Biogeochemical consequences of an oxygenated intrusion into an anoxic fjord.
This paper is based on the studies of the biogeochemical structure of the water column in the anoxic Fjord Hunnbunn (south-eastern Norway) performed in 2009, 2011 and 2012. This Fjord is an enclosed basin of brackish water separated by a narrow and shallow outlet to the sea with a permanently anoxic layer. We show how an oxygenated intrusion could lead to both positive and negative effects on the ecosystem state in Hunnbunn due to a change in the biogeochemical structure. During the stratified periods in 2009 and 2012 the anoxic layer amounted to approximately 10% of the total water volume in the Fjord, while dissolved oxygen (DO) was present in 80-90% of the water. In the autumn of 2011 the water chemistry structure observed in Fjord Hunnbunn was clearly affected by a recent oxygenated intrusion defined by abnormal salinity patterns. This led to a shift of the DO boundary position to shallower depths, resulting in a thicker anoxic layer comprising approximately 40% of the total water volume, with DO present only in approximately 60% of the water. The oxygenated water intrusions led to a twofold decrease of the concentrations of hydrogen sulphide, ammonia, phosphate and silicate in the deep layers with a simultaneous increase of these nutrients and a decrease of the pH level in the surface layers. The concentrations of manganese, iron, and mercury species changed dramatically and in particular revealed a significant supply of iron and methylmercury to the water column. Oxic water intrusions into anoxic fjords could lead not only to the flushing of the bottom anoxia, but to a dispersal of sulphidic and low oxygen conditions to the larger bottom area. The elevation of the hydrogen sulphide to the shallower layers (that can be rapidly oxidized) is accompanied by the appearance in the subsurface water of methylmercury, which is easily accumulated by organisms and can be transported to the surrounding waters, affecting the ecosystem over a larger area.


Variability in Case Durations for Common Surgical Procedures.
Under the Merit-based Incentive Payment System, physician payment will be adjusted using a composite performance score that has 4 components, one of which is resource use. The objective of this exploratory study is to quantify the facility-level variation in surgical case duration for common surgeries to examine the feasibility of using surgical case duration as a performance metric. We used data from the National Anesthesia Clinical Outcomes Registry on 404,987 adult patients undergoing one of 6 general surgical or orthopedic procedures: laparoscopic appendectomy, laparoscopic cholecystectomy, laparoscopic cholecystectomy with intraoperative cholangiogram, knee arthroscopy, laminectomy, and total hip replacement. We constructed separate mixed-effects multivariable time-to-event models (survival analysis) for each of the 6 procedures to model surgical case duration. We identified performance outliers, based on surgical case duration, using 2013 data and then quantified the gap between high- and low-performance outliers using 2014 data. After adjusting for patient risk, patients undergoing surgery at high-performance facilities were between 54% and 79% more likely to exit the operating room (OR) per unit time compared to average-performing facilities, depending on the procedure. For example, patients undergoing a laparoscopic appendectomy at high-performance facilities were 68% more likely to exit the OR per unit time (hazard ratio, 1.68; 95% CI, 1.40-2.02; P < .001) compared to average-performing facilities. Patients undergoing a laparoscopic appendectomy at low-performance facilities were 41% less likely to exit the OR per unit time (hazard ratio, 0.59; 95% CI, 0.47-0.74; P < .001) compared to average-performing facilities. The adjusted median surgical case duration for patients undergoing laparoscopic appendectomy was 69 minutes at high-performance centers and 92 minutes at low-performance centers. Similar results were obtained for the other procedures. There was wide variation in surgery case duration for patients undergoing common general surgical and orthopedic surgeries. This variability in care delivery may represent an important opportunity to promote more efficient use of health care resources.


Serum thyrotropin receptor antibodies concentrations in patients with Graves' disease before, at the end of methimazole treatment, and after drug withdrawal: evidence that the activity of thyrotropin receptor antibody and/or thyroid response modify during the observation period.
We performed a quantitative retrospective analysis of serum thyrotropin receptor antibody (TRAb) concentrations measured by a second-generation radioreceptor assay in 58 patients with Graves' disease (GD) at the onset of the disease, at the end of 18 month methimazole (MMI) treatment, and after MMI withdrawal in order to evaluate the correlation between the presence of these antibodies and the relapse of hyperthyroidism. Sixty healthy subjects were enrolled as a control group. Before MMI treatment the best cutoff TRAb value for identifying patients with GD was 1.45 UI/L (specificity, 100%; sensitivity, 98.3%). At the end of MMI treatment, serum TRAb concentrations were significantly lower (p < 0.001) than those measured at baseline, but they were still significantly higher (p < 0.001) than those found in the control subjects. At the end of MMI treatment, 44 patients (75.9%) had positive TRAb values (>1.45 UI/L). After MMI withdrawal (median, 15 months), 34 patients (58.6%) became hyperthyroid, 4 patients (6.9%) became hypothyroid, and 20 patients (34.5%) remained euthyroid. There was a significant correlation between serum TRAb concentrations at the end of MMI treatment and the percentage of patients who became hyperthyroid (r: 0.56; p < 0.001) and the time of appearance of hyperthyroidism (r: -0.38; p = 0.03). All 4 patients with TRAb values below 0.9 UI/L at the end of MMI treatment remained euthyroid throughout the follow-up period. Among the 27 patients who had serum TRAb values higher than 4.4 UI/L, 23 developed hyperthyroidism and 4 hypothyroidism. The TRAb values between 0.9 and 4.4 UI/L did not discriminate between the 27 patients (46.6%) who remained euthyroid from those who had relapse of hyperthyroidism. Thus a different TRAb end of treatment cutoff was calculated to identify patients who became again hyperthyroid. This TRAb cutoff value was 3.85 UI/L (sensitivity, 85.3%; specificity, 96.5%). All but 1 patient who had serum TRAb values above 3.85 UI/L became hyperthyroid after MMI was withdrawn (positive predictive value, 96.7%). In these patients, relapse of hyperthyroidism was independent of the changes in serum TRAb concentrations (r: 0.27; p = 0.15) and occurred after a median period of 8 weeks (range, 4-48). Hyperthyroidism also developed in 5 of 24 patients who had serum TRAb concentrations lower than 3.85 UI/L at the end of MMI treatment. In these 5 patients the relapse of hyperthyroidism occurred after a median period of 56 weeks (range, 24-120) and was always accompanied by an increase in serum TRAb concentrations. TRAb persist in the blood of most patients with GD after 18 months of MMI treatment. Both the frequency and the time of appearance of hyperthyroidism are closely correlated with serum TRAb concentrations at the end of MMI treatment. Our data would suggest that TRAb maintain stimulating activity after a full course of MMI treatment in the large majority of patients with GD. However, it is likely that the potency of these antibodies and/or the thyroid response to them change during treatment, as suggested by the different values measured in euthyroid control subjects and in euthyroid patients after MMI treatment.


Prescribing at the hospital-general practice interface. II: Impact of hospital outpatient dispensing policies in England on general practitioners and hospital consultants.
To assess the impact on general practitioners and hospital consultants of hospital outpatient dispensing policies in England. Postal questionnaire and telephone interview survey of general practitioners and hospital consultants in January 1991. 94 selected major acute hospitals in England. 20 general practitioners in the vicinity of each of 94 selected hospitals and eight consultants from each, selected by chief pharmacists. Proportions of general practitioners unable to assume responsibility for specialist drugs and of consultants wishing to retain responsibility; association between dispensing restrictions and the frequency of general practitioners being asked to prescribe hospital initiated treatments. Completed questionnaires were obtained from 1207 (64%) of 1887 general practitioners and 457 (63%) of 729 consultants. 570 (46%) general practitioners felt unable to take responsibility for certain treatments, principally because of difficulty in detecting side effects (367, 30%), uncertainty about explaining treatment to patients (332, 28%), and difficulty monitoring dosage (294, 24%). Among consultants 328 (72%) wished to retain responsibility, principally because of specialist need for monitoring (93, 20%), urgent need to commence treatment (64, 14%), and specialist need to initiate or stabilise treatment (63, 14%). The more restricted the drug supply to outpatients, the more frequently consultants asked general practitioners to prescribe (p less than 0.01) and complete a short course of treatment initiated by the hospital (p less than 0.001). Restrictive hospital outpatient dispensing shifts clinical responsibility on to general practitioners. Hospital doctors should be able to retain responsibility for prescribing when the general practitioner is unfamiliar with the drug or there is a specialist need to initiate, stabilise, or monitor treatment.


A Randomized Phase II Preoperative Study of Autophagy Inhibition with High-Dose Hydroxychloroquine and Gemcitabine/Nab-Paclitaxel in Pancreatic Cancer Patients.
We hypothesized that autophagy inhibition would increase response to chemotherapy in the preoperative setting for patients with pancreatic adenocarcinoma. We performed a randomized controlled trial to assess the autophagy inhibitor hydroxychloroquine in combination with gemcitabine and nab-paclitaxel. Participants with potentially resectable tumors were randomized to two cycles of nab-paclitaxel and gemcitabine (PG) alone or with hydroxychloroquine (PGH), followed by resection. The primary endpoint was histopathologic response in the resected specimen. Secondary clinical endpoints included serum CA 19-9 biomarker response and margin negative R0 resection. Exploratory endpoints included markers of autophagy, immune infiltrate, and serum cytokines. Thirty-four patients in the PGH arm and 30 in the PG arm were evaluable for the primary endpoint. The PGH arm demonstrated statistically improved Evans grade histopathologic responses (P = 0.00016), compared with control. In patients with elevated CA 19-9, a return to normal was associated with improved overall and recurrence-free survival (P < 0.0001). There were no differences in serious adverse events between arms and chemotherapy dose number was equivalent. The PGH arm had greater evidence of autophagy inhibition in their resected specimens (increased SQSTM1, P = 0.027, as well as increased immune cell tumor infiltration, P = 0.033). Overall survival (P = 0.59) and relapse-free survival (P = 0.55) did not differ between the two arms. The addition of hydroxychloroquine to preoperative gemcitabine and nab-paclitaxel chemotherapy in patients with resectable pancreatic adenocarcinoma resulted in greater pathologic tumor response, improved serum biomarker response, and evidence of autophagy inhibition and immune activity.


