperative value of 1.32 ± 0.19 to 1.12 ± 0.13 at the 6-month interval after surgery (p < 0.001). Before surgery, 19 (45%) patients had a relative afferent pupillary reaction with improvement in 9 (24%) after surgery. Of the 14 (33%) patients with preoperative ocular motility deficit, 7 (16%) had resolution of ocular motility deficit postoperatively. The most common surgical complications were temporalis muscle atrophy with temporal hollowing (14%), wound infection (7%), neurogenic strabismus secondary to trochlear nerve palsy (5%), restrictive strabismus (5%), and aponeurotic blepharoptosis (5%). Multidisciplinary frontotemporal orbitozygomatic for resection of SOM is a safe and effective means of tumor removal. It can provide improved visual acuity and proptosis metrics, as well as relief of optic neuropathy and ocular motility deficits.


Spin-Correlated Radical Pairs as Quantum Sensors of Bidirectional ET Mechanisms in Photosystem I.
Following light-generated electron transfer reactions in photosynthetic reaction center proteins, an entangled spin qubit (radical) pair is created. The exceptional sensitivity of entangled quantum spin states to weak magnetic interactions, structure, and local environments was used to monitor the directionality of electron transfer in Photosystem I (PSI). Electron paramagnetic resonance (EPR) spectra of radical pairs formed via each symmetric branch of cofactors, A or B, exhibit distinctive line shapes. By photochemical reduction and biochemical modification of PSI we created samples where the radical pair(s) from (1) only A branch, (2) only B branch, or (3) both A and B branches are detectable. These PSI samples were used to analyze the asymmetry of electron transfer as a function of temperature, freezing condition, and temperature cycling. The temperature dependency agrees with a dynamic model in which the conformational states of the protein regulate the directionality of electron transfer. High spectral resolution afforded by high-frequency (130 GHz) EPR, combined with extra resolution afforded by deuterated proteins, provides new mechanistic insight via structural and environmental sensitivity of the entangled electron spins of photogenerated radical pairs.


[Cognitive screening test: short and long version].
Three versions of the Cognitive Screening Test (CST), varying in length from seven to 20 items, are compared using the original data. The shortest version, the CST-7, is not inferior to the longer CST-14 and CST-20. Various psychometric properties are compared. According to the Mokken nonparametric IRT scaling technique, all three CST versions can be considered unidimensional. The Mokken scaling indices H and rho hardly differ in the three versions of the CST. The alpha indices from Classical Test Theory are also very comparable, as is the very good sensitivity and specificity (around 95%). Age and gender have no significant effect on the classification success of the CST-7. Cross-validation of the promising properties of this very short screening instrument is recommended.


Ring closing metathesis reactions of α-methylene-β-lactams: application to the synthesis of a simplified phyllostictine analogue with herbicidal activity.
Ring closing metathesis (RCM) reactions of α-methylene-β-lactams are used to construct strained 11- and 12-membered macrocycles that mimic key structural elements of phyllostictine A. The highest yield and stereoselectivity was achieved making 12-membered macrocycle Z-19 with use of a p-methoxyphenyl group on the lactam nitrogen. Interestingly, substrate concentration had an important influence on the stereochemical course of the reaction. A simplified analogue produced using this approach displays phytotoxic activity against Chlamydomonas reinhardtii suggesting that the α-methylene-β-lactam subunit is responsible, at least in part, for the herbicidal activity of phyllostictine A.


Perioperative surgical complications and learning curve associated with minimally invasive transforaminal lumbar interbody fusion: a single-institute experience.
As surgical complications tend to occur more frequently in the beginning stages of a surgeon's career, knowledge of perioperative complications is important to perform a safe procedure, especially if the surgeon is a novice. We sought to identify and describe perioperative complications and their management in connection with minimally invasive transforaminal lumbar interbody fusion (TLIF). We performed a retrospective chart review of our first 124 patients who underwent minimally invasive TLIF. The primary outcome measure was adverse events during the perioperative period, including neurovascular injury, implant-related complications, and wound infection. Pseudarthroses and adjacent segment pathologies were not included in this review. Adverse events that were not specifically related to spinal surgery and did not affect recovery were also excluded. Perioperative complications occurred in 9% of patients (11/124); including three cases of temporary postoperative neuralgia, two deep wound infections, two pedicle screw misplacements, two cage migrations, one dural tear, and one grafted bone extrusion. No neurologic deficits were reported. Eight complications occurred in the first one-third of the series and only 3 complications occurred in the last two-thirds of the series. Additional surgeries were performed in 6% of patients (7/124); including four reoperations (two for cage migrations, one for a misplaced screw, and one for an extruded graft bone fragment) and three hardware removals (one for a misplaced screw and two for infected cages). We found perioperative complications occurred more often in the early period of a surgeon's experience with minimally invasive TLIF. Implant-related complications were common and successfully managed by additional surgeries in this series. We suggest greater caution should be exercised to avoid the potential complications, especially when surgeon is a novice to this procedure.


