Secretin-enhanced MR Imaging of the Pancreas.
Secretin is a hormone that stimulates the exocrine pancreatic secretion of bicarbonate-rich fluid from the acinar cells of the pancreas that accumulates within the pancreatic ductal lumen. The exogenous administration of secretin improves the visualization of pancreatic ducts at magnetic resonance (MR) cholangiopancreatography (MRCP), because of an enlargement of the pancreatic duct system and an increase of the fluid content within the lumen of the pancreatic ducts, responsible of an increase of MR signal. In this review, the technique of secretin-enhanced MRCP, which has the aim to depict the whole pancreatic duct system, the biliary tree, the major and minor papillae, and the duodenum, will be described. Because of the anatomic contiguity between the pancreas and the gastrointestinal tract, the presence of fluid within the stomach may overlap with the pancreatic duct system and therefore the pancreatic duct may be difficult to visualize, representing a potential source of diagnostic pitfalls. The technique to reduce the signal intensity of the static fluid present within the stomach and in the duodenal lumen is also described. The technique of secretin administration will be illustrated, with emphasis on the synchronization of secretin administration and MR image acquisition. Furthermore, the frequency and number of MRCP images necessary to achieve a temporal resolution adequate to visualize the physiologic changes in the pancreatic gland, induced by the administration of secretin, is described. The assessment of pancreatic, morphologic, and functional response to the administration of secretin, as depicted on MRCP images, will be illustrated. Finally, the indications for secretin-enhanced MRCP will be discussed to define which patients will benefit from secretin-enhanced MR imaging for their treatment planning. (©) RSNA, 2016.


Enhanced Transdermal Delivery of Concentrated Capsaicin from Chili Extract-Loaded Lipid Nanoparticles with Reduced Skin Irritation.
The aim of this study was to develop lipid-based nanoparticles that entrapped a high concentration of capsaicin (0.25%) from a capsicum oleoresin extract. The solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) were strategically fabricated to entrap capsaicin without a hazardous solvent. Optimized nanosize lipid particles with high capsaicin entrapment and loading capacity were achieved from pair-wise comparison of the solid lipid mixtures consisting of fatty esters and fatty alcohols, representing small and large crystal-structure molecules combined with a compatible liquid lipid and surfactants (crystallinity index = 3%). This report was focused on selectively captured capsaicin from oleoresin in amorphous chili extract-loaded NLCs with 85.27% ± 0.12% entrapment efficiency (EE) and 8.53% ± 0.01% loading capacity (LC). The particle size, polydispersity index, and zeta potential of chili extract-loaded NLCs were 148.50 ± 2.94 nm, 0.12 ± 0.03, and -29.58 ± 1.37 mV, respectively. The favorable zero-order kinetics that prolonged capsaicin release and the significantly faster transdermal penetration of the NLC attributed to the reduction in skin irritation of the concentrated capsaicin NLCs, as illustrated by the in vitro EpiDermTM three-dimensional human skin irritation test and hen's egg test chorioallantoic membrane assay (HET-CAM).


First evidence for a restriction-modification system in Leptospira sp.
The LE1 leptophage exhibited a host range restricted to the saprophytic Leptospira biflexa [Saint Girons et al., Res. Microbiol. 141 (1990) 1131-1133] and mainly to the Patoc 1 strain (hereafter called PFRA) kept in the Paris, France collection. Results of titration of LE1 lysates indicated the presence of a host-controlled modification and restriction system within PUSA (Patoc 1 strain maintained in the Morgantown, WV, USA collection) that was absent in PFRA. Because genomic DNA of PITAL (Patoc 1 strain maintained in Trieste, Italy) appeared smeared in pulsed field gel electrophoresis (PFGE), this strain is likely to contain nucleases that are activated upon DNA isolation. Moreover, comparative NotI digestions of PUSA and PFRA DNAs, as visualized by PFGE, indicated that PUSA belonged to a different serovar than PFRA. Finally, 16S ribosomal sequence analysis indicated that PUSA belonged to the saprophytic Leptospira meyeri species, while PITAL and PFRA appertained to L. biflexa. The evolutionary significance and the importance of the restriction and modification enzymes or non-specific nucleases within strains for genetic experiments are discussed.


Impact of Infections in Patients Receiving Pembrolizumab-Based Therapies for Non-Small Cell Lung Cancer.
Background: Immune checkpoint inhibitor (ICI) therapy has significantly improved outcomes across a range of malignancies. While infections are a well-known contributor to morbidity and mortality amongst patients receiving systemic chemotherapy regimens, little is known about the impact of infections on patients receiving ICI therapy. This study aims to assess incidence, risk factors, and outcomes in patients who develop infections while on pembrolizumab-based therapies for non-small cell lung cancer (NSCLC). Methods: Patients receiving pembrolizumab for stage III/IV NSCLC from 1/1/2017-8/1/2021 across seven hospitals were identified. Incidence and type of infection were characterized. Covariates including baseline demographics, treatment information, treatment toxicities, and immunosuppressive use were collected and compared between infected and non-infected patients. Outcomes included the rate of infections, all-cause hospital admissions, median number of treatment cycles, overall survival (OS), and progression free survival (PFS). Univariable and multivariable analysis with reported odds ratio (OR) and 95% confidence intervals (CI) were utilized to evaluate infection risks. OS and PFS were analyzed by Kaplan−Meier analysis and tested by log-rank test. p-value < 0.05 was considered statistically significant. Results: There were 243 NSCLC patients that met the inclusion criteria. Of these, 111 (45.7%) had one documented infection, and 36 (14.8%) had two or more. Compared to non-infected patients, infected patients had significantly more all-cause Emergency Department (ED) [37 (33.3%) vs. 26 (19.7%), p = 0.016], hospital [87 (78.4%) vs. 53 (40.1%), p < 0.001], and ICU visits [26 (23.4%) vs. 5 (3.8%), p < 0.001], and had poorer median OS (11.53 [95% CI 6.4−16.7] vs. 21.03 [95% CI: 14.7−24.2] months, p = 0.033). On multivariable analysis, anti-infective therapy (OR 3.32, [95% CI: 1.26−8.76], p = 0.015) and ECOG of >1 (OR 5.79, [95% CI 1.72−19.47], p = 0.005) at ICI initiation conferred an increased risk for infections. At last evaluation, 74 (66.7%) infected and 70 (53.0%) non-infected patients died (p = 0.041). Conclusion: Infections occurred in nearly half of patients receiving pembrolizumab-based therapies for NSCLC. Infected patients had frequent hospitalizations, treatment delays, and poorer survival. ECOG status and anti-infective use at ICI initiation conferred a higher infection risk. Infection prevention and control strategies are needed to ameliorate the risk for infections in patients receiving ICIs.


Social-emotional difficulties in very preterm and term 2 year olds predict specific social-emotional problems at the age of 5 years.
Very preterm children have increased risk for social-emotional problems. This study examined relationships between early social-emotional difficulties and later social-emotional problems, and whether this differed by group (very preterm or term). Participants were 189 children born less than 30 weeks gestation or less than 1,250 g at birth and 78 term-born children. Parent-report questionnaires were used to assess social-emotional development at 2 (infant toddler social emotional assessment) and 5 years of age (strengths and difficulties questionnaire). Social risk and children's cognitive development were collected at the age of 5 years. Emotional symptoms at the age of 5 years were predicted by internalizing problems at the age of 2 years, conduct problems and hyperactivity/inattention at the age of 5 years were predicted by externalizing problems at the age of 2 years, and peer relationship problems and prosocial behaviors at the age of 5 years were predicted by social-emotional competence at the age of 2 years. Relationships were not moderated by group. Implications for early detection of social-emotional problems and provision of targeted interventions are discussed.


Inflammatory bowel diseases among first-generation and second-generation immigrants in Denmark: a population-based cohort study.
Our objective was to estimate the relative risk of IBD among first-generation and second-generation immigrants in Denmark compared with native Danes. Using national registries, we established a cohort of Danish residents between 1977 and 2018. Cohort members with known country of birth were followed for Crohn's disease (CD) and ulcerative colitis (UC) diagnoses. Incidence rate ratios (IRRs) served as measures of relative risk and were calculated by log-linear Poisson regression, using rates among native Danes as reference, stratified by IBD risk in parental country of birth, and among first-generation immigrants by age at immigration and duration of stay in Denmark. Among 8.7 million Danes, 4156 first-generation and 898 second-generation immigrants were diagnosed with CD or UC. Overall, comparing first-generation immigrants with native Danes, the IRR was 0.80 (95% CI 0.76 to 0.84) for CD and 0.74 (95% CI 0.71 to 0.77) for UC. The IRR of IBD increased with ≥20 years stay in Denmark. The IRR of CD increased with immigration at ≥40 years of age. Comparing second-generation immigrants with native Danes, the IRR of IBD was 0.97 (95% CI 0.91 to 1.04). There was significant interaction with sex, with higher IRR of IBD in male than in female immigrants. Relative to native Danish men and women, IBD risk among first-generation immigrants was lower, reflected the risk in their parental country of birth and increased with ≥20 years stay in Denmark. For second-generation immigrants, relative risk of IBD was lower only among women. These complex patterns suggest the role of environmental IBD risk factors.


