Nonstructural proteins NS1 and NS2 of bovine respiratory syncytial virus block activation of interferon regulatory factor 3.
We have previously shown that the nonstructural (NS) proteins NS1 and NS2 of bovine respiratory syncytial virus (BRSV) mediate resistance to the alpha/beta interferon (IFN)-mediated antiviral response. Here, we show that they, in addition, are able to prevent the induction of beta IFN (IFN-beta) after virus infection or double-stranded RNA stimulation. In BRSV-infected MDBK cells upregulation of IFN-stimulated genes (ISGs) such as MxA did not occur, although IFN signaling via JAK/STAT was found intact. In contrast, infection with recombinant BRSVs lacking either or both NS genes resulted in efficient upregulation of ISGs. Biological IFN activity and IFN-beta were detected only in supernatants of cells infected with the NS deletion mutants but not with wild-type (wt) BRSV. Subsequent analyses of IFN-beta promoter activity showed that infection of cells with the double deletion mutant BRSV DeltaNS1/2, but not with BRSV wt, resulted in a significant increase in IFN-beta gene promoter activity. Induction of the IFN-beta promoter depends on the activation of three distinct transcription factors, NF-kappaB, ATF-2/c-Jun, and IFN regulatory factor 3 (IRF-3). Whereas NF-kappaB and ATF-2/c-Jun activities were readily detectable and comparable in both wt BRSV- and BRSV DeltaNS1/2-infected cells, phosphorylation and transcriptional activity of IRF-3, however, were observed only after BRSV DeltaNS1/2 infection. NS protein-mediated inhibition of IRF-3 activation and IFN induction should have considerable impact on the pathogenesis and immunogenicity of BRSV.


Analysis of Chlamydia pneumoniae-specific oligoclonal bands in multiple sclerosis and other neurologic diseases.
Paired serum and cerebrospinal fluid (CSF) specimens were investigated for Chlamydia pneumoniae-specific oligoclonal bands (OCBs) to determine band specificity in multiple sclerosis (MS). Serum and CSF samples were collected from patients with relapsing-remitting MS (n = 56), other inflammatory (n = 18) or non-inflammatory (n = 15) neurologic diseases, and from 10 healthy controls. OCBs were determined with affinity immunoblotting of C. pneumoniae-specific IgG onto antigen-coated nitrocellulose paper after protein separation with agarose isoelectric focusing. Chlamydia pneumoniae-specific OCBs were present in 5 of 56 patients with MS, and in 3 of 18 patients with other inflammatory neurologic diseases. The intrathecal production of C. pneumoniae-specific oligoclonal IgG occurs in a minority of patients with MS. This intrathecal anti-C. pneumoniae reactivity is likely part of a polyspecific humoral immune response in MS.


Immunomodulatory effects and improved prognosis of experimental autoimmune encephalomyelitis after O-tetradecanoyl-genistein treatment.
Experimental autoimmune encephalomyelitis (EAE) is a murine autoimmune disease used to study multiple sclerosis (MS), a human inflammatory demyelinating disease of the central nervous system. Genistein, an isoflavonoid phytoestrogenic compound found in soy, is known to reverse clinical signs of EAE. Although genistein has some potential in clinical application, it has some disadvantages related to its chemical structure, such as rapid in vivo metabolism and a fast decline in serum after oral administration. The present work investigates the treatment of EAE by using 7-O-tetradecanoyl-genistein (TDG), a more lipophilic analog of genistein obtained by esterification. The clinical course of EAE was investigated in C57Bl/6 mice immunized with myelin oligodendrocyte glycoprotein peptide (MOG)(35-55) in complete Freund's adjuvant supplemented with Mycobacterium tuberculosis H37RA. After 14 days of MOG immunization, mice were treated with TDG for seven days. Numbers of IL-17-producing cells and Foxp3 by CD4(+) T cells and CTLA-4 expression by CD3(+) T cells from brain were determined by flow cytometry. Levels of IL-6, IFN-γ and IL-10 were evaluated by ELISA. Brain sections were stained by hematoxylin and eosin method. The data obtained indicate that TDG treatment ameliorates the clinical signs of EAE, which correlates with a decrease of IL-17-producing cells and an increase in Foxp3(+)CD4(+) cells in the brain. TDG is also shown to enhance IL-10 production and CTLA-4 expression and to reduce IFN-γ and IL-6. Altogether, these findings suggest an immunomodulatory therapeutic role for TDG in EAE and multiple sclerosis.


Symptomatic expression of depression among Jewish adolescents: effects of gender and age.
Depression symptomatology was assessed with the Beck Depression Inventory (BDI) in a sample of Jewish adolescents, in order to compare the frequency and severity of depression with non-Jewish adolescents as well as examine gender difference of the expression of depressive symptomatology. Subjects comprised 475 students from Jewish private schools, aged 13-17 years, who were compared with an age-matched non-Jewish sample (n=899). Kendall's definition was adopted to classify these adolescents according to level of depressive symptoms. The frequency of depression was calculated for ethnicity, gender and age strata. Discriminant analysis and principal component analysis were performed to assess the importance of depression-specific and non-specific items, along with the factor structure of the BDI, respectively. The overall mean score on the BDI in the Jewish and the non-Jewish sample was 9.0 (SD=6.4) and 8.6 (SD=7.2), respectively. Jewish girls and boys had comparable mean BDI scores, contrasting with non-Jewish sample, where girls complained more of depressive symptoms than boys (p<0.001). The frequency of depression, adopting a BDI cutoff of 20, was 5.1% for the Jewish sample and 6.3% for the non-Jewish sample. The frequency of depression for Jewish girls and boys was 5.5% (SE=1.4) and 4.6% (SE=1.5), respectively. On the other hand, the frequency of depression for non-Jewish girls and boys was 8.4% (SE=1.2) and 4.0% (SE=1.0), respectively. The female/male ratio of frequency of BDI-depression was 1.2 in the Jewish sample, but non-Jewish girls were twice (2.1) as likely to report depression as boys. Discriminant analysis showed that the BDI highly discriminates depressive symptomatology among Jewish adolescents, and measured specific aspects of depression. Factor analysis revealed two meaningful factors for the total sample and each gender (cognitive-affective dimension and somatic dimension), evidencing a difference between Jewish boys and Jewish girls in the symptomatic expression of depression akin to non-Jewish counterparts. Ethnic-cultural factor might play a role in the frequency, severity and symptomatic expression of depressive symptoms in Jewish adolescents. The lack of gender effect on depression, which might persist from adolescence to adulthood among Jewish people, should be investigated in prospective studies.


Loss of c-Met accelerates development of liver fibrosis in response to CCl(4) exposure through deregulation of multiple molecular pathways.
HGF/c-Met signaling plays a pivotal role in hepatocyte survival and tissue remodeling during liver regeneration. HGF treatment accelerates resolution of fibrosis in experimental animal models. Here, we utilized Met(fl/fl);Alb-Cre(+/-) conditional knockout mice and a carbon tetrachloride(CCl(4))-induced liver fibrosis model to formally address the role of c-Met signaling in hepatocytes in the context of chronic tissue injury. Histological changes during injury (4weeks) and healing phase (4weeks) were monitored by immunohistochemistry; expression levels of selected key fibrotic molecules were evaluated by western blotting, and time-dependent global transcriptomic changes were examined using a microarray platform. Loss of hepatocyte c-Met signaling altered hepatic microenvironment and aggravated hepatic fibrogenesis. Greater liver damage was associated with decreased hepatocyte proliferation, excessive stellate cell activation and rapid dystrophic calcification of necrotic areas. Global transcriptome analysis revealed a broad impact of c-Met on critical signaling pathways associated with fibrosis. Loss of hepatocyte c-Met caused a strong deregulation of chemotactic and inflammatory signaling (MCP-1, RANTES, Cxcl10) in addition to modulation of genes involved in reorganization of the cytoskeletal network (Actb, Tuba1a, Tuba8), intercellular communications and adhesion (Adam8, Icam1, Itgb2), control of cell proliferation (Ccng2, Csnk2a, Cdc6, cdk10), DNA damage and stress response (Rad9, Rad52, Ercc4, Gsta1 and 2, Jun). Our study demonstrates that deletion of c-Met receptor in hepatocytes results in pronounced changes in hepatic metabolism and microenvironment, and establishes an essential role for c-Met in maintaining the structural integrity and adaptive plasticity of the liver under adverse conditions.


Differences in muscarinic-receptor agonist-, oxytocin-, and prostaglandin-induced uterine contractions.
To investigate the contractile response of the perfused swine uterus to various receptor pathways (oxytocin, prostaglandins, and muscarine). An extracorporeal perfusion model of the swine uterus was used that keeps the uterus in a functional condition and is appropriate for the study of physiologic questions. Oxytocin-, prostaglandin-, and carbachol-induced uterine contractility and peristalsis were assessed using an intrauterine double-chip microcatheter. University hospital. Intrauterine pressure profiles. A dose-dependent increase in intrauterine pressure (IUP) in the isthmus uteri and corpus uteri was observed after the administration of prostaglandin F(2alpha) (PGF(2alpha)) and oxytocin, which reached a plateau after further stimulation. A dose-dependent increase in IUP in the isthmus uteri and corpus uteri was also observed after the administration of prostaglandin E(1) (PGE(1)) and prostaglandin E(2) (PGE(2)), with a plateau in IUP in the middle-concentration range and a decrease during the further course of stimulation. After administration of PGE(1), PGE(2), and PGF(2alpha), different directions of contraction waves were also observed. Carbachol also showed a unique contractility pattern, with isolated, very powerful, dose-dependent contractions with an IUP gradient, suggesting directed transport from the upper region to the lower region. This study demonstrated that oxytocin, the prostaglandins, and carbachol modulate contractility in nonpregnant swine uteri in a characteristic way, resulting in different contractility patterns.


Local delivery of insulin/IGF-1 for bone regeneration: carriers, strategies, and effects.
Bone defects caused by trauma, tumor resection, congenital malformation and infection are still a major challenge for clinicians. Biomimetic bone materials have attracted more and more attention in science and industry. Insulin and insulin-like growth factor-1 (IGF-1) have been increasingly recognized as an inducible factor for osteogenesis and angiogenesis. Spatiotemporal release of insulin may serve as the promising strategy. Considering the successful application of nanoparticles in drug loading, various insulin delivery systems have been developed, including (poly (lactic-co-glycolic acid), PLGA), hydroxyapatite (HA), gelatin, chitosan, alginate, and (γ-glutamic acid)/β-tricalcium phosphate, γ-PGA/β-TCP). Here, we have reviewed the progress on nanoparticles carrying insulin/IGF for bone regeneration. In addition, the key regulatory mechanism of insulin in bone regeneration is also summarized. The future application strategies and the challenges in bone regeneration are also discussed.