Temperament clusters in a normal population: implications for health and disease.
The object of this study was to identify temperament patterns in the Finnish population, and to determine the relationship between these profiles and life habits, socioeconomic status, and health. A cluster analysis of the Temperament and Character Inventory subscales was performed on 3,761 individuals from the Northern Finland Birth Cohort 1966 and replicated on 2,097 individuals from the Cardiovascular Risk in Young Finns study. Clusters were formed using the k-means method and their relationship with 115 variables from the areas of life habits, socioeconomic status and health was examined. Four clusters were identified for both genders. Individuals from Cluster I are characterized by high persistence, low extravagance and disorderliness. They have healthy life habits, and lowest scores in most of the measures for psychiatric disorders. Cluster II individuals are characterized by low harm avoidance and high novelty seeking. They report the best physical capacity and highest level of income, but also high rate of divorce, smoking, and alcohol consumption. Individuals from Cluster III are not characterized by any extreme characteristic. Individuals from Cluster IV are characterized by high levels of harm avoidance, low levels of exploratory excitability and attachment, and score the lowest in most measures of health and well-being. This study shows that the temperament subscales do not distribute randomly but have an endogenous structure, and that these patterns have strong associations to health, life events, and well-being.


Evaluation of the move to remote delivery of drug and alcohol services during the COVID-19 pandemic: A study protocol.
Substance misuse is a significant global health concern. In the UK, the prevalence of substance misuse has increased over the past decade and the number of alcohol and drug related deaths are increasing. Individuals with substance dependency issues are entitled to access treatment services. However, the COVID-19 pandemic created significant challenges for public services, including drug and alcohol treatment, and resulted in significant service reconfiguration and a shift from in-person to remote delivery. This study aims to evaluate the delivery of drug and alcohol services in a large metropolitan area in Northern England during the COVID-19 pandemic. It aims to understand the impact of service reconfiguration for services, staff and service users, and to use this understanding to inform the future optimised design of services. The study has five workstreams within a mixed methods framework: (1) Systematic review of literature; (2) Qualitative process evaluation with service providers (digital timelines, focus groups and interviews); (3) Qualitative process evaluation with service users (interviews, focus groups, text based conversations and case studies); (4) Quantitative outcomes and health economic analysis; and (5) Data synthesis and dissemination. The breadth of the study, its novel nature, and the importance of substance misuse as a public health issue, mean that this study will provide valuable findings for those who commission, deliver and use drug and alcohol treatment services nationally and internationally. There will also be important learning for the effective remote delivery of services in sectors beyond drug and alcohol treatment.


Recent advances in the study of candidate genes for adolescent idiopathic scoliosis.
We used a microarray approach to evaluate gene expression profiles in human AIS osteoblasts, and to identify genes that are differentially expressed following estrogen exposure in non-AIS and AIS human osteoblasts. We found that more than one gene is likely responsible for AIS. Furthermore, some of these genes are estrogen-regulated, suggesting a possible role of estrogens in the etiology of scoliosis.


Reduced glomerular hypertrophy by somatostatin analog, SMS 201-995, in the subtotal nephrectomized rats fed high-protein meals.
The chronic effects of SMS 201-995 (SMS), a long-acting somatostatin analog, on the progression of renal failure in 3/4 subtotal nephrectomized rats (NPX) fed high protein meals (40% protein) were investigated. Rats were divided into four groups, [i.e., normal control (C) (n = 6), NPX control (NPX-C) (7), NPX treated with SMS 1.0 micrograms/day (SMS-1.0) (7) and SMS-10.0 (7)]. SMS was continuously administered s.c. via an osmotically driven pump for 8 weeks. SMS had no significant changes in either body weight or hematocrit levels for NPX groups. Systolic blood pressure in NPX rats showed similar elevations, but SMS had no distinct effect on it for them. Significant changes in urine volume, creatinine clearance, and urinary protein excretion were not obtained among the NPX rats. No significant changes of glomerular sclerosis index was found among the NPX rats. Mean planar area of glomeruli in NPX rats was significantly larger than in normal control rats. NPX treated with both 1.0 and 10.0 micrograms/day SMS had statistically smaller values compared with NPX control rats. It was concluded that the chronic administration of SMS reduced glomerular hypertrophy without altering renal functions in this experimental model.


Recombineering-based dissection of flanking and paralogous Hox gene functions in mouse reproductive tracts.
Hox genes are key regulators of development. In mammals, the study of these genes is greatly confounded by their large number, overlapping functions and interspersed shared enhancers. Here, we describe the use of a novel recombineering strategy to introduce simultaneous frameshift mutations into the flanking Hoxa9, Hoxa10 and Hoxa11 genes, as well as their paralogs on the HoxD cluster. The resulting Hoxa9,10,11 mutant mice displayed dramatic synergistic homeotic transformations of the reproductive tracts, with the uterus anteriorized towards oviduct and the vas deferens anteriorized towards epididymis. The Hoxa9,10,11 mutant mice also provided a genetic setting that allowed the discovery of Hoxd9,10,11 redundant reproductive tract patterning function. Both shared and distinct Hox functions were defined. Hoxd9,10,11 play a crucial role in the regulation of uterine immune function. Non-coding non-polyadenylated RNAs were among the key Hox targets, with dramatic downregulation in mutants. We observed Hox cross-regulation of transcription and splicing. In addition, we observed a surprising anti-dogmatic apparent posteriorization of the uterine epithelium. In caudal regions of the uterus, the normal simple columnar epithelium flanking the lumen was replaced by a pseudostratified transitional epithelium, normally found near the more posterior cervix. These results identify novel molecular functions of Hox genes in the development of the male and female reproductive tracts.