Post-radiation increase in VEGF enhances glioma cell motility in vitro.
Glioblastoma multiforme (GBM) is among the most lethal of all human tumors, with frequent local recurrences after radiation therapy (RT). The mechanism accounting for such a recurrence pattern is unclear. It has classically been attributed to local recurrence of treatment-resistant cells. However, accumulating evidence suggests that additional mechanisms exist that involve the migration of tumor or tumor stem cells from other brain regions to tumor bed. VEGFs are well-known mitogens and can be up-regulated after RT. Here, we examine the effect of irradiation-induced VEGF on glioma cell motility. U251 and LN18 cell lines were used to generate irradiated-conditioned medium (IR-CM). At 72 h after irradiation, the supernatants were harvested. VEGF level in IR-CM was quantified by ELISA, and expression levels for VEGF mRNA were detected by RT-PCR. In vitro cancer cell motility was measured in chambers coated with/without Matrigel and IR-CM as a cell motility enhancer and a VEGF antibody as a neutralizer of VEGF bioactivity. Immunoblots were performed to evaluate the activity of cell motility-related kinases. Proliferation of GBM cells after treatment was measured by flow cytometry. Irradiation increased the level of VEGF mRNA that was mitigated by pre-RT exposure to Actinomycin D. U251 glioma cell motility (migration and invasion) was enhanced by adding IR-CM to un-irradiated cells (174.9 ± 11.4% and 334.2 ± 46% of control, respectively). When we added VEGF antibody to IR-CM, this enhanced cell motility was negated (110.3 ± 12.0% and 105.7 ± 14.0% of control, respectively). Immunoblot analysis revealed that IR-CM increased phosphorylation of VEGF receptor-2 (VEGFR2) secondary to an increase in VEGF, with a concomitant increase of phosphorylation of the downstream targets (Src and FAK). Increased phosphorylation was mitigated by adding VEGF antibody to IR-CM. There was no difference in the mitotic index of GBM cells treated with and without IR-CM and VEGF. These results indicate that cell motility can be enhanced by conditioned medium from irradiated cells in vitro through stimulation of VEGFR2 signaling pathways and suggest that this effect involves the secretion of radiation-induced VEGF, leading to an increase in glioma cell motility.


Changes in cyclic AMP receptor properties during adaptation in Dictyostelium discoideum.
In developing Dictyostelium discoideum cells, binding of cyclic AMP to the chemotactic receptor has been shown to oscillate. These oscillations represent cycles of activation, adaptation and deadaptation of the cyclic AMP receptor system. We studied the molecular basis of these oscillatory changes in cyclic AMP receptor binding. We developed a rapid method of lysing cells during the course of the oscillations. This method guaranteed good preservation of ligand binding properties of the cyclic AMP receptor. We found that oscillations in cyclic AMP binding resulted from changes in receptor affinity. The total number of receptors did not significantly change during oscillations. Our experiments also showed that both GTP and GDP abolished oscillations in receptor binding completely, presumably by acting via a G protein. The guanine nucleotides reduced the affinity of the receptor at all time-points of the oscillation cycle to the minimal, i.e. adapted, level. We conclude that the cyclic process of activation, adaptation and de-adaptation in D. discoideum, at cyclic AMP receptor level, involves changes in receptor-G protein interaction. During adaptation, the affinity of the cyclic AMP receptor decreases and the receptor becomes insensitive to guanine nucleotides.


High-mobility group chromatin proteins 1 and 2 functionally interact with steroid hormone receptors to enhance their DNA binding in vitro and transcriptional activity in mammalian cells.
We previously reported that the chromatin high-mobility group protein 1 (HMG-1) enhances the sequence-specific DNA binding activity of progesterone receptor (PR) in vitro, thus providing the first evidence that HMG-1 may have a coregulatory role in steroid receptor-mediated gene transcription. Here we show that HMG-1 and the highly related HMG-2 stimulate DNA binding by other steroid receptors, including estrogen, androgen, and glucocorticoid receptors, but have no effect on DNA binding by several nonsteroid nuclear receptors, including retinoid acid receptor (RAR), retinoic X receptor (RXR), and vitamin D receptor (VDR). As highly purified recombinant full-length proteins, all steroid receptors tested exhibited weak binding affinity for their optimal palindromic hormone response elements (HREs), and the addition of purified HMG-1 or -2 substantially increased their affinity for HREs. Purified RAR, RXR, and VDR also exhibited little to no detectable binding to their cognate direct repeat HREs but, in contrast to results with steroid receptors, the addition of HMG-1 or HMG-2 had no stimulatory effect. Instead, the addition of purified RXR enhanced RAR and VDR DNA binding through a heterodimerization mechanism and HMG-1 or HMG-2 had no further effect on DNA binding by RXR-RAR or RXR-VDR heterodimers. HMG-1 and HMG-2 (HMG-1/-2) themselves do not bind to progesterone response elements, but in the presence of PR they were detected as part of an HMG-PR-DNA ternary complex. HMG-1/-2 can also interact transiently in vitro with PR in the absence of DNA; however, no direct protein interaction was detected with VDR. These results, taken together with the fact that PR can bend its target DNA and that HMG-1/-2 are non-sequence-specific DNA binding proteins that recognize DNA structure, suggest that HMG-1/-2 are recruited to the PR-DNA complex by the combined effect of transient protein interaction and DNA bending. In transient-transfection assays, coexpression of HMG-1 or HMG-2 increased PR-mediated transcription in mammalian cells by as much as 7- to 10-fold without altering the basal promoter activity of target reporter genes. This increase in PR-mediated gene activation by coexpression of HMG-1/-2 was observed in different cell types and with different target promoters, suggesting a generality to the functional interaction between HMG-1/-2 and PR in vivo. Cotransfection of HMG-1 also increased reporter gene activation mediated by other steroid receptors, including glucocorticoid and androgen receptors, but it had a minimal influence on VDR-dependent transcription in vivo. These results support the conclusion that HMG-1/-2 are coregulatory proteins that increase the DNA binding and transcriptional activity of the steroid hormone class of receptors but that do not functionally interact with certain nonsteroid classes of nuclear receptors.


Pathophysiological features of the pulsatile secretion of biologically active luteinizing hormone in man.
The development of an in vitro bioassay of high specificity, sensitivity and precision for the measurement of low circulating concentrations of biologically active glycoprotein hormones has offered exciting new insights into the in vivo secretion and metabolic clearance of luteinizing hormone (LH) in various pathophysiological states. Moreover, the most recent combined application of the rat interstitial cell testosterone (RICT) bioassay and a novel multiple-parameter deonvolution model has allowed investigators to dissect plasma concentration profiles of bioactive LH into defined secretory bursts, which have numerically explicit amplitudes, locations in time, and durations, and are acted upon by determinable subject- and study-specific endogenous metabolic clearance rates. Here, we have: (i) reviewed the ability of the endogenous GnRH pulse signal to regulate the in vivo secretion of biologically active LH molecules as assessed in the RICT and by deconvolution mechanics; (ii) demonstrated that low-dose exogenous GnRH pulses effectively mimic spontaneous bioactive LH pulsatility; (iii) investigated the role of endogenous androgen and estrogen in modulating bioactive gonadotropin secretion in men and women; and (iv) described significant alterations in endogenous LH bioactivity in puberty and healthy aging.


Organization of the unr/N-ras locus: characterization of the promoter region of the human unr gene.
Investigations of the structure and expression of the N-ras gene in mammals has led to the identification of another gene designated unr, which is located immediately upstream of N-ras. These two genes are transcribed in the same orientation and the intergenic distance is of the order of 150 nucleotides. This genetic organization has been observed in the genome of guinea pig, rat, mouse and man with a very high level of sequence conservation in the intergenic region. This unusual gene clustering suggests that the transcriptional regulation of this locus could involve common regulatory sequences as well as transcriptional interference between the two genes. In this study, we have isolated and characterized the human unr promoter. A cluster of transcription initiation sites was mapped by primer extension and RNase protection and shown to be located in a CpG island devoid of TATA and CAAT boxes. Functional organization of the promoter was investigated by measuring the ability of a set of 5' deletions within a1 kb promoter region to drive the expression of the luciferase gene. These studies indicated a very strong promoter activity in NIH 3T3 cells and the presence of positive and negative regulatory domains. Nevertheless, a 90 bp fragment showed the same level of promoter activity as the 1 kb fragment. We also showed that ras genes can transactivate the unr promoter activity and that the 90 bp fragment responded to this transactivation.


Development of a gene probe assay suitable for use in routine diagnosis: a pilot study using a DNA probe for parvovirus B19.
Although DNA probes have been widely applied in research for many years, lengthy and complex protocols, together with the use of radio-labelled probes, have hindered their introduction into routine diagnosis. In this study conventional methods were adapted to make gene probes more suitable for routine work and a biotin-labelled probe for human parvovirus B19 was utilised. The gene probe assay was shown to detect 0.25 pg of viral DNA per 5 microliters of serum in 20 h. A comparative study was carried out to assess the difference in antigen detection by gene probe with that of the more conventional methods of counter-current immunoelectrophoresis and immune electron microscopy. The application of probes in this manner may lead to their increased use in routine virological diagnosis.


Charting progress.
Logbooks can be considered aggregate databases that registered nurses (RNs) have the primary responsibility of completing in most health care settings. However, RNs may be unaware of the many uses for the information contained in logbooks and the importance of these entries (Paine et al., 1988). Labor and delivery (L&D) logs provide an essential source of vital statistics birth data for the medical records staff. These data bits are used for reporting statistics, projecting trends, and planning future care for pregnant women.


Vaccination with a recombinant V alpha domain of a TCR prevents the development of collagen-induced arthritis.
A recombinant TCR domain, derived from a T cell hybridoma that recognizes an immunodominant type II collagen epitope, was used to vaccinate against collagen-induced arthritis in DBA/1 (H-2q) mice. The recombinant TCR domain comprises VA11.1-JA17 gene segments and is representative of the V alpha domains expressed by oligoclonal T cells in this disease model. Vaccination of mice 28 days before type II collagen (CII) immunization with this V alpha 11.1 domain resulted in a significantly decreased incidence of arthritis in DBA/1 mice, in contrast to vaccination with a V alpha 4-J alpha 40 domain derived from an encephalitogenic T cell hybridoma specific for MBP. Disease blockade is accompanied by a reduction in T and B cell responses to both the immunogen bovine CII and the autoantigen murine CII. V alpha 4 and V alpha 11.1 domains were found to be highly immunogenic in DBA/1 mice, inducing both T cell proliferation and the production of V alpha specific Abs, indicating that the vaccination effect of V alpha 11.1 is specific. This is the first report of V alpha-directed immunotherapy in an autoimmune disease model and demonstrates the potential use of recombinant TCR vaccines in the treatment of autoimmune diseases that involve oligoclonal autoreactive T cells.