Phase II trial of carmustine plus O(6)-benzylguanine for patients with nitrosourea-resistant recurrent or progressive malignant glioma.
We conducted a phase II trial of carmustine (BCNU) plus the O(6)-alkylguanine-DNA alkyltransferase inhibitor O(6)-benzylguanine (O(6)-BG) to define the activity and toxicity of this regimen in the treatment of adults with progressive or recurrent malignant glioma resistant to nitrosoureas. Patients were treated with O(6)-BG at an intravenous dose of 120 mg/m(2) followed 1 hour later by 40 mg/m(2) of BCNU, with cycles repeated at 6-week intervals. Eighteen patients were treated (15 with glioblastoma multiforme, two with anaplastic astrocytoma, and one with malignant glioma). None of the 18 patients demonstrated a partial or complete response. Two patients exhibited stable disease for 12 weeks before their tumors progressed. Three patients demonstrated stable disease for 6, 12, and 18 weeks before discontinuing therapy because of hematopoietic toxicity. Twelve patients experienced reversible > or = grade 3 hematopoietic toxicity. There was no difference in half-lives (0.56 +/- 0.21 hour v 0.54 +/- 0.20 hour) or area under the curve values (4.8 +/- 1.7 microg/mL/h v 5.0 +/- 1.3 microg/mL/h) of O(6)-BG for patients receiving phenytoin and those not treated with this drug. These results indicate that O(6)-BG plus BCNU at the dose schedule used in this trial is unsuccessful in producing tumor regression in patients with nitrosourea-resistant malignant glioma, although stable disease was seen in five patients for 6, 12, 12, 12, and 18 weeks. Future use of this approach will require strategies to minimize dose-limiting toxicity of BCNU such as regional delivery or hematopoietic stem-cell protection.


Increased alpha-amylase response to an acute psychosocial stress challenge in healthy adults with childhood adversity.
Childhood adversity is highly prevalent and linked to lasting psychological and physiological consequences. A potential mechanism for negative health outcomes is altered stress reactivity. While previous research has addressed associations of childhood adversity with stress system reactivity, sympathetic nervous system (SNS) stress reactivity is understudied. We therefore set out here to examining salivary alpha-amylase (sAA) reactivity in relation with childhood adversity. Forty-one healthy adult subjects (n = 24 male; n = 17 female) aged 18-34 years underwent the Trier Social Stress Test (TSST) and completed the Childhood Trauma Questionnaire (CTQ). Saliva for measurement of sAA was collected at three time points; before the TSST, immediately after, and 10 min post-TSST. We found that those with childhood trauma had a higher overall sAA response to the TSST, as seen in a repeated measures ANOVA (CTQ by time interaction: F(1.8,71.5) = 6.46, p = .01) and an independent samples t-test indicating higher sAA baseline to peak response (t = 3.22, p = .003). There was also a positive correlation between sAA reactivity and the CTQ subscales of childhood physical abuse (r = .46, p = .005) and emotional abuse (r = .37, p = .024). Healthy adults with low-to-moderate childhood adversity had a heightened sAA response immediately following the stressor. Higher SNS reactivity could be a link to negative health outcomes in adults with early adversity. Future research should address whether altered sAA reactivity is predictive of negative health outcomes in those with childhood adversity.


Evidence for cysteine persulfide as reaction product of L-Cyst(e)ine C-S-lyase (C-DES) from Synechocystis. Analyses using cystine analogues and recombinant C-DES.
The pyridoxal phosphate-dependent monomeric L-cysteine/cystine C-S-lyase (C-DES), previously isolated from Synechocystis PCC 6714 by its capacity to direct [2Fe-2S] cluster assembly of ferredoxin in vitro (Leibrecht, I., and Kessler, D. (1997) J. Biol. Chem. 272, 10442-10447), has now been cloned, sequenced, and overexpressed in Escherichia coli. The amino acid sequence of C-DES was found to be nearly identical (92% identity) to the open reading frame slr2143 of Synechocystis PCC 6803 and showed a more distant relationship to the NifS family of proteins (about 27% identity). Recombinant C-DES displayed activities equal to the isolate from Synechocystis in terms of the cyst(e)ine lyase reaction and holoferredoxin formation which recommended its use for functional and mechanistic studies. Investigation of the substrate spectrum for beta-elimination found L-cysteine to be a poor substrate (kcat approximately 0.15 s-1) in contrast to L-cystine (kcat = 36 s-1) and several related compounds. Of these compounds, desaminocystine (S-(carboxyethylthio)-L-cysteine) was used for C-DES-mediated persulfide generation. Stabilization of the linear persulfide 3-(disulfanyl)-propionic acid was achieved by cyclization as a novel intramolecular trapping reaction; this yielded 1,2-dithiolan-3-one which was isolated and identified by chemical analyses.


The discovery net system for high throughput bioinformatics.
Bioinformatics requires Grid technologies and protocols to build high performance applications without focusing on the low level detail of how the individual Grid components operate. The Discovery Net system is a middleware that allows service developers to integrate tools based on existing and emerging Grid standards such as web services. Once integrated, these tools can be used to compose reusable workflows using these services that can later be deployed as new services for others to use. Using the Discovery Net system and a range of different bioinformatics tools, we built a Grid based application for Genome Annotation. This includes workflows for automatic nucleotide annotation, annotation of predicted proteins and text analysis based on metabolic profiles and text analysis.


Regulation of HIF-1α signaling and chemoresistance in acute lymphocytic leukemia under hypoxic conditions of the bone marrow microenvironment.
Overcoming resistance to chemotherapy is the main therapeutic challenge in the treatment of acute lymphocytic leukemia (ALL). Interactions between leukemia cells and the microenvironment promote leukemia cell survival and confer resistance to chemotherapy. Hypoxia is an integral component of bone marrow (BM) microenvironment. Hypoxia-inducible factor-1α (HIF-1), a key regulator of the cellular response to hypoxia, regulates cell growth and metabolic adaptation to hypoxia. HIF-1α expression, analyzed by Reverse Phase Protein Arrays in 92 specimens from newly diagnosed patients with pre-B-ALL, had a negative prognostic impact on survival (p = 0.0025). Inhibition of HIF-1α expression by locked mRNA antagonist (LNA) promoted chemosensitivity under hypoxic conditions, while pharmacological or genetic stabilization of HIF-1α under normoxia inhibited cell growth and reduced apoptosis induction by chemotherapeutic agents. Co-culture of pre-B ALL or REH cells with BM-derived mesenchymal stem cells (MSC) under hypoxia resulted in further induction of HIF-1α protein and acquisition of the glycolytic phenotype, in part via stroma-induced AKT/mTOR signaling. mTOR blockade with everolimus reduced HIF-1α expression, diminished glucose uptake and glycolytic rate and partially restored the chemosensitivity of ALL cells under hypoxia/stroma co-cultures. Hence, mTOR inhibition or blockade of HIF-1α-mediated signaling may play an important role in chemosensitization of ALL cells under hypoxic conditions of the BM microenvironment.


Medullary carcinoma of the large intestine: a population based analysis.
Medullary carcinoma (MC) of the colorectum is a relatively new histological type of adenocarcinoma characterized by poor glandular differentiation and intraepithelial lymphocytic infiltrate. To date, there has been no epidemiological study of this rare tumor type, which has now been incorporated as a separate entity in the World Health Organization (WHO) classification of colorectal cancers. We used the population-based registries of the Surveillance, Epidemiology and End Results (SEER) database to identify all cases of colorectal MC between 1973 and 2006 and compared them to poorly and undifferentiated colonic adenocarcinomas (PDA and UDA, respectively). We observed that MCs were rare tumors, constituting approximately 5-8 cases for every 10,000 colon cancers diagnosed, with a mean annual incidence of 3.47 (+/-0.75) per 10 million population. Mean age at diagnosis was 69.3 (+/-12.5) years, with incidence increasing with age. MCs were twice as common in females, who presented at a later age, with a lower stage and a trend towards favorable prognosis. MCs were extremely rare among African-Americans. MCs were most common in the proximal colon (74%), where they present at a later age than the sigmoid colon. There were no cases reliably identified in the rectum or appendix. Serum carcinoembryonic antigen levels (CEA) were elevated prior to first course of treatment in 40% of the patients. MCs were more commonly poorly differentiated (72%), with 22% being undifferentiated. MCs commonly presented with Stage II disease, with 10% presenting with metastases. Only one patient presented with N2b disease (>7 positive nodes). Early outcome analyses showed that MCs have 1- and 2-year relative survival rates of 92.7 and 73.8% respectively. Although MCs showed a trend towards better early overall survival, undifferentiated MCs present more commonly with Stage III, with comparatively worse early outcomes.


Photosensitivity spectrum of crayfish rhodopsin measured using fluorescence of metarhodopsin.
Discrepancies exist among spectral measurements of sensitivity of crayfish photoreceptors, their absorption in situ, and the number and absorption spectra of crayfish photopigments that are extracted by digitonin solutions. We have determined the photosensitivity spectrum of crayfish rhodopsin in isolated rhabdoms using long wavelength fluorescence emission from crayfish metarhodopsin as an intrinsic probe. There is no measurable metarhodopsin in the dark-adapted receptor, so changes in the emission level are directly proportional to metarhodopsin concentration. We therefore used changes in metarhodopsin fluorescence to construct relaxation and saturation ("photoequilibrium") spectra, from which the photosensitivity spectrum of crayfish rhodopsin was calculated. This spectrum peaks at or approximately 530 nm and closely resembles the previously measured difference spectrum for total bleaches of dark-adapted rhabdoms. Measurements of the kinetics of changes in rhabdom fluorescence and in transmittance at 580 nm were compared with predictions derived from several model systems containing one or two photopigments. The comparison shows that only a single rhodopsin and its metarhodopsin are present in the main rhabdom of crayfish, and that other explanations must be sought for the multiple pigments seen in digitonin solution. The same analysis shows that there is no detectable formation of isorhodopsin in the rhabdom.


Personality and coping in first episode psychosis linked to mental health care use.
A body of literature focuses on associations of neuroticism, extraversion, passive coping and active coping with the course of psychotic illness. Less is known about other personality and coping variables - and underlying causal mechanisms between variables remain unclear. We explored causal effects from personality, coping and symptoms on mental health care consumption over two years in 208 first episode patients. Causal inference search algorithms lead to formation of a hypothetical causal model based on presumptions on (non-)mutuality between variables and consistent with data. Structural equation modelling estimated effect sizes conditionally on the causal model. Our observed model implies that none of the coping or personality variables have any effect on the number of days of hospitalisation, whereas general psychopathology symptoms do have a direct positive effect. For ambulatory care it is proposed that openness to experience, depressive symptoms and age have direct positive effects. Reassuring thoughts as a coping strategy seems to have a direct negative effect on the use of ambulatory care and mediates indirect effects of other personality and coping variables on ambulatory care. Furthermore, while previously established relations between personality and symptoms are confirmed by our model, it challenges traditional ideas about causation between personality and symptoms.