Intravenous arginine vasopressin in critically ill children: is it beneficial?
Arginine-vasopressin (AVP) may be more effective than epinephrine in shock states and as an end-of-life salvage maneuver. However, there is only limited experience using AVP in children. Our study aim was to evaluate the effect of AVP administration on hemodynamic and ventilatory parameters in critically ill children. Eight critically ill children (1 month to 12 years old) were treated with AVP during the years 2000-2001. Two patients had had head trauma, and six had surgical correction of congenital heart disease. All patients suffered severe septic or cardiogenic shock with a low cardiac output state and were considered to be near death. AVP was administered continuously at a dose of 0.0003-0.002 U/kg/min. Hemodynamic and ventilatory parameters and vasopressor doses were compared before and after AVP initiation. One patient survived with a good neurologic outcome. Seven patients succumbed while receiving AVP. Systolic and diastolic blood pressure increased significantly (P < 0.03) following AVP initiation. The epinephrine requirement decreased from 2.3 to 1.7 microg/kg/min. Blood gases improved with a significant (P < 0.05) increase of PaO2. Oxygenation index and PaO2/FiO2 ratio improved significantly, and ventilatory support requirements and positive inspiratory pressure (PIP) decreased significantly. Despite a significant improvement in hemodynamic and ventilatory support parameters, survival to hospital discharge was not achieved when AVP was used in critically ill pediatric patients. We hypothesize that earlier administration of AVP may be more beneficial.


pH Dependence of the Number of Discrete Conformers of Carbonic Anhydrase 2, as Evaluated from Collision Cross-Section Using Ion Mobility Coupled with Electrospray Ionization.
Ion mobility experiments coupled with electrospray ionization (ESI) were conducted to evaluate the folding states of bovine carbonic anhydrase 2 (CA2) under three different pH conditions. Collision cross-section (CCS) of the CA2 ions generated by ESI revealed the presence of six discrete conformers in the gas phase under the conditions employed in this study. The CCS of the most extended conformer was three times larger than that of the most compact one. The charge state distribution of the CA2 ions was indicative of three conformers being present. Although there was consistency in conformer assignment conducted by CCS and charge state distribution, the CCS measurement was shown to be more effective because the information obtained provided more detailed knowledge of the conformation of the protein.


National ICU Registries as Enablers of Clinical Research and Quality Improvement.
Clinical quality registries (CQRs) have been implemented worldwide by several medical specialties aiming to generate a better characterization of epidemiology, treatments, and outcomes of patients. National ICU registries were created almost 3 decades ago to improve the understanding of case-mix, resource use, and outcomes of critically ill patients. This narrative review describes the challenges, proposed solutions, and evidence generated by National ICU registries as facilitators for research and quality improvement. English language articles were identified in PubMed using phrases related to ICU registries, CQRs, outcomes, and case-mix. Original research, review articles, letters, and commentaries, were considered. Data from relevant literature were identified, reviewed, and integrated into a concise narrative review. CQRs have been implemented worldwide by several medical specialties aiming to generate a better characterization of epidemiology, treatments, and outcomes of patients. National ICU registries were created almost 3 decades ago to improve the understanding of case-mix, resource use, and outcomes of critically ill patients. The initial experience in European countries and in Oceania ensured that through locally generated data, ICUs could assess their performances by using risk-adjusted measures and compare their results through fair and validated benchmarking metrics with other ICUs contributing to the CQR. The accomplishment of these initiatives, coupled with the increasing adoption of information technology, resulted in a broad geographic expansion of CQRs as well as their use in quality improvement studies, clinical trials as well as international comparisons, and benchmarking for ICUs. ICU registries have provided increased knowledge of case-mix and outcomes of ICU patients based on real-world data and contributed to improve care delivery through quality improvement initiatives and trials. Recent increases in adoption of new technologies (i.e., cloud-based structures, artificial intelligence, machine learning) will ensure a broader and better use of data for epidemiology, healthcare policies, quality improvement, and clinical trials.


Fully bioresorbable vascular scaffolds: lessons learned and future directions.
Fully bioresorbable scaffolds (BRS) were designed to overcome the limitations of metallic drug-eluting stents, which permanently cage the vessel wall, thereby preventing normal coronary vasomotion, preclude bypass grafting and can provoke long-term foreign-body responses. Although multiple scaffolds have been or are in development, the Absorb Bioresorbable Vascular Scaffold (BVS; Abbott Vascular) was the first FDA-approved device and was widely expected to fulfil the dream of interventional cardiologists of a transient scaffold that would disappear 'when the job was done' and would not hamper further treatment options. Although early, small studies and even large, randomized trials showed beneficial outcomes up to 1 year of follow-up, longer-term results have been disappointing, with increased rates of device thrombosis and target-lesion revascularization. The Absorb BVS device was withdrawn from the market because of low demand. In this Review, we summarize the preclinical and clinical data available for BRS to understand how the vascular biological reactions to these devices differ from biological reactions to metallic drug-eluting stents and how these responses translate into clinical outcomes. We also discuss next-generation BRS and outline modifications that are needed to improve the long-term outcomes with these devices so that they eventually become a viable option for patients with symptomatic obstructive coronary artery disease.