Crowded task performance in visually impaired children: magnifier versus large print.
This study compares the influence of two different types of magnification (magnifier versus large print) on crowded near vision task performance. Fifty-eight visually impaired children aged 4-8 years participated. Participants were divided in two groups, matched on age and near visual acuity (NVA): [1] the magnifier group (4-6 year olds [n = 13] and 7-8 year olds [n = 19]), and [2] the large print group (4-6 year olds [n = 12] and 7-8 year olds [n = 14]). At baseline, single and crowded Landolt C acuity were measured at 40 cm without magnification. Crowded near vision was measured again with magnification. A 90 mm diameter dome magnifier was chosen to avoid measuring the confounding effect of navigational skills. The magnifier provided 1.7× magnification and the large print provided 1.8× magnification. Performance measures: [1] NVA without magnification at 40 cm, [2] near vision with magnification, and [3] response time. Working distance was monitored. There was no difference in performance between the two types of magnification for the 4-6 year olds and the 7-8 year olds (p's = .291 and .246, respectively). Average NVA in the 4-6 year old group was 0.95 logMAR without and 0.42 logMAR with magnification (p < .001). Average NVA in the 7-8 year was 0.71 logMAR without and 0.01 logMAR with magnification (p < .001). Stronger crowding effects predicted larger improvements of near vision with magnification (p = .021). A magnifier is equally effective as large print in improving the performance of young children with a range of visual acuities on a crowded near vision task. Visually impaired children with stronger crowding effects showed larger improvements when working with magnification.


Neoadjuvant chemoradiation therapy for resectable esophago-gastric adenocarcinoma: a meta-analysis of randomized clinical trials.
The efficacy and safety of preoperative chemoradiation therapy (CRT) for advanced esophago-gastric adenocarcinoma are still in question, and the prognosis of these patients is poor. We systematically searched electronic databases from January 1990 to July 2014. The primary outcome was overall survival. The secondary outcomes were a R0 resection rate, positive rate of lymph node metastasis, postoperative recurrence rate, pathological complete response (pCR) rate and perioperative mortality. Overall survival was measured with a hazard ratio (HR), while other secondary outcomes were measured with an odds ratio (OR). Seven randomized controlled trials (RCTs) including 1085 patients were searched and, of these, 869 had adenocarcinoma. Patients receiving preoperative CRT had a longer overall survival (HR 0.74; 95% confidence interval (CI) 0.63-0.88), higher likelihood of R0 resection and greater chance of pCR, while they had a lower likelihood of lymph node metastasis and postoperative recurrence. The difference of perioperative mortality was non-significant. In addition, the result of the comparison between preoperative CRT and preoperative chemotherapy (CT) in two RCTs was non-significant. Patients with resectable esophago-gastric adenocarcinoma can gain a survival advantage from preoperative CRT. However, limited to the number of RCTs, the effect of adding radiotherapy to preoperative CT separately is still uncertain and more high-quality prospective trials are needed.


Simultaneous coronary artery bypass grafting and ascending aorta bifemoral bypass in small aorta syndrome.
A 55-year-old man with severe coronary artery disease and aortoiliac occlusive disease with small aorta syndrome was admitted to our department with angina pectoris and bilateral claudication. Intravenous subtraction angiography showed total occlusion of the right common iliac artery and 99% stenosis of the left common iliac artery with a markedly hypoplastic infrarenal aorta only 9 mm in diameter. It also revealed 90% stenosis at the origin of the left subclavian artery. Coronary angiography showed total occlusion of the left anterior descending artery and 90% stenosis of the circumflex artery. Simultaneous coronary artery bypass grafting and an ascending aorta-bifemoral bypass were conducted using an in-situ right internal mammary artery graft, an autologous saphenous vein graft, and a Y-figured expanded polytetrafluoroethylene graft. Postoperative angiography showed grafts to the coronary and bifemoral arteries were patient. This combined procedure is useful for patients with coronary artery disease and aortoiliac occlusive disease, especially in those with small aorta syndrome.


Mortality and illicit drug dependence among hemodialysis patients in the United States: a retrospective cohort analysis.
Illicit drug use is common and known to cause and exacerbate a wide spectrum of kidney disease, often leading to end-stage renal disease (ESRD), but little is known about its prevalence or associated mortality among incident hemodialysis patients. This study is a retrospective cohort analysis using data obtained from the United States Renal Data System. We assembled a cohort of 511,821 incident hemodialysis patients age 20 years and older who initiated hemodialysis between January 1, 2006 and December 31, 2010. Illicit drug dependence was defined by comorbidity on the ESRD Medical Evidence Report (Form CMS-2728). We performed survival analysis to examine the association of drug dependence with overall mortality and mortality due to diagnoses that can be associated with intravenous drug use (drug-sensitive diagnoses) in the first year after initiating hemodialysis. Drug dependence was recorded for 1.5 % (n = 7,461). Drug dependence was independently associated with a 1.3-fold and 2.5-fold higher hazard of overall mortality and mortality due to a potentially drug-sensitive diagnosis [adjusted hazard ratio (AHR) 1.34 (1.27-1.41) and 2.54 (2.05-3.14), p < 0.001, respectively]. This association varied significantly by age (pinteraction < 0.001), with a 9-fold higher hazard of mortality due to a potentially drug-sensitive diagnosis among the youngest patients with drug dependence [AHR 9.21 (5.15-16.44), p < 0.001]. Illicit drug dependence is a burden within the ESRD program and is strongly associated with premature mortality, particularly among younger patients. Targeted intervention is needed to help reduce this burden.


Antifungal activities of crude extracts of Mitracarpus villosus (Rubiaceae).
Extracts of Mitracarpus villosus leaves and inflorescences were investigated individually for in vitro antifungal activities by agar-diffusion and tube-dilution techniques. Ethanolic extracts produced definite antifungal activities against Trichophyton rubrum, Microsporum gypseum, Candida albicans, Aspergillus niger and Fusarium solani. The aqueous extracts and the glycerol vehicle control did not inhibit any of the fungi tested. The zones of inhibition produced by the ethanol extracts ranged from 10 to 20.5 mm while ketoconazole control ranged from 9 to 19 mm. The minimum inhibitory concentration of the extracts ranged from 0.50 to 4.0 mg/ml while their minimum fungicidal concentration values ranged from 1 to 8 mg/ml. These results indicate that the extracts were fungistatic at lower concentrations and fungicidal at higher concentrations.


Emerging predictors of femoral artery occlusion after pediatric cardiac catheterization.
The Objective was to review the prevalence of femoral artery occlusion (FAO) after cardiac catheterization in children up to 12 years old from two centers in China and identify its related risk factors. After collecting clinical data from patients who had undergone pediatric cardiac catheterization, univariate and multivariate analysis were used to evaluate the correlations between FAO and clinical factors, including sex, age, height, weight, sheath size, operation time, therapeutic strategy, sheath/age, sheath/height and sheath/weight. The ROC curve was also used to assess the influence of risk factors to predict FAO. FAO occurred in 19 (0.9%) out of 2,084 children following cardiac catheterization. Patients with younger age, lower height, longer operation time, electrophysiological (EP) diagnosis or/and therapy for arrhythmias, higher Sheath/Age, higher Sheath/Height and higher Sheath/Weight ratios had higher risk for FAO compared to their respective control groups (p < 0.05). In the multivariate analysis, sheath/age and operation time were independent risk factors for FAO. Patients with operation time > 77.5 min or sheath/age > 0.5334 had a significantly higher risk for FAO. Operation time and sheath/age were confirmed as significant and independent risk factors associated with FAO. Operation time > 77.5 min and sheath/age > 0.5334 could effectively predict high risk of FAO after pediatric cardiac catheterization.


Evaluating Cr behaviour in two different polluted soils: Mechanisms and implications for soil functionality.
This work investigates the mechanisms determining Cr speciation and availability in two different soils polluted with two chromium sources (an industrial sludge, highly polluted with Cr, and Cr(VI) solution) and the influence of these parameters on the recovery of the soil functions related with biological quality and plant growth. The experiment was carried out in greenhouse conditions using 36 pots of 17 kg for the growth of Silene vulgaris for 21 months. Logistic Regression Model using Lasso estimator shows that soil organic matter (SOM) and pH control Cr availability in studied soils. In soils treated with the sludge, X ray Absorption spectroscopy showed that Cr was present as Cr(III), biological quality indicators increased and plants were able to grow. However, in soils polluted with Cr(VI), Cr availability was significantly different in the two soils. In the alkaline and poor in organic matter soil, 12% of Cr(VI) remained in the soil leading to the decrease of soil quality indicators and the total inhibition of plant growth. In the neutral soil, Cr(VI) was totally reduced to Cr(III) by soil organic matter (SOM), quality indicators were not affected and plants grown properly. Infrared Spectroscopy showed that different functional groups reacted with Cr in the two soils. This study highlights the importance to understand the mechanisms underlaying Cr redox and adsorption reactions in Cr polluted soils as they determine the potential recovery of the functions related with biological quality indicators and plant growth. The methodology proposed allows this study in complex soil samples at realistic concentrations and may be useful for risk assessment and for the planning of managing strategies in Cr polluted soils.


[Improving parasympathetic functioning to contain the inflammatory response of COVID-19 infection].
COVID-19 infection results in an unrestrained inflammatory reaction in serious cases. The autonomic nervous system (ANS), in particular the parasympathetic branch, helps to regulate the inflammatory response. A dysfunction of this branch, frequent in people at risk of developing COVID-19, favours a pro-inflammatory effect. Reinforcing and stimulating the parasympathetic ANS is possible and accessible to paramedical and medical professionals.


Consequences and prevention of inadvertent internal fixation of primary osseous sarcomas.
The evaluation and treatment of aggressive bone tumors continue to be diagnostic and therapeutic challenges for orthopaedic surgeons. Despite compelling data regarding the hazards of biopsy, incomplete preoperative evaluation, inappropriate biopsy techniques, and premature surgical interventions continue to compromise optimal treatment of primary bone sarcomas. We retrospectively identified eight patients who had internal fixation of a primary bone sarcoma before referral to an orthopaedic oncology service. Six of the eight patients subsequently underwent amputations and two patients underwent limb salvage for local disease control. Biopsy techniques from referring institutions were highly variable, with only two of seven rendering an accurate diagnosis. The average Musculoskeletal Tumor Society functional score was 10.6 and four of eight patients were disease-free and alive at a minimum followup of 8 months (mean, 26.9 months; range, 8-80 months). Implant violation of primary bone malignancies was associated with frequent high-level amputation for local disease control and low Musculoskeletal Tumor Society functional scores. Common errors in the initial evaluation and treatment included inadequate attention to patient history, incomplete radiographic evaluation, and improper biopsy and surgical techniques, which violated compartmental boundaries. Level IV, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.


Repeated subileus due to angioedema during renin-angiotensin system blockade.
A 77-year-old man with membranous nephropathy was treated with triple blockade of the renin-angiotensin-aldosterone system and developed subileus six times in 5 months. The resection of his sigmoid colon uncovered angioedema. It should be noted that angiotensin-converting enzyme or angiotensin receptor blocker can cause angioedema of the intestine and induce subileus.