Peer intervention effects on communicative interaction among handicapped and nonhandicapped preschoolers.
A peer-mediated intervention designed to promote communicative interaction on the part of three language-delayed children was evaluated. Two nonhandicapped preschoolers were taught strategies thought to facilitate interaction and were prompted to use these strategies during free play with three handicapped classmates. The intervention resulted in higher rates of interaction for each of the handicapped children that persisted above baseline levels after teacher prompting was withdrawn.


Pigment epithelium-derived factor, a human testis epididymis secretory product, promotes human prostate stromal cell growth in culture.
We identified and characterized unrecognized testicular secretory proteins that impact human prostate growth. Human spermatocele fluid served as a source of testicular epididymal secretions and prostatectomy specimen benign prostatic hyperplasia stromal cells as the in vitro prostate growth promoting effects indicator. RMPI plus medium supplemented with 10% fetal bovine serum MALDI-TOF, MS FBS and ITS+ (Collaborative Research-Becton Dickinson, Bedford, Massachusetts) served as positive and negative controls, respectively. Whole and fractionated spermatocele fluid or specific proteins without and with select polyclonal or monoclonal antibodies were added to routine 6-day cultures. The observation of significantly increased 6-day cell counts compared with appropriate controls (p <0.05) was judged to reflect cell growth. Amino acid microsequencing and MALDI-TOF MS sequence analysis were done on persistent protein bands from active spermatocele fluid fractions. Whole and fractionated human spermatocele fluid increased stromal cell culture numbers significantly. Sequence analysis of 47 and 17 kDa 1-dimensional gel bands in the final active fraction identified a major peptide with sequence homology to human pigment epithelium-derived factor (PEDF). The presence of PEDF was confirmed by Western blot analysis. Addition of recombinant PEDF to incomplete medium significantly increased stromal cell culture number. PEDF antibodies neutralized or markedly decreased the stromal stimulating effect of spermatocele fluid and PEDF. The observations presented provide evidence for human testis/epididymis secretion of PEDF and for a PEDF in vitro growth promoting effect on benign prostatic hyperplasia stroma. The concept that testicular epididymal secretory proteins may influence normal and abnormal prostate growth warrants continued consideration.


MIIP is downregulated in gastric cancer and its forced expression inhibits proliferation and invasion of gastric cancer cells in vitro and in vivo.
MIIP is associated with cancer progression in various cancers. However, its expression pattern, and associated molecular mechanisms in gastric cancer (GC) progression are still mysterious. We aimed to explore the role of MIIP in proliferation and invasion of GC. MIIP expression was evaluated in human GC tissues and cell lines. Public clinical database of GC patients was used to probe the correlation between MIIP expression and prognosis of patients. The effects of forced MIIP expression on GC cells were determined by MTT, cell cycle distribution, colony formation, wound-healing and Transwell assays in vitro, as well as in vivo growth of subcutaneous tumor xenografts and metastasis of xenografted tumors to the lungs in mice. The expressions of GC progression-associated genes, including HOTAIR, MALAT1, HDAC6, AC-tubulin, and cyclin D1, were assessed by Western blotting or qRT-PCR. Both GC tissues and GC cell lines had lower MIIP expression. Higher level of MIIP in GC tissues predicts better survival in patients. Ectopic expression of MIIP in GC cell lines BGC823 and HGC27 induced G0/G1 cell cycle arrest and inhibited cell proliferation, colony formation, migration and invasion in vitro, as well as the growth of GC xenografts and metastasis of tumors in vivo. Furthermore, overexpression of MIIP suppressed mRNA expressions of HOTAIR and MALAT1, decreased protein expression of HDAC6 and cyclin D1, and elevated AC-tubulin protein expression. MIIP is a suppressor for GC progression and is a potential therapeutic target for treating GC.


Yellow fever: epidemiology and prevention.
Yellow fever continues to occur in regions of Africa and South America, despite the availability of effective vaccines. Recently, some cases of severe neurologic disease and multiorgan system disease have been described in individuals who received yellow fever vaccine. These events have focused attention on the need to define criteria for judicious use of yellow fever vaccine and to describe the spectrum of adverse events that may be associated with yellow fever vaccine. Describing host factors that would increase risk of these events and identifying potential treatment modalities for yellow fever and yellow fever vaccine-associated adverse events are subjects of intense investigation.


Localized delivery of methylprednisolone sodium succinate with polymeric nanoparticles in experimental injured spinal cord model.
With important social and economic consequences, spinal cord injuries (SCIs) still exist among major health problems. Although many therapeutic agents and methods investigated for the treatment of acute SCI, only high dose methylprednisolone (MP) is being used currently in practice. Due to the serious side effects, high dose systemic MP administration after SCI is a critical issue that is mostly considered controversial. In our study, it is aimed to develop a nanoparticle-gel combined drug delivery system for localization of MP on trauma site and eliminating dose-dependent side effects by lowering the administered dose. For this purpose, methyl prednisolone sodium succinate (MPSS) loaded polycaprolactone based nanoparticles were developed and embedded in an implantable fibrin gel. The effects of MPSS delivery system are evaluated on an acute SCI rat model, by quantification the levels of three inflammatory cytokines (interleukin-1β, interleukin-6 and caspase-3) and assessment of the damage on ultrastructural level by transmission electron microscopy. Developed NP-gel system showed very similar results with systemic high dose of MPSS. It is believed that developed system may be used as a tool for the safe and effective localized delivery of several other therapeutic molecules on injured spinal cord cases.


Chemical analysis of the Alphaproteobacterium strain MOLA1416 associated with the marine lichen Lichina pygmaea.
Alphaproteobacterium strain MOLA1416, related to Mycoplana ramosa DSM 7292 and Chelativorans intermedius CC-MHSW-5 (93.6% 16S rRNA sequence identity) was isolated from the marine lichen, Lichina pygmaea and its chemical composition was characterized by a metabolomic network analysis using LC-MS/MS data. Twenty-five putative different compounds were revealed using a dereplication workflow based on MS/MS signatures available through GNPS (https://gnps.ucsd.edu/). In total, ten chemical families were highlighted including isocoumarins, macrolactones, erythrinan alkaloids, prodiginines, isoflavones, cyclohexane-diones, sterols, diketopiperazines, amino-acids and most likely glucocorticoids. Among those compounds, two known metabolites (13 and 26) were isolated and structurally identified and metabolite 26 showed a high cytotoxic activity against B16 melanoma cell lines with an IC50 0.6 ± 0.07 μg/mL.


Discriminative feature co-occurrence selection for object detection.
This paper describes an object detection framework that learns the discriminative co-occurrence of multiple features. Feature co-occurrences are automatically found by Sequential Forward Selection at each stage of the boosting process. The selected feature co-occurrences are capable of extracting structural similarities of target objects leading to better performance. The proposed method is a generalization of the framework proposed by Viola and Jones, where each weak classifier depends only on a single feature. Experimental results obtained using four object detectors, for finding faces and three different hand gestures, respectively, show that detectors trained with the proposed algorithm yield consistently higher detection rates than those based on their framework while using the same number of features.


Role of bone scintigraphy and tumor marker-Ca 15-3 in detection of bone metastases in patients with breast cancer.
Breast cancer is one of the most frequent types of cancer affecting women. After hematogenous spreading of cancer, axial skeleton is most frequently involved. Bone scintigraphy is commonly performed in detection and evaluation of bone metastases. In breast cancer, marker Ca 15-3 is widely accepted in follow-up and detection of disease recurrence. Aim of the study was to correlate levels of tumor marker Ca 15-3 and presence of bone metastases detected by bone scintigraphy. Study included 25 patients with breast cancer, previously surgically treated. All patients underwent total body scintigraphy. Ca 15-3 was measured by radioimmunoassay. Presence, number and location of bone metastases were correlated with Ca 15-3 levels. Bone scintigraphy revealed bone metastases in 16 (64%) patients. 11 (44%) patients with metastases and 1 patient (4%) without scintigraphically visible metastases had elevated Ca 15-3 levels. Significant difference in distribution of metastases was found for spine (t=3.930, p=0.008). Correlation between intensity of radiopharmaceutical uptake and level of Ca 15-3 in patients was positive (r =0.405). A weak correlation was found between number of metastases and level of Ca 15-3 (r=0.139). Significant differences in Ca 15-3 level was found in patients with metastases compared to patients without metastases (chi square 0, p =1.0). Since no significant correlation was found between level of Ca 15-3 and number of metastases, we consider scintigraphy an appropriate method for assessment of bone metastases in breast cancer.


Characterization of Imidazopyridine Compounds as Negative Allosteric Modulators of Proton-Sensing GPR4 in Extracellular Acidification-Induced Responses.
G protein-coupled receptor 4 (GPR4), previously proposed as the receptor for sphingosylphosphorylcholine, has recently been identified as the proton-sensing G protein-coupled receptor (GPCR) coupling to multiple intracellular signaling pathways, including the Gs protein/cAMP and G13 protein/Rho. In the present study, we characterized some imidazopyridine compounds as GPR4 modulators that modify GPR4 receptor function. In the cells that express proton-sensing GPCRs, including GPR4, OGR1, TDAG8, and G2A, extracellular acidification stimulates serum responsive element (SRE)-driven transcriptional activity, which has been shown to reflect Rho activity, with different proton sensitivities. Imidazopyridine compounds inhibited the moderately acidic pH-induced SRE activity only in GPR4-expressing cells. Acidic pH-stimulated cAMP accumulation, mRNA expression of inflammatory genes, and GPR4 internalization within GPR4-expressing cells were all inhibited by the GPR4 modulator. We further compared the inhibition property of the imidazopyridine compound with psychosine, which has been shown to selectively inhibit actions induced by proton-sensing GPCRs, including GPR4. In the GPR4 mutant, in which certain histidine residues were mutated to phenylalanine, proton sensitivity was significantly shifted to the right, and psychosine failed to further inhibit acidic pH-induced SRE activation. On the other hand, the imidazopyridine compound almost completely inhibited acidic pH-induced action in mutant GPR4. We conclude that some imidazopyridine compounds show specificity to GPR4 as negative allosteric modulators with a different action mode from psychosine, an antagonist susceptible to histidine residues, and are useful for characterizing GPR4-mediated acidic pH-induced biological actions.


