Quantitative analysis of the A, B and H isoantigens in single transitional carcinoma cells.
To obtain objective data on deletion of the ABH isoantigens in bladder carcinoma, microfluorometry was used. Slides were scanned in phase contrast to lessen fading of the immuno- or lectin-fluorescence stained cells. The fluorescence intensity was measured in relation to an external uranyl standard. Staining was most intense in the peripheral and cytoplasmic parts of the cells. The intra specimen fluorescence intensity varied as 1 to 10. In nondeleted cell populations fluorescence intensity means ranged from 1025 to 12,550 and in deleted populations from 304 to 510. Microfluorometry accurately separates deleted cell populations from those with a normal ABH antigen content.


Point source influences on the carbon and nitrogen geochemistry of sediments in the Stockholm inner archipelago, Sweden.
This study reports analyses of carbon and nitrogen content, and delta(15)N and delta(13)C in sediments of the Höggarnsfjärden Bay near Stockholm. Samples have been taken upstream, near, and downstream of a point source of processed leach water from a garbage dump. The surface sediment at the upstream and downstream sites has delta(15)N and delta(13)C close to the expected background of the area, even though a contribution from the leach water can be observed downstream of the point source. The sediment close to the outflow is strongly influenced by the carbon and nitrogen in the leach water.


Deficiency of microRNA-10b promotes DSS-induced inflammatory response via impairing intestinal barrier function.
Inflammatory bowel disease (IBD) is a non-specific inflammatory disease of the intestine with the pathogenesis to be largely unknown. We found that microRNA (miR)-10b knock-out mice displayed mild IBD symptoms, suggesting that miR-10b may be involved in the onset and development of IBD. This study focuses on elucidating the role of miR-10b in IBD. The colitis model was induced by feeding the mice with 2.5% dextran sodium sulfate (DSS), and the expression levels of miR-10b in colon tissue and blood samples were examined. The severity of colitis was assessed by disease activity index, colon length, histopathological damage, intestinal permeability and ELISA. Then, after transfection of Caco-2 cells with miR-10b mimic and inhibitor, qRT-PCR was used to detect the expression levels of intestinal barrier related genes in colon tissues and cells. miR-10b levels were significantly reduced in mice with DSS-induced acute colitis. Compared with wild-type (WT) mice, miR-10b knockout mice were more sensitive to DSS-induced colitis characterized by increased inflammatory cell infiltration and more severe disruption of colonic barrier function. In addition, by inhibiting miR-10b and thus increasing intestinal barrier gene expression in Caco-2 cells, we found that miR-10b suppressed inflammatory responses and enhanced intestinal barrier function both in vivo and in vitro. miR-10b inhibits the inflammatory response in DSS-induced acute colitis mice in vivo and enhances intestinal barrier function in vitro, suggesting that miR-10b plays a key role in the developmental process of IBD. Thus, miR-10b may be expected to be a new target for the treatment of IBD.


A risk-assessment model to rate the occurrence and relevance of adventitious agents in the production of influenza vaccines.
Influenza vaccine production has traditionally relied on the use of embryonated chicken eggs for virus isolation and propagation, but recently, cell-culture-derived manufacturing methods have been introduced. During influenza vaccine production, by either conventional or cell culture methods, there is a risk of incidental contamination by adventitious agents. Thus, a risk-assessment model has been developed to qualitatively assess the potential risk of vaccine process contamination by viral pathogens. The model takes into account the basic growth characteristics of each virus, its ability to grow in different cell substrates and resistance to processing steps during vaccine manufacture. The risk-assessment model has been applied to various pathogens to determine potential risk and relevance in different manufacturing scenarios, using different cell substrates for virus propagation, including Madin-Darby canine kidney (MDCK) cells. Avian viruses, introduced via use of embryonated eggs for virus isolation, were found to present the greatest risk, irrespective of the substrate used for influenza virus propagation. The use of MDCK cells to propagate vaccine virus from egg-isolated influenza virus strains does not introduce a new or greater adventitious virus risk, compared with egg-based vaccine production. Indeed, the adventitious virus risk is potentially reduced as fewer viruses are able to grow in MDCK cells.


Cloning and characterization of the C. elegans gas1 homolog: phas-1.
Among the set of genes expressed during the quiescent G0 phase of the cell cycle (gas genes), gas1 encodes for a GPI anchor protein associated to the plasma membrane, which is able to induce growth arrest when overexpressed in proliferating fibroblasts. In this report we describe the isolation and characterization of a gas1 Caenorhabditis elegans homolog, phas-1, that seems to be transcribed as an operon together with a gene encoding for a protein similar to human acid ceramidases. Phas-1 structure is very similar to its mammalian homolog conserving almost all cysteine residues and it is expressed in the pharynx from its early formation, in the two-fold embryo, until the adult stage. Surprisingly, while phas-1 is expressed in all developmental stages, with the exception of the dauer larva, the ceramidase-like encoding gene, co-expressed in the same operon together with phas-1, is absent in embryos and is very abundantly expressed in the dauer larva. Overexpression of phas-1 in growing NIH3T3 fibroblasts is able to inhibit the S-phase entry in a similar manner as its murine homolog. On the other hand, when phas-1 is overexpressed or ablated in C. elegans, no specific phenotype due to its transcription alteration can be observed, despite its localized expression suggesting a role in pharynx function or development.


Infective endocarditis presenting as ST-elevation myocardial infarction: an angiographic diagnosis.
While systemic embolic events occur with relative frequency in infective endocarditis (IE), coronary embolization remains an uncommon cause of ST elevation myocardial infarction. Herein we report a case of ventricular fibrillation and anterior ST elevation myocardial infarction occurring in a patient initially presenting with septic shock. Angiography proved diagnostic for IE of a native bicuspid aortic valve complicated by root abscess and left anterior descending artery occlusion. Histologic examination of the embolectomy specimen from the left anterior descending artery confirmed the presence of thrombus and bacteria. The present case highlights difficulties in identifying and managing patients with coronary embolism of vegetations from IE.


Effect of age on the induction of in vitro drug metabolism by pregnenolone-16 alpha-carbonitrile (PCN); effect of age and PCN on immune responses.
The drug metabolizing capacity and the immune responses of normal and PCN treated young, adult and old rats were studied. In normal young and old rats the drug metabolism in general and the immune responses were reduced in comparison to adult animals. PCN treatment caused significant increase of drug metabolism in all age groups of animals due to induction of the microsomal enzymes of the liver. However, there were certain drug dependant variations in the different age groups of rats. PCN given in vivo affected differently the responses of T and B-cells in the young, adult and old animals. PCN is a non-hormonal microsomal enzyme inducer and the question a-rises as to whether there is any connection between this process and the immune system.


Secretion of growth hormone and thyroid-stimulating hormone in patients with dementia.
We studied the growth hormone (GH) response to GH-releasing hormone (GHRH) and the thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) in four groups of patients with dementia and examined whether GH and TSH secretion is altered in patients with Alzheimer's disease. The four groups included those with Alzheimer's disease (n = 28), parkinsonism with dementia (n = 10), progressive supranuclear palsy with dementia (n = 10), and dementia of vascular origin (n = 28). The results showed no differences among the four groups in GH response to GHRH (12.2 +/- 2, 10.7 +/- 2, 8.9 +/- 1.1, and 9.9 +/- 1.9 micrograms/ml, respectively); there was no correlation between GH response to GHRH and sex, stage of the disease, or cerebral atrophy. The proportion of patients with exaggerated, normal, or lower GH response was similar in the four groups in terms of TSH response to TRH (9.2 +/- 0.9, 11.1 +/- 1, 11.1 +/- 1, and 10.3 +/- 1 mU/ml, respectively), nor was there a correlation between TSH response to TRH and sex, stage of the disease, cerebral atrophy, or GH response to GHRH. The proportion of those with exaggerated, normal, or lower TSH response was similar in the four groups. Cerebrospinal somatostatin levels were similar in Alzheimer's disease and vascular dementia patients. These findings indicate that neither GH response to GHRH nor TSH response to TRH provides a useful diagnostic adjunct in Alzheimer's disease patients.


Comparative Proteomics Study of Yak Milk from Standard and Naturally Extended Lactation Using iTRAQ Technique.
Extended lactation is a common phenomenon in lactating yaks under grazing and natural reproduction conditions. To elucidate differences in milk protein compositions and mammary gland functions between yaks of standard lactation (TL yaks) and prolonged lactation (HL yaks), whole milk samples of TL yaks and HL yaks (n = 15 each) were collected from a yak pasture at the northwest highland of China. The iTRAQ technique was used to compare the skim milk proteins in the two yak groups. A total of 202 differentially expressed proteins (DEPs) were revealed, among which 109 proteins were up-regulated and 93 were down-regulated in the milk of HL yaks compared to TL yaks. Caseins including κ-casein, αs1-casein, αs2-casein, and β-casein were up-regulated in HL yak milk over 1.43-fold. The GO function annotation analysis showed that HL yaks produced milk with characteristics of milk at the degeneration stage, similar to that of dairy cows. KEGG enrichment showed that the metabolic pathways with the most differences are those that involve carbohydrate metabolism and the biosynthesis of amino acids. The present results highlight detailed differences in skim milk proteins produced by HL yaks and TL yaks and suggest that the mammary gland of HL yak is at the degeneration stage.


Processing variant forms in spoken word recognition: the role of variant frequency.
Recognition of a spoken word phonological variant--schwa vowel deletion (e.g., corporate --> corp'rate)--was investigated in vowel detection (absent/present) and syllable number judgment (two or three syllables) tasks. Variant frequency corpus analyses (Patterson, LoCasto, & Connine, 2003) were used to select words with either high or low schwa vowel deletion rates. Speech continua were created for each word in which schwa vowel length was manipulated (unambiguous schwa-present and schwa-absent endpoints, along with intermediate ambiguous tokens). Matched control nonwords were created with identical schwa vowel continua and surrounding segments. The low-deletion-rate words showed more three-syllable judgments than did the high-deletion-rate words. Matched control nonwords did not differ as a function of deletion rate. Experiments 2 and 3 showed a lexical decision reaction time advantage for more frequent surface forms, as compared with infrequent ones, for schwa-deleted (Experiment 2) and schwa-present (Experiment 3) stimuli. The results are discussed in terms of representations of variant forms of words based on variant frequency.