Capturing information needs of care providers to support knowledge sharing and distributed decision making.
This paper reports on work carried out to elicit information needs at a trans-disciplinary, nurse-managed health care clinic that serves a medically disadvantaged urban population. The trans-disciplinary model provides a "one-stop shop" for patients who can receive a wide range of services beyond traditional primary care. However, this model of health care presents knowledge sharing challenges because little is known about how data collected from the non-traditional services can be integrated into the traditional electronic medical record (EMR) and shared with other care providers. There is also little known about how health information technology (HIT) can be used to support the workflow in such a practice. The objective of this case study was to identify the information needs of care providers in order to inform the design of HIT to support knowledge sharing and distributed decision making. A participatory design approach is presented as a successful technique to specify requirements for HIT applications that can support a trans-disciplinary model of care. Using this design approach, the researchers identified the information needs of care providers working at the clinic and suggested HIT improvements to integrate non-traditional information into the EMR. These modifications allow knowledge sharing among care providers and support better health decisions. We have identified information needs of care providers as they are relevant to the design of health information systems. As new technology is designed and integrated into various workflows it is clear that understanding information needs is crucial to acceptance of that technology.


Electrophoretic separation of large DNAs using steric confinement.
We report an alternative method for electrophoretic separation of large DNAs using steric confinement between solid walls, without gel or obstacles. The change of electrophoretic mobility vs confinement thickness is investigated using fluorescence video microscopy. We observe separation at small confinement thicknesses followed by a transition to the bulk behavior (no separation) at a thickness of about 4 mum (a few radii of gyration for the studied DNA chains). We present tentative explanations of our original observations.


Bioavailability of enteral yeast-selenium in preterm infants.
There is no data or literature on the effects of supplementing infants with yeast selenium, although its intestinal absorption and bioavailability are higher in adults compared with other selenium compounds. The aim of the present investigation was to study the impact of selenium enriched yeast on the serum selenium concentration of preterm infants living in a low selenium area (Hungary). Twenty-eight preterm infants with mean+/-SD birth weight of 962+/-129 g and gestational age 27+/-1 wk were randomized into two groups at birth with respect to selenium supplementation. In the supplemented group (n=14) infants received 4.8 mg yeast selenium containing 5 microg selenium daily via nasogastric drip during the first 14 postnatal days. The nonsupplemented infants were used as a reference group. In the supplemented group, the serum selenium concentration increased from 32.1+/-8.5 microg/L to 41.5+/-6.5 microg/L and in the nonsupplemented group it decreased from 25.9+/-6.8 microg/L to 18.2+/-6.4 microg/L from birth in two weeks time. Compared with previous studies, our results suggest that the bioavailability of selenium in the form of yeast selenium is higher than that of other selenium compounds used for preterm infants. We did not observe any complications or side-effects owing to enteral yeast selenium supplementation. We conclude that selenium enriched yeast is a safe and an effective form of short-term enteral selenium supplementation for infants.


NCI-H295R, a human adrenal cortex-derived cell line, expresses purinergic receptors linked to Ca²⁺-mobilization/influx and cortisol secretion.
Purinergic receptor expression and involvement in steroidogenesis were examined in NCI-H295R (H295R), a human adrenal cortex cell line which expresses all the key enzymes necessary for steroidogenesis. mRNA/protein for multiple P1 (A(2A) and A(2B)), P2X (P2X₅ and P2X₇), and P2Y (P2Y₁, P2Y₂, P2Y₆, P2Y₁₂, P2Y₁₃, and P2Y₁₄) purinergic receptors were detected in H295R. 2MeS-ATP (10-1000 µM), a P2Y₁ agonist, induced glucocorticoid (GC) secretion in a dose-dependent manner, while other extracellular purine/pyrimidine agonists (1-1000 µM) had no distinct effect on GC secretion. Extracellular purines, even non-steroidogenic ones, induced Ca²⁺-mobilization in the cells, independently of the extracellular Ca²⁺ concentration. Increases in intracellular Ca²⁺ concentration induced by extracellular purine agonists were transient, except when induced by ATP or 2MeS-ATP. Angiotensin II (AngII: 100 nM) and dibutyryl-cyclic AMP (db-cAMP: 500 µM) induced both GC secretion and Ca²⁺-mobilization in the presence of extracellular Ca²⁺ (1.2 mM). GC secretion by AngII was reduced by nifedipine (10-100 µM); whereas the Ca²⁺ channel blocker did not inhibit GC secretion by 2MeS-ATP. Thapsigargin followed by extracellular Ca²⁺ exposure induced Ca²⁺-influx in H295R, and the cells expressed mRNA/protein of the component molecules for store-operated calcium entry (SOCE): transient receptor C (TRPC) channels, calcium release-activated calcium channel protein 1 (Orai-1), and the stromal interaction molecule 1 (STIM1). In P2Y₁-knockdown, 2MeS-ATP-induced GC secretion was significantly inhibited. These results suggest that H295R expresses a functional P2Y₁ purinergic receptor for intracellular Ca²⁺-mobilization, and that P2Y₁ is linked to SOCE-activation, leading to Ca²⁺-influx which might be necessary for glucocorticoid secretion.


The effect of black barberry hydroalcoholic extract on immune mediators in patients with active rheumatoid arthritis: A randomized, double-blind, controlled clinical trial.
Rheumatoid arthritis (RA) is an autoimmune disease associated with inflammation. In this trial, we aimed to investigate the Immunomodulatory effect of hydroalcoholic extract of black barberry on immune mediators in patients with active rheumatoid arthritis. In this randomized, double-blind, placebo-controlled clinical trial, 80 women with active RA were randomly assigned into two groups of two capsules, each containing 1,000 mg black barberry extract (n = 40) or maltodextrin placebo (n = 40) daily for 12 weeks. Demographic indices, physical activity, dietary intake, and disease activity were investigated using suitable questionnaires. Concentration of cytokines IL-2, IL-4, IL-10, and IL-17 in blood sample were measured using PBMC method. Statistical analysis was performed using SPSS (version 22). At baseline, there were no differences between the two groups in terms of demographic indices, physical activity, and dietary intake (p > .05). Black barberry supplementation reduced the severity of RA. It showed no significant effect on IL-2 and IL-4 cytokines (p > .05). IL-17 levels decreased significantly after the intervention within the black barberry group, while IL-10 had a significant increase in this group (p < .05). Barberry extract may reduce inflammatory and increase anti-inflammatory cytokines in RA, and stimulates the immune response by increasing Th2 production.


1-Hy-droxy-3,4-dimeth-oxy-10-methyl-acridin-9-one.
There are two independent mol-ecules in the asymmetric unit of the title compound, C16H15NO4, which was isolated from fruits of Zanthoxylum leprieurii. The atoms of the three rings of each mol-ecule are close to coplanar with the largest deviations from the least-squares planes being 0.084 (3) Å and 0.069 (2) Å. Each molecule features an intramolecular O-H⋯·O hydrogen bond. In the crystal, C-H⋯·O hydrogen-bonding inter-actions link the mol-ecules into a three-dimensional network.


Cancer immunotherapy: Challenges and limitations.
Although cancer immunotherapy has taken center stage in mainstream oncology inducing complete and long-lasting tumor regression, only a subset of patients receiving treatment respond and others relapse after an initial response. Different tumor types respond differently, and even in cancer types that respond (hot tumors), we still observe tumors that are unresponsive (cold tumors), suggesting the presence of resistance. Hence, the development of intrinsic or acquired resistance is a big challenge for the cancer immunotherapy field. Resistance to immunotherapy, including checkpoint inhibitors, CAR-T cell therapy, oncolytic viruses, and recombinant cytokines arises due to cancer cells employing several mechanisms to evade immunosurveillance.


Health-related factors associated with the healthcare costs of office workers.
The purpose of this study was to assess the relative importance of factors associated with total health care costs (THC) among office workers. Biometric and anthropometric values, health-related survey responses, and THC for 214 employees were analyzed. Factors that had a statistically significant (P < 0.05) bivariate correlation with logarithmically transformed THC data were entered into multiple regression analysis. Age, gender, and SF-36 physical component summary score were identified as THC predictors (F3210 = 20.78, P < 0.001, Radj = 0.218). With physical component summary score excluded, age, gender, and exercise level collectively accounted for an almost identical amount of variance (F3210 = 19.64, P < 0.001, Radj = 0.212). Factorial ANOVA identified a significant interaction between age category and exercise level (F3198 = 3.04, P = 0.030). Inactivity was the only modifiable factor found to be predictive of THC, which appears to have an increasing effect with advancing age.


Establishment of local searching methods for orbitrap-based high throughput metabolomics analysis.
Our method aims to establish local endogenous metabolite databases economically without purchasing chemical standards, giving strong bases for following orbitrap based high throughput untargeted metabolomics analysis. A new approach here is introduced to construct metabolite databases on the base of biological sample analysis and mathematic extrapolation. Building local metabolite databases traditionally requires expensive chemical standards, which is barely affordable for most research labs. As a result, most labs working on metabolomics analysis have to refer public libraries, which is time consuming and limited for high throughput analysis. Using this strategy, a high throughput orbitrap based metabolomics platform can be established at almost no cost within a couple of months. It enables to facilitate the application of high throughput metabolomics analysis to identify disease-related biomarkers or investigate biological functions using orbitrap.


Therapeutic hypothermia associated with increased survival after resuscitation in children.
Brain injury after resuscitation is associated with high morbidity and mortality in children. Therapeutic hypothermia has theoretical benefits on brain preservation. It has been shown to be effective in improving neurological outcomes after adult ventricular arrhythmia-induced cardiac arrest and neonatal asphyxia. However, there have only been a few reports about therapeutic hypothermia after pediatric resuscitation. We conducted this retrospective cohort study in a tertiary pediatric intensive care unit between January 2010 and June 2012. All children from 2 months to 18 years of age with resuscitation and a history of at least 3 minutes of chest compressions with survival for 12 hours or more after return of circulation were eligible. Forty-three patients met the eligibility criteria for the study. Forty-two patients (97.6%) were asphyxial in etiology; 29 (67.4%) of them occurred out-of-hospital. Excluding one child with cardiac etiology, the overall survival rate to hospital discharge was 57.1%. Fourteen (33.3%) patients received hypothermia therapy and were cooled to 33°C for 72 hours. The survival rate was higher in the therapeutic hypothermia group (11/14, 78.6%) than in the normothermia group (13/28, 46.4%). In conclusion, therapeutic hypothermia was associated with increased survival rate after pediatric resuscitation.


