Pathological lesions in the right and left porcine lung: evaluation of an alternative method for scoring pneumonic lesions based on right lung examination.
Plucks from 2,372 sows, gilts and slaughterswine (originating from 3 independent sources) were evaluated for presence and severeness of 6 different pathological entities. Results were calculated for each of the lungs separately and compared to the combined findings of both lungs. Both qualitatively (comparing relative test sensitivities) and quantitatively (comparing lung scores), the right lung results were more optimal than the left lung outcomes and relatively consistent among the 3 data sets. The over-all right lung relative sensitivities for the detection of catarrhal pneumonia or chronic pleuritis were 81.3% and 72.0%, respectively. The over-all differences in the right minus left lung scores for the 2 lesions were +13.0% and +9.0%, respectively. The necessary sample size of right lungs to detect at least 1 lung with catarrhal pneumonia or chronic pleuritis is presented along with a method for calculating confidence intervals.


Biochar loaded with CoFe2O4 enhances the formation of high-valent Fe(IV) and Co(IV) and oxygen vacancy in the peracetic acid activation system for enhanced antibiotic degradation.
Corn straw and sludge-derived biochar composite (BC) loaded with CoFe2O4 was successfully prepared to activate peracetic acid (PAA) for efficient degradation of tetracycline hydrochloride (TCH). Within 60 s, 96 % TCH removal efficiency was achieved through a non-free radical degradation pathway, primarily driven by singlet oxygen (1O2). The mechanism involves the electron-rich groups on the biochar surface, which facilitate the cleavage of the PAA OO bond to generate •O2-/1O2 and provide electrons to induce the formation of high-valent Fe(IV) and Co(IV). The oxygen vacancies on the surface of the CoFe2O4-loaded biochar composite (CFB-2) contribute partially to 1O2 production through their transformation into a metastable intermediate with dissolved oxygen. Moreover, elevated temperatures further enhance PAA activation by CFB-2, leading to increased reactive oxygen species (ROS) production through PAA decomposition, thereby promoting TCH removal. This study offers new insights into the catalysis of metal-loaded biochar for efficient TCH degradation via non-free radical generation.


Human dendritic cell subsets in the glioblastoma-associated microenvironment.
Glioblastoma (GBM) is the most aggressive type of glioma (Grade IV). The presence of cytotoxic T lymphocyte (CTLs) has been associated with improved outcomes in patients with GBM, and it is believed that the activation of CTLs by dendritic cells may play a critical role in controlling the growth of GBM. DCs are professional antigen-presenting cells (APC) that orchestrate innate and adaptive anti-GBM immunity. DCs can subsequently differentiate into plasmacytoid DCs (pDC), conventional DC1 (cDC1), conventional (cDC2), and monocyte-derived DCs (moDC) depending on environmental exposure. The different subsets of DCs exhibit varying functional capabilities in antigen presentation and T cell activation in producing an antitumor response. In this review, we focus on recent studies describing the phenotypic and functional characteristics of DC subsets in humans and their respective antitumor immunity and immunotolerance roles in the GBM-associated microenvironment. The critical components of crosstalk between DC subsets that contribute significantly to GBM-specific immune responses are also highlighted in this review with reference to the latest literature. Since DCs could be prime targets for therapeutic intervention, it is worth summarizing the relevance of DC subsets with respect to GBM-associated immunologic tolerance and their therapeutic potential.


Review of the Ambrysus stali La Rivers species complex (Heteroptera: Nepomorpha: Naucoridae) with the description of a new species from Mesoamerica.
The Neotropical Ambrysus stali La Rivers species complex is reviewed and includes A. bifidus La Rivers & Nieser, A. scolius La Rivers, A. stali La Rivers, and A. tricuspis La Rivers. Ambrysus oblongulus Montandon is removed as a member of this complex. Features uniting these species are related to male genitalia and associated structures. Ambrysus maya n. sp. is the fifth species in the complex and is described from Belize, Guatemala, and Mexico based on specimens from recent collecting and museum collections.