Experimental infection of European flat oyster Ostrea edulis with ostreid herpesvirus 1 microvar (OsHV-1μvar): Mortality, viral load and detection of viral transcripts by in situ hybridization.
Ostreid herpesvirus 1 (OsHV-1) infections have been reported in several bivalve species. Mortality of Pacific oyster Crassostrea gigas spat has increased considerably in Europe since 2008 linked to the spread of a variant of OsHV-1 called μvar. In the present study we demonstrated that O. edulis juveniles can be infected by OsHV-1μvar when administered as an intramuscular injection. Mortality in the oysters injected with OsHV-1μvar was first detected 4 days after injection and reached 25% mortality at day 10. Moreover, the high viral load observed and the detection of viral transcripts by in situ hybridization in several tissues of dying oysters suggested that OsHV-1μvar was the cause of mortality in the O. edulis juveniles. This is therefore the first study to provide evidence about the pathogenicity of OsHV-1μvar in a species that does not belong to the Crassostrea genus. Additionally, we present a novel method to detect OsHV-1 transcripts in infected individuals' using in situ hybridization.


Preparation and cyclodextrin solubilization of the antibacterial agent benzoyl metronidazole.
A one-pot method for the preparation of benzoyl metronidazole was achieved by using N,N'-carbonyldiimidazole as a coupling reagent. Moreover, it was found that the byproduct imidazole as the catalyst promoted the reaction. In addition, the β-cyclodextrin solubilization of benzoyl metronidazole was investigated by phase-solubility method. The phase-solubility studies indicated that the solubility of benzoyl metronidazole (S = 0.1435 g/L) was substantially increased 9.7-fold (S' = 1.3881 g/L) by formation of 1 : 1 benzoyl metronidazole/β-cyclodextrin complexes in water, and the association constant K(a) value was determined to be 251 (±23) dm(3)/mol. Therefore, β-cyclodextrin can work as a pharmaceutical solubilizer for benzoyl metronidazole and may improve its oral bioavailability.


Isolated PTH Renal Resistance Pseudohypoparathyroidism 1b: A Rare Cause of Hypocalcemia.
A case of Pseudohypoparathyroidism 1b is reported, who presented with signs and symptoms of hypocalcemia. Causes, diagnosis and management with new insight into genetic novel mutations in PHP are discussed. The objectives are to provide information regarding problems of Calcium balance, causes and making diagnosis of pseudohypoparathyroidism, learn complexities of PTH cellular interactions and calcium homeostasis and learn the genetic novel mutations of various types of PHP.


Phylogenetic relationships within the genus Tetrahymena inferred from the cytochrome c oxidase subunit 1 and the small subunit ribosomal RNA genes.
Details of the phylogenetic relationships among tetrahymenine ciliates remain unresolved despite a rich history of investigation with nuclear gene sequences and other characters. We examined all available species of Tetrahymena and three other tetrahymenine ciliates, and inferred their phylogenetic relationships using nearly complete mitochondrial cytochrome c oxidase subunit 1 (cox1) and small subunit (SSU) rRNA gene sequences. The inferred phylogenies showed the genus Tetrahymena to be monophyletic. The three "classical" morphology-and-ecology-based groupings are paraphyletic. The SSUrRNA phylogeny confirmed the previously established australis and borealis groupings, and nine ribosets. However, these nine ribosets were not well supported. Using cox1 gene, the deduced phylogenies based on this gene revealed 12 well supported groupings, called coxisets, which mostly corresponded to the nine ribosets. This study demonstrated the utility of cox1 for resolving the recent phylogeny of Tetrahymena, whereas the SSU rRNA gene provided resolution of deeper phylogenetic relationships within the genus.


Stretch reflex responses in Complex Regional Pain Syndrome-related dystonia are not characterized by hyperreflexia.
To evaluate if hyperreflexia (exaggerated reflexes) due to disinhibition is associated with dystonia in Complex Regional Pain Syndrome (CRPS). Stretch reflexes at the wrist were assessed in healthy controls (n=10) and CRPS-patients with dystonia (n=10). Subjects exerted a wrist flexion torque of 5% of maximum voluntary contraction torque (T(MVC)) to a manipulandum which applied ramp-and-hold stretches to the wrist flexors. Since reflex responses scale with background contraction, controls additionally performed the task at 1% and 3% T(MVC) to attain similar torques as patients who have reduced T(MVC). The M1 onset and the magnitudes of the short latency M1 and long latency M2 were assessed using the electromyographic signals (EMG) of the flexor carpi radialis. EMG of the extensor carpi radialis was recorded to monitor cocontraction. Compared to controls, patients had a substantially reduced T(MVC). Ramp velocity had a significant effect on M1 onset time and magnitude. Since M1 magnitude decreased with flexion torque, no significant difference was found between patients and controls at 5% T(MVC), while comparison at similar absolute torques (controls at 1% T(MVC)) resulted in significantly smaller M1 magnitudes for patients with dystonia. This study suggests that CRPS-patients with dystonia are not hyperreflexive.


One Carbon Metabolism and Mammalian Pregnancy Outcomes.
One-carbon metabolism is involved in varieties of physiological processes in mammals, including nucleic acid synthesis, amino acid homeostasis, epigenetic regulation, redox balance and neurodevelopment. The current evidence linking levels of one-carbon nutrients during pregnancy to the development of oocytes, embryos, and placentas, as well as maternal and offspring health, is reviewed. The sources of mammalian one-carbon units, the pathways active in mammalian one-carbon metabolism, the maternal and fetal needs for one-carbon units and their functions during pregnancy are described. The demand for one-carbon metabolism is highest during pregnancy compared to the entire lifetime of a mammal. The primary types of one-carbon metabolism in mammals are the folate cycle, methionine cycle and transsulfuration pathway, which varies at different pregnancy stages (e.g., methylation programming of embryo, neural development of fetus, fetal growth and placenta development). Therefore, an overall consideration of one-carbon metabolism requirements for different pregnancy stages, is called for, specifically, the balance of all nutrients involved, not just one single nutrient in one-carbon metabolism. Moreover, the establishment of an ideal one-carbon metabolism requirement model is suggested according to the requirements for different pregnancy stages to support optimal pregnancy outcomes and maternal and offspring health.


Failure of rituximab in human immunodeficiency virus-associated multicentric Castleman disease.
Two human immunodeficiency virus-infected patients who needed etoposide therapy to control exacerbations of Castleman disease received four infusions of rituximab. Clinical and virologic relapses with increased blood human herpesvirus-8 DNA levels occurred in both patients 4 and 24 weeks later and were associated with a worsening of Kaposi sarcoma.


Centrin 3 is an inhibitor of centrosomal Mps1 and antagonizes centrin 2 function.
Centrins are a family of small, calcium-binding proteins with diverse cellular functions that play an important role in centrosome biology. We previously identified centrin 2 and centrin 3 (Cetn2 and Cetn3) as substrates of the protein kinase Mps1. However, although Mps1 phosphorylation sites control the function of Cetn2 in centriole assembly and promote centriole overproduction, Cetn2 and Cetn3 are not functionally interchangeable, and we show here that Cetn3 is both a biochemical inhibitor of Mps1 catalytic activity and a biological inhibitor of centrosome duplication. In vitro, Cetn3 inhibits Mps1 autophosphorylation at Thr-676, a known site of T-loop autoactivation, and interferes with Mps1-dependent phosphorylation of Cetn2. The cellular overexpression of Cetn3 attenuates the incorporation of Cetn2 into centrioles and centrosome reduplication, whereas depletion of Cetn3 generates extra centrioles. Finally, overexpression of Cetn3 reduces Mps1 Thr-676 phosphorylation at centrosomes, and mimicking Mps1-dependent phosphorylation of Cetn2 bypasses the inhibitory effect of Cetn3, suggesting that the biological effects of Cetn3 are due to the inhibition of Mps1 function at centrosomes.


The effect of willow leaf extracts on human leukemic cells in vitro.
The young developing leaves of willow (Salix safsaf, Salicaceae) trees have antileukemic activity. After a 24-h incubation in vitro, the crude water extracts of the leaves killed a majority of the blasts of acute myeloid leukemia (AML, 73.8%).


Multidrug resistant Enterococcus faecium isolate from cholangitis/cholecystitis in a dog.
Mucocele and cholecystitis were diagnosed in a 10 year-old Shetland-sheepdog presenting aspecific clinical signs. Blood examinations and ultrasonography investigation were performed before to surgical approach, which allowed to collect biopsies and samples for bacteriological analyses. In addition, the patient was subjected to cholecystectomy. A multidrug resistant Enterococcus faecium was isolated from the gallbladder specimens. On the basis of antimicrobial susceptibility test, nitrofurantoin was used. The correct bacteriological diagnosis is necessary to set up effective therapy, influencing the patient's prognosis and improving the recovery time.


Effects of the initial level of milk production and of the dietary protein intake on the course of natural nematode infection in dairy goats.
The level of dietary protein is known to alter the establishment and the pathophysiology of gastrointestinal nematodes in sheep. On the other hand, high-producing dairy goats are less resistant and/or resilient than low-producing ones to experimental nematode infection. During a 2-year study, we have investigated the course of a natural nematode infection (mainly T. colubriformis) in a high-producing dairy goat flock. In year 1, 50 grazing goats divided in high (HP) or low producer (LP) were compared from April to October for parasitological and milk parameters. In year 2, the 25 HP goats were only considered and were allocated to two levels of dietary protein, high level (HPr) with a protein coverage of 125% or normal level (NPr) with a protein coverage of 106%. They were monitored as above. In year 1, HP goats showed a greater nematode egg output (1856 vs. 1000epg) associated with higher values in T. colubriformis IgG in autumn than LP ones whereas the decrease in serum phosphate concentration was similar in both groups. In year 2, HPr goats exhibited lower egg output in autumn (2219 vs. 2817) vs. NPr ones. Moreover, milk yield and fat content were significantly higher in HPr vs. NPr in the 2nd part of the study. HP goats are less resistant to nematode infection in natural conditions. Resistance and resilience of HP goats may partially be improved by a protein supplementation in the diet.