Structure, anti-tumor activity, and potential anti-tumor mechanism of a fungus polysaccharide from Fomes officinalis.
In our ongoing process of discovering bioactive macromolecules, a homogeneous polysaccharide (FOP80-1) was first purified from Fomes officinalis. FOP80-1 with molecular weight of 4560 Da was mainly composed of →3)-d-Galp-(1→, →4)-β-d-Manp-(1→, →6)-α-d-Glcp-(1→, →3,6)-d-Glcp-(1→, and t--d-Glcp. Besides the structure features, the anti-tumor activity and potential mechanism of FOP80-1 were also investigated. The cellular and zebrafish experiments revealed that FOP80-1 inhibited tumor proliferation, invasion, and metastasis by increasing ROS, arresting cell cycle, inducing apoptosis, and suppressing angiogenesis. Corresponding to the inhibition of angiogenesis, the surface plasmon resonance (SPR) experiments revealed that FOP80-1 had good affinity with VEGF, a crucial protein to regulate angiogenesis. Molecular docking indicated that FOP80-1 could interact with the protein VEGF.


Replacement of maize by rumen filtrate fermented corn-cob in layer diets.
Laying hens (50 weeks in-lay) were fed for 8 weeks on diets containing corn-cobs fermented with rumen filtrate. The fermented corn-cob was included in the diets at 0%, 5.0%, 10.0%, 15.0% and 20.0% of the total diet at the expense of maize. Feed intake was not significantly (P>0.05) different, although birds on the control diet consumed slightly more feed than birds on the fermented corn-cob based diets. Hen day production and feed per dozen eggs decreased with increase in dietary level of corn-cob (P<0.05). Yolk colour was significantly (P<0.05) affected, rumen filtrate fermented corn-cob appear to promote better yolk coloration. Egg weight and shell thickness were not significantly influenced by dietary treatment. The overall results appear to suggest that rumen filtrate fermentated corn-cob could provide a material that holds promise as a good alternative to maize because of its enhanced crude protein value and reduced crude fibre content.


Fermentation of dried distillers' grains and solubles (DDGS) hydrolysates to solvents and value-added products by solventogenic clostridia.
Pretreatment and hydrolysis of lignocellulosic biomass using either dilute acid, liquid hot water (LHW), or ammonium fiber expansion (AFEX) results in a complex mixture of sugars such as hexoses (glucose, galactose, mannose), and pentoses (xylose, arabinose). A detailed description of the utilization of representative mixed sugar streams (pentoses and hexoses) and their sugar preferences by the solventogenic clostridia (Clostridium beijerinckii BA101, C. acetobutylicum 260, C. acetobutylicum 824, Clostridium saccharobutylicum 262, and C. butylicum 592) is presented. In these experiments, all the sugars were utilized concurrently throughout the fermentation, although the rate of sugar utilization was sugar specific. For all clostridia tested, the rate of glucose utilization was higher than for the other sugars in the mixture. In addition, the availability of excess fermentable sugars in the bioreactor is necessary for both the onset and the maintenance of solvent production otherwise the fermentation will become acidogenic leading to premature termination of the fermentation process. During an investigation on the effect of some of the known lignocellulosic hydrolysate inhibitors on the growth and ABE production by clostridia, ferulic and p-coumaric acids were found to be potent inhibitors of growth and ABE production. Interestingly, furfural and HMF were not inhibitory to the solventogenic clostridia; rather they had a stimulatory effect on growth and ABE production at concentrations up to 2.0g/L.


Myofibrillar myopathy in the genomic context.
Myofibrillar myopathy (MFM) is a group of inherited muscular disorders characterized by myofibril dissolution and abnormal accumulation of degradation products. The diagnosis of muscular disorders based on clinical presentation is difficult due to phenotypic heterogeneity and overlapping symptoms. In addition, precise diagnosis does not always explain the disease etiopathology or the highly variable clinical course even among patients diagnosed with the same type of myopathy. The advent of high-throughput next-generation sequencing (NGS) has provided a successful and cost-effective strategy for identification of novel causative genes in myopathies, including MFM. So far, pathogenic mutations associated with MFM phenotype, including atypical MFM-like cases, have been identified in 17 genes: DES, CRYAB, MYOT, ZASP, FLNC, BAG3, FHL1, TTN, DNAJB6, PLEC, LMNA, ACTA1, HSPB8, KY, PYROXD1, and SQSTM + TIA1 (digenic). Most of these genes are also associated with other forms of muscle diseases. In addition, in many MFM patients, numerous genomic variants in muscle-related genes have been identified. The various myopathies and muscular dystrophies seem to form a single disease continuum; therefore, gene identification in one disease impacts the genetic etiology of the others. In this review, we describe the heterogeneity of the MFM genetic background focusing on the role of rare variants, the importance of whole genome sequencing in the identification of novel disease-associated mutations, and the emerging concept of variant load as the basis of the phenotypic heterogeneity.


Phosphorylation prevents C/EBPβ from the calpain-dependent degradation.
CCAAT/enhancer-binding protein (C/EBP) β plays an important role in proliferation and differentiation of 3T3-L1 preadipocytes. C/EBPβ is sequentially phosphorylated during the 3T3-L1 adipocyte differentiation program, first by MAPK/Cyclin A/cdk2 on Thr(188) and subsequently by GSK3β on Ser(184) or Thr(179). Dual phosphorylation is critical for the gain of DNA binding activity of C/EBPβ. In this manuscript, we found that phosphorylation also contributed to the stability of C/EBPβ. Both ex vivo and in vitro experiments showed that phosphorylation by MAPK/Cyclin A/cdk2 and GSK3β protected C/EBPβ from μ-calpain-mediated proteolysis, while phosphorylation on Thr(188) by MAPK/Cyclin A/cdk2 contributed more to the stabilization of C/EBPβ, Further studies indicated that phosphorylation mimic C/EBPβ was insensitive to both calpain accelerator and calpain inhibitor. Thus, phosphorylation might contribute to the stability as well as the gain of DNA binding activity of C/EBPβ.


Right ventricular dysfunction following cold potassium cardioplegia.
Right coronary artery stenoses limit cardioplegic delivery to the right ventricle and may contribute to postoperative right ventricular dysfunction. Right ventricular function was evaluated in 39 patients with right coronary artery stenoses following elective coronary bypass operations. Hemodynamic and nuclear ventriculographic measurements, made between 3 and 6 hours postoperatively, revealed a progressive increase in pulmonary arterial pressure, pulse rate, and right ventricular ejection fraction (p less than 0.05). Right ventricular end-diastolic volume index (calculated from the thermodilution stroke index divided by the nuclear ejection fraction) decreased, but right atrial pressure increased (suggesting a decrease in compliance). The response to the infusion of 2 units of plasma (volume loading) was evaluated 3 hours postoperatively (EARLY) and again 5 hours postoperatively (LATE) in 21 patients. Right ventricular performance (the relation between cardiac index or right ventricular stroke work index and right ventricular end-diastolic volume index) and right ventricular systolic function (the relation between systolic pulmonary arterial pressure and right ventricular end-systolic volume index) were depressed EARLY and improved LATE (p less than 0.01 in analysis of covariance). Left ventricular performance (the relation between cardiac index or left ventricular stroke work index and left ventricular end-diastolic volume index) and left ventricular systolic function (the relation between systolic blood pressure and left ventricular end-systolic volume index) were similar EARLY and LATE. Right ventricular diastolic function (the relation between right atrial pressure and right ventricular end-diastolic volume index) and left ventricular diastolic function (the relation between left atrial pressure and left ventricular end-diastolic volume index) were significantly greater LATE than EARLY. Right, but not left, ventricular performance and systolic function were transiently depressed, and right and left ventricular diastolic stiffness were transiently decreased in the EARLY postoperative period. In patients with right coronary artery stenoses, current methods of cardioplegia may inadequately protect the right ventricle, but further studies are required to establish the relation between intraoperative protection and postoperative function.


Radiotherapy combined with gefitinib for patients with locally advanced non-small cell lung cancer who are unfit for surgery or concurrent chemoradiotherapy: a phase II clinical trial.
The objectives of this study were to determine the objective effective response rate, survival, and safety of radiotherapy combined with gefitinib in patients with locally advanced non-small cell lung cancer (NSCLC) who were unfit for surgery or concurrent chemoradiotherapy. The patients with the locally advanced NSCLC who were unfit to receive surgery or concurrent chemoradiotherapy, received thoracic intensity-modulated radiotherapy (IMRT) combined with gefitinib 250 mg daily. 29 patients were enrolled between July 2014 and March 2017. 28 patients was in the analysis. Of the 28 patients, 21 (75.0%) experienced a partial response, 5 (17.9%) had stable disease, and 2 (7.1%) experienced progression of disease. The objective response rate was 75.0%, and the disease control rate was 92.9%. The median follow-up time was 51 months. The disease progression showed in 25 (89.3%) patients, including local progression in 19 (67.9%) and distant metastasis in 16 (57.1%). The median overall survival and progression-free survival time (PFS) were 26 and 11 months, respectively. The 3-, 4-, 5-year survival rates were 39.0, 30.1 and 30.1%, respectively. The 3-, 4-, 5-year PFS rates were 14.3, 9.5 and 9.5%. Two patients developed grade 3 acute adverse events. Seven patients developed grade 2 acute irradiation pneumonitis, and there was no grade 3 acute irradiation pneumonitis. For patients with locally advanced NSCLC who are not eligible for surgery or concurrent chemoradiotherapy, IMRT combined with gefitinib can improve the objective effective rate and is generally well-tolerated.


Carpal tunnel syndrome due to fibrolipomatous hamartoma of the median nerve.
Nervous lipofibromatous hamartoma is a rare tumor-like condition involving the peripheral nerves, whereby the epineurium and perineurium are enlarged and distorted by excess of fatty and fibrous tissues that infiltrate between and around nerve boundaries. The median nerve is much more likely to develop a hamartoma than other nerves with a predilection for the carpal tunnel. We present a case of carpal tunnel syndrome in an adult caused by fibrolipomatous hamartoma of the median nerve, successfully removed by excision of the fibrolipomatous tissue and decompression.


A familial congenital heart disease with a possible multigenic origin involving a mutation in BMPR1A.
The genetics of many congenital heart diseases (CHDs) can only unsatisfactorily be explained by known chromosomal or Mendelian syndromes. Here, we present sequencing data of a family with a potentially multigenic origin of CHD. Twelve of nineteen family members carry a familial mutation [NM_004329.2:c.1328 G > A (p.R443H)] which encodes a predicted deleterious variant of BMPR1A. This mutation co-segregates with a linkage region on chromosome 1 that associates with the emergence of severe CHDs including Ebstein's anomaly, atrioventricular septal defect, and others. We show that the continuous overexpression of the zebrafish homologous mutation bmpr1aap.R438H within endocardium causes a reduced AV valve area, a downregulation of Wnt/ß-catenin signalling at the AV canal, and growth of additional tissue mass in adult zebrafish hearts. This finding opens the possibility of testing genetic interactions between BMPR1A and other candidate genes within linkage region 1 which may provide a first step towards unravelling more complex genetic patterns in cardiovascular disease aetiology.