Risk of stroke and other thromboembolic complications after interruption of DOAC therapy compared with warfarin therapy in patients with atrial fibrillation: a retrospective cohort analysis.
Direct oral anticoagulants (DOACs) have become the treatment of choice in thromboembolism prophylaxis for non-valvular atrial fibrillation, surpassing warfarin. While interruption of DOAC therapy for various reasons is a common eventuality, the body of data from real-world clinical practice on the implications of such interruptions in different clinical settings is still limited. We assessed complication rates from DOAC (apixaban, rivaroxaban, dabigatran) interruption compared with warfarin in hospitalized patients. We performed a retrospective cohort analysis of electronic records of patients hospitalized in Rabin Medical Center between 2010 and 2017. Incidents of anticoagulation interruptions for various reasons (including unintended interruptions) were collected. DOAC-treated patients were excluded if they reported non-compliance, and warfarin-treated patients were excluded if their international normalized ratio measurement on admission was subtherapeutic. Outcomes included ischemic stroke, systemic thromboembolism, myocardial infarction, and all-cause mortality within 90 days of anticoagulation interruption. The median CHA2DS2-VASc score was 5.0 (IQR 4.0-6.0) in both treatment groups. The associated risk of stroke, thromboembolic complications, myocardial infarction, and all-cause mortality after interruption of anticoagulation was not significantly different between the 2 treatment groups. Selective comparison of patients who were well balanced on warfarin before treatment interruption to DOAC-treated patients did not significantly influence the outcomes. This study did not find a significant difference in the complication rate after interruption of DOAC therapy compared with interruption of warfarin therapy in hospitalized patients with a high risk of thromboembolism.


[Torsion of the pregnant uterus].
Pathological version of the pregnant uterus is a rare complication. A case of 180 degrees sinistrotorsion of the uterus in the 39th gestational week is reported. The case was asymptomatic with the exception of preterm labor in the 30th week of pregnancy and was discovered during a cesarean section carried out because of myoma obstructing the birth canal. Mother and child were discharged in perfect health.


Proactive strategies for countering the detrimental outcomes of qualitative job insecurity in academia.
Against the backdrop of various and sometimes unexpected transformations of working conditions, qualitative job insecurity has become increasingly prevalent in academia and beyond. As a result, there is a great need for identifying factors that may mitigate its detrimental outcomes on employee well-being. To do so, the current study aimed to investigate the role of two proactive participation strategies-participatory decision-making and job crafting-as a means of counteracting the effects of qualitative job insecurity on burnout, work engagement and job satisfaction. The study was based on a sample of higher education employees in Belgium and Switzerland (N = 915). To test the hypotheses, moderation analyses were conducted in the overall sample and across different staff categories (i.e., senior and junior academic staff, administrative employees). Around 30% of the tested moderation effects were statistically significant, revealing that the negative outcomes of job insecurity were less salient at high values of the moderators. In particular, our findings suggest that encouraging participative decision-making may serve as a means to maintain academic employees' job satisfaction and prevent burnout in turbulent times. Moreover, job crafting may be additionally targeted at preserving work engagement, even though its moderator effects were not universal.


Views of depressed patients in Pakistan concerning their illness, its causes, and treatments.
Although the core symptoms of depression appear uniform across cultures, their presentations might vary from one culture to another. This interview study was part of a project to establish whether cognitive behavior therapy could be effective for the treatment of depression in a developing country. We interviewed outpatients from a university teaching hospital in Pakistan who were diagnosed as having depression. We tried to elicit their knowledge and perceptions of depression, its causes, and treatments, and their views about nonpharmacological treatments. We discovered that patients had very little knowledge of mental illnesses in general, and depression in particular. They believed that mental health problems were the result of stress or trauma, and that only medicines could help them. Patients had no knowledge of the roles of psychologists or psychotherapy. Their model of understanding mental illnesses appeared to represent a psychosocial understanding, with physical symptoms being their main concern.


Ribosome biogenesis factor Ltv1 chaperones the assembly of the small subunit head.
The correct assembly of ribosomes from ribosomal RNAs (rRNAs) and ribosomal proteins (RPs) is critical, as indicated by the diseases caused by RP haploinsufficiency and loss of RP stoichiometry in cancer cells. Nevertheless, how assembly of each RP is ensured remains poorly understood. We use yeast genetics, biochemistry, and structure probing to show that the assembly factor Ltv1 facilitates the incorporation of Rps3, Rps10, and Asc1/RACK1 into the small ribosomal subunit head. Ribosomes from Ltv1-deficient yeast have substoichiometric amounts of Rps10 and Asc1 and show defects in translational fidelity and ribosome-mediated RNA quality control. These defects provide a growth advantage under some conditions but sensitize the cells to oxidative stress. Intriguingly, relative to glioma cell lines, breast cancer cells have reduced levels of LTV1 and produce ribosomes lacking RPS3, RPS10, and RACK1. These data describe a mechanism to ensure RP assembly and demonstrate how cancer cells circumvent this mechanism to generate diverse ribosome populations that can promote survival under stress.


Synthesis, characterization and thermal degradation kinetics of a new pyrazole derived methacrylate polymer, poly(1,3-diphenyl-1H-pyrazol-5-yl methacrylate).
A new pyrazole derived methacrylate monomer, 1,3-diphenyl-1H-pyrazol-5-yl methacrylate, was synthesized from the reaction of 1,3-diphenyl-5-pyrazolone with methacryloyl chloride in the presence of triethylamine. After that, its homopolymerization was carried out by free radical polymerization method at 60 °C initiated with benzoyl peroxide. Spectral characterizations were achieved by 1H-NMR and FTIR spectroscopies. The kinetics of thermal degradation of the new polymer, poly(1,3-diphenyl-1H-pyrazol-5-yl methacrylate), poly(DFPMA), were investigated by thermogravimetric analysis (TGA) at different heating rates. The initial decomposition temperature of the polymer changed from 216.3 °C to 243.5 °C depending on the increasing heating rate. The thermal decomposition activation energies in a conversion range of 7-19% were 79.45 kJ/mol and 81.56 kJ/mol by the Flynn-Wall-Ozawa and Kissinger methods, respectively. Thermodegradation mechanism of the poly(DFPMA) were investigated in detail by using different kinetic methods available in the literature such as Coats-Redfern, Tang, Madhusudanan and Van Krevelen. Among all these methods, the best result was obtained for Coats-Redfern method (E =90.93 kJ/mol) at the optimum heating rate of 15 °C/min for D1 mechanism. That means the thermodegradation mechanism of poly(DFPMA) proceeds over a one-dimensional diffusion type deceleration mechanism.


High-frequency repetitive transcranial magnetic stimulation at dorsolateral prefrontal cortex for migraine prevention: A protocol for a systematic review of controlled trials.
Migraine may lead to a negative impact on the patients' quality of life with a subsequent substantial burden to society. Therapy options for treatment and prevention of migraine have progressed over the years and repetitive transcranial magnetic stimulation (rTMS) is one of the promising non-pharmacological options. It induces and alters electric current in the brain via repetitive non-invasive brain stimulation in high frequency. In migraine patients, two common stimulation sites are the M1 cortex and dorsolateral prefrontal cortex (DLPFC). The mechanism on how rTMS exerts therapeutic effects on migraine is not fully established, but the main postulation is that the neuromodulation via high-frequency rTMS (hf-rTMS) might inhibit pain perception. However, evidence from studies has been conflicting, thus the usefulness of hf-rTMS as migraine preventive treatment is still uncertain at this moment. This is a systematic review protocol describing essential reporting items based on the PRISMA for systematic review protocols (PRISMA-P) (Registration number: CRD42020220636). We aim to review the effectiveness, tolerability, and safety of hf-rTMS at DLPFC in randomised controlled trials (RCTs) as migraine prophylactic treatment. We will search Scopus, Cumulative Index to Nursing and Allied Health Literature Plus, PubMed, Cochrane Central Register of Controlled Trials and Biomed Central for relevant articles from randomised controlled clinical trials that used hf-rTMS applied at DLPFC for the treatment of migraine. The risk of bias will be assessed using the version 2 "Risk of bias" tool from Cochrane Handbook for Systematic Reviews of Interventions Version 6.1. We will investigate the evidence on efficacy, tolerability and safety and we will compare the outcomes between the hf-rTMS intervention and sham groups. This systematic review will further determine the efficacy, safety, and tolerability of hf-rTMS applied at DLPFC for migraine prophylaxis. It will provide additional data for health practitioners and policymakers about the usefulness of hf-rTMS for migraine preventive treatment.


A prospective randomized trial comparing the infectious and noninfectious complications of an externalized catheter versus a subcutaneously implanted device in cancer patients.
To compare the frequency of infectious episodes or other problems occurring with an externalized catheter (Hickman) versus a subcutaneously implanted device (Port-a-Cath, Pharmacia, Piscataway, NJ) in cancer patients, we performed a prospective, randomized study in 100 cancer patients (age range, 5 to 74 years). Patients who were chemotherapy candidates and required an indwelling catheter were monitored prospectively and evaluated during the 180 days after the insertion of the catheter and again at time of study closure. The frequency of catheter use, reason for access, and any problems that might have been related to catheter use were noted. All data were collected prospectively and included the patient's age, sex, underlying malignancy, temperature, and leukocyte and absolute granulocyte counts at the time of catheter insertion and when complications occurred. The time to and reason for removal of the catheter, as well as any intercurrent infectious or mechanical problems, were also determined. Most of the infections that occurred were caused by gram-positive organisms, especially staphylococci or streptococci. A total of 22 complications (11 in each group) resulted in removal of the central line. Only one infection in the Hickman catheter group and four in the Port-a-Cath group led to removal of the central line. All other infectious episodes were successfully treated without removal of the catheters. The mean device life was 230 days for the Hickman catheter and 318 days for the Port-a-Cath (not significant). There were no differences between the two study groups regarding incidence of documented infections or mechanical or thrombotic complications.


Quantitative nuclear-cytoplasmic ratios in human hepatomas.
This report presents quantitative data on nuclear-cytoplasmic (N/C) ratios of human hepatomas, normal liver specimens, and cirrhotic liver specimens. The N/C ratios were determined by point-counting, using an intraocular microscopic grid as the source of the points. The N/C ratios of hepatoma cells were chiefly greater than 0.21, while those of normal and cirrhotic liver cells were chiefly less than 0.21. The N/C ratios of hepatoma cells had a variance significantly greater than those of normal and cirrhotic cells. Quantitative N/C ratios can yield information useful in characterizing cell types for diagnostic purposes.