[Effect of metaphos on the bile-forming function of the liver].
In experiments with albino male rats the effect of a single introduction into the stomach of methaphos in doses of DL50, 1/10 DL50, 1/20 DL50, 1/50 DL50 and also of a daily consumption of the compound for a month was studied. Metaphos was found to exert a manysided action on the cholopoietic function of the liver, viz. it increases the intensity of the bile secretion, inhibits the synthesis of primary bile acids and conjugation of cholic acid with taurine and glycine, stimulates the formation, conjugation and secretion of bilirubin.


The effects of sensorimotor training on anticipatory postural adjustment of the trunk in chronic low back pain patients.
[Purpose] This study aimed to examine the effects of sensorimotor training on the anticipatory postural adjustment (APA) of chronic low back pain (CLBP) patients. [Subjects and Methods] Fourteen CLBP patients were randomly assigned to Group II (ordinary physical therapy, n=7) and Group III (sensorimotor training, n=7). In addition, a normal group (Group I) consisting of seven subjects was chosen as the control group. The two CLBP groups received their own treatment five times per week, for four weeks, for 40 minutes each time. Changes in pain and functional performance evaluation were examined by the visual analogue scale (VAS) and the Oswestry Disability Index (ODI). In order to look at the change in APA, muscle onset time was examined using electromyography (EMG). [Results] Group III showed significant changes in both VAS and ODI. According to comparison of the results for muscle onset time, there were significant decreases in Group III's transversus abdominis muscle (TrA) and external oblique muscle (EO) in the standing and sitting positions. There were significant differences between Group II and III in terms of the TrA in the sitting position. [Conclusion] Sensorimotor training makes patients capable of learning how to adjust muscles, thereby alleviating pain and improving muscle performance.


[Topographic correlation between basilar artery occlusion and cerebellar involvement--a clinicopathological study].
Nineteen patients (15 men, 4 women) with occlusion of the vertebrobasilar artery were studied in order to identify possible pathomechanism and to define the site of arterial occlusion and the topography of ischemic lesion of the cerebellum. Their mean age at onset was 66.7 years and the final clinicopathological diagnosis were thrombosis of the basilar artery (BA) in 15 patients and embolism in 4. The occlusion of the BA was contiguous to that of the vertebral artery in ten patients. Of these, the occlusion was localized to the caudal portion of the BA in two, to the middle portion in six, and extended to the rostral portion in two. In eight patients, the arterial occlusion was restricted to the BA. Occlusions of the middle portion were observed in four and that of rostral portion in two; in the other two patients, the whole BA was occluded. In one patient, there was no occlusion in the vertebro-basilar artery at the postmortem examination, but infarctions of the base of pons, bilateral cerebellar hemispheres and occipital lobes were confirmed, suggesting recanalization of the occluded BA. Cerebellar lesions were observed in all nineteen patients. Involvements of the area supplied by the superior cerebellar artery (SCA) were found in seventeen, while that of the posterior inferior cerebellar artery (PICA) only in ten. Eight patients had cerebellar lesions supplied by both SCA and PICA. These facts suggest that cerebellar lesions are rather frequent and the SCA areas are more involved than those of the PICA in fatal patients with occlusion of the BA.(ABSTRACT TRUNCATED AT 250 WORDS)


Collecting in collections: a PCR strategy and primer set for DNA barcoding of decades-old dried museum specimens.
Natural history museums are vastly underutilized as a source of material for DNA analysis because of perceptions about the limitations of DNA degradation in older specimens. Despite very few exceptions, most DNA barcoding projects, which aim to obtain sequence data from all species, generally use specimens collected specifically for that purpose, instead of the wealth of identified material in museums, constrained by the lack of suitable PCR methods. Any techniques that extend the utility of museum specimens for DNA analysis therefore are highly valuable. This study first tested the effects of specimen age and PCR amplicon size on PCR success rates in pinned insect specimens, then developed a PCR primer set and amplification strategy allowing greatly increased utilization of older museum specimens for DNA barcoding. PCR success rates compare favourably with the few published studies utilizing similar aged specimens, and this new strategy has the advantage of being easily automated for high-throughput laboratory workflows. The strategy uses hemi-nested, degenerate, M13-tailed PCR primers to amplify two overlapping amplicons, using two PCRs per amplicon (i.e. four PCRs per DNA sample). Initial PCR products are reamplified using an internal primer and a M13 primer. Together the two PCR amplicons yield 559 bp of the COI gene from Coleoptera, Lepidoptera, Diptera, Hemiptera, Odonata and presumably also other insects. BARCODE standard-compliant data were recovered from 67% (56 of 84) of specimens up to 25 years old, and 51% (102 of 197) of specimens up to 55 years old. Given the time, cost and specialist expertise required for fieldwork and identification, 'collecting in collections' is a viable alternative allowing researchers to capitalize on the knowledge captured by curation work in decades past.


Caveolar localization dictates physiologic signaling of beta 2-adrenoceptors in neonatal cardiac myocytes.
There is a growing body of evidence that G protein-coupled receptors function in the context of plasma membrane signaling compartments. These compartments may facilitate interaction between receptors and specific downstream signaling components while restricting access to other signaling molecules. We recently reported that beta(1)- and beta(2)-adrenergic receptors (AR) regulate the intrinsic contraction rate in neonatal mouse myocytes through distinct signaling pathways. By studying neonatal myocytes isolated from beta(1)AR and beta(2)AR knockout mice, we found that stimulation of the beta(1)AR leads to a protein kinase A-dependent increase in the contraction rate. In contrast, stimulation of the beta(2)AR has a biphasic effect on the contraction rate. The biphasic effect includes an initial protein kinase A-independent increase in the contraction rate followed by a sustained decrease in the contraction rate that can be blocked by pertussis toxin. Here we present evidence that caveolar localization is required for physiologic signaling by the beta(2)AR but not the beta(1)AR in neonatal cardiac myocytes. Evidence for beta(2)AR localization to caveolae includes co-localization by confocal imaging, co-immunoprecipitation of the beta(2)AR and caveolin 3, and co-migration of the beta(2)AR with a caveolin-3-enriched membrane fraction. The beta(2)AR-stimulated increase in the myocyte contraction rate is increased by approximately 2-fold and markedly prolonged by filipin, an agent that disrupts lipid rafts such as caveolae and significantly reduces co-immunoprecipitation of beta(2)AR and caveolin 3 and co-migration of beta(2)AR and caveolin-3 enriched membranes. In contrast, filipin has no effect on beta(1)AR signaling. These observations suggest that beta(2)ARs are normally restricted to caveolae in myocyte membranes and that this localization is essential for physiologic signaling of this receptor subtype.


Analysis of selective target engagement by small-molecule sphingosine kinase inhibitors using the Cellular Thermal Shift Assay (CETSA).
The recently renewed interest in scientific rigor and reproducibility is of critical importance for both scientists developing new targeted small-molecule inhibitors and those employing these molecule in cellular studies, alike. While off-target effects are commonly considered as limitations for any given small-molecule inhibitor, the ability of a given compound to distinguish between enzyme isoforms is often neglected when employing compounds in cellular studies. To call attention to this issue, we have compared the results of an assay for "direct target engagement", the Cellular Thermal Shift Assay (CETSA), to the published isoform selectivity of 12 commercially available sphingosine kinase 1 and 2 (SphK 1 and SphK2) inhibitors. Our results suggest that, at the concentrations commonly employed in cellular assay systems, none of the tested SKIs can be considered isoform selective. Thus, caution and complimentary assay strategies must be employed to fully discern isoform selectivity for the SphKs. Moreover, caution must be employed by the scientific community as a whole when designing experiments that aim to discern the effects of one enzyme isoform versus another to ensure that the concentration ranges used are able to distinguish isoform selectivity.


Examination of lymphocyte membranes of athymic "nude" mice by scanning electron microscopy.
Recent reports 1-3 have proposed that T-lymphocytes (thymus derived) could be distinguished from B-lymphocytes (thymus independent) by examining their features under the scanning electron microscope. T-cells were designated as having relatively smooth surfaced cells, whereas B-cells had "hairy" surfaces with many microvilli. We have examined this hypothesis in congenitally athymic "nude" mice, animals lacking T-cells,4 and have not been able to confirm these reports. We have found that lymphocytes from nude (nu/nu) mice are indistinguishable from lymphocytes obtained from normal littermates (NLM) and CBA/J mice. We have found that in all the murine lymphoid tissue examined, including nude, the complete gamut of cell surface types, ranging from smooth to "hairy" are present. Our studies indicate that the proposed T- and B-cell classification based upon human surface morphology under the scanning electron microscope is questionable in a mouse model. It is presently unclear whether the smooth lymphocytes seen in nude mice are immature B-cells, pre-T-cells, or another unidentified population of cells.


Biomechanical Differences Between Japanese and American Professional Baseball Pitchers.
Although baseball injuries are common in both Japan and the United States, the majority of pitching injuries in Japanese players occur at the shoulder, whereas most pitching injuries in American players occur at the elbow. A biomechanical comparison between Japanese and American pitchers may help to identify the different injury mechanisms. Japanese pitchers produce greater shoulder kinetics whereas American pitchers generate greater elbow kinetics. Also, kinematic differences will be found between the 2 groups, including longer stride and greater lead knee flexion for Japanese pitchers. Descriptive laboratory study. Biomechanical data for 19 Japanese professional baseball pitchers and an age-matched group of 19 American professional baseball pitchers were collected by use of a 3-dimensional, automated, high-speed optical motion capture system. Anthropometric, kinetic, and kinematic data for both groups were compared by use of t tests (P < .05). American pitchers were taller and heavier and generated greater ball velocity (38.1 ± 1.6 vs 34.7 ± 1.1 m/s; P < .001) than their Japanese counterparts. Most elbow and shoulder kinetic parameters, including elbow varus torque (99 ± 17 vs 86 ± 17 N·m; P = .018), were greater for American pitchers. However, when normalized by bodyweight and height, shoulder horizontal adduction torque was greater for Japanese pitchers (6.8% ± 1.0% vs 5.8% ± 1.1%; P = .005). Japanese pitchers had longer stride (86% ± 5% vs 82% ± 6% of height; P = .023), greater shoulder abduction at ball release (101° ± 8° vs 94° ± 9°; P = .014), and greater knee flexion after ball release (39° ± 18° vs 28° ± 14°; P = .039). Japanese pitchers also demonstrated greater shoulder internal rotation velocity, elbow flexion, and elbow extension velocity. Greater elbow varus torque may predispose American pitchers to greater risk of elbow injury. Japanese pitchers may have increased risk of shoulder injury due to greater normalized horizontal adduction torque and greater abduction angle. Japanese pitchers may be able to reduce their shoulder torque and risk of injury by shortening their stride, reducing their lead knee flexion, and decreasing their throwing arm abduction. Understanding anthropometric, kinetic, and kinematic differences between pitchers from the 2 countries may be of value to clinicians and coaches working to maximize performance of the pitchers while minimizing the risk of injury.