Author Correction: Requirements for the differentiation of innate T-bethigh memory-phenotype CD4+ T lymphocytes under steady state.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


Anti-Lipoxygenase Activity of Leaf Gall Extracts of Terminalia chebula (Gaertn.) Retz. (Combretaceae).
Lipoxygenase (LOX) inhibitors are the promising therapeutic target for treating a wide spectrum of inflammatory-related diseases such as cancer, asthma, lymphoma, leukemia, and autoimmune disorders. In the present study, the photochemical constituents and the anti-LOX potential of leaf galls of Terminalia chebula are evaluated to exemplify its further potential development as medicine. Extracts of T. chebula galls were tested for anti-LOX activity using linoleic acid as substrate and lipoxidase as an enzyme and also the total content of polyphenols with phytochemical analysis of the extract were determined. The presence of highest total phenolic and flavonoid content of 141 ± 2.2 mg of gallic acid equivalent/g d.w and 125 ± 1.4 mg of quercetin equivalent/g d.w and maximal LOX inhibitory activity (52.67%) at 800 μg/mL concentrations were identified in the ethanolic extracts of leaf galls of T.chebula. The higher LOX inhibitory activity was positively correlated to the high content of total polyphenols/flavonoids. The results of this study confirm the folklore use of T. chebula leaves gall extracts as a natural anti-inflammatory agent and justify its ethnobotanical use. Therefore, the results encourage the use of T. chebula leave gall extracts for medicinal health, functional food, and nutraceuticals applications. The present investigation demonstrated promising anti-LOX proper-ties of T. chebula leaves gall extracts. Presumably, these activities could be attributed in part to the polyphenolic features of the extract, as there was a strong correlation of higher LOX inhibiting activities with that of high total phenolic and flavonoid content in the methanolic leaf gall extracts of T. chebula. The results of this study confirm the folklore use of T. chebula leaves gall extracts as a natural anti-inflammatory agent and justify the ethnobotanical approach in the search for novel bioactive com-pounds.


Effect of the khat alkaloid (+)norpseudoephedrine on uteroplacental blood flow in the guinea pig.
In order to investigate effects of khat chewing on uteroplacental blood flow (+)norpseudoephedrine (NPE) infusions were given to 11 anesthetized guinea pigs in late pregnancy (62-66 days) after unilateral uterine artery ligation at days 30-32. Regional blood flows were determined with radioactive microspheres. Mean arterial blood pressure increased with 25% and heart rate with 9% during NPE infusion. Myoendometrial blood flow was reduced by 31%. Placental vascular resistance (PVR) increased by 56% in the control horn (17 fetuses) and by 82% in the ligated horn (17 fetuses). This vasoconstriction was counteracted by the systemic vasopressor response since placental blood flow remained unchanged. When considering only the 13 growth-retarded fetuses, however, PVR increased by 98% and a 19% reduction of placental blood flow could be demonstrated. These results suggest that the placenta of the growth-retarded fetus may be more sensitive to adrenergic stimulation than the normal placenta. Furthermore, since one of the active constituents of khat, (+)norpseudoephedrine, causes vasoconstriction in the uteroplacental vascular bed it is possible that khat chewing could reduce placental blood flow and, as a consequence, impair fetal growth.


Deep-learning systems for diagnosing cleft palate on panoramic radiographs in patients with cleft alveolus.
The aim of the present study was to create effective deep learning-based models for diagnosing the presence or absence of cleft palate (CP) in patients with unilateral or bilateral cleft alveolus (CA) on panoramic radiographs. The panoramic images of 491 patients who had unilateral or bilateral cleft alveolus were used to create two models. Model A, which detects the upper incisor area on panoramic radiographs and classifies the areas into the presence or absence of CP, was created using both object detection and classification functions of DetectNet. Using the same data for developing Model A, Model B, which directly classifies the presence or absence of CP on panoramic radiographs, was created using classification function of VGG-16. The performances of both models were evaluated with the same test data and compared with those of two radiologists. The recall, precision, and F-measure were all 1.00 in Model A. The area under the receiver operating characteristic curve (AUC) values were 0.95, 0.93, 0.70, and 0.63 for Model A, Model B, and the radiologists, respectively. The AUCs of the models were significantly higher than those of the radiologists. The deep learning-based models developed in the present study have potential for use in supporting observer interpretations of the presence of cleft palate on panoramic radiographs.


Identification of biomarkers associated with the recurrence of osteosarcoma using ceRNA regulatory network analysis.
The aim of the present study was to identify the important mRNAs, micro (mi)RNAs and long non‑coding (lnc)RNAs that are associated with osteosarcoma recurrence. The GSE3905 dataset, which contains two sub‑datasets (GSE39040 and GSE39055), was downloaded from the Gene Expression Omnibus (GEO). Prognosis‑associated RNAs were identified by performing Cox regression univariate analysis and were subsequently used to construct a competing endogenous (ce)RNA regulatory network for Gene Set Enrichment Analysis (GSEA). Kaplan‑Meier survival analysis was used to determine the associations between expression levels and survival prognosis. In addition, another independent miRNA profile, GSE79181, was downloaded from GEO for validation. Among the differentially expressed RNAs, 417 RNAs (5 lncRNAs, 19 miRNAs, and 393 mRNAs) were observed to be associated with prognosis. The GSEA for the ceRNA regulatory network revealed that 'Mitogen‑activated protein kinase (MAPK) signaling pathway', 'Chemokine signaling pathway' and 'Spliceosome' were markedly associated with osteosarcoma. In addition, three lncRNAs [long intergenic non‑protein coding RNA 28 (LINC00028), LINC00323, and small nucleolar RNA host gene 1 (SNHG1)] and two miRNAs (hsa‑miR‑124 and hsa‑miR‑7) regulating three mRNAs [Ras‑related protein Rap‑1b (RAP1B), activating transcription factor 2 (ATF2) and protein phosphatase Mg2+/Mn2+ dependent 1B (PPM1B)] participated in the MAPK signaling pathway. The Kaplan‑Meier survival analysis also demonstrated that samples with lower expression levels of LINC00323 and SNHG1 had better prognosis, and samples with increased expression levels of LINC00028, hsa‑miR‑124 and hsa‑miR‑7 had better prognosis. Overexpression of RAP1B, ATF2 and PPM1B was positively associated with osteosarcoma recurrence. The roles of hsa‑miR‑124 and hsa‑miR‑7 in osteosarcoma recurrence were also validated using GSE79181. Thus, in conclusions, the three lncRNAs (LINC00028, LINC00323 and SNHG1), two miRNAs (hsa‑miR‑124 and hsa‑miR‑7) and three mRNAs (RAP1B, ATF2, and PPM1B) were associated with osteosarcoma recurrence.


Mammalian CARMIL inhibits actin filament capping by capping protein.
Actin polymerization in cells occurs via filament elongation at the barbed end. Proteins that cap the barbed end terminate this elongation. Heterodimeric capping protein (CP) is an abundant and ubiquitous protein that caps the barbed end. We find that the mouse homolog of the adaptor protein CARMIL (mCARMIL) binds CP with high affinity and decreases its affinity for the barbed end. Addition of mCARMIL to cell extracts increases the rate and extent of Arp2/3 or spectrin-actin seed-induced polymerization. In cells, GFP-mCARMIL concentrates in lamellipodia and increases the fraction of cells with large lamellipodia. Decreasing mCARMIL levels by siRNA transfection lowers the F-actin level and slows cell migration through a mechanism that includes decreased lamellipodia protrusion. This phenotype is reversed by full-length mCARMIL but not mCARMIL lacking the domain that binds CP. Thus, mCARMIL is a key regulator of CP and has profound effects on cell behavior.


Analyzing the dynamics of cell growth and protein production in mammalian cell fed-batch systems using logistic equations.
The logistic modeling approach was used to describe experimental viable cell density (X) and product concentration (P) data from two industrial fed-batch mammalian cell culture processes with maximum product concentrations in the 3.0-9.4 g/l range. In both cases, experimental data were well described by the logistic equations and the resulting specific growth rate and protein productivity profiles provided useful insights into the process kinetics. Subsequently, sensitivity equations for both the X and P models were analyzed which helped characterize the influence of model parameters on X and P time courses. This was augmented by conventional sensitivity analyses where five values of each model parameter, 25% apart, were used to generate X and P time courses. Finally, results from sensitivity analysis were used to simulate X and P time courses that were reflective of typical early- and late-stage fed-batch cell culture processes. Different combinations of the logistic model parameters were used to arrive at the same final product concentration demonstrating the ability of the logistic approach to describe the multitude of process paths that result in the same final product concentration. Overall, the capability of the logistic equations to well describe X and P data from fed-batch cultures, coupled with their ability to simulate the multitude of paths leading up to the desired cell density and product concentration profiles, make them a useful tool during mammalian cell fed-batch process development.


Scope and utility of hydrogen exchange as a tool for mapping landscapes.
The ability to determine conformational parameters of protein-folding landscapes is critical for understanding the link between conformation, function, and disease. Monitoring hydrogen exchange (HX) of labile protons at equilibrium enables direct extraction of thermodynamic or kinetic landscape parameters in two limiting extremes. Here, we establish a quantitative framework for relating HX behavior to landscape. We use this framework to demonstrate that the range of predicted global HX behavior for the majority of a set of characterized two-state proteins under near-native conditions does not readily span between both extremes. For most, stability may be quantitatively determined under physiological conditions, with semiquantitative boundaries on kinetics additionally determined using modest experimental perturbations to shift HX behavior. The framework and relationships derived in the simple context of two-state global folding highlight the importance of understanding HX across the entire continuum of behavior, in order to apply HX to map landscapes.


Proprioception: A New Era Set in Motion by Emerging Genetic and Bionic Strategies?
The generation of an internal body model and its continuous update is essential in sensorimotor control. Although known to rely on proprioceptive sensory feedback, the underlying mechanism that transforms this sensory feedback into a dynamic body percept remains poorly understood. However, advances in the development of genetic tools for proprioceptive circuit elements, including the sensory receptors, are beginning to offer new and unprecedented leverage to dissect the central pathways responsible for proprioceptive encoding. Simultaneously, new data derived through emerging bionic neural machine-interface technologies reveal clues regarding the relative importance of kinesthetic sensory feedback and insights into the functional proprioceptive substrates that underlie natural motor behaviors.