A health state utility valuation study to assess the impact of treatment mode of administration in Gaucher disease.
This study aimed to obtain UK societal-based utility values for health states related to treatment mode of administration using Gaucher disease as the background condition. A review of relevant literature and expert clinical input informed the development of five health states characterising the impact of Gaucher disease and its management on patients' lives. A base-state characterising the "controlled disease" was developed as well as four subsequent health states which varied in description of the method (intravenous versus oral) and frequency of treatment administration. Health state utilities were obtained using the time trade-off (TTO) method via face-to-face interviews with 100 members from the UK general population. Before the valuation exercise, participants provided informed consent, completed a demographic form and the EQ-5D, and ranked the health states from best to worst on a 0-100 visual analogue scale (VAS). Mean age of the participants (n = 100) was 35 years and 66% were female. Participants reported high EQ-5D VAS (86.1) and index scores (0.95) indicating very good health status. The "controlled disease" state had the highest mean TTO-derived utility value (0.89). There was only a marginal reduction in utility for the generic state for "Oral treatment" (0.85), while the reduction was more pronounced for the generic state for "Intravenous treatment" (0.73). The findings suggest that the avoidance of the need for intravenous treatment administration is associated with a notable positive increase in health-related quality of life. Patient benefit arising from less invasive treatment could be an important consideration when undertaking economic evaluation of future therapies for Gaucher disease.


Modified protocol for Enhanced Recovery After Surgery is beneficial for achalasia patients undergoing peroral endoscopic myotomy: a randomized prospective trial.
Enhanced Recovery After Surgery (ERAS) protocols have been proven to promote postoperative recovery. However, limited evidence is available on ERAS protocols in patients undergoing peroral endoscopic myotomy (POEM). To study the safety and effectiveness of an ERAS protocol in terms of the standard postoperative length of stay (LOS) and QoR-15 (Quality of Recovery) score of patients undergoing POEM. Eighty patients were randomly divided into the ERAS or conventional group. The ERAS group received ERAS management, while the conventional group received normal management. The ERAS protocol included sufficient preoperative education, shortening time of preoperative fasting, maintaining intraoperative normothermia, intraoperative fluid management, and improving analgesia. We compared the results between the two groups in term of standard postoperative LOS and cost, QoR-15 score, postoperative pain and complications. Patients showed an improvement in the ERAS group in terms of earlier readiness for hospital discharge (40.21 ±8.42 h vs. 48.63 ±10.42 h; p < 0.001), earlier resumption of oral feeding (31.80 ±8.7 h vs. 42.35 ±10.80 h; p < 0.001), lower VAS, and higher QoR-15 score (139.29 ±2.21 vs. 137.03 ±3.77; p = 0.002) on postoperative day 2. For post-operative complications, there was no significant difference between the two groups. The ERAS protocol is feasible and safe for POEM, and may decrease standard postoperative LOS, shorten recovery of gastrointestinal function, and improve postoperative patient satisfaction.


Five-year Safety Data From OPUS, a European Observational Safety Registry for Adults With Ulcerative Colitis Treated With Originator Infliximab [Remicade®] or Conventional Therapy.
The Observational Postmarketing Ulcerative colitis Study [OPUS] was conducted to obtain the first long-term [5 years] safety data assessing treatment with originator infliximab versus conventional therapies in patients with ulcerative colitis [UC] in real-world clinical practice. The OPUS registry was a prospective, non-randomised, observational study that measured adverse events in nine prespecified categories of interest in UC patients whose treatment with either originator infliximab or conventional therapy [defined as initiation or dose-increase of corticosteroids and/or immunosuppressants] was determined by their treating physician. Data for 2239 patients were available: N = 1180 enrolled to conventional therapy [including N = 296 who switched to originator infliximab during follow-up] and N = 1059 enrolled to originator infliximab. Patients in the originator infliximab group, compared with the conventional therapy group, had more severe disease at baseline, based on partial Mayo score [PMS]: 46.0% of patients in the originator infliximab group had severe disease (PMS of 7-9 [out of 9]), compared with 30.5% in the conventional therapy group. In adjusted time-to-event analyses, enrolment into the originator infliximab group was associated with a higher risk of serious infection (hazard ratio = 1.98 [95% confidence interval: 1.34, 2.91; p <0.001]) compared with enrolment into the conventional therapy group. No notable risk differences between groups were identified for haematological disorder, autoimmune disorder, malignancy/lymphoproliferative disorder, hepatobiliary disorder or fatality. UC patients treated with infliximab had higher risk for serious infection, compared with conventional therapies. No new safety concerns were observed with originator infliximab in the OPUS registry. [ClinicalTrials.gov: NCT00705484.].


Use of Immune Checkpoint Inhibitors in Patients With Pre-established Inflammatory Bowel Diseases: Retrospective Case Series.
The etiology of inflammatory bowel disease (IBD) has yet to be fully understood; however, it is thought to be a result of genetic, immunologic, and environmental factors, including changes in the gut microbiome.1,2 Immune checkpoint inhibitors (ICI) have revolutionized treatment of advanced cancer. They activate the immune system by promoting cytotoxic T-cell survival and antitumor effects. A total of 7 ICIs currently are approved by the United States Food and Drug Administration, and target cytotoxic T lymphocyte-associated protein 4 (ipilimumab); anti-programmed cell death 1 (PD-1) (nivolumab, pembrolizumab, and cemiplimab), or anti-PD-ligand 1 (atezolizumab, durvalumab, and avelumab). However, by activating the immune system, these medications also can lead to off-target inflammation and autoimmunity, including ICI-induced colitis, which has been reported in up to 13.6% of patients.3.


Endoscopic management of adult subglottic stenosis: an alternative to open surgery.
Various surgical techniques could be used to treat subglottic stenosis (SGS). The aim of this study is to present our experience in endoscopic management of SGS and show the impact of symptoms' evaluation, clinical examination and spirometry in the therapeutic decision. Endoscopic treatment was performed in patients referred for SGS and consisted of CO2 scar lysis associated with balloon dilation and concomitant steroids' injection for patients with grade II or higher on the mMRC (modified Medical Research Council) dyspnea scale associated with a DI (Dyspnea Index) score higher than 10/40 and objective stenosis equal or higher than grade II. The preoperative DI score, EDI (expiratory disproportion index) and voice parameters were compared to postoperative results. The mean interval between endoscopic procedures (IEP) was calculated and we looked for the evolution of the IEP during repeated procedures. Nineteen patients were included. 35 dilations were performed. The mean IEP was 86 weeks. There was a significant decrease of the postoperative DI scores by 18.6 points ± 11 (SD). An important difference of 20.1 ± 13.5 (SD) was identified between the pre and postoperative EDI. Minimal changes occured in voice parameters. Endoscopic treatment with CO2 scar lysis associated with balloon dilation and concomitant steroids' injection is a safe, reliable and minimally invasive endoscopic procedure to treat SGS. Decision to treat has to be on an individual basis taking into account subjective symptoms including Dyspnea Index score and objective laryngoscopic findings and spirometry.


The effect of cyclophosphamide and vincristine on intestinal protein loss in rats.
24 and 48 hours after a single intraperitoneal dose of 80 mg/kg cyclophosphamide (I. group) and 0.20 mg/kg vincristine (II. group) the intestinal protein loss has been studied using the 51CrCl3 isotope method. 16 animals were used as control (III. group). In case of both cytostatics, the intestinal protein loss was significantly higher. Histologically the small bowel mucosa, on the first day after injection, showed, in the crypts, necrotic cells and mitoses arrested in metaphase. By the second day, after injection, severe villous atrophy and occasional mucosal erosions were seen. The causes of these changes are discussed together with the question of the disrupted barrier function of the small bowel.


Characterization of papillary squamotransitional cell carcinoma of the cervix.
Does papillary squamotransitional cell carcinoma (PSTCC) behave differently from conventional squamous cell carcinoma of the cervix and does PSTCC have true transitional cell differentiation? Twenty cases of PSTCC were identified from archival files. Clinical data were compiled. Immunoperoxidase stains for uroplakin III, p63 and p16 were performed on available tissue blocks. Patients ranged in age from 27 to 85 years. Twelve patients were FIGO Stage I, 4 were Stage II, and 2 were Stage III. Thirteen patients had clinical follow-up ranging from 5 to 132 months. Three patients subsequently had more extensive disease than initial clinical staging indicated. Nine patients had no tumor progression, three had local recurrence and one had metastatic disease. Eight cases were strongly immunoreactive for p63 and p16 and 14 were negative for uroplakin III. PSTCC lacks true transitional cell differentiation and probably shares similar clinicopathologic features with conventional cervical squamous cell carcinoma.


SAPHO and Recurrent Multifocal Osteomyelitis.
SAPHO and recurrent multifocal osteomyelitis are complex inflammatory conditions that clinical radiologists play an essential part in diagnosing. They present with a wide range of musculoskeletal and skin manifestations, and exhibit several key diagnostic features that, when present, make the diagnoses unequivocal. The overall population group is young. Diagnostic delay is common with a relapsing and remitting clinical course and often subtle early radiologic findings. This article provides an up-to-date insight into both conditions, including their multifaceted pathogenesis, effective therapeutic options, and advanced imaging features, to arm radiologists with the knowledge required to make the diagnoses confidently in a timely manner.


Perforation of the hypopharynx after transesophageal echocardiography.
A 65-year-old obese woman with an oversized neck and dysphagia underwent transesophageal echocardiography (TEE). The procedure was complicated by difficulty in insertion from the pharynx to esophagus, and her head and neck gradually swelled. Computed tomography (CT) revealed extensive emphysema from the neck to superior mediastinum, which suggested pharyngeal perforation. A nasogastric tube was inserted, and the patient received antibiotics to prevent secondary mediastinitis. CT performed 1 week later showed improvement of emphysema and no evidence of mediastinitis. Perforation along the orogastric pathway during TEE is a rare but life-threatening complication to which physicians performing TEE should pay attention.


[The laboratory diagnosis of deep localized candidiasis].
A survey on the presently used methods for isolation and differentiation of Candida yeasts as well as on serological methods is presented. The difficulties of the pathognomonic evaluation of laboratory parameters are discussed.


Bumetanide and frusemide: a comparison of dose-response curves in healthy men.
1 Log dose-responses for the loop diuretics bumetanide and frusemide in healthy subjects deviated significantly from parallelism as regards urine volume and sodium excretion. Ignoring the nonparallelism the best estimate of natriuretic potency (bumetanide: frusemide) was 46:1 in the bumetanide dose range 0.5-2 mg. 2 For a given natriuresis the urinary potassium excretion following bumetanide was significantly lower than that for frusemide within this dose range. 3 The data illustrate the limitations of studies comparing diuretics at a single dose level. Extrapolation of the observed log dose-response curves provides one possible explanation for the relative potency (bumetanide: frusemide) of 20:1 reported when the drugs are used at high dosage in patients with renal failure.