The Effects of Requiring Parental Consent for Research on Adolescents' Risk Behaviors: A Meta-analysis.
Requiring parental consent may result in sampling biases that confound scientific conclusions and stifle the representation of children most at risk for adverse outcomes. This study aims to investigate whether active parental consent, compared with passive parental consent, creates a bias in response rate, demographic makeup, and adverse outcomes in adolescent samples. A meta-analysis was performed on peer-reviewed articles and unpublished dissertations from 1975 to 2016 in five computerized databases ERIC, PsycINFO, MEDLINE, PubMed and ProQuest. Quantitative studies were retained if they included the following keywords: active consent (or informed consent or parental consent), passive consent (or waiver of consent), risk behavior, adolescen*. Fifteen studies were identified with a total number of 104,074 children. Results showed (1) response rates were significantly lower for studies using active consent procedure than those using passive consent procedure (Z = 3.05, p = .002); (2) more females, younger participants, and less African-Americans were included in studies using active consent procedures than studies using passive procedures (Z = -2.73, p = .006; Z = -12.06, p < .00001; Z = 2.19, p = .03, respectively); (3) studies with passive consent procedures showed higher rates of self-reported substance use than studies using active consent procedures (Z = 3.07, p = .002). Requiring active parental consent can lead to a systematic bias in the sample where the population under study is misrepresented. Institutional review board committees should collaborate with researchers to find solutions that protect minors without silencing the voice of high-risk youth in the literature.


Community violence and asthma morbidity: the Inner-City Asthma Study.
We examined the association between exposure to violence and asthma among urban children. We obtained reports from caretakers (n = 851) of violence, negative life events, unwanted memories (rumination), caretaker-perceived stress, and caretaker behaviors (keeping children indoors, smoking, and medication adherence). Outcomes included caretaker-reported wheezing, sleep disruption, interference with play because of asthma, and effects on the caretaker (nights caretaker lost sleep because of child's asthma). Increased exposure to violence predicted higher number of symptom days (P =.0008) and more nights that caretakers lost sleep (P =.02) in a graded fashion after control for socioeconomic status, housing deterioration, and negative life events. Control for stress and behaviors partially attenuated this gradient, although these variables had little effect on the association between the highest level of exposure to morbidity, which suggests there are other mechanisms. Mechanisms linking violence and asthma morbidity need to be further explored.


Pediatric allergy and immunology in China.
Over the past 30 years, China has enjoyed rapid economic development along with urbanization at a massive scale that the world has not experienced before. Such development has also been associated with a rapid rise in the prevalence of allergic disorders. Because of the large childhood population in the country, the burden of childhood allergic disorders has become one of the major challenges in the healthcare system. Among the Chinese centers participating in the International Study of Asthma and Allergies in Childhood, the data clearly showed a continuing rise in the prevalence of asthma, allergic rhinitis, and atopic eczema. However, the discipline of pediatric allergy in mainland China is still in its infancy due to the lack of formal training program and subspecialty certification. Clinicians and researchers are increasingly interested in providing better care for patients with allergies by establishing pediatric allergy centers in different regions of the country. Many of them have also participated in national or international collaborative projects hoping to answer the various research questions related to the discipline of pediatric allergy and immunology. It is our hope that the research findings from China will not only improve the quality of care of affected children within this country but also the millions of patients with allergies worldwide.


[Comparative characterization of laboratory-made selective nutrient media for Salmonella accumulation].
In this work the results of the trial of three selective nutrient media for Salmonella accumulation, viz. Leifson's selenite broth produced by the Research and Manufacturing Amalgamation (RMA) "Nutrient Media", tetrarathionate broth (Müller's medium), laboratory-prepared, and newly developed MA-broth produced by the RMA "Nutrient Media", are presented. The results of 6- and 24-hour incubation in these selective media was evaluated. As found in this study, the laboratory-prepared medium was most effective for the accumulation of salmonellae (S. paratyphi, S. typhi, S. gallinarum). With respect to the possible concomitant microflora (Escherichia coli and shigellae), the inhibiting properties of MA-broth were superior to those of Leifson's medium, but inferior to those of Müller's medium.


Bleomycin exerts ambivalent antitumor immune effect by triggering both immunogenic cell death and proliferation of regulatory T cells.
Bleomycin (BLM) is an anticancer drug currently used for the treatment of testis cancer and Hodgkin lymphoma. This drug triggers cancer cell death via its capacity to generate radical oxygen species (ROS). However, the putative contribution of anticancer immune responses to the efficacy of BLM has not been evaluated. We make here the observation that BLM induces immunogenic cell death. In particular, BLM is able to induce ROS-mediated reticulum stress and autophagy, which result in the surface exposure of chaperones, including calreticulin and ERp57, and liberation of HMBG1 and ATP. BLM induces anti-tumor immunity which relies on calreticulin, CD8(+) T cells and interferon-γ. We also find that, in addition to its capacity to trigger immunogenic cell death, BLM induces expansion of Foxp3+ regulatory T (Treg) cells via its capacity to induce transforming growth factor beta (TGFβ) secretion by tumor cells. Accordingly, Treg cells or TGFβ depletion dramatically potentiates the antitumor effect of BLM. We conclude that BLM induces both anti-tumor CD8(+) T cell response and a counteracting Treg proliferation. In the future, TGFβ or Treg inhibition during BLM treatment could greatly enhance BLM anti-tumor efficacy.