Reperfused hemorrhagic myocardial infarction in rats.
Intramyocardial hemorrhage following reperfusion is strongly associated with major adverse cardiovascular events in myocardial infarction (MI) patients; yet the mechanisms contributing to these outcomes are not well understood. Large animal models have been used to investigate intramyocardial hemorrhage, but they are exorbitantly expensive and difficult to use for mechanistic studies. In contrast, rat models are widely used to investigate mechanistic aspects of cardiovascular physiology, but a rat model that consistently recapitulates the characteristics of an hemorrhagic MI does not exist. To bridge this gap, we investigated the physiological conditions of MI that would create intramyocardial hemorrhage in rats so that a reliable model of hemorrhagic MI would become available for basic research. Sprague-Dawley rats underwent either a 90-minute (90-min) ischemia and then reperfusion (I/R) (n = 22) or 30-minute (30-min) I/R (n = 18) of the left anterior descending coronary artery. Sham rats (n = 12) were used as controls. 90-min I/R consistently yielded hemorrhagic MI, while 30-min I/R consistently yielded non-hemorrhagic MI. Twenty-four hours post-reperfusion, ex-vivo late-gadolinium-enhancement (LGE) and T2* cardiac MRI performed on excised hearts from 90-min I/R rats revealed colocalization of iron deposits within the scarred tissue; however, in 30-min I/R rats scar was evident on LGE but no evidence of iron was found on T2* CMR. Histological studies verified tissue damage (H&E) detected on LGE and the presence of iron (Perl's stain) observed on T2*-CMR. At week 4 post-reperfusion, gene and protein expression of proinflammatory markers (TNF-α, IL-1β and MMP-9) were increased in the 90-min I/R group when compared to 30-min I/R groups. Further, transmission electron microscopy performed on 90-min I/R myocardium that were positive for iron on T2* CMR and Perl's stain showed accumulation of granular iron particles within the phagosomes. Ischemic time prior to reperfusion is a critical factor in determining whether a MI is hemorrhagic or non-hemorrhagic in rats. Specifically, a period of 90-min of ischemia prior to reperfusion can produce rat models of hemorrhagic MI, while 30-minutes of ischemia prior to reperfusion can ensure that the MIs are non-hemorrhagic. Hemorrhagic MIs in rats result in marked increase in iron deposition, proinflammatory burden and adverse left-ventricular remodeling compared to rats with non-hemorrhagic MIs.


A test for adequacy of chromium nutrition in humans--relation to type 2 diabetes mellitus.
When Na(2)51CrO(4) is added to blood the 51CrO(4)(2-) ions enter the erythrocytes readily, and nearly exclusively, and are reduced to 51Cr(III) ions. We have observed that a fraction of these ions becomes bound to the cell membrane in a concentration which seemingly depends on that of the dietary derived intracellular Cr(III) ions. Thus, when constant amounts of 51CrO(4)(2-) ions enter constant amounts of erythrocytes, the resulting 51Cr(III) ions become bound to the cell membrane in a concentration that varies inversely as the initial, intracellular concentration of Cr(III) ions which, in turn, depends directly on the adequacy of chromium nutrition. Therefore, we have determined an arbitrary set of conditions under which the concentration of 51Cr(III) ions bound to the erythrocyte membrane becomes an indicator of the adequacy of chromium nutrition. The application of this test to 25 Type 2 diabetes mellitus subjects and 35 normal controls, both randomly selected, indicates that the concentrations of membrane bound 51Cr(III) ions in the two groups were not significantly different. Consequently, it is concluded that the level of chromium nutrition which is normally adequate in humans has only a minor role, if any, in the genesis of Type 2 diabetes mellitus.


Dose verification for liver target volumes undergoing respiratory motion.
Respiratory motion has a significant impact on dose delivered to abdominal targets during radiotherapy treatment. Accurate treatment of liver tumours adjacent to the diaphragm is complicated by large respiratory movement, as well as differing tissue densities at the lung-liver interface. This study aims to evaluate the accuracy of dose delivered to superior liver tumours using passive respiratory monitoring, in the absence of gating technology, for a range of treatment techniques. An in-house respiratory phantom was designed and constructed to simulate the lung and liver anatomy. The phantom consisted of adjacent slabs of lung and liver equivalent materials and a cam drive system to emulate respiratory motion. A CC04 ionisation chamber and Gafchromic EBT3 film were used to perform point dose and dose plane measurements respectively. Plans were calculated using an Elekta Monaco treatment planning system (TPS) on exhale phase study sets for conformal, volume modulated arc therapy (VMAT) and intensity modulated radiation therapy (IMRT) techniques, with breathing rates of 8, 14 and 23 bpm. Analysis confirmed the conformal delivery protocol currently used for this site within the department is suitable. The experiments also determined that VMAT is a viable alternative technique for treatment of superior liver lesions undergoing respiratory motion and was superior to IMRT. Furthermore, the measurements highlighted the need for respiratory management in these cases. Displacements due to respiration exceeding planned margins could result in reduced coverage of the clinical target volume and much higher doses to the lung than anticipated.


Once more unto the breech: the firearms evidence in the Sacco and Vanzetti case revisited: Part I.
The Sacco and Vanzetti case has a timeless appeal. It raises trenchant issues of the fairness of a criminal trial in the face of the public's hue and cry. It is a sorry reminder that physical evidence must be closeted with care and punctiliously marked for later courtroom uses. Claims of unfairness at the trial of Sacco and Vanzetti have evoked doubts of their guilt. On this issue, a Select Committee of firearms experts in 1983 reevaluated the existing firearms evidence from the Sacco and Vanzetti trial. Its conclusions, a number of which point unerringly to the guilt of Sacco and none of which add a scintilla to the case against Vanzetti, are analyzed in this paper, which is in two parts. Part I sets the stage by focussing on the facts of the crime in South Braintree, MA and the prosecutorial strategies in the use of the firearms evidence at the trial in Dedham, MA. The firearms evidence against Vanzetti is analyzed separately from that marshalled against Sacco. Part II will address the rampant charges of governmental misconduct in the handling of the firearms evidence. A concluding section of Part II reveals startling new evidence relevant to the guilt of Nicola Sacco.


[The efficiency of self-regulated learning in the teaching of scientific concepts to health sciences students].
In health sciences, the predominant teaching methodology is traditional and emphasizes conveying knowledge. Nonetheless, new abilities must be taught now. This change shifts the prominence from professor to student and incorporates a concept called self-regulated learning, which involves the professor as a mediator and incorporates guidelines that facilitate learning diverse skills. To compare the effects of two teaching methodologies on the learning of key scientific concepts among health science students. Two subgroups of equally complex concepts were randomly chosen to be taught either using traditional or self-regulation methodology. For the self-regulation methodology, two groups were formed. One learned only through self-regulation guidelines and the other learned through classes where the professor was a mediator. One hundred thirty seven freshman students from medicine, physical therapy, and nursing careers participated voluntarily in the study. Self-regulation methodology impacted the learning process of scientific concepts in a positive way and showed significant differences with traditional teaching. The sole use of self-regulation guidelines alone generated similar results, compared to those obtained by students who attended lectures. Self-regulated learning would improve in learning efficiency and would reduce face-to-face class time.


Functional acetylcholine receptors expressed in Xenopus oocytes after injection of Torpedo beta, gamma, and delta subunit RNAs are a consequence of endogenous oocyte gene expression.
The nicotinic acetylcholine receptor (AChR) is an oligomeric transmembrane glycoprotein consisting of four homologous subunits in a stoichiometry alpha 2 beta gamma delta. Xenopus oocytes were used to study the effects of selectively deleting the alpha subunit of the Torpedo californica AChR on functional receptor expression. Oocytes microinjected with only Torpedo beta, gamma, and delta subunit RNAs showed small acetylcholine-elicited currents. These "alpha-less" AChRs were pharmacologically similar to the wild-type (i.e., Torpedo alpha 2 beta gamma delta) receptor. Actinomycin D, which blocks endogenous RNA transcription, completely inhibited the expression of alpha-less but not wild-type receptor. Coinjection of antisense RNA to the alpha subunit of the Xenopus muscle AChR with Torpedo beta, gamma, and delta subunit RNAs significantly reduced expression of the alpha-less AChRs without altering expression of wild-type receptors. These results indicate that Xenopus oocytes express low levels of AChR alpha subunit mRNA that, when translated, can lead to the formation of functional Xenopus-Torpedo AChR hybrids. These results strongly suggest that, unless the potential contribution of endogenous subunits can be determined, caution must be exercised when analyzing the effects of subunit deletions on multisubunit protein expression in Xenopus oocytes.


Remote asymmetric induction in an intramolecular ionic Diels-Alder reaction: application to the total synthesis of (+)-dihydrocompactin.
The total synthesis of (+)-dihydrocompactin via an intramolecular ionic Diels-Alder reaction that proceeds with remote stereocontrol is described. This reaction proceeds by an intermediate vinyl-oxocarbenium ion (6), the conformational constraints of which lead to the observed asymmetric induction. The sense of asymmetric induction appears contrasteric and is explained by the proposed reactive conformation shown in Figure 1.


Generation and self-healing of vector Bessel-Gauss beams with variant state of polarizations upon propagation.
We propose a generalized model for the creation of vector Bessel-Gauss (BG) beams having state of polarization (SoP) varying along the propagation direction. By engineering longitudinally varying Pancharatnam-Berry (PB) phases of two constituent components with orthogonal polarizations, we create zeroth- and higher-order vector BG beams having (i) uniform polarizations in the transverse plane that change along z following either the equator or meridian of the Poincaré sphere and (ii) inhomogeneous polarizations in the transverse plane that rotate during propagation along z. Moreover, we evaluate the self-healing capability of these vector BG beams after two disparate obstacles. The self-healing capability of spatial SoP information may enrich the application of BG beams in light-matter interaction, polarization metrology and microscopy.