Fast and slow dynamics of malaria model with relapse.
Two mathematical models of malaria with relapse are studied. When the vector population size is constant, complete analyses of the dynamics are conducted. The geometric singular perturbation theory is used to analyze the full dynamics. On the critical manifold, from next generation matrix method, we obtain the basic reproduction number. The global stability of disease-free equilibrium and the uniformly persistence of malaria have also been analyzed. While the vector population size is variable, the basic reproduction number and the stability of disease-free as well as the malaria-infected equilibrium have been obtained in a similar way. Some numerical simulations are also given.


Repeated immunosuppressive rabbit antithymocyte globulin therapy for adult patients with relapsed or refractory aplastic anemia.
Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporin A is the standard treatment for aplastic anemia (AA). However, the efficacy of repeated IST with rabbit ATG (rATG) as salvage therapy remains unclear in patients with relapsed or refractory AA. We retrospectively evaluated the efficacy and safety of IST2 with rATG (IST2-rATG) in 19 consecutive patients with relapsed or refractory AA who received first-line IST with rATG in two centers between 2009 and 2020. The overall 6-month response rate of the patients was 58%. The response rates were similar between patients with relapsed and refractory AA. The presence of glycophosphatidylinositol-deficient blood cells was associated with a better response to IST2-rATG. Despite retreatment with the same rATG, serum disease and severe allergic reactions were not observed. IST2-rATG is effective and safe for the treatment of adult patients with relapsed and refractory AA after receiving first-line IST with rATG.


Total-, LDL-, and HDL-cholesterol, apolipoproteins, and triglycerides with risk of total and fatal prostate cancer in Black and White men in the ARIC study.
Cholesterol reduction is considered a mechanism through which cholesterol-lowering drugs including statins are associated with a reduced aggressive prostate cancer risk. While prior cohort studies found positive associations between total cholesterol and more advanced stage and grade in White men, whether associations for total cholesterol, low (LDL)- and high (HDL)-density lipoprotein cholesterol, apolipoprotein B (LDL particle) and A1 (HDL particle), and triglycerides are similar for fatal prostate cancer and in Black men, who experience a disproportionate burden of total and fatal prostate cancer, is unknown. We conducted a prospective study of 1553 Black and 5071 White cancer-free men attending visit 1 (1987-1989) of the Atherosclerosis Risk in Communities Study. A total of 885 incident prostate cancer cases were ascertained through 2015, and 128 prostate cancer deaths through 2018. We estimated multivariable-adjusted hazard ratios (HRs) of total and fatal prostate cancer per 1-standard deviation increments and for tertiles (T1-T3) of time-updated lipid biomarkers overall and in Black and White men. Greater total cholesterol concentration (HR per-1 SD = 1.25; 95% CI = 1.00-1.58) and LDL cholesterol (HR per-1 SD = 1.26; 95% CI = 0.99-1.60) were associated with higher fatal prostate cancer risk in White men only. Apolipoprotein B was nonlinearly associated with fatal prostate cancer overall (T2 vs. T1: HR = 1.66; 95% CI = 1.05-2.64) and in Black men (HR = 3.59; 95% CI = 1.53-8.40) but not White men (HR = 1.13; 95% CI = 0.65-1.97). Tests for interaction by race were not statistically significant. These findings may improve the understanding of lipid metabolism in prostate carcinogenesis by disease aggressiveness, and by race while emphasizing the importance of cholesterol control.


Gas chromatographic determination of ethyl 2-cyanoacrylate in the workplace environment.
Low levels of airborne ethyl 2-cyanoacrylate (ECA) were monitored by drawing air through sampling tubes containing Tenax GC. After desorption with acetone, ECA was quantified by gas chromatography using a thermionic specific detector in the nitrogen mode. Polymerised ECA was shown to yield ECA monomer under the conditions of gas chromatographic analysis.


The Association Between Suicide Attempts, Anxiety, and Childhood Maltreatment Among Adolescents and Young Adults With First Depressive Episodes.
Objective: Adolescents and young adults are susceptible to high-risk behaviors such as self-harm and suicide. However, the impact of childhood maltreatment on suicide attempts in adolescents and young adults with first episode of depression remains unclear. This study examined the association between suicide attempts and childhood maltreatment among adolescents and young adults with first depressive episodes. Methods: A total of 181 adolescents and young adults with first depressive episodes were included. The Child Trauma Questionnaire (CTQ), Beck Anxiety Inventory (BAI), and Patient Health Questionnaire-2 (PHQ-2) were used to assess childhood maltreatment and the severity of anxiety and depressive symptoms, respectively. The suicide item in the MINI-International Neuropsychiatric Interview (M.I.N.I.) 5.0 was used to assess the suicide attempts. Logistic regression analyses were used to explore the associated factors of suicide attempts. Results: The prevalence of SA in the total sample was 31.5% (95% CI = 24.9-38.1%). Multivariate logistic regression analyses revealed that the diagnosis of bipolar disorder (OR = 2.18, 95% CI = 1.07-4.40), smoking (OR = 2.64, 95% CI = 1.10-6.37), anxiety symptoms (OR = 1.05, 95% CI = 1.02-1.08), and childhood maltreatment (OR = 1.04, 95% CI = 1.01-1.07) were potential associated factors of SA. In addition, anxiety symptoms had a mediating effect on the relationship between childhood maltreatment and SA. Conclusion: Adolescents and young adults with first depressive episodes and having experiences of childhood maltreatment are at a high risk of suicide. The severity of anxiety symptoms may mediate the relation between childhood maltreatment and suicide attempts in this group of patients.


Responses to species-specific vocalizations in the auditory cortex of awake and anesthetized guinea pigs.
Species-specific vocalizations represent an important acoustical signal that must be decoded in the auditory system of the listener. We were interested in examining to what extent anesthesia may change the process of signal decoding in neurons of the auditory cortex in the guinea pig. With this aim, the multiple-unit activity, either spontaneous or acoustically evoked, was recorded in the auditory cortex of guinea pigs, at first in the awake state and then after the injection of anesthetics (33 mg/kg ketamine with 6.6 mg/kg xylazine). Acoustical stimuli, presented in free-field conditions, consisted of four typical guinea pig calls (purr, chutter, chirp and whistle), a time-reversed version of the whistle and a broad-band noise burst. The administration of anesthesia typically resulted in a decrease in the level of spontaneous activity and in changes in the strength of the neuronal response to acoustical stimuli. The effect of anesthesia was mostly, but not exclusively, suppressive. Diversity in the effects of anesthesia led in some recordings to an enhanced response to one call accompanied by a suppressed response to another call. The temporal pattern of the response to vocalizations was changed in some cases under anesthesia, which may indicate a change in the synaptic input of the recorded neurons. In summary, our results suggest that anesthesia must be considered as an important factor when investigating the processing of complex sounds such as species-specific vocalizations in the auditory cortex.


Emergency department management of thyrotoxic crisis with esmolol.
A previously healthy 26-year-old woman presented to the emergency department complaining of a severe, throbbing, and bifrontal headache. Initial vital signs were pulse rate, 130 beats/min; blood pressure, 128/50 mm Hg; temperature, 100.1 degrees F. Shortly thereafter the patient's pulse and temperature increased to 170 beats/min and 103 degrees F, respectively. Physical examination showed a tremulous, anxious woman in moderate distress who had a diffusely and symmetrically enlarged thyroid gland. A diagnosis of thyrotoxic crisis was made, and appropriate therapy instituted, including the use of an esmolol infusion for control of hypersympathetic activity. A review of the clinical presentation, diagnosis, and management of thyrotoxic crisis is presented.


Prevalence of radiographic findings of femoroacetabular impingement in the Japanese population.
Femoroacetabular impingement (FAI) is one factor known to cause pain and osteoarthritis (OA) of the hips. Although secondary OA due to hip dysplasia is common among Japanese populations, primary OA is seldom observed. Concomitantly, FAI is also thought to be uncommon in Japan, but relatively few epidemiological studies have addressed this issue. This study aimed to clarify the prevalence of radiographic findings of FAI in a Japanese population and to evaluate whether FAI is a risk factor for the development of arthritic changes. We retrospectively examined 87 patients who underwent unilateral hip osteotomy with a Charnley category A hip joint on the contralateral side. Anteroposterior-view radiographs of the non-operated hip joint were assessed for the presence of hip dysplasia, as well as pistol grip deformity and crossover sign indicative of cam-type and pincer-type impingement, respectively. The presence of arthritic changes in the non-operated hip joint was assessed in follow-up radiographs, and factors contributing to the development of arthritis were determined by survival analysis. Of the 87 hips examined, dysplasia was noted in 38 (43.6%). While no pistol grip deformity was observed, crossover sign, which is indicative of pincer-type impingement, was identified in 9 of 38 dysplastic hips (23.7%) and 15 of 49 non-dysplastic hips (30.6%). Arthritic changes were present in 13 of 38 dysplastic hips (34.2%) and 11 of 49 non-dysplastic hips (22.4%). Survival analysis revealed that the presence of the crossover sign in non-dysplastic hips was significantly associated with the development of arthritis. The prevalence of the crossover sign in hips in a Japanese population is similar to that reported in Western populations, despite the fact that FAI is believed to be less prevalent in the Japanese population. Furthermore, the presence of the crossover sign in non-dysplastic hip joints is associated with the development of arthritis. Based on our results, pincer-type impingement could be commonly associated with the development of arthritis in Japanese populations.


Biophysical cues of bone marrow-inspired scaffolds regulate hematopoiesis of hematopoietic stem and progenitor cells.
Hematopoietic stem cells (HSCs) are adult multipotential stem cells with the capacity to differentiate into all blood cells and immune cells, which are essential for maintaining hematopoietic homeostasis throughout the lifespan and reconstituting damaged hematopoietic system after myeloablation. However, the clinical application of HSCs is hindered by the imbalance of its self-renewal and differentiation during in vitro culture. Considering the fact that HSC fate is uniquely determined by natural bone marrow microenvironment, various elaborate cues in this hematopoietic micro-niche provide an excellent reference for the regulation of HSCs. Inspired by the bone marrow extracellular matrix (ECM) network, we designed degradable scaffolds by orchestrating the physical parameters to investigate the decoupling effects of Young's modulus and pore size of three-dimensional (3D) matrix materials on the fate of hematopoietic stem and progenitor cells (HSPCs). We ascertained that the scaffold with larger pore size (80 μm) and higher Young's modulus (70 kPa) was more favorable for HSPCs proliferation and the maintenance of stemness related phenotypes. Through in vivo transplantation, we further validated that scaffolds with higher Young's modulus were more propitious in maintaining the hematopoietic function of HSPCs. We systematically screened an optimized scaffold for HSPC culture which could significantly improve the cell function and self-renewal ability compared with traditional two-dimensional (2D) culture. Together, these results indicate the important role of biophysical cues in regulating HSC fate and pave the way for the parameter design of 3D HSC culture system.