Analysis of Factors Influencing the Efficiency of Catalysts Used in Waste PU Degradation.
Polyurethane (PU) is an indispensable part of people's lives. With the development of polyurethane, the disposal of polyurethane waste has become a significant issue around the world. Conventional degradation catalysts have poor dispersion and low degradation efficiency when used in the process of solid degradation into liquid. Therefore, this paper innovatively adopts self-made core-shell nanoscale titanium catalysis, traditional alkali metal catalyst (KOH), and polyol to carry out the glycolysis of waste polyurethane (PU) pipeline foam. The homogenized nanoscale titanium catalyst coated with alcohol gel has an obvious core-shell structure. The alcohol gel not only protects the catalyst but also dissolves with the alcoholysis agent in the process of glycolysis and disperses more evenly into the alcoholysis agent to avoid the phenomenon of nanocatalyst agglomeration, so as to facilitate catalytic cracking without reducing catalyst activity. In this study, investigated and compared the production of renewable polyurethane foam via a one-step method based on use of a homogeneous core-shell nanostructured titanium catalyst vs. a traditional alkaline catalyst in terms of the properties of regenerated polyether polyols as well as of the foams produced from these polyols. The physicochemical properties of regenerated polyether polyols that were analyzed included viscosity, hydroxyl value, and average molecular weight. The regenerated polyurethane foams were characterized based on water absorption, TG, SEM, and thermal conductivity analyses. The results show that, when the addition of homogeneous titanium catalyst was T2 0.050 wt.%, the viscosity of regenerated polyether polyols was the lowest, at 5356.7 mPa·s, which was reduced by 9.97% compared with those obtained using the alkali metal catalyst (KOH). When the amount of titanium catalyst was T3 0.075 wt.%, the hard foam made of regenerated polyurethane prepared by the catalyst showed the best properties, with a compressive strength of 0.168 MPa, which is 4.76% higher than that of the foam prepared using KOH catalyst.


ComCo: Complementary supervised contrastive learning for complementary label learning.
Complementary label learning (CLL) is an important problem that aims to reduce the cost of obtaining large-scale accurate datasets by only allowing each training sample to be equipped with labels the sample does not belong. Despite its promise, CLL remains a challenging task. Previous methods have proposed new loss functions or introduced deep learning-based models to CLL, but they mostly overlook the semantic information that may be implicit in the complementary labels. In this work, we propose a novel method, ComCo, which leverages a contrastive learning framework to assist CLL. Our method includes two key strategies: a positive selection strategy that identifies reliable positive samples and a negative selection strategy that skillfully integrates and leverages the information in the complementary labels to construct a negative set. These strategies bring ComCo closer to supervised contrastive learning. Empirically, ComCo significantly achieves better representation learning and outperforms the baseline models and the current state-of-the-art by up to 14.61% in CLL.


Prognostic relevance of coronary collateral function: confounded or causal relationship?
To expand the limited information on the prognostic impact of quantitatively obtained collateral function in patients with coronary artery disease (CAD) and to estimate causality of such a relation. Prospective cohort study with long-term observation of clinical outcome. University Hospital. One thousand one hundred and eighty-one patients with chronic stable CAD undergoing 1771 quantitative, coronary pressure-derived collateral flow index measurements, as obtained during a 1-min coronary balloon occlusion (CFI is the ratio between mean distal coronary occlusive pressure and mean aortic pressure both subtracted by central venous pressure). Subgroup of 152 patients included in randomised trials on the longitudinal effect of different arteriogenic protocols on CFI. Collection of long-term follow-up information on clinical outcome. All-cause mortality and major adverse cardiac events. Cumulative 15-year survival rate was 48% in patients with CFI<0.25 and 65% in the group with CFI≥0.25 (p=0.0057). Cumulative 10-year survival rate was 75% in patients without arteriogenic therapy and 88% (p=0.0482) in the group with arteriogenic therapy and showing a significant increase in CFI at follow-up. By proportional hazard analysis, the following variables predicted increased all-cause mortality: age, low CFI, left ventricular end-diastolic pressure and number of vessels with CAD. A well-functioning coronary collateral circulation independently predicts lowered mortality in patients with chronic CAD. This relation appears to be causal, because augmented collateral function by arteriogenic therapy is associated with prolonged survival.


Integration testing of heterotic systems.
Computational theory and practice generally focus on single-paradigm systems, but relatively little is known about how best to combine components based on radically different approaches (e.g. silicon chips and wetware) into a single coherent system. In particular, while testing strategies for single-technology artefacts are generally well developed, it is unclear at present how to perform integration testing on heterotic systems: can we develop a test-set generation strategy for checking whether specified behaviours emerge (and unwanted behaviours do not) when components based on radically different technologies are combined within a single system? In this paper, we describe an approach to modelling multi-technology heterotic systems using a general-purpose formal specification strategy based on Eilenberg's X-machine model of computation. We show how this approach can be used to represent disparate technologies within a single framework, and propose a strategy for using these formal models for automatic heterotic test-set generation. We illustrate our approach by showing how to derive a test set for a heterotic system combining an X-machine-based device with a cell-based P system (membrane system).