Evaluating preschool children's attitudes and beliefs about intimate partner violence.
Few studies have considered how intimate partner violence (IPV) impacts children's overarching attitudes and beliefs about the prevalence and acceptability of aggression. This pilot study included 92 preschool children exposed to IPV who reported on attitudes and beliefs about violence using a new, theoretically driven measure. Findings illustrate that preschoolers were able to respond reliably on this measure, and that most report at least one maladaptive attitude or belief about violence. Maternal posttraumatic avoidance symptoms, increased child aggression, and decreased child self-blame were associated with maladaptive attitudes and beliefs. These findings, although preliminary, indicate that clinicians may need to address both children's individual adjustment following violence exposure as well as their attitudes and beliefs concerning the acceptability of violence in interpersonal relationships.


Caring for data: Value creation in a data-intensive research laboratory.
Drawing upon ethnographic observations of staff working within a research laboratory built around research and clinical data from twins, this article analyzes practices underlying the production and maintenance of a research database. While critical data studies have discussed different forms of 'data work' through which data are produced and turned into effective research resources, in this paper we foreground a specific form of data work, namely the affective and attentive relationships that humans build with data. Building on STS and feminist scholarship that highlights the importance of care in scientific work, we capture this specific form of data work as care. Treating data as relational entities, we discuss a set of caring practices that staff employ to produce and maintain their data, as well as the hierarchical and institutional arrangements within which these caring practices take place. We show that through acts of caring, that is, through affective and attentive engagements, researchers build long-term relationships with the data they help produce, and feel responsible for its flourishing and growth. At the same time, these practices of care - which we found to be gendered and valued differently from other practices within formal and informal reward systems - help to make data valuable for the institution. In this manner, care for data is an important practice of valuation and valorisation within data-intensive research that has so far received little explicit attention in scholarship and professional research practice.


Helicobacter pylori: the new bug on the (paraffin) block.
A nameless spirillar organism in search of a disease only a few years ago, Helicobacter pylori has seen its fortunes suddenly reversed. After a rapid succession of name changes and some acrimonious disputes across continents, in less than a decade H. pylori has been catapulted to the centre stage of gastroenterological and microbiological research and has topped the most-wanted list of the pharmaceutical industry. The discovery of H. pylori has provided the momentum for the formation of the group that eventually created the Sydney System. Today, H. pylori is increasingly recognized as one of the most prevalent human pathogens worldwide. Its causal association with chronic active gastritis is undisputed and its role in the pathogenesis of peptide ulcer disease, although still poorly understood, is universally accepted. Furthermore, possible connections between chronic H. pylori infection and gastric carcinoma and primary gastric lymphoma are now being explored with increasing alacrity. With a few notable exceptions, pathologists have remained passive spectators of these exciting discoveries and have allowed gastroenterologists and microbiologists to set the pace in the quest for the determinants of gastritis, peptic ulcer and gastric cancer. This article is intended to outline some of the accepted facts on the development, progression, and pathology of H. pylori gastritis and to pose questions about this elusive infection. The authors hope that it might also contribute to stimulate further research, particularly on those aspects that are eminently suited to be addressed by pathologists.


An extreme lateral access for the surgery of lumbar disc herniations inside the spinal canal using the full-endoscopic uniportal transforaminal approach-technique and prospective results of 463 patients.
Prospective study of patients with lumbar disc herniations who were operated on with a full-endoscopic uniportal transforaminal approach using an extreme lateral access. To examine the technical possibilities of an extreme lateral access for full-endoscopic uniportal transforaminal surgery of lumbar disc herniations within the spinal canal. Also, to assess sufficient decompression, and the advantages and disadvantages of the minimally invasive procedure. Conventional prolapsed disc operations can result in consecutive damage as a result of traumatization. The usual transforaminal access is posterolateral, and is associated with problems in reaching the epidural space directly with unhindered vision and, thus, with problems of sufficient decompression in lumbar disc herniations within the spinal canal. A total of 463 patients were observed for 1 year. In addition to general and specific parameters, the following measuring instruments were used: visual analog scale, German version North American Spine Society Instrumentarium, Oswestry low back pain disability questionnaire. There were no complications. Of the patients, 81% reported no longer having leg pain, and 14% had occasional pain. There was no worsening. The results were constant and are equal to those of conventional procedures. No patients presented with neural scarring; 7% had recurrence of the prolapse. The extreme lateral access was necessary to reach the sequestered material. The technique presented is an adequate and safe alternative to conventional procedures, and has the advantages of a truly minimally invasive procedure. The extreme lateral access is required for the indications described. There are clear limitations outside these indications. The possibility of selecting an access from posterolateral to extreme lateral now enables surgery of lumbar disc herniations inside and outside the spinal canal.


Ratiometric Inclusion of Fibroblasts Promotes Both Castration-Resistant and Androgen-Dependent Tumorigenic Progression in Engineered Prostate Cancer Tissues.
To investigate the ratiometric role of fibroblasts in prostate cancer (PCa) progression, this work establishes a matrix-inclusive, 3D engineered prostate cancer tissue (EPCaT) model that enables direct coculture of neuroendocrine-variant castration-resistant (CPRC-ne) or androgen-dependent (ADPC) PCa cells with tumor-supporting stromal cell types. Results show that the inclusion of fibroblasts within CRPC-ne and ADPC EPCaTs drives PCa aggression through significant matrix remodeling and increased proliferative cell populations. Interestingly, this is observed to a much greater degree in EPCaTs formed with a small number of fibroblasts relative to the number of PCa cells. Fibroblast coculture also results in ADPC behavior more similar to the aggressive CRPC-ne condition, suggesting fibroblasts play a role in elevating PCa disease state and may contribute to the ADPC to CRPC-ne switch. Bulk transcriptomic analyses additionally elucidate fibroblast-driven enrichment of hallmark gene sets associated with tumorigenic progression. Finally, the EPCaT model clinical relevancy is probed through a comparison to the Cancer Genome Atlas (TCGA) PCa patient cohort; notably, similar gene set enrichment is observed between EPCaT models and the patient primary tumor transcriptome. Taken together, study results demonstrate the potential of the EPCaT model to serve as a PCa-mimetic tool in future therapeutic development efforts.


Chronic glenohumeral dislocation.
The evaluation and management of chronic glenohumeral dislocations can be challenging. By definition, chronic glenohumeral dislocations represent injuries that were not identified at the time of injury. Therefore, the primary goal is to avoid circumstances in which these injuries are not recognized. This includes undertaking a comprehensive clinical evaluation as well as appropriate imaging studies to understand the pathoanatomic changes-specifically, the humeral head impression fracture and any associated glenoid changes. The size of the impression fracture and duration of the dislocation are important factors in determining the appropriate treatment approach. Satisfactory outcomes can be achieved by using a variety of techniques, including open reduction combined with tendon transfers, allograft reconstruction, disimpaction and bone grafting and prosthetic replacement. Equally important, however, is recognizing patients in whom successful outcomes can be achieved with nonsurgical management.


Long Noncoding RNA TUG1 Promotes Autophagy-Associated Paclitaxel Resistance by Sponging miR-29b-3p in Ovarian Cancer Cells.
Paclitaxel (PTX) is a first-line chemotherapeutic agent for treating ovarian cancer. However, PTX resistance has become a major obstacle in ovarian cancer therapy. The underlying mechanism associated with PTX resistance is still unclear. We used qPCR to detect taurine up-regulated 1 (TUG1) expression in normal ovarian tissues and ovarian tumor tissues. A combination of small interfering RNA (siRNA), cell counting kit 8 (CCK8), colony formation assay and nude mouse model were used to detect the effect of TUG1 on ovarian cancer cell PTX-resistance. Autophagy/cytotoxicity dual staining assay, luciferase reporter assay, Western blot and RNA-binding protein immunoprecipitation assay were used for further mechanistic studies. TUG1 is highly expressed not only in ovarian tumor tissues compared with normal ovarian tissues but also in the chemo-resistant group compared with the sensitive group. Knockdown of TUG1 by siRNA decreased ovarian cancer cell and xenograft tumor PTX resistance with or without PTX treatment. Moreover, deletion of TUG1 in ovarian cancer cells decreased autophagosome formation and increased apoptosis as demonstrated by autophagy/cytotoxicity dual staining and Western blot assays. Furthermore, microRNA-29b-3p (miR-29b-3p) was found as the direct target of TUG1. Additionally, TUG1 could directly bind Ago2, a key protein of the RNA-induced silencing complex. Our findings suggest that TUG1, through targeting miR-29b-3p, induces autophagy and consequently results in PTX resistance in ovarian cancer.


Effect of systematic parturition induction of long gestation Holstein dairy cows on calf survival, cow health, production, and reproduction on a commercial farm.
The objective of this study was to evaluate the effect of parturition induction on dairy cattle with long gestation (past due-date) single pregnancies on calf survivability, cow health, production, and reproduction. There was an induction period during which all cows and heifers reaching 282 days of gestation were induced with dexamethasone (n = 614). Control cows calved the year after, had a gestation length > 282 d and were not induced (n = 508). As the induced and non-induced groups were not contemporaneous, data were standardized using the ratio between the herd baselines for each period. Multivariate analyses of the data showed that induced cows were 1.41 times more likely (P = 0.020) to become pregnant in the lactation following the studied calving than non-induced cows with long gestation. There was no difference in the risk of difficult calvings, stillbirths, culling due to reproductive reasons, average milk production, average days open or risk of abortion in the following lactation between induced and non-induced cows. There seemed to be a relationship between parturition induction and a lower risk of post-partum death, although this was not statistically significant (P = 0.162), because including induction as a factor in the model markedly improved the fit of the data. There was no information on incidence of retained placenta (RP) for the non-induced group. In conclusion, parturition induction resulted in more cows becoming pregnant and a seemingly lower risk of post-spartum death without affecting calving difficulty, calf viability, or milk production.


Biomarkers of Cancer Stem Cells for Experimental Research and Clinical Application.
The use of biomarkers in cancer diagnosis, therapy, and prognosis has been highly effective over several decades. Studies of biomarkers in cancer patients pre- and post-treatment and during cancer progression have helped identify cancer stem cells (CSCs) and their related microenvironments. These analyses are critical for the therapeutic application of drugs and the efficient targeting and prevention of cancer progression, as well as the investigation of the mechanism of the cancer development. Biomarkers that characterize CSCs have thus been identified and correlated to diagnosis, therapy, and prognosis. However, CSCs demonstrate elevated levels of plasticity, which alters their functional phenotype and appearance by interacting with their microenvironments, in response to chemotherapy and radiotherapeutics. In turn, these changes induce different metabolic adaptations of CSCs. This article provides a review of the most frequently used CSCs and stem cell markers.