Modeling the initial-volume dependent approximate compressibility of porcine liver tissues using a novel volumetric strain energy model.
Experimental observations in the open literature indicate that soft tissues are slightly compressible, and this characteristic affects not only their overall elastic response but also their damage evolution and failure mechanism. In this study, we find that the compressibility of liver tissues is also closely related to the initial specimen volume according to the confined compression tests: the samples with smaller initial volume exhibit more compressible behavior compared to the larger ones. To include this initial-volume dependent effect, we developed a novel volumetric strain energy model with two variables, i.e., the bulk modulus and the compressibility factor. A detailed scheme was proposed as well to identify these two parameters, and the relationship between the bulk modulus and the initial volume was clarified. Findings from this study will help to deepen the understanding of the biomechanical properties of soft tissues. STATEMENT OF SIGNIFICANCE: Liver is a highly vascular organ and traditionally assumed to be an incompressible medium. However, through the confined compression tests, we found that the samples with smaller initial volumes exhibit more compressible behavior. Hence, we developed a novel strain energy density model to characterize the initial-volume dependent hyperelastic response, and found that the bulk modulus of liver tissues is positively related to the initial volume. Our results suggest that the compressibility of liver tissues should be considered in the future study of liver biomechanics.


Quality Assurance of UMLS Semantic Type Assignments Using SNOMED CT Hierarchies.
The Unified Medical Language System (UMLS) is one of the largest biomedical terminological systems, with over 2.5 million concepts in its Metathesaurus repository. The UMLS's Semantic Network (SN) with its collection of 133 high-level semantic types serves as an abstraction layer on top of the Metathesaurus. In particular, the SN elaborates an aspect of the Metathesaurus's concepts via the assignment of one or more types to each concept. Due to the scope and complexity of the Metathesaurus, errors are all but inevitable in this semantic-type assignment process. To develop a semi-automated methodology to help assure the quality of semantic-type assignments within the UMLS. The methodology uses a cross-validation strategy involving SNOMED CT's hierarchies in combination with UMLS semantic types. Semantically uniform, disjoint concept groups are generated programmatically by partitioning the collection of all concepts in the same SNOMED CT hierarchy according to their respective semantic-type assignments in the UMLS. Domain experts are then called upon to review the concepts in any group having a small number of concepts. It is our hypothesis that a semantic-type assignment combination applicable only to a very small number of concepts in a SNOMED CT hierarchy is an indicator of potential problems. The methodology was applied to the UMLS 2013AA release along with the SNOMED CT from January 2013. An overall error rate of 33% was found for concepts proposed by the quality-assurance methodology. Supporting our hypothesis, that number was four times higher than the error rate found in control samples. The results show that the quality-assurance methodology can aid in effective and efficient identification of UMLS semantic-type assignment errors.


Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases. In vivo selective brain monoamine oxidase inhibition and prevention of MPTP-induced striatal dopamine depletion.
Several multifunctional iron chelators have been synthesized from hydroxyquinoline pharmacophore of the iron chelator, VK-28, possessing the monoamine oxidase (MAO) and neuroprotective N-propargylamine moiety. They have iron chelating potency similar to desferal. M30 is a potent irreversible rat brain mitochondrial MAO-A and -B inhibitor in vitro (IC50, MAO-A, 0.037 +/- 0.02; MAO-B, 0.057 +/- 0.01). Acute (1-5 mg/kg) and chronic [5-10 mg/kg intraperitoneally (i.p.) or orally (p.o.) once daily for 14 days]in vivo studies have shown M30 to be a potent brain selective (striatum, hippocampus and cerebellum) MAO-A and -B inhibitor. It has little effects on the enzyme activities of the liver and small intestine. Its N-desmethylated derivative, M30A is significantly less active. Acute and chronic treatment with M30 results in increased levels of dopamine (DA), serotonin(5-HT), noradrenaline (NA) and decreases in DOPAC (dihydroxyphenylacetic acid), HVA (homovanillic acid) and 5-HIAA (5-hydroxyindole acetic acid) as determined in striatum and hypothalamus. In the mouse MPTP (N-methy-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease (PD) it attenuates the DA depleting action of the neurotoxin and increases striatal levels of DA, 5-HT and NA, while decreasing their metabolites. As DA is equally well metabolized by MAO-A and -B, it is expected that M30 would have a greater DA neurotransmission potentiation in PD than selective MAO-B inhibitors, for which it is being developed, as MAO-B inhibitors do not alter brain dopamine.


Optimal feeding strategy of the temperate herbivorous fish Aplodactylus punctatus: the effects of food availability on digestive and reproductive patterns.
In this study we examined differences in feeding behevior of populations of the marine temperate herbivorous fish Aplodactylus punctatus, in three different localities off the Chilean coast, which differ qualitatively and quantitatively in food availability. We test whether food selection follows optimal foraging strategics, whether there is any modification of the fishes' digestive tracts in relation to their diets, and whether differences in diet quality affect the allocation of energy into reproduction and maintenance in these populations. Samples of this fish and of the understore algal assemblages were taken seasonally from May 1989 to February 1990. For each population we analyzed dietary composition, weight of the digestive tract and of the food content, the condition factor (K), and the gonadosomatic index (GSI). Our results showed that the diet observed in the three populations closely resembled the differences in macro-algal abundance and composition among the three localities studied. Local differences in diet quality were inversely related to the amount of food consumption and size of the digestive tract, suggesting that under differential conditions of food availability A. punctatus is able to compensate for variations in food quality through a flexibility in its digestive strategies. The nutritional status (K) of individuals, and their reproductive pattern (GSI) were directly related to diet quality. These results indicate that although A. punctatus is able to adjust its digestive processes to different algal food regimes, the digestive modifications observed in food-poor environments are not sufficient to compensate for the lack of food and allow fish to reach the nutritional status and reproductive output reached in a food-rich environment. This study represents the first natural experiment demonstrating a direct relationship among food availability, feeding patterns, digestive processes, and reproductive effort.


Development of the blood-CSF barrier.
The development of the blood-CSF barrier was investigated by establishing total protein, individual protein levels and cell-counts in the CSF and serum of 185 healthy children, with an age range from 27 fetal weeks to 16 years. Albumin, alpha 2-macroglobulin and immunoglobulin G were found in all CSF specimens. With the exception of IgG, their concentrations decreased continuously until the end of the first year of life. IgM was not present in the CSF and IgA was found in only a few cases. Serum:CSF ratios of individual proteins increased continuously from the fetal period to the first year and there was a decline in barrier selectivity during the same period. Maturation of the barrier was maximal during the third month of life, decreasing quickly thereafter. The barrier condition of preterm infants was closely related to conceptional age, but not to the time of birth.


The metabolism of cyclic AMP and glucose in isolated islets from Acomys cahirinus.
Glucose-induced cyclic (3H) AMP accumulation, insulin secretory responses and the metabolism of glucose were studied in pancreatic islets from Acomys cahirinus. 27.7 mmol/l of glucose stimulated neither islet cyclic (3H) AMP accumulation nor insulin release during the first 5 min of incubation. Stimulation by glucose of cyclic (3H) AMP was observed after 15 min of incubation and insulin release was markedly stimulated between 15 and 30 min. The utilization of glucose, measured as the production of (3H)2O from (5--3H) glucose was stimulated by glucose after 10 min and proceeded at an apparently linear rate during a 20 min incubation period. In incubations of 5 min, glibenclamide, glucagon or chloromercuribenzene-p-sulphonic acid failed to stimulate islet cyclic (3H) AMP accumulation. 3-isobutyl-l-methylxanthine in a concentration of 1.0 mmol/l was the only agent tested that elevated rapidly (1 min) islet cyclic (3H) AMP. None of the agents tested elicited an insulin secretory response in 5 min incubations. It is concluded that 1) no gross defect is apparent in the utilization of glucose by Acomys islets, 2) the secretory derangement of the Acomys is associated with a delayed cyclic AMP response to glucose, 3) however a decreased level of cyclic AMP cannot be the sole explanation for the delayed insulin secretion in the Acomys.


Lipopolysaccharide and a social stressor influence behaviour, corticosterone and cytokine levels: divergent actions in cyclooxygenase-2 deficient mice and wild type controls.
Administration of the endotoxin, lipopolysaccharide (LPS) diminished motor activity and increased plasma corticosterone as well as circulating levels of interleukin-1beta (IL-1beta), IL-6, tumor necrosis-factor-alpha (TNF-alpha) and IL-10. Among cyclooxygenase-2 (COX-2) knockout mice the behavioural, corticosterone and cytokine variations promoted by LPS were moderately (home cage activity, corticosterone, TNF-alpha) or largely (IL-6) reduced. However, if mice were exposed to a psychosocial stressor (social disruption associated with grouping mice with novel cage-mates after a period of isolation) coupled with LPS treatment, then the effects of the COX-2 deletion were absent, or there was a synergistic or additive elevation apparent (e.g., in the case of TNF-alpha, IL-6 and corticosterone). Evidently, COX-2 deletion may have either pro- or anti-inflammatory actions, depending upon the psychosocial context in which immune activation occurs.


Novel treatments in non-small cell lung cancer.
Although it has been exciting for lung cancer doctors to observe objective remissions with gefitinib and erlotinib in heavily pretreated NSCLC patients, all of the reported phase III trials testing noncytotoxic, targeted therapies in NSCLC have been negative. Two basic strategies have been employed in developing and conducting these randomized studies. In the case of gefitinib and the matrix metalloproteinase inhibitors, phase III trials were launched based on preclinical data. The second strategy was based on survival results from phase II trials involving regimens consisting of the targeted agent and chemotherapy. Unfortunately, negative results have been observed with the first phase III study (chemotherapy +/- ISIS 3521), which was based on the results of a phase II trial. The initial negative results with targeted agents suggest that a paradigm shift in cancer drug development is needed. Typically, the development of a cytotoxic agent involves determination of the maximum tolerated dose, followed by an assessment of activity as defined by the objective response rate in specific tumor types. "Active" drugs are then moved into phase III testing to determine the effect on survival. Other than targeting the specific tumor type and defining the usual eligibility parameters, no attempt is made to select patients for treatment with new agents. It seems unlikely that there will be significant progress with the targeted therapies unless there is a paradigm shift from this classic model of cancer drug development to a model in which much greater effort is directed toward identifying the target or targets in preclinical models. Intensive effort should be devoted to the development of reliable, clinically applicable assays for the targets that could identify patients who are most likely to benefit from a specific treatment. Rothenberg et al recently made similar recommendations with respect to improving the drug discovery process for cancer. These investigators have emphasized testing new agents in the most appropriate setting, increasing efforts to understand the role of the target, and collection of tissue in an effort to select appropriate patients. Although results from initial randomized trials of targeted therapies in NSCLC have been relatively disappointing, this is not a time to be discouraged. Rather, it is a time to increase the collaborative efforts between basic scientists and clinical investigators.