Current use of imaging and electromagnetic source localization procedures in epilepsy surgery centers across Europe.
In 2014 the European Union-funded E-PILEPSY project was launched to improve awareness of, and accessibility to, epilepsy surgery across Europe. We aimed to investigate the current use of neuroimaging, electromagnetic source localization, and imaging postprocessing procedures in participating centers. A survey on the clinical use of imaging, electromagnetic source localization, and postprocessing methods in epilepsy surgery candidates was distributed among the 25 centers of the consortium. A descriptive analysis was performed, and results were compared to existing guidelines and recommendations. Response rate was 96%. Standard epilepsy magnetic resonance imaging (MRI) protocols are acquired at 3 Tesla by 15 centers and at 1.5 Tesla by 9 centers. Three centers perform 3T MRI only if indicated. Twenty-six different MRI sequences were reported. Six centers follow all guideline-recommended MRI sequences with the proposed slice orientation and slice thickness or voxel size. Additional sequences are used by 22 centers. MRI postprocessing methods are used in 16 centers. Interictal positron emission tomography (PET) is available in 22 centers; all using 18F-fluorodeoxyglucose (FDG). Seventeen centers perform PET postprocessing. Single-photon emission computed tomography (SPECT) is used by 19 centers, of which 15 perform postprocessing. Four centers perform neither PET nor SPECT in children. Seven centers apply magnetoencephalography (MEG) source localization, and nine apply electroencephalography (EEG) source localization. Fourteen combinations of inverse methods and volume conduction models are used. We report a large variation in the presurgical diagnostic workup among epilepsy surgery centers across Europe. This diversity underscores the need for high-quality systematic reviews, evidence-based recommendations, and harmonization of available diagnostic presurgical methods.


Ndfip1 regulates itch ligase activity and airway inflammation via UbcH7.
The ubiquitin-ligating enzyme (E3) Itch plays a crucial role in the regulation of inflammation, and Itch deficiency leads to severe airway inflammation. However, the molecular mechanisms by which Itch function is regulated remain elusive. In this study, we found that nontypeable Haemophilus influenzae induces the association of Itch with Ndfip1. Both Itch(-/-) and Ndfip1(-/-) mice exhibited severe airway inflammation in response to nontypeable Haemophilus influenza, which was associated with elevated expression of proinflammatory cytokines. Ndfip1 enhanced Itch ligase activity and facilitated Itch-mediated Tak1 ubiquitination. Mechanistically, Ndfip1 facilitated recruitment of ubiquitin-conjugating enzyme (E2) UbcH7 to Itch. The N-terminal region of Ndfip1 binds to UbcH7, whereas the PY motif binds to Itch. Hence, Ndfip1 acts as an adaptor for UbcH7 and Itch. Reconstitution of full-length Ndfip1 but not the mutants that fail to interact with either UbcH7 or Itch, restored the defect in Tak1 ubiquitination and inhibited elevated proinflammatory cytokine expression by Ndfip1(-/-) cells. These results provide new mechanistic insights into how Itch function is regulated during inflammatory signaling, which could be exploited therapeutically in inflammatory diseases.


Acetylation of E2 by P300 Mediates Topoisomerase Entry at the Papillomavirus Replicon.
Human papillomavirus (HPV) E2 proteins are integral for the transcription of viral genes and the replication and maintenance of viral genomes in host cells. E2 recruits the viral DNA helicase E1 to the origin. A lysine (K111), highly conserved among almost all papillomavirus (PV) E2 proteins, is a target for P300 (EP300) acetylation and is critical for viral DNA replication (E. J. Quinlan, S. P. Culleton, S. Y. Wu, C. M. Chiang, et al., J Virol 87:1497-1507, 2013, https://doi.org/10.1128/JVI.02771-12; Y. Thomas and E. J. Androphy, J Virol 92:e01912-17, 2018, https://doi.org/10.1128/JVI.01912-17). Since the viral genome exists as a covalently closed circle of double-stranded DNA, topoisomerase 1 (Topo1) is thought to be required for progression of the replication forks. Due to the specific effect of K111 mutations on DNA unwinding (Y. Thomas and E. J. Androphy, J Virol 92:e01912-17, 2018, https://doi.org/10.1128/JVI.01912-17), we demonstrate that the E2 protein targets Topo1 to the viral origin, and this depends on acetylation of K111. The effect was corroborated by functional replication assays, in which higher levels of P300, but not its homolog CBP, caused enhanced replication with wild-type E2 but not the acetylation-defective K111 arginine mutant. These data reveal a novel role for lysine acetylation during viral DNA replication by regulating topoisomerase recruitment to the replication origin.IMPORTANCE Human papillomaviruses affect an estimated 75% of the sexually active adult population in the United States, with 5.5 million new cases emerging every year. More than 200 HPV genotypes have been identified; a subset of them are linked to the development of cancers from these epithelial infections. Specific antiviral medical treatments for infected individuals are not available. This project examines the mechanisms that control viral genome replication and may allow the development of novel therapeutics.