Sparse System Identification of Leptin Dynamics in Women With Obesity.
The prevalence of obesity is increasing around the world at an alarming rate. The interplay of the hormone leptin with the hypothalamus-pituitary-adrenal axis plays an important role in regulating energy balance, thereby contributing to obesity. This study presents a mathematical model, which describes hormonal behavior leading to an energy abnormal equilibrium that contributes to obesity. To this end, we analyze the behavior of two neuroendocrine hormones, leptin and cortisol, in a cohort of women with obesity, with simplified minimal state-space modeling. Using a system theoretic approach, coordinate descent method, and sparse recovery, we deconvolved the serum leptin-cortisol levels. Accordingly, we estimate the secretion patterns, timings, amplitudes, number of underlying pulses, infusion, and clearance rates of hormones in eighteen premenopausal women with obesity. Our results show that minimal state-space model was able to successfully capture the leptin and cortisol sparse dynamics with the multiple correlation coefficients greater than 0.83 and 0.87, respectively. Furthermore, the Granger causality test demonstrated a negative prospective predictive relationship between leptin and cortisol, 14 of 18 women. These results indicate that increases in cortisol are prospectively associated with reductions in leptin and vice versa, suggesting a bidirectional negative inhibitory relationship. As dysregulation of leptin may result in an abnormality in satiety and thereby associated to obesity, the investigation of leptin-cortisol sparse dynamics may offer a better diagnostic methodology to improve better treatments plans for individuals with obesity.


[Is ginger a clinically relevant antiemetic? A systematic review of randomized controlled trials].
The aim of this systematic review was to evaluate the clinical impact of ginger (Zingiber officinale) as an antiemetic. A systematic search of the literature was performed using the databases of MEDLINE, EMBASE, and the Cochrane-Library. Of 100 published reports discerned as potentially relevant, 24 randomized controlled trials were evaluated, covering 1073 patients which had received ginger. Of these reports, 16 contained information regarding the antiemetic activity of the phytotherapeutic agent against kinetosis, postoperative nausea and vomiting (PONV), and morning sickness and hyperemesis gravidarum, respectively. Only a few studies were eligible for a quantitative analysis (meta-analysis). Thus, the majority of the reports were analyzed descriptively. To analyze the potential side effects of the drug, 15 reports with 777 patients were eligible. Of these, 3.3% suffered from slight side effects, mainly mild gastrointestinal symptoms and sleepiness, both not requiring specific treatments. One severe adverse event was reported in a study: an abortion occurred in the 12th week of gestation. However, a total of 136 patients were treated with ginger within the first trimenon of pregnancy without complications. There is no clear evidence for the efficacy of ginger in the treatment of PONV and of kinetosis. The results for the treatment of nausea and vomiting in pregnancy are encouraging, however, ginger should be applied for the time being only in controlled clinical studies. Applied in daily doses up to 6 g ginger seems to be a drug with few side effects.


Fragile X mental retardation protein is required for rapid experience-dependent regulation of the potassium channel Kv3.1b.
Fragile X mental retardation protein (FMRP) is an RNA-binding protein that regulates synaptic plasticity by repressing translation of specific mRNAs. We found that FMRP binds mRNA encoding the voltage-gated potassium channel Kv3.1b in brainstem synaptosomes. To explore the regulation of Kv3.1b by FMRP, we investigated Kv3.1b immunoreactivity and potassium currents in the auditory brainstem sound localization circuit of male mice. The unique features of this circuit allowed us to control neuronal activity in vivo by exposing animals to high-frequency, amplitude-modulated stimuli, which elicit predictable and stereotyped patterns of input to the anterior ventral cochlear nucleus (AVCN) and medial nucleus of the trapezoid body (MNTB). In wild-type (WT) animals, Kv3.1b is expressed along a tonotopic gradient in the MNTB, with highest levels in neurons at the medial, high-frequency end. At baseline, Fmr1(-/-) mice, which lack FMRP, displayed dramatically flattened tonotopicity in Kv3.1b immunoreactivity and K(+) currents relative to WT controls. Moreover, after 30 min of acoustic stimulation, levels of Kv3.1b immunoreactivity were significantly elevated in both the MNTB and AVCN of WT, but not Fmr1(-/-), mice. These results suggest that FMRP is necessary for maintenance of the gradient in Kv3.1b protein levels across the tonotopic axis of the MNTB, and are consistent with a role for FMRP as a repressor of protein translation. Using numerical simulations, we demonstrate that Kv3.1b tonotopicity may be required for accurate encoding of stimulus features such as modulation rate, and that disruption of this gradient, as occurs in Fmr1(-/-) animals, degrades processing of this information.


Alcohol screening, brief intervention, and referral in the emergency department: an implementation study.
Alcohol is the single greatest contributor to injury in the United States. Numerous studies have reported that a standardized screening, brief intervention, and referral to treatment (SBIRT) intervention can effectively minimize future alcohol consumption, reduce injury recurrence, and decrease the number of repeat ED visits. To date, SBIRT studies have been conducted in settings in which physicians or research assistants carried out SBIRT. Little is known about ED nurses carrying out SBIRT. The purpose of this study was to examine ED nurse training needs and identify both barriers to, and enablers of, SBIRT implementation in the emergency department. Two coordinators from each of the 5 ED sites selected for the study attended a 1-day SBIRT educational session. Site coordinators then trained their staff nurses to conduct SBIRT. Site coordinators were surveyed at the midpoint and end of the 6-month implementation study period. Patient data from each facility was collected. Ten site coordinators were trained and held subsequent training sessions with nursing staff in their respective emergency departments. All sites encountered barriers to implementation, but 2 of 5 sites were able to implement the SBIRT process fully by the end of the evaluation period. A total of 3265 patients were screened for alcohol use problems. Of those screened, 678 (21%) were classified as hazardous drinkers. Overall, 56% of the positive-screened patients received 3 to 5 minutes of a brief intervention. After the brief intervention, between 9% and 82% of patients were referred for further care. The SBIRT process can be conducted successfully by emergency nurses. However, substantial operational barriers to widespread routine implementation exist. These barriers need to be addressed before emergency nurses incorporate SBIRT as routine part of ED care.


Inherited C3 deficiency with recurrent infections and glomerulonephritis.
A 10-year-old Laotian boy had homozygous deficiency of the third component of complement and recurrent bacterial infections beginning at age 5 months. Cellular and humoral immunity were normal, as were polymorphonuclear leukocyte chemotaxis and bactericidal activities. Serum complement-mediated hemolytic, chemotactic, and opsonic activities were deficient. In vitro addition of purified C3 to patient serum restored hemolytic complement to normal levels, and plasma infusion during each of four episodes of pneumonia significantly enhanced serum opsonic activity for as long as 36 hours. A renal biopsy specimen revealed mesangiopathic glomerulonephritis, although significant levels of circulating IgG immune complexes were not detected. These findings further support the association of C3 deficiency with immune-complex disease and suggest that plasma infusion may be an adjunct to antibiotic therapy in the management of severe pyogenic infections in patients with C3 deficiency.


Development of purine-derived 18F-labeled pro-drug tracers for imaging of MRP1 activity with PET.
Multidrug resistance-associated protein 1 (MRP1) is a drug efflux transporter that has been implicated in the pathology of several neurological diseases and is associated with development of multidrug resistance. To enable measurement of MRP1 function in the living brain, a series of 6-halopurines decorated with fluorinated side chains have been synthesized and evaluated as putative pro-drug tracers. The tracers were designed to undergo conjugation with glutathione within the brain and hence form the corresponding MRP1 substrate tracers in situ. 6-Bromo-7-(2-[(18)F]fluoroethyl)purine showed good brain uptake and rapid metabolic conversion. Dynamic PET imaging demonstrated a marked difference in brain clearance rates between wild-type and mrp1 knockout mice, suggesting that the tracer can allow noninvasive assessment of MRP1 activity in vivo.


Anesthetic management of hysterosalpingooophorectomy in a case with severe idiopathic dilated cardiomyopathy.
Idiopathic dilated cardiomyopathy is a primary myocardial disease with unknown aetiology. This disease follows a prospective course that is characterized by ventricular dilation and impaired myocardial dilation. Congestive heart failure and malignant arrhythmias are the most widespread complications. The incidence of idiopathic dilated cardiomyopathy in the general population is 5-8/100.000. Because of the increased risks of perioperative complications, anesthetic management of this disease requires the application of a specific technique. This case report demonstrates the application of successful regional anesthetic management (thoracic epidural anesthesia) in a patient who had been diagnosed with severe idiopathic dilated cardiomyopathy.


Distinct histone modifications in stem cell lines and tissue lineages from the early mouse embryo.
A unique property of the mammalian embryo is that stem cells can be derived from its early tissue lineages. These lineages will give rise to the fetus as well as essential extraembryonic tissues. Understanding how chromatin regulation participates in establishment of these lineages in the embryo and their derived stem cells provides insight that will critically inform our understanding of embryogenesis and stem cell biology. Here, we compare the genomewide location of active and repressive histone modifications in embryonic stem cells, trophoblast stem cells, and extraembryonic endoderm stem cells from the mouse. Our results show that the active modification H3K4me3 has a similar role in the three stem cell types, but the repressive modification H3K27me3 varies in abundance and genomewide distribution. Thus, alternative mechanisms mediate transcriptional repression in stem cells from the embryo. In addition, using carrier chromatin immunoprecipitation we show that bivalent histone domains seen in embryonic stem cells exist in pluripotent cells of the early embryo. However, the epigenetic status of extraembryonic progenitor cells in the embryo did not entirely reflect the extraembryonic stem cell lines. These studies indicate that histone modification mechanisms may differ between early embryo lineages and emphasize the importance of examining in vivo and in vitro progenitor cells.