Behavioral and Regional Brain Responses to Inhalation of Capsaicin Modified by Painful Conditioning in Humans.
Cough is a defense mechanism that protects the airways and lungs in response to airway irritation. The sensory neurons involved in detecting airway irritants and the neural pathways mediating cough share similarities with those that encode pain from the body. Painful conditioning stimuli applied to one body site are known to reduce the perception of pain at another. However, whether the neural regulation of cough is influenced by painful stimuli is not known. What are the behavioral and neural outcomes of painful conditioning stimuli on urge-to-cough (UTC) and cough evoked by inhaled capsaicin? Sixteen healthy participants underwent psychophysical testing and functional MRI while completing a series of capsaicin inhalations to induce UTC and cough. The responses associated with capsaicin inhalation without pain were compared with those after the application of painful conditioning stimuli. Significant decreases were seen behaviorally of 18.7% ± 17.3% (P < .001) and 47.0% ± 30.8% (P < .001) in participants' UTC ratings and cough frequencies, respectively, during the application of pain. UTC ratings were reduced by 24.2% ± 36.5% (P < .005) and increased by 67% ± 40% (P < .001) for capsaicin and saline inhalation, respectively, during the scanning session. Painful conditioning stimuli were associated with widespread decreases in regional brain responses to capsaicin inhalation (P < .001). Several brain regions showed levels of reduced activation attributable to painful conditioning that correlated with related changes in behavioral responses during scanning (R2 = 0.53). Pain-related decreases of cough and UTC are accompanied by widespread changes in brain activity during capsaicin inhalation, suggesting that pain can modify the central processing of inputs arising from the airways. A mechanistic understanding of how cough and pain processing interact within the brain may help develop more effective therapies to reduce unwanted coughing.


Diagnostic uncertainty in a severely demented male patient: a case report.
Current trends in dementia research focus on early and accurate diagnosis. In clinical practice however, this is not always possible, as multiple underlying pathologies produce mixed dementia syndromes. Furthermore, patients with severe dementia are often underestimated. We present a case of a 71 year old Caucasian male with severe Alzheimer's Disease, bedridden and fully dependent in activities of everyday living, whose general cognitive function is almost intact. We emphasize on the diverse underlying pathologies contributing to this intriguing clinical presentation and to diagnostic uncertainty. Understanding the complexity of the dementia process in every patient using a multidimensional approach, contributes to more rational management strategies and finally to high quality care for patients and caregivers.


Immunological characteristics of MAV/06 strain of varicella-zoster virus vaccine in an animal model.
Varicella-zoster virus (VZV) is a pathogen that causes chickenpox and shingles in humans. Different types of the varicella vaccines derived from the Oka and MAV/06 strains are commercially available worldwide. Although the MAV/06 vaccine was introduced in 1990s, little was known about immunological characteristics. Here, we evaluated B and T cell immune response in animals inoculated with the Oka and MAV/06 vaccines as well as a new formulation of the MAV/06 vaccine. A variety of test methods were applied to evaluate T and B cell immune response. Plaque reduction neutralization test (PRNT) and fluorescent antibody to membrane antigen (FAMA) assay were conducted to measure the MAV/06 vaccine-induced antibody activity against various VZVs. Glycoprotein enzyme-linked immunosorbent assay (gpELISA) was used to compare the degree of the antibody responses induced by the two available commercial VZV vaccines and the MAV/06 vaccine. Interferon-gamma enzyme-linked immunosorbent spot (IFN-γ ELISpot) assays and cytokine bead array (CBA) assays were conducted to investigate T cell immune responses. Antibodies induced by MAV/06 vaccination showed immunogenicity against a variety of varicella-zoster virus and cross-reactivity among the virus clades. It is indicating the similarity of the antibody responses induced by commercial varicella vaccines and the MAV/06 vaccine. Moreover, VZV-specific T cell immune response from MAV/06 vaccination was increased via Th1 cell response. MAV/06 varicella vaccine induced both humoral and cellular immune response via Th1 cell mediated response.


Impact of age, various forms of cataract, and visual acuity on whole-field scotopic sensitivity screening for glaucoma in rural Taiwan.
To evaluate the impact of age, various forms of cataract, and visual acuity on whole-field scotopic sensitivity screening for glaucoma in a rural population. Clinic-based study with population-based recruitment. Jin Shan Township near Taipei, Taiwan. Three hundred forty-six residents (ages, > or = 40 years) of Jin Shan Township. Whole-field scotopic testing, ophthalmoscopy with dilation of the pupils, cataract grading against photographic standards, and screening visual field testing in a random one-third subsample. Whole-field scotopic sensitivity (in decibels) and diagnostic status as a case of glaucoma, glaucoma suspect, or normal. Participants in Jin Shan Township did not differ significantly in the rate of blindness, low visual acuity, or family history of glaucoma from a random sample of nonrespondents. Scotopic sensitivity testing detected 100% (6/6) of subjects with open-angle glaucoma at a specificity of 80.2%. The mean +/- SE scotopic sensitivity for six subjects with open-angle glaucoma (32.78 +/- 1.51 dB) differed significantly from that of 315 normal individuals (38.51 +/- 0.22 dB), when adjusted for age and visual acuity (P = .05, t test). With linear regression modeling, factors that correlated significantly with scotopic sensitivity were intraocular pressure, screening visual field, best corrected visual acuity, presence of cortical cataract, and increasing age. Although cataract affects the whole-field scotopic threshold, it appears that scotopic testing may be of value in field-based screening for glaucoma.


Apolipoprotein E phenotypes in hyperlipidaemic patients and their implications for treatment.
Apolipoprotein E phenotypes were determined on 417 consecutive lipid clinic patients using an isoelectric focussing technique. Of the 15 patients with phenotype E2/2, 13 (3.1%) had type III hyperlipoproteinaemia and 2 obese identical twins had type V. A further 20 patients (4.8%) had similar plasma and lipoprotein lipid levels but were E2 heterozygotes (14 E3/2 and 6 E4/2). They displayed a widened pre-beta-band almost confluent with the beta-band rather than the broad beta-band shown in classical E2/2 type III patients. In view of the similarities between these heterozygotes and the classical homozygous (E2/2) type III patients and their occurrence in the same families we suggest the nomenclature homozygous and heterozygous type III. In a subsequent comparison between 30 E2/2, 22 E3/2 and 8 E4/2 type III individuals the only significant difference in plasma and lipoprotein lipid parameters was a lower VLDL cholesterol to triglyceride ratio of 0.85 in E3/2 patients than that of 1.24 in E2/2 patients (P less than 0.01). Both homozygous and heterozygous patients showed premature ischaemic heart disease and both responded dramatically and similarly to treatment with clofibrate. These observations indicate that apo E phenotyping is worthwhile in all patients with combined hyperlipidaemia and that homozygous and heterozygous type III hyperlipoproteinaemia is not uncommon.


Volume and Acuity of Emergency Department Visits Prior To and After COVID-19.
There are scant data regarding the change in volume and acuity of patients presenting to emergency departments (EDs) after Coronavirus Disease 2019 (COVID-19), compared with the pre-COVID-19 era. To determine ED volumes and triage acuity prior to and after COVID-19. We determined the volume of patients presenting to four large EDs affiliated with general, cardiac, cancer, and obstetrics hospitals, and the acuity of presenting illness (using the Canadian Triage Acuity Scale [CTAS]) for March and April 2020 and compared them with the same months in 2019 and January 2020. Together, these facilities see over 80% of the ED visits in Qatar. The first COVID-19 patient in Qatar was diagnosed on February 29, 2020. A total of 192,157 ED visits were recorded during the study period. There was a 20-43% overall drop in number of ED visits, with significant variability across hospitals. The Heart Hospital experienced the sharpest decline (33-89%), and the National Center for Cancer Care and Research experienced the least decline in volumes. The decline was observed across all CTAS levels, with the largest decline observed in individuals presenting with CTAS 1 and 2 (26-69% decline month by month). No increase in overall number of deaths or crude mortality rate was observed in the COVID-19 era, according to national statistics. Sharp declines in ED visits and the triage acuity seen in both general and specialty hospitals raise the concern that severely ill patients may not be seeking timely care, and a surge may be expected once current restrictions on movement are lifted.


ALDH1 expression indicates chemotherapy resistance and poor outcome in node-negative rectal cancer.
The cancer stem cell marker aldehyde dehydrogenase 1 (ALDH1) associates with treatment resistance and adverse outcome in several human cancers. We studied ALDH1 expression in rectal cancer, with special emphasis on its association with treatment response and disease outcome. Immunohistochemical staining for ALDH1 was conducted for 64 biopsies and 209 operative samples from rectal cancer patients treated with short- (n = 89) or long-course (n = 46) (chemo)radiotherapy plus surgery, or with surgery only (n = 74). The staining results were compared to clinicopathological variables, tumor regression grade (TRG) and disease outcome. Nuclear β-catenin expression pattern was analyzed from 197 operative samples. Positive ALDH1 expression was present in 149 operative samples (71%), correlating with deficient nuclear β-catenin regulation (P = .018). In a pairwise comparison of respective biopsy and operative samples, ALDH1 expression remained stable or increased after preoperative (chemo)radiotherapy in most of the cases, while it decreased in few cases only (P = .02 for positive/negative category; P <.001 for intensity). ALDH1 expression did not, however, relate to tumor regression grade. In node-negative rectal cancer, ALDH1 expression was an independent predictor of short disease-free and disease-specific survival (P = .044; P = .049), specifically among patients treated with adjuvant chemotherapy. We conclude that ALDH1 associates with deregulated β-catenin signaling, supporting the role of ALDH1 in rectal cancer stemness. ALDH1 expression relates to poor outcome in early stage rectal cancer, a group where new prognostic tools are particularly needed, and may indicate chemo- and radioresistance.