Neuronal Fc gamma receptor I as a novel mediator for IgG immune complex-induced peripheral sensitization.
Chronic pain often accompanies immune-related diseases with an elevated level of IgG immune complex (IgG-IC) in the serum and/or the affected tissues though the underlying mechanisms are largely unknown. Fc gamma receptors (FcγRs), known as the receptors for the Fc domain of immunoglobulin G (IgG), are typically expressed on immune cells. A general consensus is that the activation of FcγRs by IgG-IC in such immune cells induces the release of proinflammatory cytokines from the immune cells, which may contribute to the IgG-IC-mediated peripheral sensitization. In addition to the immune cells, recent studies have revealed that FcγRI, but not FcγRII and FcγRIII, is also expressed in a subpopulation of primary sensory neurons. Moreover, IgG-IC directly excites the primary sensory neurons through neuronal FcγRI. These findings indicate that neuronal FcγRI provides a novel direct linkage between immunoglobulin and primary sensory neurons, which may be a novel target for the treatment of pain in the immune-related disorders. In this review, we summarize the expression pattern, functions, and the associated cellular signaling of FcγRs in the primary sensory neurons.


Conjugated linoleic acid supplementation enhances insulin sensitivity and peroxisome proliferator-activated receptor gamma and glucose transporter type 4 protein expression in the skeletal muscles of rats during endurance exercise.
This study examined whether conjugated linoleic acid (CLA) supplementation affects insulin sensitivity and peroxisome proliferator-activated receptor gamma (PPAR-γ) and glucose transporter type 4 (GLUT-4) protein expressions in the skeletal muscles of rats during endurance exercise. Sprague-Dawley male rats were randomly divided into HS (high-fat diet (HFD) sedentary group, n = 8), CS (1.0% CLA supplemented HFD sedentary group, n = 8), and CE (1.0% CLA supplemented HFD exercise group, n = 8). The rats in the CE swam for 60 min a day, 5 days a week for 8 weeks. The serum glucose and insulin contents and homeostasis model assessment of insulin resistance (HOMA-IR) value of the CS and CE were significantly decreased compared to those of the HS. The PPAR-γ protein expressions in the soleus muscle (SOM) and extensor digitorum longus muscle (EDL) were significantly higher in the CE than in the HS. In addition, the PPAR-γ protein expression in the SOM of the CS was significantly higher than that in the HS. On the other hand, the GLUT-4 protein expression of the SOM in the CE was significantly higher compared to that in the HS. However, there was no significant difference in GLUT-4 protein expression in the EDL among the groups. CLA supplementation with/without endurance exercise has role in improvement of insulin sensitivity. Moreover, when CLA supplementation was accompanied by endurance exercise, the PPAR-γ protein expression in SOM and EDL and the GLUT-4 protein expression in SOM were enhanced compared with the control group.


Exploring the Role of Gut Bacteria in Health and Disease in Preterm Neonates.
The mortality rate of very preterm infants with birth weight <1500 g is as high as 15%. The survivors till discharge have a high incidence of significant morbidity, which includes necrotising enterocolitis (NEC), early-onset neonatal sepsis (EONS) and late-onset neonatal sepsis (LONS). More than 25% of preterm births are associated with microbial invasion of amniotic cavity. The preterm gut microbiome subsequently undergoes an early disruption before achieving bacterial maturation. It is postulated that bacterial gut colonisation at birth and postnatal intestinal dysbacteriosis precede the development of NEC and LONS in very preterm infants. In fact, bacterial colonization patterns in preterm infants greatly differ from term infants due to maternal chorioamnionitis, gestational age, delivery method, feeding type, antibiotic exposure and the environment factor in neonatal intensive care unit (NICU). In this regard, this review provides an overview on the gut bacteria in preterm neonates' meconium and stool. More than 50% of preterm meconium contains bacteria and the proportion increases with lower gestational age. Researchers revealed that the gut bacterial diversity is reduced in preterm infants at risk for LONS and NEC. Nevertheless, the association between gut dysbacteriosis and NEC is inconclusive with regards to relative bacteria abundance and between-sample beta diversity indices. With most studies show a disruption of the Proteobacteria and Firmicutes preceding the NEC. Hence, this review sheds light on whether gut bacteria at birth either alone or in combination with postnatal gut dysbacteriosis are associated with mortality and the morbidity of LONS and NEC in very preterm infants.


Recent developments in depsipeptide research.
This review focuses on the major developments in depsipeptide research since 1995. Depsipeptides are bio-oligomers composed of hydroxy and amino acids linked by amide and ester bonds. Many depsipeptides show very promising biological activities, including anticancer, antibacterial, antiviral, antifungal, anti-inflammatory, and anti-clotting or anti-antherogenic properties. In this report depsipeptides exhibiting these properties are discussed. Their isolation, structural determination, and notable structural features are discussed, but their biological properties and therapeutic potentials are emphasized. Depsipeptides have shown the greatest therapeutic potential as anticancer agents. Four depsipeptides have entered clinical trials for cancer treatment. Among the antiviral compounds discovered, the callipeltins and the quinoxapeptins are particularly promising due to their inhibitory activities against HIV. These compounds have the potential to be developed as anti-AIDS drugs or to serve as lead compounds for the discovery of structurally related anti-AIDS compounds. Antifungal compounds, such as the jaspamides, may lead to therapies against many of the opportunistic infections that accompany AIDS. Anti-inflammatory compounds such as SCH217048 act as neurokinin antagonists and may lead to anti-inflammatory treatments. Some depsipeptides such as micropeptins and A90720A have been found to be effective plasmin inhibitors, which have implications as treatments for cardiovascular diseases. Compounds such as SCH58149 help control the levels of HDL and LDL.