Satiety scores and satiety hormone response after sucrose-sweetened soft drink compared with isocaloric semi-skimmed milk and with non-caloric soft drink: a controlled trial.
Observational studies indicate that sugar-sweetened soft drinks (SSSD) may promote obesity, among other factors, owing to low-satiating effects. The effect of energy in drinks on appetite is still unclear. We examined the effect of two isocaloric, but macronutrient, different beverages (SSSD versus semi-skimmed milk) and two non-energy-containing beverages (aspartame-sweetened soft drink (ASSD) and water) on appetite, appetite-regulating hormones and energy intake (EI). In all, 24 obese individuals were included in a crossover trial. Each subject was served either 500 ml of SSSD (regular cola: 900 kJ), semi-skimmed milk (950 kJ), ASSD (diet cola: 7.5 kJ), or water. Subjective appetite scores, ghrelin, GLP-1, and GIP concentrations were measured at baseline and continuously 4-h post intake. Ad libitum EI was measured 4 h after intake of the test drinks. Milk induced greater subjective fullness and less hunger than regular cola (P<0.05). Also, milk led to 31% higher GLP-1 (95% CI: 20, 44; P<0.01) and 45% higher GIP (95% CI: 23, 72; P<0.01) concentrations compared with SSSD. Ghrelin was equally 20% lower after milk and SSSD compared with water. The total EI (ad libitum EI+EI from the drink) was higher after the energy-containing drinks compared with diet cola and water (P<0.01). Milk increased appetite scores and GLP-1 and GIP responses compared with SSSD. The energy containing beverages were not compensated by decreased EI at the following meal, emphasizing the risk of generating a positive energy balance by consuming energy containing beverages. Furthermore, there were no indications of ASSD increased appetite or EI compared with water.


Signatures of a magnetic superstructure phase induced by ultrahigh magnetic fields in a breathing pyrochlore antiferromagnet.
The mutual coupling of spin and lattice degrees of freedom is ubiquitous in magnetic materials and potentially creates exotic magnetic states in response to the external magnetic field. Particularly, geometrically frustrated magnets serve as a fertile playground for realizing magnetic superstructure phases. Here, we observe an unconventional two-step magnetostructural transition prior to a half-magnetization plateau in a breathing pyrochlore chromium spinel by means of state-of-the-art magnetization and magnetostriction measurements in ultrahigh magnetic fields available up to 600 T. Considering a microscopic magnetoelastic theory, the intermediate-field phase can be assigned to a magnetic superstructure with a three-dimensional periodic array of 3-up-1-down and canted 2-up-2-down spin molecules. We attribute the emergence of the magnetic superstructure to a unique combination of the strong spin-lattice coupling and large breathing anisotropy.


Beware of hemolytic uremic syndrome presenting as colorectal disease in adults. Report of two cases.
Hemolytic uremic syndrome is seen occasionally by the surgeon in adult patients with colorectal manifestations. Two cases of hemolytic uremic syndrome are presented here, one misdiagnosed clinically as acute appendicitis and the other as acute ulcerative colitis. In each case the diagnosis was only established postoperatively and both patients died of this disease. These cases serve to remind colorectal surgeons that this potentially lethal disease may occur with symptoms and signs suggestive of more common colorectal pathology.


Targeting stress granules: A novel therapeutic strategy for human diseases.
Stress granules (SGs) are assemblies of mRNA and proteins that form from mRNAs stalled in translation initiation in response to stress. Chronic stress might even induce formation of cytotoxic pathological SGs. SGs participate in various biological functions including response to apoptosis, inflammation, immune modulation, and signalling pathways; moreover, SGs are involved in pathogenesis of neurodegenerative diseases, viral infection, aging, cancers and many other diseases. Emerging evidence has shown that small molecules can affect SG dynamics, including assembly, disassembly, maintenance and clearance. Thus, targeting SGs is a potential therapeutic strategy for the treatment of human diseases and the promotion of health. The established methods for detecting SGs provided ready tools for large-scale screening of agents that alter the dynamics of SGs. Here, we describe the effects of small molecules on SG assembly, disassembly, and their roles in the disease. Moreover, we provide perspective for the possible application of small molecules targeting SGs in the treatment of human diseases.


A rat model of vascular dementia for evaluating Chinese medicine prescriptions.
To develop a new model of vascular dementia for evaluating Chinese medicine prescriptions. Eighty-eight male Wistar rats were randomly divided into 4 groups. At d00, d42, d70, d98 (ni=20, 20, 24, 24) during fatty-feeding, rats in each group were further divided into 10 or 12 subgroups (ni=2), respectively. Lacunar stroke were replicated with the injection of thrombi which coagulated artificially from itself blood. The median lethal doses (LD50) were regressed from accumulative mortality in each geometric thrombus doses (k=0.75, 0.5, 0.85, 0.85), respectively. The degree of vascular dementia was evaluated as exploratory, learning and memorizing abilities. The median effective dose of thrombus for replicating rat model was regressed from dementia scores which were derived from the abilities. The linear correlation was regressed between the values of LD50 or effective dose (ED50) and the durations (days) of hypercholesterolemia. This model of vascular dementia was pathologically confirmed as the neural injuries from lacunar stroke in rats. The hypercholesterolemia was indicated as elevated total cholesterol, triglyeerides low-density lipoprotein cholesterol, and decreased high-density lipoprotein cholesterol. The values of LD50 with its 95% confidence intervals (CI) were 1525.0 (1361.0-1709.0), 584.3 (490.1-696.6), 168.7 (163.7-173.8), or 62.4 (59.5-65.4) mg/mL, at d00, d42, d70, and d98, respectively. There is a linear regression between the values of LD50 and the durations of hypercholesterolemia (y=-15.33x+1390.0, r=0.963, P<0.05). The values of ED50 with its 95% CI were 528.8 (340.5-821.4), 217.0 (20.84-2259.0), 96.3 (23.4-402.6), or 47.0 (43.7-50.6) mg/mL from dementia score, at d00, d42, d70, and d98, respectively. There is a linear regression between the values of ED50 and the durations of hypercholesterolemia (y=-4.992x+484.2, r=0.965, P<0.05). The neural injuries were demonstrated as neural degeneration and necrosis. For evaluating Chinese medicine, a model of vascular dementia in rats is set up with the lacunar stroke from self-thrombosis during hypercholesterolemia. This model from lacunar stroke is useful to investigate the pathogenesis and treatment of vascular dementia.


[Post-phlebitis cutaneous calcinosis. Histochemical study].
A case of cutaneous localized calcinosis of the left upper limb is reported and classified as dystrophic calcinosis because the antecedent of superficial phlebitis. This kind of manifestation is rare in relationship with the frequence of superficial inflammatory processus of veins.


Theoretical Health Risk Assessment Based on Potentially Toxic Element Profiling of Cosmetic Products in Istanbul Street Bazaars.
Toxic elements that pose a potential threat to human health are found as impurities in various cosmetic products. In this study, the inorganic profile of 19 elements (Li, B, Mg, Al, Cr, Mn, Co, Ni, Cu, Zn, As, Se, Sr, Mo, Cd, Sb, Ba, Hg, and Pb) in 90 cosmetic products (lipsticks, lip glosses, lip pencils and eye shadows) were detected by inductively coupled plasma-mass spectrometry after microwave acid digestion method and hazard indices (HI) of 9 toxic elements (Pb, Cd, Cr, Ni, Co, As, Hg, Sb, and Al) were calculated for the assessment of theoretical health risk. Satisfactory method performance parameters were found for each analyte. The results were compared with the maximum permissible limits set by regulatory agencies; 38 of 41 lip products (92.68%) and all eye shadows (n = 49) exceeded the established limits. The HI was found to be ≥ 1 in 82.76% of lip products for oral exposure, whereas HI was ≤ 1 for dermal exposure in all lip products (n = 41) and only one eye shadow sample was ≥ 1 (2.04%). Remarkable results were also detected for 19 elements in this study, which conducted a comprehensive inorganic profiling for the first time. Wide-range concentrations of Mg, Al, Ba, Mn, Cu, Zn, and Sr elements were remarkable. HI values were firstly brought out in this study, although Al, as a well-known toxic element, has not been listed in regulations yet. In conclusion, it is obviously seen that continuous monitoring of cosmetics is crucial not only for toxic elements but also for other essential or non-toxic elements to prevent consumers from long-term exposure.


Use of a post-production fractionation process improves the nutritional value of wheat distillers grains with solubles for young broiler chicks.
Post-production fractionation of wheat distillers grains with solubles (DDGS) increases their crude protein content and reduces their fiber content. This experiment was conducted to determine the effects of fractionation of wheat DDGS on apparent total tract digestibility (ATTD) and performance when fed to broiler chicks (0-21 d). A total of 150, day-old, male broiler chicks (Ross-308 line; Lilydale Hatchery, Wynyard, Saskatchewan) weighing an average of 49.6 ± 0.8 g were assigned to one of five dietary treatments in a completely randomized design. The control diet was based on wheat and soybean meal and contained 20% regular wheat DDGS. The experimental diets contained 5, 10, 15 or 20% fractionated wheat DDGS added at the expense of regular wheat DDGS. The ATTD of dry matter and gross energy were linearly increased (P < 0.01) as the level of fractionated wheat DDGS in the diet increased. Nitrogen retention was unaffected by level of fractionated wheat DDGS (P > 0.05). Weight gain increased linearly (P = 0.05) as the level of fractionated wheat DDGS in the diet increased. Feed intake, feed conversion and mortality were unaffected by level of fractionated wheat DDGS in the diet (P > 0.05). Post-production fractionation of wheat DDGS improves their nutritional value by lowering their fiber content and increasing their content of crude protein and energy. These changes in chemical composition supported increased weight gain of broilers fed wheat DDGS.


Perfusion of rabbit colon with ricinoleic acid: dose-related mucosal injury, fluid secretion, and increased permeability.
Morphology of the rabbit colon was examined by light and scanning electron microscopy after perfusion of the organ with 2.5, 5.0, 7.5, and 10 mM sodium ricinoleate. Colons perfused with control buffer showed the expected normal appearances, whereas ricinoleate produced desquamation of surface epithelial cells. Surface changes in the colon were comparable with those reported after similar treatment of the rabbit ileum. Concomitant with these histological changes was loss of DNA into the lumen of the colon. Dose-related changes in net fluid transport and mucosal permeability (as assessed by lumen to plasma flux of low molecular weight polyethylene glycols and plasma to lumen flux of urea and creatinine) were also associated with ricinoleate perfusion. These structural and functional alterations may contribute to intraluminal accumulation of fluid and catharsis that can result from administration of ricinoleic acid (castor oil). The findings might also pertain to the pathophysiology of steatorrheal diseases, because dietary fatty acids of similar chemical structure are known to have comparable effects on the intestinal mucosa.


Current Strategies of Muscular Dystrophy Therapeutics: An Overview.
Muscular dystrophies are a group of genetic disorders characterized by varying degrees of progressive muscle weakness and degeneration. They are clinically and genetically heterogeneous but share the common histological features of dystrophic muscle. There is currently no cure for muscular dystrophies, which is of particular concern for the more disabling and/or lethal forms of the disease. Through the years, several therapies have encouragingly been developed for muscular dystrophies and include genetic, cellular, and pharmacological approaches. In this chapter, we undertake a comprehensive exploration of muscular dystrophy therapeutics under current development. Our review includes antisense therapy, CRISPR, gene replacement, cell therapy, nonsense suppression, and disease-modifying small molecule compounds.