Lymphoblastic Lymphoma Involving Multiple Vertebrae.
Acute lymphoblastic lymphoma is a malignant hematologic disease in childhood but rarely initially involves epidural compartment in adults. A 20-year-old male presented with progressive osphyalgia with constipation. Contrasted magnetic resonance imaging showed multiple vertebrae of hypointense T1 signals and an intraspinal epidural lesion. Subtotal resection was achieved. Histopathology suggested malignant B-cell lymphoma with Ki-67 of 90% and positivity of leukocyte common antigen. A bone marrow biopsy was unequivocally diagnostic of B-cell acute lymphoblastic lymphoma followed by chemotherapy (methotrexate) and partial recovery was observed. The marrow biopsy was necessary if without hypercalcemia and abnormal peripheral blood examination.


Cost-effectiveness of rivaroxaban versus warfarin in non-valvular atrial fibrillation patients with chronic kidney disease in China.
In non-valvular atrial fibrillation (NVAF) patients with chronic kidney disease (CKD), rivaroxaban was not inferior to warfarin in preventing stroke and systemic embolism. However, a comparative evaluation of the cost-effectiveness of rivaroxaban and warfarin therapies for NVAF patients at different renal function levels has not yet been reported, and this study aimed to estimate the cost-effectiveness of rivaroxaban compared with warfarin in Chinese NVAF patients with CKD. A Markov model was constructed to estimate quality-adjusted life years (QALYs) and lifetime costs associated with the use of rivaroxaban relative to warfarin in patients with NVAF at different estimated glomerular filtration rate (eGFR) levels as follows: 30 to <50, 50 to <80 and ≥80 mL/min. Input parameters were sourced from the clinical literature. Probabilistic sensitivity analyses were performed to assess model uncertainty. The incrementalQALYs with rivaroxaban was slightly increased by approximately 0.3 QALY as compared with that with warfarin in all the subgroups, resulting in an ICER of $9,736/QALY (eGFR, 30 to <50 mL/min), $9,758/QALY (50 to <80 mL/min) and $9,969/QALY (≥80 mL/min). The probabilistic sensitivity analysis suggested a chance of >80% that the ICER would be lower than the willingness-to-pay threshold of three times the GDP of China in 2019 in all the subgroups. Results were consistent even under the assumption of anticoagulant discontinuation after major bleeding events. The model was most sensitive to event-free-related utility and survival rates. The existing evidence supports the cost-effectiveness of rivaroxaban therapy as an alternative anticoagulant to warfarin for patients with NVAF at different renal function levels.


The effect of a quality improvement project on post-operative opioid use following outpatient spinal surgery.
Prescribing opioids upon discharge after surgery is common practice; however, there are many inherent risks including dependency, diversion, and medical complications. Our prospective pre- and post-intervention study investigates the effect of a standardized analgesic prescription on the quantity of opioids prescribed and patients' level of pain and satisfaction with pain control in the early post-operative period. With the implementation of an electronic medical record, a standardized prescription was built employing multimodal analgesia and a stepwise approach to analgesics based on level of pain. Patients received an education handout pre-operatively explaining the prescription. Consecutive patients over a three-month period undergoing elective spine surgery as day or overnight stay cases who received usual care were compared to a similar cohort who received the standardized prescription and education. Patient satisfaction with post-operative pain control, post-operative pain scores, number of refills required, and opioids prescribed in oral morphine equivalents (OMEs) were compared before and after implementation of the standardized analgesic prescription. Twenty-six patients received usual care (Control group) and 26 patients received the standardized prescription and education handout (Intervention group). There were significantly fewer OMEs prescribed in the Intervention group compared to the Control group. There was no difference between groups in: patient post-operative pain intensity score, post-operative satisfaction score, or number of refills required. This study demonstrates that a standardized prescription consisting of an appropriate amount of opioid and non-opioid analgesics is effective in reducing the OMEs prescribed post-operatively in elective spine surgery procedures, without compromising patient pain control or satisfaction or increasing the number of refills required.


Local and controlled release of growth factors (combination of IGF-I and TGF-beta I, and BMP-2 alone) from a polylactide coating of titanium implants does not lead to ectopic bone formation in sheep muscle.
The osteoinductive potential of growth factors leads not only to a stimulated bone formation in bony tissue but also in extra skeletal tissue. This potential depends on the dosage and potentially on the application method and may limit the clinical use. The aim of the present study was to investigate the potential of IGF-I, TGF-beta1 and BMP-2 released from a newly developed application systems of orthopaedic implants to induce ectopic bone formation in muscles. This bioactive coating showed a stimulating effect on fracture healing in several experimental studies before. Titanium discs were coated on one side with the drug carrier poly(d,l-lactide) (PDLLA), with the carrier plus IGF-I and TGF-beta1 or with the carrier plus BMP-2. The discs were implanted in the Musculus cleidomastoideus of sheep and followed up for 3 months. X-rays were taken after the operation and the day of sacrifice. The muscles plus implant were harvested and prepared for histology. Neither the radiology nor the histology revealed any signs of ectopic ossification in the implant/muscle interface or in a distance to the plate in any group. An influence of the locally applied growth factor, however, was seen in the formation of a soft tissue capsule. Histomorphometric analysis revealed a significantly larger capsule area over the growth factor coated side in comparison to the uncoated side or the pure titanium plate, indicating an effect of the applied growth factors on cells, however, not resulting in osteoinduction in muscle. The result showed that the local and controlled release of growth factors from PDLLA coated implants does not induce ectopic bone formation in sheep muscle and could be used in orthopaedic surgery to increase healing without the risk of ectopic bone formation in the surrounding soft tissue.


Measurement adequacy of the CES-D among a sample of older African-Americans.
This manuscript examines the measurement adequacy of the CES-D when applied in older African-Americans (n=227). The response distribution was skewed towards less symptomatology on all items, and the internal consistency of the CES-D was acceptable (alpha=0.86). An exploratory factor analysis revealed four underlying factors of depressive symptomatology: (1) depressive/somatic; (2) positive; (3) interpersonal; and (4) social well-being. The primary factor was a combination of depression and somatic symptoms, a commonly reported uni-dimensional factor among ethnic groups. Additionally, a fourth factor emerged that has not previously been identified, labeled 'social well-being'. This factor consisted of three items that may tap into the social interactions of the elderly: appetite, hopeful, and talk. These findings contribute to the growing body of evidence on the unique measurement properties of the CES-D across diverse populations.


Suicidal ideation among postmenopausal women on hormone replacement therapy: The Korean National Health and Nutrition Examination Survey (KNHANES V) from 2010 to 2012.
Suicide is a major public health problem around the world. Some studies have found that hormone replacement therapy (HRT) is associated with depression in postmenopausal women. Depression is a well-known risk factor for suicide; therefore, we investigated the relationship between HRT and suicidal ideation in postmenopausal Korean women. We included 2286 postmenopausal women with or without HRT from the Korean National Health and Nutrition Examination Survey 2010-2012. The use and duration of HRT and mental health status, including stress, depressive mood, and suicidal ideation and attempts, were assessed by self-report questionnaires. The proportion of participants with depressive mood and suicidal ideation was higher in the HRT group than the non-HRT group (all p values<0.05). As the duration of HRT increased, the percentage of participants with suicidal ideation increased (p for trend=0.006). After adjusting for all covariates, the odds ratio (95% confidence intervals) for suicidal ideation was 1.742 (1.223-2.482) in the women with HRT, compared to women without HRT. HRT duration longer than 10 years was associated with suicidal ideation (odds ratio=2.089 and 95% confidence intervals=1.069-4.084). The cross-sectional design, a possibility of incorrect answer about menopausal status, and no assessment of the type of HRT are the main limitations of this study. Postmenopausal women receiving HRT, especially for more than 10 years, showed increased suicidal ideation compared with postmenopausal women without HRT. Physicians should pay attention to mood symptoms and suicidal ideation in postmenopausal women with HRT.


Error of uptake in dual energy acquisition with 201Tl and 123I labeled radiopharmaceuticals.
In myocardial scintigraphy, simultaneous injection of two radionuclides and dual energy acquisition are potentially useful in the assessment of regional perfusion and metabolism. The feasibility of dual radionuclide study with 201Tl and 123I labeled radiopharmaceuticals (meta-iodobenzylguanidine I 123, in this study) was investigated in phantoms and patients. The crosstalk of one radionuclide to the other pulse height window was defined as the ratio of the 201Tl count in the 123I and 201Tl windows, R[I/Tl], and the ratio of the 123I count in the 201Tl and 123I windows, R[Tl/I]. The ratios were determined in planar images and SPECT studies. In clinical studies with whole body scintigraphy (n = 8), the value of R differed significantly in various organs. In the SPECT study (n = 13), R was not uniform and varied with time and location, resulting in significant errors in uptake and regional count ratio. Thus, dual energy acquisition with 201Tl and 123I labeled radiopharmaceuticals is generally not recommended because of varying amounts of crosstalk interference. Possible solutions to this problem are discussed. The feasibility of dual radionuclide study must be confirmed in human as well as in phantom studies.


[Effect of dibunol and isoptin on the creatine kinase and myoglobin content of the blood serum in dogs undergoing postischemic coronary reperfusion].
The effect of an antioxidant dibunol and calcium antagonist verapamil on postperfusion release of myoglobin (Mb) and MB-creatine kinase (MB-CK) has been assessed in 30 dogs with experimental coronary occlusive myocardial infarction. It has been shown that reperfusion after 3-hour ischemia does not only accelerate the release of intracellular proteins, but also leads to pronounced myoglobinemia and blood enzymes. In postischemic blood flow recovery with combined dibunol and verapamil preliminary injections, an almost threefold decrease in MB-CK and Mb blood content, as compared to "reperfusion" indexes, was observed by the 10th minute of reperfusion.