HOW DO SPATIAL AND ANGULAR RESOLUTION AFFECT BRAIN CONNECTIVITY MAPS FROM DIFFUSION MRI?
Diffusion tensor imaging (DTI) is sensitive to the directionally- constrained flow of water, which diffuses preferentially along axons. Tractography programs may be used to infer matrices of connectivity (anatomical networks) between pairs of brain regions. Little is known about how these computed connectivity measures depend on the scans' spatial and angular resolutions. To determine this, we scanned 8 young adults with DTI at 2.5 and 3 mm resolutions, and an additional subject at 4 resolutions between 2-4 mm. We computed 70×70 connectivity matrices, using whole-brain tractography to measure fiber density between all pairs of 70 cortical and subcortical regions. Spatial and angular resolution affected the computed connectivity for narrower tracts (internal capsule and cerebellum), but also for the corticospinal tract. Data resolution affected the apparent role of some key structures in cortical anatomic networks. Care is needed when comparing network data across studies, and interpreting apparent disagreements among findings.


The effects of interspecific interactions between bloom forming cyanobacteria and Scenedesmus quadricauda (chlorophyta) on their photophysiology.
Eutrophication and enhanced external nutrient loading of lakes and seas are most clearly reflected by increased cyanobacterial blooms, which are often toxic. Freshwater cyanobacteria produce a number of bioactive secondary metabolites, some of which have allelopathic properties, significantly influencing the biological processes of other algae, thereby affecting species composition and succession of the phytoplankton. The goal of this work was to investigate the influence of bloom-forming cyanobacterial exudates on the photophysiology of the green alga Scenedesmus quadricauda by chlorophyll fluorescence analysis. We were able to prove the effect of algal cell-free filtrates on the performance of S. quadricauda and demonstrate for the first time that the freshwater picocyanobacterium Cyanobium gracile has strong negative impact on the coexisting green alga. Neither the cyanotoxin (MYC, CYN and ATX) producing, nor the non-toxic strains showed any systematic effect on the production of S. quadricauda. Various strains of the cyanobacterium Cylindrospermopsis raciborskii inhibited the performance of the green alga independently of their origin. Our results urge further studies for a better understanding of the factors affecting the release of allelopathic compounds and the mechanisms of their effects on target organisms.


Bipolar disorders: treatment options and patient satisfaction.
Functional recovery, the goal of treatment, has long been overlooked in the assessment of effectiveness of pharmacological treatments. However, with the recent shift in paradigm, from syndromal-symptomatic recovery to functional recovery, there appears to be a new interest in the definition and evaluation of functional recovery. Since functional recovery lags symptomatic recovery, sometimes by months or years, the attainment of functional recovery will be determined by both efficacy and long-term compliance. Quetiapine, due to its efficacy in both mania and depression, and effect on cognition may lead to improved functioning in patients with bipolar disorder.


The CCCTC-binding factor CTCF represses hepatitis B virus enhancer I and regulates viral transcription.
Hepatitis B virus (HBV) infection is of global importance with over 2 billion people exposed to the virus during their lifetime and at risk of progressive liver disease, cirrhosis and hepatocellular carcinoma. HBV is a member of the Hepadnaviridae family that replicates via episomal copies of a covalently closed circular DNA (cccDNA) genome. The chromatinization of this small viral genome, with overlapping open reading frames and regulatory elements, suggests an important role for epigenetic pathways to regulate viral transcription. The chromatin-organising transcriptional insulator protein, CCCTC-binding factor (CTCF), has been reported to regulate transcription in a diverse range of viruses. We identified two conserved CTCF binding sites in the HBV genome within enhancer I and chromatin immunoprecipitation (ChIP) analysis demonstrated an enrichment of CTCF binding to integrated or episomal copies of the viral genome. siRNA knock-down of CTCF results in a significant increase in pre-genomic RNA levels in de novo infected HepG2 cells and those supporting episomal HBV DNA replication. Furthermore, mutation of these sites in HBV DNA minicircles abrogated CTCF binding and increased pre-genomic RNA levels, providing evidence of a direct role for CTCF in repressing HBV transcription.


Availability of disaggregated greenhouse gas emissions from beef cattle production: a systematic review.
Agriculture is a significant source of anthropogenic greenhouse gas (GHG) emissions, and beef cattle are particularly emissions intensive. GHG emissions are typically expressed as a carbon dioxide equivalent (CO2e) 'carbon footprint' per unit output. The 100-year Global Warming Potential (GWP100) is the most commonly used CO2e metric, but others have also been proposed, and there is no universal reason to prefer GWP100 over alternative metrics. The weightings assigned to non-CO2 GHGs can differ significantly depending on the metric used, and relying upon a single metric can obscure important differences in the climate impacts of different GHGs. This loss of detail is especially relevant to beef production systems, as the majority of GHG emissions (as conventionally reported) are in the form of methane (CH4) and nitrous oxide (N2O), rather than CO2. This paper presents a systematic literature review of harmonised cradle to farm-gate beef carbon footprints from bottom-up studies on individual or representative systems, collecting the emissions data for each separate GHG, rather than a single CO2e value. Disaggregated GHG emissions could not be obtained for the majority of studies, highlighting the loss of information resulting from the standard reporting of total GWP100 CO2e alone. Where individual GHG compositions were available, significant variation was found for all gases. A comparison of grass fed and non-grass fed beef production systems was used to illustrate dynamics that are not sufficiently captured through a single CO2e footprint. Few clear trends emerged between the two dietary groups, but there was a non-significant indication that under GWP100 non-grass fed systems generally appear more emissions efficient, but under an alternative metric, the 100-year global temperature potential (GTP100), grass-fed beef had lower footprints. Despite recent focus on agricultural emissions, this review concludes there are insufficient data available to fully address important questions regarding the climate impacts of agricultural production, and calls for researchers to include separate GHG emissions in addition to aggregated CO2e footprints.


Parent presence during invasive procedures and resuscitation: evaluating a clinical practice change.
Parent presence during invasive procedures and/or resuscitation is a relatively underdeveloped and controversial practice. Much of the concern stems from the apprehension of the medical community. To evaluate whether implementation of formal practice guidelines and corresponding interprofessional education would improve clinicians' sense of preparation and comfort in providing parents with options during their children's procedures. Multiphase pre-post survey of (1) clinician perceptions and (2) practice from the perspective of clinicians and parents experiencing the same procedure. Data were collected over 4 years from a cardiovascular and critical care program in one U.S. children's hospital. More than 70% of clinicians participated in the perception surveys (n = 782) and 538 clinicians and 274 parents participated in the practice surveys. After the intervention, clinicians reported that parents were present during more invasive procedures and reported higher levels of comfort with the practice of providing options to parents during resuscitative events. Levels of comfort were higher in clinicians who had practiced skills in a simulated learning environment. During both phases, few clinicians reported that parent presence affected their technical performance (4%), therapeutic decision-making (5%), or ability to teach (9%). During the post phase, clinicians reported more active parent behaviors during procedures. Parents who reported receiving information to help them prepare for their children's procedures reported higher levels of procedural understanding and emotional support. Implementation of practice guidelines and interprofessional education had a positive impact on clinicians' perceptions and practice when providing parents with options and support during their children's invasive procedures and/or resuscitation.


End Point Versus Backbone Specificity Governs Characteristics of Antibody Binding to Poly(ethylene glycol) Brushes.
End-grafted poly(ethylene glycol) (PEG) brushes are widely used in order to suppress undesired protein adsorption to surfaces exposed to blood or other biological fluids. The specific adsorption of antibodies (Abs) to PEG brushes associated with PEG's antigenicity is drawing increasing attention because it can affect clinical applications. Here, the adsorption to PEG brushes of two Ab types, specifically binding the polymer backbone and the polymer endpoints, is structurally characterized by neutron reflectometry. The measurements yield volume fraction profiles of PEG and of the adsorbed Abs with sub-nanometer resolution perpendicular to the surface. For all brush parameters in terms of grafting density and polymerization degree, the Ab profiles clearly differ between backbone binders and endpoint binders. The adsorbed Ab amount per unit area is substantial for both Ab types and for all brush parameters investigated, even for dense brushes, which impose a considerable osmotic barrier to Ab insertion. The results therefore indicate that variation of brush parameters alone is insufficient to prevent undesired Ab adsorption. Instead, our work motivates further efforts in the search for nonantigenic brush chemistry.


Inhibition of putrescine uptake by polypyridinium quaternary salts in B16 melanoma cells treated with difluoromethylornithine.
Several bipyridinium, tetrapyridinium and hexapyridinium quaternary salts have been found to be potent inhibitors of putrescine uptake into B16 melanoma cells which had previously been treated with difluoromethylornithine. In general, the potency of inhibitors increased as the number of quaternary centres increased. A relationship between the distance apart of the positively charged nitrogen atoms and the potency of the salts as inhibitors of uptake has been established by comparison with a number of diaminoalkanes. It was found that an inter-nitrogen distance of 0.6-0.7 nm or 1.0-1.1 nm was optimal for high activity. This finding is significant in determining structural features of the polyamine transport system.


Risk of complications after a peptic ulcer diagnosis: effectiveness of proton pump inhibitors.
Few studies have evaluated the prevention of upper gastrointestinal complications (UGIC; bleeding or perforation) in patients with uncomplicated peptic ulcer (PU). We assessed the effect of proton pump inhibitors (PPI) in a non-randomized setting. To maximize exchangeability of exposed and unexposed groups we restricted the study to patients with a new diagnosis of PU, i.e., a clear indication. To minimize selection bias we mimicked an intention to treat approach by assessing the effect of PPI prescription after PU diagnosis. Within a population of subjects aged 40-84 years from The Health Improvement Network database, 1997-2006, we identified 3,850 patients with incident PU. Among them, we confirmed 74 first UGIC episodes during a mean follow-up of 4 years. Exposure was prescription coverage during the month following PU diagnosis. We performed a nested case-control analysis and compared UGIC cases with 400 controls matched for age, sex, year and duration of follow-up. Relative risks (RR) and 95 % confidence intervals (CI) were estimated. The overall incidence of UGIC was 4.6 cases/1,000 person-years; it was highest during the months after PU diagnosis, increased with age, and it was higher in men and subjects with Helicobacter pylori infection, anemia, and alcohol use at PU diagnosis. The RR for UGIC associated with PPI prescriptions during the month after PU diagnosis was 0.56 (95 % CI 0.31-1.0). The RR for NSAIDs with and without a PPI was 1.72 (0.68-4.45) and 3.27 (0.85-12.67), respectively. Findings suggest that prescription of PPIs after a PU diagnosis is associated with a reduced risk of UGIC.