Naloxone blockade of (-)pentazocine-induced changes in auditory function.
In a previous report, we found that intravenous (i.v.) (-)pentazocine improved auditory sensitivity and significantly altered compound action potential (CAP) amplitudes. Its sigma (sigma)-receptor-selective optical isomer (+)pentazocine administered at the same dose was without effect, suggesting that the observed auditory neural effects might be mediated by an opioid receptor. To directly test this hypothesis, in the present investigation we attempted to antagonize the auditory neural effects of (-)pentazocine using the pure, nonspecific drug antagonist naloxone. In 25 normal-hearing, male, pigmented chinchillas, amplitude and latency changes in the click-evoked auditory nerve CAP (N1) and cochlear microphonic (CM) were tracked at six stimulus intensities during a baseline period and after the postbaseline administration of the opioid drug agonist (-)pentazocine (16 mg/kg; i.v.). In separate groups of chinchillas, (-)pentazocine was given alone or administered in combination with the standard opioid receptor antagonist naloxone administered at two doses. Robust changes in CAP amplitudes after (-)pentazocine occurred in the absence of measurable alterations in CAP response latencies, CM amplitudes, or blood chemistries and were significantly antagonized when naloxone (5 mg/kg) was added to the i.v. infusion. The observed blockade clearly indicates that the agonist effects of (-)pentazocine are opioid receptor-mediated and suggests a connection between opioid receptors and auditory neural function. Mechanisms of action and the connection between an opioid modulation of auditory function and stress, hyperacusis, and tinnitus are discussed.


Mental disorders associated with recent cancer diagnosis: Results from a nationally representative survey.
Receiving a diagnosis of cancer may be associated with increased risk of mental disorders. Yet, in this context, no factor predicts the onset of a mental disorder besides the diagnosis of cancer itself. If patients with a history of mental disorder are at particular risk is unknown. Data were derived from a large national sample of the US population. Face-to-face surveys were conducted on 36309 adults during 2012-2013 period. Data were used to examine the associations among the past-year prevalence of mental disorders (according to the Diagnostic and Statistical Manual of Mental Disorders-5), the treatment-seeking rates and a recent cancer diagnosis. Data were analysed according to the antecedents of mental disorder in participants and according the presence of a recent cancer diagnosis. Participants recently diagnosed with cancer (n = 1300) were significantly at higher risk to present suicide attempt (adjusted odds ratio [AOR] = 3.52; 95% confidence interval [CI] = 1.23-10.04), post-traumatic stress disorder (AOR = 2.25; 95% CI = 1.71-2.96), bipolar disorder (AOR = 2.22; 95% CI = 1.46-3.38) and drug use disorder (AOR = 1.64; 95% CI = 1.13-3.39). The prevalence of most of the mental disorders considered was significantly higher for participants with a history of mental disorder compared with participants without such a history. Conversely, a recent diagnosis of cancer was not associated with significant differences in the incidence of mental disorders in participants with no history of mental disorder. Patients with a history of mental disorder receiving a cancer diagnosis are at high risk of relapse and should be closely monitored.


Intrapulmonary location of benign solitary fibrous tumor.
Intrapulmonary solitary fibrous tumors (SFTs) are sporadic mesenchymal neoplasms that typically arise from visceral or parietal pleura. While accounting for <5% of all pleural tumors, SFTs are known to occur in nearly all bodily organs, including nasopharynx, bladder, prostate, soft tissue of neck, buttocks, extremities, and abdominal wall. Such tumors have been previously designated localized fibrous mesothelioma or pleural fibroma. SFTs have no genetic basis and are unrelated to environmental factors such as tobacco smoking or asbestos exposure. Herein, we describe a 24-year-old woman whose clinical presentation mimicked atypical carcinoid tumor. A diagnosis of intrapulmonary SFT was achieved by surgical resection.


[Changes in the ionic mechanisms of the electro-excitability of the somatic membrane of rat sensory neurons during ontogenesis. Distribution of ion channels of the inward current].
Distribution of different types of ionic channels carrying inward currents was studied in the somatic membrane of rat dorsal root ganglion neurons within three age groups: 5-9 days, 45 days and 90 postnatally. The number of neurons whose membrane contained simultaneously four types of inward current channels ("fast" tetrodotoxin-sensitive and "slow" tetrodotoxin-resistant sodium low- and high-threshold calcium one's) was progressively reduced in successive groups. The first group contained 14.5%, the second 5% and the third group 1% of such neurons. These changes were due to disappearance of "slow" sodium and low-threshold calcium channels from the membrane; the number of neurons whose somatic membrane contained only two types of inward current channels ("fast" sodium and high-threshold calcium) has increased, respectively.


The effects of facial expressions on judgments of others when observing two-person confrontation scenes from a third person perspective.
When building personal relationships, it is important to select optimal partners, even based on the first meeting. This study was inspired by the idea that people who smile are considered more trustworthy and attractive. However, this may not always be true in daily life. Previous studies have used a relatively simple method of judging others by presenting a photograph of one person's face. To move beyond this approach and examine more complex situations, we presented the faces of two people confronted with each other to participants and asked them to judge them from a third-person perspective. Through three experiments, participants were asked to judge which of the two persons was more appropriate for forming alliances, more trustworthy, or more attractive, respectively. In all experiments, images were shown for a short (500 ms) or a long time (5 s). In all three experiments, the results showed that participants were more likely to choose persons with happy faces than those with neutral, sad, or angry faces when the image presentation was short. Contrarily, the facial expressions did not affect those judgments when the image presentation was long. Instead, judgments were correlated with personality estimated from the model's neutral face in a single-person presentation. These results suggest that although facial expressions can affect the judgments of others when observing two-person confrontations from a third-person perspective, when participants have more time to elaborate their judgments, they go beyond expressions.


Degradation of Hole Transport Materials via Exciton-Driven Cyclization.
Organic light-emitting diode (OLED) displays have been an active and intense area of research for well over a decade and have now reached commercial success for displays from cell phones to large format televisions. A more thorough understanding of the many different potential degradation modes which cause OLED device failure will be necessary to develop the next generation of OLED materials, improve device lifetime, and to ultimately improve the cost vs performance ratio. Each of the different organic layers in an OLED device can be susceptible to unique decomposition pathways, however stability toward excitons is critical for emissive layer (EML) materials as well as any layer near the recombination zone. This study will specifically focus on degradation modes within the hole transport layer (HTL) with the goal being to identify the general decomposition paths occurring in an operating device and use this information to design new derivatives which can block these pathways. Through post-mortem analyses of several aged OLED devices, an apparently common intramolecular cyclization pathway has been identified that was not previously reported for arylamine-containing HTL materials and that operates parallel to but faster than the previously described fragmentation pathways.


A phase II study of carboplatin and paclitaxel in the treatment of patients with advanced esophageal and gastric cancer.
We initiated a phase II study to determine the efficacy of carboplatin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in patients with advanced esophageal or gastric cancer. Objective tumor responses, duration of response, time to disease progression, overall survival, and toxicity profile are the end points evaluated in this study. The study includes patients with locally advanced metastatic or recurrent esophageal or gastric cancer with no history of prior chemotherapy or radiation treatment. Patients are required to have a performance status of 0 to 2 and no organ failure. Staging diagnostics include computed tomography scans and endoscopic ultrasound when appropriate. Starting dose of paclitaxel is 200 mg/m2, and carboplatin is given to achieve an area under the concentration-time curve of 5.0. Dose escalation is attempted if nadir counts permit. Seventeen patients have registered so far. Of those, three are not evaluable for efficacy analysis: one has not been on study long enough to be assessed for response and the other two are not assessable for objective tumor response. Three patients with gastric cancer have achieved partial responses. Two of five patients with esophageal cancer responded (partial response) to this treatment. Dose escalation by one step was feasible in approximately half the patients. There were no episodes of neutropenic fever. Carboplatin and paclitaxel given on an outpatient basis is well tolerated and an interesting regimen for the treatment of patients with advanced gastric or esophageal cancer.


The pre- and post-authorisation data published by the European medicines agency on the use of biologics during pregnancy and lactation.
The effects of biologics on reproduction/lactation are mostly unknown although many patients that receive biologics are women of reproductive age. The first objective of this study was to investigate the publicly available data on pregnancy/lactation before and after marketing authorization in Europe of biologics for the indications of rheumatologic inflammatory autoimmune diseases and inflammatory bowel disease. Secondary objectives included the assessment of the clinical relevance of the provided data and comparison of initial and post-authorization data. Initial and post-authorization data were extracted from the European Public Assessment Reports and the latest versions of Summary of Product Characteristics using publicly available documents on the European Medicines Agency's website. Four sections were categorized regarding pregnancy outcomes: pre-clinical/animal studies, human female fertility, pregnancy-related outcomes and congenital malformations in the human fetus. Three sections were categorized regarding lactation outcomes: pre-clinical/animal studies, excretion in human breast milk and absorption in children through breastfeeding. The clinical applicability of each category was scored by specified criteria, based on scientific literature, and further as defined by the authors. For the 16 included biologics, post-authorization data were delivered only for adalimumab, certolizumab pegol, etanercept and infliximab. For the 12 remaining biologics limited data on pregnancy and lactation during the post-marketing period of 2-21 years were available. In this article several suggestions are provided for improving a multidisciplinary approach to these issues. The initiation of suitable registries by marketing authorization holders and data transparency for clinicians and academics are highly endorsed.


The development of face orienting mechanisms in infants at-risk for autism.
A popular idea related to early brain development in autism is that a lack of attention to, or interest in, social stimuli early in life interferes with the emergence of social brain networks mediating the typical development of socio-communicative skills. Compelling as it is, this developmental account has proved difficult to verify empirically because autism is typically diagnosed in toddlerhood, after this process of brain specialization is well underway. Using a prospective study, we directly tested the integrity of social orienting mechanisms in infants at-risk for autism by virtue of having an older diagnosed sibling. Contrary to previous accounts, infants who later develop autism exhibit a clear orienting response to faces that are embedded within an array of distractors. Nevertheless, infants at-risk for autism as a group, and irrespective of their subsequent outcomes, had a greater tendency to select and sustain attention to faces. This pattern suggests that interactions among multiple social and attentional brain systems over the first two years give rise to variable pathways in infants at-risk.


Nuclear protein matrix: association with newly synthesized DNA.
The residual structural framework of the cell nucleus termed the nuclear protein matrix, is associated with newly synthesized DNA in regenerating rat liver. One minute after rats are injected with [3-H] thymidine, more than 90 percent of the total tritium in nuclear DNA is associated with the matrix DNA although this DNA comprises only 25 percent of the total nuclear DNA. In contrast, the bulk DNA, 75 percent of total nuclear DNA, contains less than 8 percent of the total labeled DNA. The percentage of total labeled DNA associated with the bulk DNA increases for 30 minutes after injection and decreases correspondingly in the matrix DNA.