Activation of Na+/H+ exchange by epidermal growth factor elevates intracellular pH in A431 cells.
Epidermal growth factor (EGF) increases Na+ uptake in several cell types through an electroneutral, amiloride-sensitive pathway putatively identified as Na+/H+ countertransport. We have previously shown (Rothenberg, P., Glaser, L., Schlesinger, P., and Cassel, D. (1983) J. Biol. Chem. 257, 4883-4889) that EGF rapidly activates amiloride-sensitive net Na+ influx in the A431 human epidermoid carcinoma cell line. We also described the presence of transmembrane, amiloride-sensitive Na+/H+ exchange in A431 cells using a new fluorescence technique for the measurement of intracellular pH (pHi) based on the incorporation of fluorescein-dextran into the cell cytoplasm. The low pKa of fluorescein (approximately 6.4) prevented the direct assessment of the inferred, EGF-induced cytoplasmic alkalinization, mediated by stimulated Na+/H+ exchange. In this paper, 4',5'-dimethylfluorescein (pKa 6.75) was coupled to dextran, allowing increased pH sensitivity of the fluorescence assay in the physiological range. Using this improved assay, basic features of pHi regulation in A431 cells are documented, including the role of Na+/H+ exchange and Na+-linked C1-/HCO3-exchange in acid extrusion. We directly demonstrate a rapid elevation of pHi by addition of EGF as well as by serum in A431 cells. The pHi increase is half-maximal at 5-10 ng/ml of EGF, is dependent on external Na+, independent of external Ca2+, and inhibited by millimolar amiloride. EGF and serum also enhance Na+/H+ exchange-mediated cytosolic acidification when the transmembrane Na+ concentration gradient favors Na+ efflux from the cells. An alkaline pHi shift, caused by activation of Na+/H+ exchange, may be an important primary event in the mechanism of EGF action.


Burnout in nurses and physicians working at an oncology department.
Burnout is associated with decreased job performance and commitment, predicts stress-related health problems, and low career satisfaction. The specific objectives in our study were to assess the levels of burnout and to investigate the interrelationships between demographic characteristics and burnout health-care professionals working with cancer patients in Turkey. A questionnaire-based study was conducted in 77 physicians and 56 nurses working in an oncology clinic at the university hospital. We used quantitative survey to assess burnout levels in participants as well as sociodemographic variables. Data were collected using a Turkish version of the Maslach Burnout Inventory (MBI). Nurses had significantly higher scores of emotional exhaustion (EE) when compared with the physicians, but no significant difference was found between two groups regarding other burnout components. Significant correlations were found in three different components of the MBI, as well as between each component, age and work experience in nurses and physicians. There were statistical significant differences for each of MBI subscales according to age groups in physicians. EE and depersonalization (D) were significantly higher in the < or =29 years of age group than in the older age groups, while personal accomplishment (PA) score was significantly lower in this age group. EE, D, PA were significantly higher in single physicians compared with married physicians. Low level of PA was relatively high among Turkish physicians and nurses working in oncology department compared with previous studies. Younger and single physicians had higher burnout levels compared with older and married ones.


Infliximab, Immunomodulators and Treatment Failures in Paediatric and Adolescent Patients with Crohn's Disease: a Nationwide Cohort Study.
In paediatric patients with Crohn's disease, the role of combination therapy, infliximab plus immunomodulators [thiopurine or methotrexate], is debated and data are sparse. We examined whether infliximab plus immunomodulators, compared to infliximab therapy alone, reduces the risk of treatment failure measured by intestinal surgery or switching type of anti-tumour necrosis factor [TNF] α agent within 24 months. Using Danish registries, we identified patients with Crohn's disease, aged ≤ 20 years at the time of the first infliximab treatment, and retrieved data on their co-medications. We used Cox regression models to examine surgery or switching type of anti-TNFα agent from January 1, 2003 to December 31, 2015. We included 581 patients. The 2-year cumulative percentage of surgery was 8.5% among patients receiving combination therapy and 14.5% in those receiving infliximab alone. The adjusted 2-year hazard ratio [HR] of surgeries was 0.53 (95% confidence interval [CI] 0.32-0.88) in patients receiving combination therapy, compared to patients receiving infliximab alone. When examining a switch of anti-TNFα we included 536 patients. Within 2 years, 18.3% experienced a switch among patients receiving combination therapy and 24.8% in patients treated with infliximab alone, corresponding to an adjusted HR of 0.66 [95% CI 0.45-0.97] in patients receiving combination therapy. The HR of intestinal surgeries and the risk of a switch to another anti-TNFα was reduced in paediatric and adolescent patients receiving combination therapy, compared to patients receiving only infliximab. These results suggest a benefit for infliximab therapy combined with immunomodulators, but these need to be confirmed in data with additional clinical information.


Potential of personal health record portals in the care of individuals with spinal cord injuries and disorders: Provider perspectives.
Although personal health record (PHR) portals are designed for patients, healthcare providers are a key influence in how patients use their features and realize benefits from them. A few studies have examined provider attitudes toward PHR portals, but none have focused on those who care for individuals with spinal cord injuries and disorders (SCI/D). We characterize SCI/D provider perspectives of PHR portals, including perceived advantages and disadvantages of PHR portal use in SCI/D care. Cross-sectional; semi-structured interviews. Spinal Cord Injury (SCI) Centers in the Veterans Health Administration. Twenty-six SCI/D healthcare providers. None. Perceived advantages and disadvantages of PHR portals. The complex situations of individuals with SCI/D shaped provider perspectives of PHR portals and their potential role in practice. Perceived advantages of PHR portal use in SCI/D care included the ability to coordinate information and care, monitor and respond to outpatient requests, support patient self-management activities, and provide reliable health information to patients. Perceived disadvantages of PHR portal use in SCI/D care included concerns about the quality of patient-generated health data, other potential liabilities for providers and workload burden, and the ability of individuals with SCI/D to understand clinical information accessed through a portal. Our study highlights advantages and disadvantages that should be considered when promoting engagement of SCI/D healthcare providers in use of PHR portals, and portal features that may have the most utility in SCI/D care.


Towards sustainable integrated watershed ecosystem management: a case study in Dingxi on the loess plateau, China.
The Chinese government initiated a massive conservation program called "Grain-for-Green" in 1999 to reduce soil erosion and improve ecosystem function. Implementing practical sustainable development in the loess plateau still remains problematic, particularly in its eco-fragile areas. Here we discussed an approach for sustainable development at the watershed scale by integrating land use suitability, ecosystem services and public participation in the loess hilly area. We linked land use scenario analysis and economic modeling to compare the outcomes of three scenarios, CLU (Current Land Use), GOLU (Grain-production Oriented Land Use) and PSLU (Potential Sustainable Land Use). The results indicated that compared to PSLU, GOLU may provide a higher economic productivity in the short-term, but not in the long-term. CLU ranked lowest in terms of economic benefits and did not meet the daily needs of the local farmers. To reconcile the land use adjustments with farmers' basic needs, a labor-saving land use strategy is necessary. Since the PSLU scenario assumes that slope cropland should be converted to pastures or orchards, more time may be available for off-farm work and for more public participation in integrated ecosystem management. Financial support to the local farmers for environmental conservation should be modulated in function of their positive contribution to ecosystem management.


Modulation of tryptophan hydroxylase activity by phospholipids: stimulation followed by inactivation.
The activity of tryptophan hydroxylase from the rat brainstem was stimulated rapidly three- to fourfold by the addition of phosphatidylinositol or phosphatidylserine. However, the activity of the enzyme once stimulated was decreased gradually by subsequent incubation with the phospholipid at 37 degrees C, reaching a level below the original activity after 1 h of incubation. The presence of ferrous ion almost perfectly protected the enzyme against this phospholipid inactivation. The activity of the enzyme inactivated by incubation with the phospholipid was not only restored, but also increased further by incubation at 37 degrees C with ferrous ion and dithiothreitol. Gel filtration analysis revealed that the enzyme stimulated by phosphatidylinositol was eluted in a void volume together with the phospholipid vesicles, but the enzyme inactivated by incubation with phosphatidylinositol was eluted at a later region apart from the vesicles. These results, taken together, suggest the possible involvement of cellular membranes in the regulation of tryptophan hydroxylase in the central nervous system.


Fowlpox virus encodes a protein related to human deoxycytidine kinase: further evidence for independent acquisition of genes for enzymes of nucleotide metabolism by different viruses.
It is demonstrated that fowlpox virus (FPV) protein FP26 located in the HindIII D fragment of the genome is related to the human deoxycytidine kinase (dCK) and probably possesses the same enzymatic activity. A homologous protein is not encoded by vaccinia virus. A multiple alignment of the amino acid sequences of the human and FPV dCKs, the thymidine kinases (TK) of herpesviruses, and cellular and vaccinia virus thymidylate kinases (ThyK) was generated and the conserved motifs, at least two of which are implicated in ATP binding, were characterized. An apparent duplication of ATP-binding motif B in the dCKs was revealed, leading to the reassignment of one of the catalytic residues. Phylogenetic analysis based on the multiple alignment suggested that the putative dCK of FPV probably has diverged from the common ancestor with the human dCK at a later stage of evolution than the herpesvirus TKs, with the ThyKs being peripheral members of the family. These results are compatible with hypothesis that genes for enzymes of nucleotide metabolism could be acquired independently by different DNA viruses (Koonin, E.V. and Senkevich, T.G., Virus Genes 6:187-196, 1992).


Spring viraemia of carp (SVC) in the UK: the road to freedom.
Spring viraemia of carp (SVC) is a disease of international importance that predominantly affects cyprinid fish and can cause significant mortality. In the United Kingdom (UK), SVC was first detected in 1977 with further cases occurring in fisheries, farms, wholesale and retail establishments throughout England and Wales (but not Scotland, where few cyprinid populations exist, nor Northern Ireland where SVC has never been detected) over the subsequent 30 years. Following a control and eradication programme for the disease initiated in 2005, the UK was recognised free of the disease in 2010. This study compiles historic records of SVC cases in England and Wales with a view to understanding its routes of introduction and spread, and assessing the effectiveness of the control and eradication programme in order to improve contingency plans to prevent and control future disease incursions in the cyprinid fish sectors. Between 1977 and 2010 the presence of SVC was confirmed on 108 occasions, with 65 of the cases occurring in sport fisheries and the majority of the remainder occurring in the ornamental fish sector. The study found that throughout the history of SVC in the UK, though cases were widely distributed, their occurrence was sporadic and the virus did not become endemic. All evidence indicates that SVC was not able to persist under UK environmental conditions, suggesting that the majority of cases were a result of new introductions to the UK as opposed to within-country spread. The control and eradication programme adopted in 2005 was highly effective and two years after its implementation cases of SVC ceased. Given the non-persistent nature of the pathogen the most important aspect of the control programme focused on preventing re-introduction of the virus to the UK. Despite the effectiveness of these controls against SVC, this approach is likely to be less effective against more persistent pathogens such as koi herpesvirus, which are likely to require more stringent measures to prevent within-country spread.