The role of kinin B1 and B2 receptors in the scratching behaviour induced by proteinase-activated receptor-2 agonists in mice.
Activation of the proteinase-activated receptor-2 (PAR-2) induces scratching behaviour in mice. Here, we have investigated the role of kinin B(1) and B(2) receptors in the pruritogenic response elicited by activators of PAR-2. Scratching was induced by an intradermal (i.d.) injection of trypsin or the selective PAR-2 activating peptide SLIGRL-NH(2) at the back of the mouse neck. The animals were observed for 40 min and their scratching response was quantified. I.d. injection of trypsin or SLIGRL-NH(2) evoked a scratching behaviour, dependent on PAR-2 activation. Mice genetically deficient in kinin B(1) or B(2) receptors exhibited reduced scratching behaviour after i.d. injection of trypsin or SLIGRL-NH(2). Treatment (i.p.) with the non-peptide B(1) or B(2)receptor antagonists SSR240612 and FR173657, respectively, prevented the scratching behaviour caused by trypsin or SLIGRL-NH(2). Nonetheless, only treatment i.p. with the peptide B(2)receptor antagonist, Hoe 140, but not the B(1)receptor antagonist (DALBK), inhibited the pruritogenic response to trypsin. Hoe 140 was also effective against SLIGRL-NH(2)-induced scratching behaviour when injected by i.d. or intrathecal (i.t.) routes. Also, the response to SLIGRL-NH(2) was inhibited by i.t. (but not by i.d.) treatment with DALBK. Conversely, neither Hoe 140 nor DALBK were able to inhibit SLIGRL-NH(2)-induced scratching behaviour when given intracerebroventricularly (i.c.v.). The present results demonstrated that kinins acting on both B(1) and B(2) receptors played a crucial role in controlling the pruriceptive signalling triggered by PAR-2 activation in mice.


Population diversity in oncology drug responses and implications to drug development.
Cancer drug development is proceeding at a rapid pace, with drug approvals in oncology outpacing the other disease indications. With high population growth and economic development of Asian countries, access to cancer drugs becomes a paramount necessity. Approval of these drugs is dependent on establishing their safety and efficacy in populations living in these countries. Ethnic and racial differences in drug pharmacokinetics, or drug receptor sensitivities may lead to differences in drug responses between populations. These differences may be due to intrinsic or extrinsic factors, and understanding of the magnitude of these differences and their etiologies is important. One key pharmacogenetic reason for ethnic variability of drug response arises from the different allelic frequencies of polymorphic drug-metabolising enzyme genes, resulting in altered drug disposition. Using race or ethnicity as a "biomarker" for pharmacotherapeutics is fraught with issues as they are difficult to define scientifically, and are considered more social constructs. Nonetheless, studying the genetics of ethno-geographical variability of drug response will allow genetic biomarkers to be uncovered, which would greatly facilitate precision medicine, and should justify broadening the involvement and accrual of patients from global diverse populations during the early phases of drug development for an oncology drug.


The Cassava Source-Sink project: opportunities and challenges for crop improvement by metabolic engineering.
Cassava (Manihot esculenta Crantz) is one of the important staple foods in Sub-Saharan Africa. It produces starchy storage roots that provide food and income for several hundred million people, mainly in tropical agriculture zones. Increasing cassava storage root and starch yield is one of the major breeding targets with respect to securing the future food supply for the growing population of Sub-Saharan Africa. The Cassava Source-Sink (CASS) project aims to increase cassava storage root and starch yield by strategically integrating approaches from different disciplines. We present our perspective and progress on cassava as an applied research organism and provide insight into the CASS strategy, which can serve as a blueprint for the improvement of other root and tuber crops. Extensive profiling of different field-grown cassava genotypes generates information for leaf, phloem, and root metabolic and physiological processes that are relevant for biotechnological improvements. A multi-national pipeline for genetic engineering of cassava plants covers all steps from gene discovery, cloning, transformation, molecular and biochemical characterization, confined field trials, and phenotyping of the seasonal dynamics of shoot traits under field conditions. Together, the CASS project generates comprehensive data to facilitate conventional breeding strategies for high-yielding cassava genotypes. It also builds the foundation for genome-scale metabolic modelling aiming to predict targets and bottlenecks in metabolic pathways. This information is used to engineer cassava genotypes with improved source-sink relations and increased yield potential.


Impermeability of the blood-brain barrier to intravenous high-iodine-dose meglumine diatrizoate in the normal dog.
The effect of an intravenous bolus of 4.3 ml/kg of 60% meglumine diatrizoate on the blood-brain barrier (BBB) was studied in five adult unanesthetized dogs. Intravenous 3% Evans blue dye (4 ml/kg) was used as an indicator of BBB disruption. The animals were observed for signs of neurotoxicity for 1 hr after contrast-medium injection and then sacrificed. Their brains were removed and sectioned. None of the dogs displayed clinical evidence of neurotoxicity, and none of the brain specimens showed evidence of BBB disruption. The authors concluded that there is a statistically significant lack of correlation between the intravenous administration of 4.3 ml/kg of 60% meglumine diatrizoate and BBB disruption (p less than 0.05 with a probability of 90%). A previous publication reported focal BBB disruption in anesthetized dogs with dosages of 4 ml/kg and 6 ml/kg of 60% intravenous contrast agent given as an initial bolus followed by a drip infusion. The present study duplicated this prior experiment using the 6 ml/kg dose followed by infusion in three additional unanesthetized dogs and failed to substantiate the previous findings. This discrepancy leads to the assumption that the BBB damage noted in the previous experiment was somehow related to a factor(s) other than the intravenous contrast-medium injection. The BBB cannot be disrupted in the unanesthetized dog with intravenous doses of 60% contrast media of even 6 ml/kg.


What clinicians want: findings from a psychotherapy practice research network survey.
Practice research networks may be one way of advancing knowledge translation and exchange (KTE) in psychotherapy. In this study, we document this process by first asking clinicians what they want from psychotherapy research. Eighty-two psychotherapists in 10 focus groups identified and discussed psychotherapy research topics relevant to their practices. An analysis of these discussions led to the development of 41 survey items. In an online survey, 1,019 participants, mostly practicing clinicians, rated the importance to their clinical work of these 41 psychotherapy research topics. Ratings were reduced using a principal components analysis in which 9 psychotherapy research themes emerged, accounting for 60.66% of the variance. Two postsurvey focus groups of clinicians (N = 22) aided in interpreting the findings. The ranking of research themes from most to least important were-Therapeutic Relationship/Mechanisms of Change, Therapist Factors, Training and Professional Development, Client Factors, Barriers and Stigma, Technology and Adjunctive Interventions, Progress Monitoring, Matching Clients to Therapist or Therapy, and Treatment Manuals. Few differences were noted in rankings based on participant age or primary therapeutic orientation. Postsurvey focus group participants were not surprised by the top-rated items, as they were considered most proximal and relevant to therapists and their work with clients during therapy sessions. Lower ranked items may be perceived as externally imposed agendas on the therapist and therapy. We discuss practice research networks as a means of creating new collaborations consistent with KTE goals. Findings of this study can help to direct practitioner-researcher collaborations.


Landscape and well-being: A conceptual framework and an example.
This article explores why landscape is a crucial element in researching the relationship between environment and well-being. The main point we make is that human social agents are embedded in particular landscapes, and it is in landscapes that environmental changes are experienced, which can have implications for well-being. We draw from a variety of perspectives on landscape that understands a fundamental creative relation between humans and landscape and recent developments in neo-materialism theorising. Landscape is understood here as an assemblage of different forms of matter, animate and inanimate objects, as well as symbolic and cultural processes. A case study is also presented to indicate how landscape can be studied in relation to environment and change. Using the conceptual ideas laid out in the first section of the article, we analyse landscape, environment and well-being in Xuan Thuy National Park in North Vietnam. The area is part of a precarious coastal region where extreme weather events have impacted on the well-being of both humans and other matter. This article concludes with suggestions on the use of this landscape approach in researching environment and well-being.


Childhood Abuse, Religious Involvement, and Lifetime Substance Use Disorders among Latinas Nationwide.
Childhood abuse is a major behavioral health concern and imposes lasting sequelae on mental and physical health, including lifetime substance use disorders (LT-SUD). Yet, gender-specific research examining this early trauma and substance use in Latina-Americans (Latinas) is scarce. No study has explored the relationship between collectivist cultural factors and LT-SUD in this largest minority-female subgroup of the United States' population. Based on coping theory, this study investigated the association between childhood abuse, cultural factors, and LT-SUD among Latinas nationwide. Using the National Latino and Asian American Study we performed three-step logistic regressions to investigate LT-SUD for 1,427 Latinas, following three preplanned steps: (1) childhood physical and sexual abuse (CPA and CSA) with LT-SUD; (2) known correlates as controls; and (3) cultural strength factors. The prevalence rates of CPA and CSA were 28.0% and 18.4%, and that of LT-SUD was 4.8%. Religious attendance at a weekly level was negatively related to LT-SUD. Alongside English proficiency, discrimination, and social support, however, CPA and religious coping were positively associated with LT-SUD. Conclusion/Importance: Childhood physical abuse is an early risk factor for long-term substance use, viewed as a negative coping strategy. Religious attendance may have potential protection for Latinas. The victimization history may lead to coexisting positive (e.g., pursing social support, religious coping) and negative (e.g., SUD) coping behaviors within Latino communities.