Study protocol of IMAGINE-HD: Imaging iron accumulation and neuroinflammation with 7T-MRI + CSF in Huntington's disease.
Strong evidence suggests a significant role for iron accumulation in the brain in addition to the well-documented neurodegenerative aspects of Huntington's disease (HD). The putative mechanisms by which iron is linked to the HD pathogenesis are multiple, including oxidative stress, ferroptosis and neuroinflammation. However, no previous study in a neurodegenerative disease has linked the observed increase of brain iron accumulation as measured by MRI with well-established cerebrospinal fluid (CSF) and blood biomarkers for iron accumulation, or with associated processes such as neuroinflammation. This study is designed to link quantitative data from iron levels and neuroinflammation metabolites obtained from 7T MRI of HD patients, with specific and well-known clinical biofluid markers for iron accumulation, neurodegeneration and neuroinflammation. Biofluid markers will provide quantitative measures of overall iron accumulation, neurodegeneration and neuroinflammation, while MRI measurements on the other hand will provide quantitative spatial information on brain pathology, neuroinflammation and brain iron accumulation, which will be linked to clinical outcome measures. This is an observational cross-sectional study, IMAGINE-HD, in HD gene expansion carriers and healthy controls. We include premanifest HD gene expansion carriers and patients with manifest HD in an early or moderate stage. The study includes a 7T MRI scan of the brain, clinical evaluation, motor, functional, and neuropsychological assessments, and sampling of CSF and blood for the detection of iron, neurodegenerative and inflammatory markers. Quantitative Susceptibility Maps will be reconstructed using T2* weighted images to quantify brain iron levels and Magnetic Resonance Spectroscopy will be used to obtain information about neuroinflammation by measuring cell-specific intracellular metabolites' level and diffusion. Age and sex matched healthy subjects are included as a control group. Results from this study will provide an important basis for the evaluation of brain iron levels and neuroinflammation metabolites as an imaging biomarker for disease stage in HD and their relationship with the salient pathomechanisms of the disease on the one hand, and with clinical outcome on the other.


Lipid composition of plasma membranes isolated from light-grown barley (Hordeum vulgare) leaves: identification of cerebroside as a major component.
The total lipid composition of highly purified plasma membranes from light-grown barley (Hordeum vulgare) leaves was investigated. The plasma membranes were separated from intracellular membranes by subfractionation of the microsomal fraction using aqueous polymer two-phase partitioning. A novel finding was that glucocerebroside was a major lipid of the plasma membrane (23 mol%). The most abundant lipid class in the plasma membrane was phospholipid (42 mol%), consisting mainly of phosphatidylcholine and phosphatidylethanolamine, together with free sterols at a level of 28 mol%. The only free sterols of the plasma membrane were campesterol (15%), stigmasterol (23%), and sitosterol (62%). The plasma membrane contained a relatively high proportion of saturated fatty acids compared to the bulk of intracellular membranes, the major components of the plasma membrane being palmitic (16:0), linoleic (18:2), and linolenic (18:3) acids in approximately equal amounts.


Outcomes of hip arthroplasty with concomitant hardware removal: influence of the type of implant retrieved and impact of positive intraoperative cultures.
The impact of residual internal fixation devices on subsequent procedures about the hip has not been clearly well defined. The objective of the current study is to evaluate the outcome of hip arthroplasty after hardware retrieval as a one-stage replacement, to analyze possible differences related to the type of removed implant, and to assess the impact of unexpected intraoperative cultures during implant retrieval. We present a retrospective study including all those cases undergoing hip arthroplasty with concomitant hardware removal (cannulated screws, intramedullary nail, or dynamic hip screw) from 2005 to 2018. We evaluated demographics, intraoperative cultures, early infection rate, and other complications. A total of 55 cases were included in the study. The median time between the implant surgery and the hip arthroplasty was 113 days. The removed devices included 6 cannulated screws, 34 intramedullary nails, and 15 dynamic hip screws. Up to 74.5% of the failed osteosynthesis belonged to intertrochanteric femoral fractures. Dislocation rate was 9.1% (1.8% requiring revision surgery), 25.5% of the cases needed further new surgeries after the hip arthroplasty, and 49.1% died during the follow-up period. Any-cause revision surgery and mortality rates were significantly increased after intramedullary nail removal. Intraoperative cultures were performed in 46 cases, and in 9 (16.4%), there was bacterial contamination: 6 cases (10.9%) presented one single positive culture and 3 (5.5%) presented ≥ 2 positive cultures for the same microorganism. A total of five cases (9.1%) presented early prosthetic joint infection that required debridement. None of these five cases had presented positive cultures at the implant removal. According to our results, hip arthroplasty with concomitant hardware removal is related to a high 5-year mortality rate, mainly when intramedullary nail is retrieved. Whereas a high risk of early prosthetic joint infection is associated, it seems not to be related to the elevated presence of unexpected positive cultures.


Platelet activating factor in the eye: Physiological roles, diseases and future perspectives.
Platelet Activating Factor (PAF) is a known phospholipid mediator of inflammation. Since its first description in 1972, it has emerged as a key regulator of vital cellular signaling functions, as proliferation, cell adhesion, and apoptosis. Evidence suggests that interactions between PAF and its receptor (PAFR) play a critical role in nervous system tissues, including the retina. The retina is a very important constituent of the visual system, along with the cornea, sclera, choroid, iris, and ciliary body, that acts synergistically to provide vision and to maintain optical homeostasis. There is evidence that PAF may regulate a wide range of physiological functions in the visual system tissues, such as eye development, inflammation, epithelial wound healing, and synapsis. Due to their multiple functions, PAF and PAFR also have important pathological and clinical implications in ocular disorders such as Choroidal Neovascularization (CNV), Age Macular Degeneration, (AMD), Diabetic Retinopathy (DR), transplant responses, and pharmacological interactions. Studies with PAFR antagonists have shown promising results such as inhibition of neovascularization and chloroquine-induced retinopathies, as well as reducing inflammation and retinal cell death. Due to the importance of PAFR signaling in the visual system and ophthalmology research, this review aims to provide a general overview of current and future perspectives about PAF in eye biology.


Tumor volume and local control probability: clinical data and radiobiological interpretations.
It is well established for certain human tumor histologies that increasing tumor volume leads to a decreasing probability of tumor control. The simplest explanation for these findings is that the number of tumor clonogens that must be sterilized to control a tumor increases with tumor volume. In this investigation we consider whether clinical evidence favors a further hypothesis, namely, that clonogen number increases in direct proportion to tumor volume. Previously published data on the volume-cure relationship for breast tumors, neck nodes, malignant melanoma, and squamous cell carcinomas of the oropharynx and the uterine cervix were analyzed. We found in all these data sets evidence that the effect of tumor volume on tumor control probability was less than what would be expected under the assumption of proportionality between number of clonogens and volume. We describe good reasons to believe that this is the result of patient-to-patient variability in radiocurability, and possibly other factors as well. Clinical data do provide evidence for a highly significant reduction of tumor control probability with increasing tumor volume. However, because of heterogeneity in patient and tumor characteristics, the volume effect is less pronounced than would be expected from a simple proportionality between number of clonogens and volume. In principle this simple proportionality does hold in individual patients, so that standard approaches for treatment plan optimization in individuals may still be valid.


Isolation of photosynthetic catalysts from cyanobacteria.
Methods are described for the isolation of ferredoxins I and II, cytochrome c-553, cytochrome f, cytochrome c-550 and plastocyanin from large quantities of various cyanobacteria. The amino acid composition of cytochrome c-550 is reported. There is a variation in the relative amounts of these proteins in different batches of cells which may relate to the nutritional status of the organisms.


Seed predation and patterns of fruit production in Asclepias syriaca L.
Seed predation in relation to patterns of pod (and seed) distribution was examined in five samples of the common milkweed (Asclepias syriaca L.), in tests of the "resource-concentration" effect both within- and beween-plants. The proportion of pods in a cluster that were attacked, particularly by the weevil Rhyssomatus lineaticollis, was not consistently related to the number of pods contained in a cluster, the frequency of cluster sizes in a population, or the variance of cluster sizes on a stem. Proportions of pods attacked per stem were not correlated with stem density in one sample and were not associated with stem height in any sample. Large clusters of pods produced more undamaged pods and, by this measure, were more successful than smaller clusters, but there was no tendency in any population for stems to produce the more successful cluster sizes more frequently. Stems producing more clusters of pods also produced more undamaged pods. We found no evidence that weevil predation contributed to the regulation of the distribution of pods among clusters on a stem.


Cytotoxic, migration, and angiogenic effects of intracanal irrigants on cells involved in revascularization of immature teeth.
To evaluate protocols of root canal irrigation and dentin pretreatment in a cell culture model simulating immature teeth. Cytotoxic, migration, and angiogenic effects of Sodium hypochlorite associated with EDTA (NaOCl/EDTA), NaOCl associated with Smear Clear (NaOCl/SC), and QMix were compared. Three roots of mandibular first premolars had their length and root canal diameter standardized. Root canals were irrigated, and the resulting solutions were diluted in culture medium. Sulforhodamine B (SRB) assay was performed with apical papilla cells and with endothelial cells (HUVECs) to assess cytotoxicity. Polarity index and migration assays of apical papilla cells and sprouting of HUVECs were evaluated. Data were analyzed by ANOVA and Tukey post-hoc tests (p < .05). In apical papilla cells, NaOCl/SC and QMix promoted higher cytotoxicity, decreased fraction of elongated cells, and had lower migration speed and shorter migration distance of cells compared to NaOCl/EDTA. Also, HUVECs treated with NaOCl/SC and QMix showed decreased tubule formation in comparison with NaOCl/EDTA. NaOCl/SC and QMix showed unfavorable biological responses of cells involved in revascularization in comparison to NaOCl/EDTA. Further studies with other intracanal irrigants should be performed to improve the balance of root canal disinfection with biological responses.


Micro- and Macrovascular Effects of Inflammation in Peripheral Artery Disease-Pathophysiology and Translational Therapeutic Approaches.
Inflammation has a critical role in the development and progression of atherosclerosis. On the molecular level, inflammatory pathways negatively impact endothelial barrier properties and thus, tissue homeostasis. Conformational changes and destruction of the glycocalyx further promote pro-inflammatory pathways also contributing to pro-coagulability and a prothrombotic state. In addition, changes in the extracellular matrix composition lead to (peri-)vascular remodelling and alterations of the vessel wall, e.g., aneurysm formation. Moreover, progressive fibrosis leads to reduced tissue perfusion due to loss of functional capillaries. The present review aims at discussing the molecular and clinical effects of inflammatory processes on the micro- and macrovasculature with a focus on peripheral artery disease.