Oseltamivir treatment prevents the increased influenza virus disease severity and lethality occurring in chronic ethanol consuming mice.
Chronic consumption of ethanol (EtOH) is well recognized to lead to defective innate and adaptive immune responses and increase the severity of pulmonary infections. Our own studies have demonstrated that chronic EtOH consumption decreases CD8 T-cell immunity to influenza virus infections (IAV) leading to severe infections and mortality. Interestingly, antiviral treatment of IAVs has been shown to be compromised in mice and humans that are immuno-deficient. It is known that EtOH can alter the pharmacokinetics of antivirals. Therefore, the effectiveness of influenza antiviral therapy during chronic ethanol consumption remains in question. BALB/c mice were placed on 18% (w/v) EtOH in their drinking water for 8 weeks. Chronic EtOH consuming and water controls were then treated with 10 mg/kg oseltamivir orally and infected intranasally with influenza virus 4 hours post-oseltamivir treatment. The mice were then treated with oseltamivir twice daily until day 7 postinfection. Influenza disease severity was measured by morbidity and mortality, pulmonary viral titers, and histology. Chronic EtOH consuming mice infected with IAV and treated with oseltamivir have decreased morbidity and mortality, pulmonary viral titers, and pulmonary pathology compared to untreated EtOH mice. Despite the severe immune defect seen in chronic EtOH mice as well as the potential for EtOH to inhibit the conversion of oseltamivir into an active form, treatment with oseltamivir reduces viral shedding as well as disease severity. These data suggest that the combination of a limited adaptive immune response plus the anti-IAV drug oseltamivir is sufficient to curb high mortality and mediate resolution of IAVs in mice chronically consuming ethanol.


Flexible hardware concept of pulsed laser deposition for large areas and combinatorial composition spreads.
Pulsed laser deposition (PLD) is one of the most flexible physical growth techniques for thin films of functional materials at the research and demonstrator level. We describe here a relatively simple and reliable concept of the PLD hardware that allows both deposition on large areas up to 4 in. diameter and deposition of tailored lateral and vertical composition spreads without time-consuming hardware changes. Different PLD approaches have been implemented in various chambers via specific and correlated computer-controlled movements of the target, substrate, and masks in conjunction with an appropriate target phase composition. The design of the chambers benefits from our long-term experience to find the most reliable solutions for the critical mechanical and high-temperature parts.


Isolated neck extensor myopathy: is it responsive to immunotherapy?
To determine if isolated neck extensor myopathy (INEM) is responsive to immunosuppressive treatment. We retrospectively reviewed charts of patients with INEM from 2002 to 2008 to identify patients and determine the response to immunomodulatory therapy. Clinical, electrodiagnostic, histologic, and radiographic data were reviewed. Four patients were identified during the study period. Three were women. The age of onset of neck extensor weakness ranged from 58 to 78 years. Serum creatine kinase levels were within normal limits in all patients. None had clinical, laboratory, or electrophysiological findings to suggest a generalized neuromuscular disorder. On electrodiagnostic studies, all patients had myopathic changes with or without irritative features in cervical paraspinal muscles. No inflammation was present on muscle biopsy from three of the patients. All patients received one or more immunosuppressive agents. Neck strength improved by 1 point or greater on the Medical Research Council scale in all subjects with a peak response observed between 3 and 6 months after treatment initiation. A trial of immunosuppressive agents should be offered to patients with INEM because a subset will improve. Rigorously defined, INEM is a noninflammatory myopathy. However, a focal myositis could be missed on muscle biopsy and may explain the favorable response to treatment.


Long non-coding RNAs harboring miRNA seed regions are enriched in prostate cancer exosomes.
Long non-coding RNAs (lncRNAs) form the largest transcript class in the human transcriptome. These lncRNA are expressed not only in the cells, but they are also present in the cell-derived extracellular vesicles such as exosomes. The function of these lncRNAs in cancer biology is not entirely clear, but they appear to be modulators of gene expression. In this study, we characterize the expression of lncRNAs in several prostate cancer exosomes and their parental cell lines. We show that certain lncRNAs are enriched in cancer exosomes with the overall expression signatures varying across cell lines. These exosomal lncRNAs are themselves enriched for miRNA seeds with a preference for let-7 family members as well as miR-17, miR-18a, miR-20a, miR-93 and miR-106b. The enrichment of miRNA seed regions in exosomal lncRNAs is matched with a concomitant high expression of the same miRNA. In addition, the exosomal lncRNAs also showed an over representation of RNA binding protein binding motifs. The two most common motifs belonged to ELAVL1 and RBMX. Given the enrichment of miRNA and RBP sites on exosomal lncRNAs, their interplay may suggest a possible function in prostate cancer carcinogenesis.