Vimentin-positive gastric carcinomas with rhabdoid features. A clinicopathologic and immunohistochemical study.
We studied 71 patients with solid-type gastric adenocarcinoma selected from 5,437 surgically resected specimens during the period from 1975 to 1988; six had vimentin-positive adenocarcinomas, and five of these were advanced. One was at an early stage. All six tumors showed the same histologic features and had either a diffuse or alveolar arrangement, with tumor cells having either poor or no cohesiveness. Many tumor cells were round to polygonal, with eosinophilic or clear cytoplasm and large, eccentric vesicular nuclei, as seen in malignant rhabdoid tumors of the kidney. In all cases, the cytoplasm showed coexpression of vimentin and cytokeratin as revealed by double immunostaining. Four of the five cases with advanced carcinoma died of the disease 1 to 6 months after surgery. The cases with vimentin-positive tumors had significantly poorer prognoses than those with vimentin-negative tumors. We also studied adenocarcinomas of various histologic types randomly selected from our file (160 intestinal type and 69 diffuse type of Lauren) but failed to detect any vimentin positive ones. These results indicate that vimentin is expressed in some of the solid-type adenocarcinomas, which have a poor prognosis, and indicating that rhabdoid-like cells may be found in a variety of adenocarcinomas of the stomach.


Shape Up Somerville two-year results: a community-based environmental change intervention sustains weight reduction in children.
The objective of this study was to test the hypothesis that community-based environmental change intervention prevents undesirable weight gain in children. The method used in this study was a two-year, non-randomized, controlled trial (2003-2005) using community-based participatory methodology in three diverse cities in Massachusetts: one intervention and two socio-demographically-matched control communities (pooled for analysis). Children (n=1028), with a mean age=7.61+1.04years participated. Interventions were made to improve energy balance by increasing physical activity options and availability of healthful foods (Year 1). To firmly secure sustainability, the study team supported policies and shifted intervention work to community members (Year 2). Change in body mass index z-score (BMIz) was assessed by multiple regression, accounting for clustering within communities and adjusting for baseline covariates. Sex-specific overweight/obesity prevalence, incidence and remission were assessed. Over the two-year period, BMIz of children in the intervention community decreased by -0.06 [p=0.005, 95% confidence interval: -0.08 to -0.04] compared to controls. Prevalence of overweight/obesity decreased in males (OR=0.61, p=0.01) and females (OR=0.78, p=0.01) and remission increased in males (OR 3.18, p=0.03) and females (OR 1.93, p=0.03) in intervention compared to controls. Results demonstrate promise for preventing childhood obesity using a sustainable multi-level community-based model and reinforce the need for wide-reaching environmental and policy interventions.


Imaging pathobiology of carotid atherosclerosis with ultrasmall superparamagnetic particles of iron oxide: an update.
To provide brief overview of the developments regarding use of ultrasmall superparamagnetic particles of iron oxide in imaging pathobiology of carotid atherosclerosis. MRI is a promising technique capable of providing morphological and functional information about atheromatous plaques. MRI using iron oxide particles, called ultrasmall superparamagnetic iron oxide (USPIO) particles, allows detection of macrophages in atherosclerotic tissue. Ferumoxytol has emerged as a new USPIO agent, which has an excellent safety profile. Based on the macrophage-selective properties of ferumoxytol, there is increasing number of recent reports suggesting its effectiveness to detect pathological inflammation. USPIO particles allow magnetic resonance detection of macrophages in atherosclerotic tissue. Ferumoxytol has emerged as a new USPIO agent, with an excellent safety profile. This has the potential to be used for MRI of the pathobiology of atherosclerosis.


Protein restriction does not affect body temperature pattern in female mice.
Daily torpor is a physiological adaptation in mammals and birds characterized by a controlled reduction of metabolic rate and body temperature during the resting phase of circadian rhythms. In laboratory mice, daily torpor is induced by dietary caloric restriction. However, it is not known which nutrients are related to daily torpor expression. To determine whether dietary protein is a key factor in inducing daily torpor in mice, we fed mice a protein-restricted (PR) diet that included only one-quarter of the amount of protein but the same caloric level as a control (C) diet. We assigned six non-pregnant female ICR mice to each group and recorded their body weights and core body temperatures for 4 weeks. Body weights in the C group increased, but those in the PR group remained steady or decreased. Mice in both groups did not show daily torpor, but most mice in a food-restricted group (n=6) supplied with 80% of the calories given to the C group exhibited decreased body weights and frequently displayed daily torpor. This suggests that protein restriction is not a trigger of daily torpor; torpid animals can conserve their internal energy, but torpor may not play a significant role in conserving internal protein. Thus, opportunistic daily torpor in mice may function in energy conservation rather than protein saving.


What impact will DRGs have on group practice?
The US Congress has approved a prospective payment plan for Medicare using DRGs, which becomes effective October 1, 1983. This article explains DRGs, demonstrates the specific ways DRGs may affect group practice physicians, and discusses how group practices can avoid being adversely affected. A brief history of the DRG concept is presented along with a discussion of the evolution of DRGs and case-mix reimbursement. Actions hospital administrators are taking relative to the new reimbursement plan and the impact these actions will have on medical groups are examined.


Etanercept improves aging-induced cognitive deficits by reducing inflammation and vascular dysfunction in rats.
Normal aging may lead to cognitive deficits, which is associated with endothelial dysfunction and neuroinflammation. Dysregulation of TNFα expression contributes to vascular aging and dementia. In this study, we investigated the effects of etanercept, which is a TNFα inhibitor, on cognitive and endothelial function in aged rats. Male Wistar albino rats were divided into 3 groups: Young (4 month), aged (24 month) aged+ETA (24 month+etanercept). Etanercept (0.8 mg/kg/weekly) was given to the aged+ETA group subcutaneously for 8 weeks. Then passive avoidance test (PAT) and the Morris water maze test (MWMT) were used to evaluate cognitive functions of rats. After the behavioral tests, the rats were subjected to systolic blood pressure (SBP) measurement, and then endothelial function of thoracic aorta was evaluated by isolated organ bath system. Thoracic eNOS expression, hippocampal BDNF expression and serum and hippocampal TNF levels were also measured. In aged rats, it was shown that cognitive performances in MWMT and PAT were abolished whereas SBP unchanged. Furthermore, aging resulted in endothelial dysfunction, decreased expressions of thoracic eNOS and hippocampal BDNF, and increased level of TNF in serum and hippocampus. In contrast, ETA improved age-related cognitive deficits and endothelial dysfunction. In addition, ETA reversed changes in protein expression in aged rats. The results of this study indicate that ETA prevents cognitive deficits, endothelial dysfunction, peripheral and neuro-inflammation and decreament of neurotrophin expression in aged rats. These findings suggest that ETA may be beneficial with neuroprotective and vasculoprotective effects in elderly patients.


Research evaluation support services in biomedical libraries.
The paper provides a review of current practices related to evaluation support services reported by seven biomedical and research libraries. A group of seven libraries from the United States and Canada described their experiences with establishing evaluation support services at their libraries. A questionnaire was distributed among the libraries to elicit information as to program development, service and staffing models, campus partnerships, training, products such as tools and reports, and resources used for evaluation support services. The libraries also reported interesting projects, lessons learned, and future plans. The seven libraries profiled in this paper report a variety of service models in providing evaluation support services to meet the needs of campus stakeholders. The service models range from research center cores, partnerships with research groups, and library programs with staff dedicated to evaluation support services. A variety of products and services were described such as an automated tool to develop rank-based metrics, consultation on appropriate metrics to use for evaluation, customized publication and citation reports, resource guides, classes and training, and others. Implementing these services has allowed the libraries to expand their roles on campus and to contribute more directly to the research missions of their institutions. Libraries can leverage a variety of evaluation support services as an opportunity to successfully meet an array of challenges confronting the biomedical research community, including robust efforts to report and demonstrate tangible and meaningful outcomes of biomedical research and clinical care. These services represent a transformative direction that can be emulated by other biomedical and research libraries.


Characteristics of Adult Cigarette Smokers Who "Relight" and the Effects of Exposure to Tobacco Smoke Constituents.
About half of smokers relight their cigarette, a habit that is a risk factor for chronic bronchitis and possibly lung cancer. Little is known about the characteristics of smokers who relight and their dependence on nicotine. It is unknown whether relighting affects exposure to tobacco smoke constituents. This study examined the characteristics of relighters of usual brand cigarettes and whether relighting affects exposure to selected tobacco smoke constituents. We explored relighting status and frequency, using baseline data from 248 adult smokers participating in studies of reduced nicotine cigarettes in relation to demographic and cigarette characteristics, smoking behaviors, nicotine dependence, biomarkers of exposure (exhaled carbon monoxide, blood cotinine), and biomarkers of oxidative stress (ratio of oxidized/reduced glutathione). 69.4% (n = 172) of subjects reported relighting, and they relit an average of five cigarettes out of 20. Both relighters and non-relighters smoked a mean of 20 cigarettes per day (p = .6). Relighting was significantly associated with higher nicotine dependence, use of longer rod cigarettes, older age, lower income, and unemployment. There were no significant associations between relighting and blood cotinine, exhaled carbon monoxide or measures of oxidized/reduced blood glutathione. The majority of subjects were relighters, who had higher levels of nicotine dependence than non-relighters. Relighters had similar levels of plasma cotinine and exhaled carbon monoxide to non-relighters. No study has compared the cigarette characteristics and biomarkers of exposure of adult cigarette smokers who relight with those who do not. Relighting behavior was common in our sample and was associated with low income, not currently working, higher nicotine dependence, cigarette rod length, daily cigarette use years, and a lifetime history of depressed mood.