The Variable Strength of Electrical Synapses.
In contrast to chemical synapses, less is known regarding the determinants of the strength of electrical synapses. New evidence from Szoboszlay et al. (2016) shows that the number of gap junctions is the dominant factor underlying the strength of electrical coupling between cerebellar interneurons.


[Effects of indomethacin on cellular resistance and synthesis of prostaglandins in epithelial cells isolated from rat gastric mucosa].
This study was done to test effects of indomethacin (IND) on cell damage and prostaglandin (PG) synthesis in mucosal epithelial cells isolated from rat stomach in vitro. IND caused the cell damage in a dose-related way at concentrations over 5 X 10(-4) M. This damage was inhibited by 16,16-dimethyl PGE2 (10(-6) M). IND abolished the synthesis of PGE2, PGI2, and TXA2 at the concentration of 10(-4) M at which IND alone did not cause cell damage. The cells treated with 10(-4) M IND were significantly susceptible to damage caused by 15% ethanol compared to the cells not treated with IND. 16,16-Dimethyl PGE2 also inhibited the damage caused by IND + ethanol. These results suggest that the IND-induced susceptibility of the cells to damage is related to PG deficiency.


Does correlation of cellulase gene expression and cellulolytic activity in the gut of termite suggest synergistic collaboration of cellulases?
Termites play an important role in degradation of dead plant materials in nature. Over the last century, many researchers have investigated the mechanisms of their lignocellulose digesting system. A recent publication by Zhou et al. (Zhou, X., Smith, J.A., Oi, F.M., Koehler, P.G., Bennett, G.W., Scharf, M.E., 2007. Correlation of cellulase gene expression and cellulolytic activity throughout the gut of the termite Reticulitermes flavipes. Gene 395, 29-39) dealt with the cellulolytic system of the flagellate-harboring termite R. flavipes and suggested "the presence of a single unified cellulose digestion system" in the termite, as an alternative hypothesis of a "dual (i.e. endogenous and symbiotic) cellulose digesting system" proposed by Nakashima et al. (Nakashima, K., Watanabe, H., Saitoh, H., Tokuda, G., Azuma, J.-I., 2002. Dual cellulose-digesting system of the wood-feeding termite, Coptotermes formosanus Shiraki. Insect Biochem. Mol. Biol. 32, 777-784). Here we show that their results actually support a dual cellulose digesting system rather than "a single unified cellulose digestion system". In addition, potential problems with their results are highlighted.


Methylphenidate reduces functional connectivity of nucleus accumbens in brain reward circuit.
Release of dopamine in the nucleus accumbens (NAcc) is essential for acute drug reward. The present study was designed to trace the reinforcing effect of dopamine release by measuring the functional connectivity (FC) between the NAcc and brain regions involved in a limbic cortical-subcortical circuit during a dopaminergic challenge. Twenty healthy volunteers received single doses of methylphenidate (40 mg) and placebo on separate test days according to a double-blind, cross-over study design. Resting state functional magnetic resonance imaging (fMRI) was measured between 1.5 and 2 h postdosing. FC between regions of interest (ROI) in the NAcc, the medial dorsal nucleus (MDN) of the thalamus and remote areas within the limbic circuit was explored. Methylphenidate significantly reduced FC between the NAcc and the basal ganglia (i.e., subthalamic nucleus and ventral pallidum (VP)), relative to placebo. Methylphenidate also decreased FC between the NAcc and the medial prefrontal cortex (mPFC) as well as the temporal cortex. Methylphenidate did not affect FC between MDN and the limbic circuit. It is concluded that methylphenidate directly affects the limbic reward circuit. Drug-induced changes in FC of the NAcc may serve as a useful marker of drug activity in in the brain reward circuit.


Granular cell tumour of tongue: A case report.
Granular cell tumour, also known as Abrikossoff tumour, is a relatively uncommon benign neoplasm, which is more commonly found in females in the 4th to 6th decades of life even though it can occur in all ages. It occurs in all areas of the body but about 45-65% of all lesions are reported in the head and neck region. Intraoral lesions represent about 70% of the granular cell tumours of the head and neck, and account for 1/3 of all cases affecting the whole body. Most of the intraoral lesions occur on the tongue, usually on the lateral aspect, followed by the buccal mucosa and hard palate. Although majority of granular cell tumours are benign, some are clinically aggressive and a few frankly malignant forms have been reported. Some benign lesions exhibit surface ulcerations and this clinical appearance, combined with the overlying pseudoepitheliomatous hyperplasia, seen histologically, may lead to misdiagnosis of malignancy if adequate biopsy material was not taken. A case of granular cell tumour which occurred on the midline area of the dorsum of the posterior 1/3 of the tongue is reported in a 20-year-old female patient. It is interesting because the patient was younger than the average age of occurrence and the tumour occurred in a similar site to that of a lingual thyroid.


Effects of metalloporphyrins on hemoglobin formation in mouse Friend virus-transformed erythroleukemia cells. Stimulation of heme biosynthesis by cobalt protoporphyrin.
Mouse Friend virus-transformed erythroleukemia cells in culture undergo erythroid differentiation when treated with a variety of compounds including iron protoporphyrin IX, i.e. hemin. Exogenous hemin is not only incorporated into hemoglobin in these cells but also stimulates heme biosynthesis (Granick, J. L., and Sassa, S. (1978) J. Biol. Chem. 253, 5402-5406). In this study, we examined whether metalloporphyrins other than hemin can also induce differentiation, and if so, whether they can also be incorporated into hemoglobin. Among eight metalloporphyrins examined in culture of these cells, i.e. Co, Mn, Cu, Mg, Ni, Zn, Sn, and Cd protoporphyrin IX, only Co protoporphyrin (10(-4) M) was found to significantly increase the biosynthesis of heme and hemoglobin. In contrast to hemin-mediated induction of erythroid differentiation, Co protoporphyrin was not incorporated into hemoglobin in Friend cells. These data indicate that Co protoporphyrin induces the formation of heme and hemoglobin in Friend cells and that these increases are due to the enhancement of heme biosynthetic activity.


Film thickness and flow properties of resin-based cements at different temperatures.
For a luting agent to allow complete seating of prosthetic restorations, it must obtain an appropriate flow rate maintaining a minimum film thickness. The performance of recently introduced luting agents in this regard has not been evaluated. To measure and compare the film thickness and flow properties of seven resin-containing luting cements at different temperatures (37°C, 25°C and10°C). Specimens were prepared from five resin luting cements; seT (SDI), Panavia F (Kuraray), Varioloink II (Ivoclar), Maxcem (Kerr), Nexus2 (Kerr) and two resin-modified glass-ionomer luting cements (RM-GICs); GC Fuji Plus (GC Corporation), and RelyX Luting 2 (3 M/ESPE). The film thickness and flow rate of each cement (n=15) was determined using the test described in ISO at three different temperatures. There was a linear correlation between film thickness and flow rate for most of the materials. Cooling increased fluidity of almost all materials while the effect of temperature on film thickness was material dependent. At 37°C, all products revealed a film thickness of less than 25µm except for GC Fuji Plus. At 25°C, all cements produced a film thickness of less than 27 µm except for seT. At 10°C, apart from seT and Rely X Luting 2, the remaining cements showed a film thickness smaller than 20 µm. Cooling increased fluidity of almost all materials, however. the film thickness did not exceed 35 µm in either condition, in spite of the lowest film thickness being demonstrated at the lowest temperature.


Dexmedetomidine versus propofol for operator-directed nurse-administered procedural sedation during catheter ablation of atrial fibrillation: A randomized controlled study.
Operator-directed nurse-administered (ODNA) sedation with propofol (PRO) is the preferred sedation technique for catheter ablation of atrial fibrillation (AF) in many centers. The purpose of this study was to investigate whether dexmedetomidine (DEX), an α2-adrenergic receptor agonist, is superior to propofol. We randomized 160 consecutive patients undergoing first AF ablation to ODNA sedation by DEX (DEX group) vs PRO (PRO group), according to a standardized protocol. Patients were unaware of treatment allocation. The primary endpoint was a composite of inefficient sedation, termination/change of sedation protocol or procedure abortion, hypercapnia (transcutaneous CO2 >55 mm Hg), hypoxemia (SpO2 <90%) or intubation, prolonged hypotension (systolic blood pressure <80 mm Hg), and sustained bradycardia necessitating cardiac pacing. Secondary endpoints were the components of the primary endpoint and patient satisfaction with procedural sedation, as assessed by a standardized questionnaire given the day after ablation. The primary endpoint occurred in 15 DEX group and 25 PRO group patients (19% vs 31%; P = .068). Hypercapnia was significantly more frequent in PRO group patients (29% vs 10%; P = .003). There was no significant difference for the other components of the primary endpoint, and no procedure was aborted. Patient satisfaction was significantly better among PRO group patients (visual analogue scale 0-100; median 100 in PRO group vs median 93 in DEX group; P <.001). Efficacy of ODNA sedation with DEX was not different from that with PRO. Hypercapnia occurs less frequently with DEX, but patient satisfaction is better with PRO sedation. In selected patients, DEX may be used as an alternative to PRO for ODNA sedation during AF ablation.


Definite stent thrombosis among Malaysian population: predictors and insights of mechanisms from intracoronary imaging.
Stent thrombosis (ST) is an uncommon, but significant complication following angioplasty. We aimed to examine the predictors, clinical outcomes and mechanism of definite ST cases among patients who underwent percutaneous coronary intervention (PCI). This was a retrospective observational registry of 14,935 patients from the year 2011 till 2015. Clinical characteristics, clinical outcome and intracoronary imaging data were recorded in all the patients. The SPSS Statistic version 24 was used for statistical analysis. The Cox regression hazard model was used to report calculate the hazard ratio (HR) with a 95% confidence interval (95%CI). Independent predictors of ST were identified by univariate logistic regression analysis. Variables that showed a statistically significant effect in univariate analyses were entered in a multivariate Cox proportional hazards model. A p-value<0.05 was regarded as significant. The incidence of definite ST was 0.25% (37 out of 14935 patients). 75% of ST group patients presented with ST elevation myocardial infarction (75% vs. 19.8%, p<0.01). There was higher mortality among patients with ST when compared to the group without ST (Hazard Ratio, HR=10.69, 95%CI: 1.13, 100). Two independent predictors of ST were 1) previous history of acute myocardial infarction (HR=2.36, 95%CI: 1.19, 4.70) and 2) PCI in the context of acute coronary syndrome when compared to elective PCI (HR=37, 95%CI: 15.7, 91.5). Examination of 19 ST cases with intracoronary imaging identified nine cases (47%) of underexpanded stents and five cases (26%) of malopposition of stents. ST is associated with high mortality. PCI in acute coronary syndrome setting and a previous history of acute myocardial infarction were significant predictors for ST. Intracoronary imaging identified stent underexpansion and malopposition as common reasons for ST. In cases where the risk of ST is high, the use of intracoronary imaging guided PCI is recommended.