Making connections and promoting the profession: Social media use by World Federation of Occupational Therapists member organisations.
World Federation of Occupational Therapists (WFOT) member organisations comprise 77 national occupational therapy organisations across the world. Each national organisation interacts with its members and the public using diverse methods. Increasingly, national organisations are broadening their communication methods. The objective of this study was to examine if and how occupational therapy organisations are using social media for communication, and if so, the types of concerns or barriers they experience and what role they anticipate social media might play in the near future. An online survey was developed; 57 of 77 WFOT member organisations responded. This study identified that WFOT national organisations are using social media, to varying degrees, with or without an individual formally assigned to manage social media. Respondents reported that they used social media to: communicate with members, promote the organisation and promote the profession. Commonly expressed needs included assistance with guidelines for ethical social media use, developing technical expertise, and recognition of limits of time and competing priorities. Recommendations arising from this research are at the global, national, local and individual levels and incorporate active dissemination and pure diffusion approaches. Taking steps to increase the use of social media could indirectly impact occupational therapy practice through enhancing organisations' abilities to support practitioners to enhance their practice. Although 57% of WFOT member organisations returned usable responses, there may be some additional perspectives that were not captured. It would be helpful to contact non-responding organisations to explore their social media use and plans. Further research could examine how future initiatives put in place by WFOT impact social media use by member organisations.


[Use of intestinal plasty in ureterohydronephrosis].
One-sided and two-sided intestinal plasty was conducted in 217 patients for congenital and acquired diseases of ureters. Preoperative and intraoperative visual diagnosis of the ureteric wall changes extent is imperfect and causes a majority of poor results in ureterocystoneostomy. Diagnosis was improved, indications were specified for application of intestinal ureteric plasty for achalasia, ureteric hypoplasia, megaureter, ureterohydronephrosis, while initial sufficient kidney function present.


PET response criteria in solid tumors predicts progression-free survival and time to local or distant progression after chemotherapy with regional hyperthermia for soft-tissue sarcoma.
We evaluated the prognostic accuracy of established PET and CT response criteria in patients with soft-tissue sarcoma (STS) after combined chemotherapy plus regional hyperthermia (RHT). Seventy-three patients underwent (18)F-FDG PET/CT before and after 2-4 cycles of neoadjuvant chemotherapy with RHT for STS. Progression-free survival (PFS) and time to local and distant progression were among other factors correlated with response according to PET Response Criteria in Solid Tumors (PERCIST 1.0) and Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Metabolic response by PERCIST (n = 44/73) was an independent predictor for PFS (P = 0.002; hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.18-0.68) and time to local or distant progression. Other independent predictors for PFS by multivariate analysis were adjuvant radiotherapy (P = 0.010; HR, 0.39; 95% CI, 0.20-0.80) and a baseline tumor size less than 5.7 cm (P = 0.012; HR, 0.43; 95% CI, 0.22-0.83). Response by RECIST 1.1 was seen in a small group of patients (n = 22/73) and allowed prediction of PFS for patients with sarcoma outside the abdomen (P = 0.048; HR, 0.13; 95% CI, 0.02-0.98). Metabolic response by (18)F-FDG PET predicts PFS and time to local and distant progression after 2-4 cycles of neoadjuvant chemotherapy plus RHT for STS.


5-Fluorouracil toxicity-attributable IVS14 + 1G > A mutation of the dihydropyrimidine dehydrogenase gene in Polish colorectal cancer patients.
DPYD gene encodes dihydropyrimidine dehydrogenase which is the initial and rate-limiting enzyme in the metabolism of 5-fluorouracil (5-FU). The aim of our study was PCR-RFLP based-genetic testing for the most common 5-FU toxicity-attributable IVS14 + 1G > A DPYD mutation (DPYD(*)2A) in 252 Polish colorectal cancer (CRC) patients treated with this adjuvant chemotherapeutic regimen after surgery. The DPYD(*)2A allele was identified only in one patient: a male who was one of 4 CRC patients suffering from grades 3-4 myelotoxicity upon 5-FU chemotherapy. We conclude that IVS14 + 1G > A DPYD (DPYD(*)2A) variant occurs in the Polish population and is responsible for a significant proportion of life-threatening toxicity of 5-FU.


Efficient transduction of nondividing cells by optimized feline immunodeficiency virus vectors.
Second- and third-generation three-plasmid vector systems, termed FELIX, were constructed from feline immunodeficiency virus (FIV). To enhance vector production, the weak FIV long terminal repeat promoter was replaced with the human cytomegalovirus enhancer/promoter. To construct a minimal system in which Gag-Pol was the only viral protein present, the cytoplasmic transport element was used in place of the FIV Rev-RRE system to facilitate nuclear export of Gag-Pol and the transfer vector. Unconcentrated vector titers routinely exceeded 1 x 10(6) IU/mL for most constructs tested. Second- and optimized third-generation vectors were capable of efficiently infecting G1/S- and G2/M-arrested cells. FIV-based FELIX vectors transduced human dendritic cells, hepatocytes, and aortic smooth muscle with efficiencies similar to that of a control 3T3 cell line. All three of these primary cell types were transducible by both the second- and third-generation FELIX vectors, demonstrating that FIV Gag-Pol alone contains the determinants necessary for transduction of primary cells. In cross-packaging tests, we observed that HIV Gag-Pol does not substantially package FIV vectors; consequently, use of such vectors in human immunodeficiency virus-infected cells should not lead to efficient mobilization of the inserted gene. Thus, this FIV-based vector system offers high efficiency and stable delivery of genes to numerous nondividing and primary cell types, opening new avenues for biological inquiry into normal human cells.


[Motionless dissipative structures formed by soil bacteria].
A model of the stationary distribution of bacteria in soil, formed upon filtration of soil solution was constructed. The region of parameter values was determined at which the distribution is dissipative and has the form of alternating strips. Regularities in the degeneration of the dissipative structure as the parameters approach the boundary of the region were discovered. The analysis was made using qualitative, analytical and quantitative investigation of differential equations of the transfer. Data on the growth, nourishment, and death of copiotrophic bacteria were used in the calculations.


Pharmacokinetic/pharmacodynamic analysis to evaluate ceftaroline fosamil dosing regimens for the treatment of community-acquired bacterial pneumonia and complicated skin and skin-structure infections in patients with normal and impaired renal function.
In this study, the probability of pharmacokinetic/pharmacodynamic target attainment (PTA) of ceftaroline against clinical isolates causing community-acquired bacterial pneumonia (CABP) and complicated skin and skin-structure infection (cSSSI) in Europe was evaluated. Three dosing regimens were assessed: 600 mg every 12 h (q12 h) as a 1-h infusion (standard dose) or 600 mg every 8 h (q8 h) as a 2-h infusion in virtual patients with normal renal function; and 400 mg q12 h as a 1-h infusion in patients with moderate renal impairment. Pharmacokinetic and microbiological data were obtained from the literature. The PTA and the cumulative fraction of response (CFR) were calculated by Monte Carlo simulation. In patients with normal renal function, the ceftaroline standard dose (600 mg q12 h as a 1-h infusion) can be sufficient to treat CABP due to ceftazidime-susceptible (CAZ-S) Escherichia coli, CAZ-S Klebsiella pneumoniae, meticillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis (CFR>90%). However, against meticillin-resistant S. aureus (MRSA), the CFR was 72%. In cSSSI, the CFR was also <80% for MRSA. Administration of ceftaroline 600 mg q8 h as a 2-h infusion or 400 mg q12 h as a 1-h infusion in patients with moderate renal insufficiency provided a high probability of treatment success (CFR ca. 100%) for most micro-organisms causing CABP and cSSSI, including MRSA and penicillin-non-susceptible S. pneumoniae. These results suggest that in patients with normal renal function, ceftaroline 600 mg q8 h as a 2-h infusion may be a better option than the standard dose, especially if the MRSA rate is high.


Antioxidant efficacy of thymol and carvacrol in microencapsulated walnut oil triacylglycerols.
Antioxidant efficiency of thymol and carvacrol in walnut oil triacylglycerols (WO-TAGs) was investigated. WO-TAGs alone or fortified with thymol/carvacrol were emulsified with sodium caseinate-lactose mixture. Oxidative stability of freeze dried emulsions was assessed via Rancimat and accelerated oven tests. Bulk WO-TAGs with and without thymol/carvacrol were also tested for comparison. Higher induction periods (IPs) were recorded for encapsulated and antioxidant fortified WO-TAGs compared to non-encapsulated and non-fortified counterparts. IP of thymol included and encapsulated WO-TAGs were found to be 1.5-2 fold higher than that of carvacrol at all concentrations (0.05-0.20%). IP of WO-TAGs was increased dose-dependent manner in the case of thymol and the highest protection was obtained with 0.20% thymol concentration (p < 0.05). Peroxide formation in bulk WO-TAGs fortified with carvacrol showed a slightly higher oxidative stability compared to thymol after 24 d of storage whereas thymol was a bit more effective in encapsulated WO-TAGs.


Longitudinal changes in body composition and metabolic profile between exercise clinical trials in men with chronic spinal cord injury.
Longitudinal design. The study was undertaken to determine the effects of cessation of exercise interventions on body composition and metabolic profiles in men with chronic SCI. Clinical trials within a Medical Center. Eleven men with motor complete SCI were followed on average over a period of 2.5 years. Six men were involved in two different exercise interventions (functional electrical stimulation cycling versus arm cycling ergometer), 5 days/week for 16 weeks (exercise group), and five men served as a control (control group). Anthropometrics and dual energy X-ray absorptiometry (DXA) were captured to measure changes in lean mass (LM), fat mass (FM), percentage FM before, immediately after exercise, and after a period of 2.5 years. Basal metabolic rate (BMR) and lipid panel were also measured. Thigh circumference increased by 8.5% following exercise (P = 0.042) and remained 6.4% greater than baseline measurements (P = 0.012). Leg LM increased by 9% following the exercise intervention (P = 0.03) and decreased by 16% in the follow-up visit (P = 0.02). Percentage trunk and total body FM increased by 4.5% (P = 0.008) and 3.5% (P = 0.019) in the follow-up visit, respectively, and whole body LM increased by 8.4% and decreased back by 5.4% following a 2.5 year-period. BMR significantly decreased by 15.5% following the exercise (P = 0.029) interventions. Exercise training is accompanied with positive changes in body composition as well as compensatory decrease in BMR, that regressed back following 2.5 years of exercise cessation. Participation in an exercise trial is unlikely to confound the measurements of a follow-up trial.