Nitric oxide concentrations, estradiol-17β progesterone ratio in follicular fluid, and COC quality with respect to perifollicular blood flow in cows.
The objectives were to investigate relationships among concentrations of nitric oxide (NO), estradiol 17 beta (E2), and progesterone (P4) in follicular fluids (FF), and quality of cumulus oocyte complexes (COCs) with respect to perifollicular blood flow (FBF). In Experiment I, follicles (138) were classified according to the presence or absence of FBF (assessed with transvaginal Doppler ultrasonography) and diameter of follicles (small, 2-4 mm; medium, 5-8 mm; and large, ≥9 mm). Concentrations of NO in FF did not differ significantly among these size categories. However, NO concentrations in FF with FBF (54.4 ± 7.4 μmol/l) were higher (P<0.05) than in those without FBF (36.6 ± 4.1 μmol/l). There was a positive correlation (r=0.30, P<0.05) between NO concentrations and the E2:P4 in FF. Rate of E2 active (E2:P4 ≥ 1) follicles were numerically 1.2 (0.8-1.8) times higher in follicles with FBF (38.1%) compared to those without FBF (25.0%). Moreover, rates of E2 active follicles were 6.1 (0.7-55.2) and 1.3 (0.1-17.3) times higher (P<0.06) in large (43.3%) and medium (14.3%) compared to small follicles (11.1%), respectively. In Experiment II, quality of COCs from 2 to 8 mm follicles, obtained by transvaginal ovum pick up (OPU), was investigated with respect to FBF. Odds ratio to obtain higher quality COCs from follicles with FBF (47.1%) was 3.3 (1.1-9.6) fold higher (P<0.05) compared to those from follicles without FBF (14.6%). In conclusion, E2:P4, and NO concentrations in FF, as well as FBF, could be used to determine the functionality of ovarian follicles in cows. Moreover, determination of FBF could be useful to predict quality of COCs in cattle.


[Subantral graft: clinical application of the biological principles osseoinduction in the treatment of posterior maxillary atrophy].
Severe resorption in the posterior maxilla following the loss of natural teeth is frequently associated with severe pneumatization of the maxillary sinus. This condition reduces the possibility of using implants in the subantral maxilla to surgical and prosthetic limits that cannot be resolved by simple techniques. For these cases, maxillary sinus elevation surgery and subantral grafting are required in order to increase this segment of the maxilla. The availability of new biomaterials has increased the possibilities of performing these techniques by reducing the amount of autogenous bone that must be harvested. Osteogenesis, osteoinduction, osteoconduction, osteotrophism, and osteophilia are the biologic mechanisms involved in the formation of new bone. Presence of these mechanisms permit augmentation of the subantral osseous band and bone to dimensions needed for implant placement. Conductive biomaterials permit bone neoformation to begin at the margins of the defect and advance towards the center. In a clinical study of 42 months, 228 implants (Steri-Oss, Yorba Linda, CA were placed; 180 of them are loaded and functional. The threaded design, HA-coating, hex lock head, and a resorbable membrane promote osseointegration and longevity. A subantral graft was placed in the space created after release and elevation of the sinus mucosa. The histologic evidence and the supportive clinical and radiologic findings clearly demonstrate consolidation and integration of the graft and the implant.


SOMA: a single oligonucleotide mutagenesis and cloning approach.
Modern biology research requires simple techniques for efficient and restriction site-independent modification of genetic material. Classical cloning and mutagenesis strategies are limited by their dependency on restriction sites and the use of complementary primer pairs. Here, we describe the Single Oligonucleotide Mutagenesis and Cloning Approach (SOMA) that is independent of restriction sites and only requires a single mutagenic oligonucleotide to modify a plasmid. We demonstrate the broad application spectrum of SOMA with three examples. First, we present a novel plasmid that in a standardized and rapid fashion can be used as a template for SOMA to generate GFP-reporters. We successfully use such a reporter to assess the in vivo knock-down quality of morpholinos in Xenopus laevis embryos. In a second example, we show how to use a SOMA-based protocol for restriction-site independent cloning to generate chimeric proteins by domain swapping between the two human hRMD5a and hRMD5b isoforms. Last, we show that SOMA simplifies the generation of randomized single-site mutagenized gene libraries. As an example we random-mutagenize a single codon affecting the catalytic activity of the yeast Ssy5 endoprotease and identify a spectrum of tolerated and non-tolerated substitutions. Thus, SOMA represents a highly efficient alternative to classical cloning and mutagenesis strategies.


Transitional care interventions prevent hospital readmissions for adults with chronic illnesses.
Transitional care interventions aim to improve care transitions from hospital to home and to reduce hospital readmissions for chronically ill patients. The objective of our study was to examine if these interventions were associated with a reduction of readmission rates in the short (30 days or less), intermediate (31-180 days), and long terms (181-365 days). We systematically reviewed twenty-six randomized controlled trials conducted in a variety of countries whose results were published in the period January 1, 1980-May 29, 2013. Our analysis showed that transitional care was effective in reducing all-cause intermediate-term and long-term readmissions. Only high-intensity interventions seemed to be effective in reducing short-term readmissions. Our findings suggest that to reduce short-term readmissions, transitional care should consist of high-intensity interventions that include care coordination by a nurse, communication between the primary care provider and the hospital, and a home visit within three days after discharge.


Discovery of aliphatic-chain hydroxamates containing indole derivatives with potent class I histone deacetylase inhibitory activities.
Histone deacetylase (HDAC) is a validated drug target for various diseases. This study combined indole recognition cap with SAHA, an FDA-approved HDAC inhibitor used to treat cutaneous T-cell lymphoma (CTCL). The structure activity relationship of the resulting compounds that inhibited HDAC was disclosed as well. Some compounds exhibited much stronger inhibitory activities than SAHA. We identified two meta-series compounds 6j and 6k with a two-carbon linker had IC50 values of 3.9 and 4.5 nM for HDAC1, respectively. In contrast, the same oriented compounds with longer carbon chain linkers showed weaker inhibition. The result suggests that the linker chain length greatly contributed to enzyme inhibitory potency. In addition, comparison of enzyme-inhibiting activity between the compounds and SAHA showed that compounds 6j and 6k displayed higher inhibiting activity for class I (HDAC1, -2, -3 and -8). The molecular docking and structure analysis revealed structural differences with the inhibitor cap and metal-binding regions between the HDAC isozymes that affect interactions with the inhibitors and play a key role for selectivity. Further biological evaluation showed multiple cellular effects associated with compounds 6j- and 6k-induced HDAC inhibitory activity.


Commentary on: Xbp1s-Ddit3, DNA damage and pulmonary hypertension.
In this commentary, we discuss new observations stating that spliced X-box-binding protein 1 (Xbp1s)-DNA damage-inducible transcript 3 (Ddit3) promotes monocrotaline (MCT)-induced pulmonary hypertension (Jiang et al., Clinical Science (2021) 135(21), https://doi.org/10.1042/CS20210612). Xbp1s-Ddit3 is involved in the regulation of endoplasmic reticulum stress but is also associated with DNA damage repair machinery. Pathologic DNA damage repair mechanisms have emerged as critical determinants of pulmonary hypertension development. We discuss the potential relationship among Xbp1s-Ddit3, DNA damage, and pulmonary hypertension. Although Xbp1s-Ddit3 contributes to the regulation of cell proliferation and apoptosis and the development of vascular lesions, whether Xbp1s is a friend or foe remains controversial.


Synthesis of dopamine and serotonin derivatives for immobilization on a solid support.
The two important neurotransmitters dopamine and serotonin are synthesized with short PEG tethers and immobilized on a magnetic solid support. The tether is attached to the aromatic moiety of the neurotransmitters to conserve their original functional groups. This approach causes minimal alteration of the original structure with the aim of optimizing the immobilized neurotransmitters for aptamer selection by SELEX. For the dopamine derivative, the tether is attached to the aromatic core of a dopamine precursor by the Sonogashira reaction. For serotonin, a link to the indole core is introduced by a Claisen rearrangement from the allylated phenol moiety of serotonin. The tethers are azide-functionalized, which enables coupling to alkyne-modified magnetic beads. The coupling to the magnetic beads is quantified by UV spectroscopy using Fmoc-monitoring of the immobilized dopamine and serotonin derivatives.


The mechanism underlying the effects of the cell surface ATP synthase on the regulation of intracellular acidification during acidosis.
The F1F0 ATP synthase has recently become the focus of anti-cancer research. It was once thought that ATP synthases were located strictly on the inner mitochondrial membrane; however, in 1994, it was found that some ATP synthases localized to the cell surface. The cell surface ATP synthases are involved in angiogenesis, lipoprotein metabolism, innate immunity, hypertension, the regulation of food intake, and other processes. Inhibitors of this synthase have been reported to be cytotoxic and to induce intracellular acidification. However, the mechanisms by which these effects are mediated and the molecular pathways that are involved remain unclear. In this study, we aimed to determine whether the inhibition of cell proliferation and the induction of cell apoptosis that are induced by inhibitors of the cell surface ATP synthase are associated with intracellular acidification and to investigate the mechanism that underlines the effects of this inhibition, particularly in an acidic tumor environment. We demonstrated that intracellular acidification contributes to the cell proliferation inhibition that is mediated by cell surface ATP synthase inhibitors, but not to the induction of apoptosis. Intracellular acidification is only one of the mechanisms of ecto-ATP synthase-targeted antitumor drugs. We propose that intracellular acidification in combination with the inhibition of cell surface ATP generation induce cell apoptosis after cell surface ATP synthase blocked by its inhibitors. A better understanding of the mechanisms activated by ecto-ATP synthase-targeted cancer therapies may facilitate the development of potent anti-tumor therapies, which target this enzyme and do not exhibit clinical limitations.


Alpha 1 adrenergic bronchomotor tone in guinea-pigs.
The bronchial reactivity of fifty-one Hartley strain guinea-pigs, anesthetized with pentobarbital, was tested for aerosolized norepinephrine (NE) or phenylephrine (PE) in 1% saline solutions (total inhaled dose: 2 mg in 2 min). No changes in their total airways resistances was observed at the end of the tests. When the same animals were pretreated by inhalation of nebulized propanolol (4 mg in 5 min), NE provoked a significant increase in these airway resistances in 72% of the animals for a mean inhaled dose of 1.07 mg. The NE challenge was stopped as soon as ventilatory asynchronism developed. Similar responses were induced by PE inhalation. These increases in airways resistance were prevented when phentolamine aerosol (1.3 mg inhaled in 5 min) was inhaled before NE or PE tests. An alpha 1-adrenergic bronchoconstriction is thus provoked by NE or PE when the protection resulting from the bronchial beta-adrenergic dilation has been suppressed. This constriction presents important individual variations depending on the activity or on the number of the corresponding alpha-receptors; in 28% of the guinea-pigs, the bronchomotor tone remained unaffected by NE in spite of beta-antagonist pretreatment.