Conformation-sensitive antibody reveals an altered cytosolic PAS/CNBh assembly during hERG channel gating.
The human ERG (hERG) K+ channel has a crucial function in cardiac repolarization, and mutations or channel block can give rise to long QT syndrome and catastrophic ventricular arrhythmias. The cytosolic assembly formed by the Per-Arnt-Sim (PAS) and cyclic nucleotide binding homology (CNBh) domains is the defining structural feature of hERG and related KCNH channels. However, the molecular role of these two domains in channel gating remains unclear. We have previously shown that single-chain variable fragment (scFv) antibodies can modulate hERG function by binding to the PAS domain. Here, we mapped the scFv2.12 epitope to a site overlapping with the PAS/CNBh domain interface using NMR spectroscopy and mutagenesis and show that scFv binding in vitro and in the cell is incompatible with the PAS interaction with CNBh. By generating a fluorescently labeled scFv2.12, we demonstrate that association with the full-length hERG channel is state dependent. We detect Förster resonance energy transfer (FRET) with scFv2.12 when the channel gate is open but not when it is closed. In addition, state dependence of scFv2.12 FRET signal disappears when the R56Q mutation, known to destabilize the PAS-CNBh interaction, is introduced in the channel. Altogether, these data are consistent with an extensive structural alteration of the PAS/CNBh assembly when the cytosolic gate opens, likely favoring PAS domain dissociation from the CNBh domain.


Purification and characterization of Bordetella bronchiseptica dermonecrotic toxin.
Dermonecrotic toxin produced by Bordetella bronchiseptica was purified by chromatography on DEAE Toyopearl 650M and on Bio-Gel HTP, gel filtration on Sephadex G-200, and subsequent chromatography on Bio-Gel HTP and on SP Toyopearl 650M. The purified toxin was homogeneous by sodium dodecyl sulfate polyacrylamide gel electrophoresis and high performance liquid chromatography. There was a 90-fold increase in the dermonecrotic titer per mg protein in guinea pigs and the recovery of activity was 17.6% of that of the original cell extract. The purified toxin is a single-chain protein with a molecular weight of 145,000 and an isolelectric point of 6.3-6.7. Its minimal necrotizing dose is approximately 0.4 ng. It was completely inactivated by heating for 20 min at 56 degrees C. It contained no endotoxin, carbohydrates, nucleic acids, or hemagglutinins.


Light-induced maculopathy and cystoid macular edema.
We present two patients with paramacular burns induced by the operative light microscope. In one case there was associated cystoid macular edema. Of the 34 total reported cases of paramacular burns, there have been only two cases of cystoid macular edema. Thus, although the total number of reported cases of light-induced maculopathy is small, this disorder does not appear to predispose to cystoid macular edema. Loss of visual acuity is mainly caused by the proximity of the burn to the fovea.


Assessment of the clinical usefulness of the 'Queenan' chart versus the 'Liley' chart in predicting severity of rhesus iso-immunization.
In 1961 Liley developed a chart of changing amniotic fluid bilirubin levels (delta OD450) and gestation, with three zones delineating the severity of rhesus disease. This chart ranged from 27 to 40 weeks and was found to be clinically useful. Extrapolating the use of the Liley chart to earlier gestations however, was unsuccessful. Currently, cordocentesis is the only reliable means of assessing the fetal condition accurately prior to 27 weeks. In 1993, Queenan proposed a chart of delta OD450 from 14 to 40 weeks, with four zones to guide management. The aim of the current study is to assess the clinical usefulness of the 'Queenan' chart vs. the 'Liley' chart. There were 35 pregnancies affected by rhesus disease between 1990 and 1997 at the Mater Mothers' Hospital, Brisbane. The quantitative anti-D and delta OD450 levels obtained before intra-uterine transfusions were recorded. Each sample was labelled with the fetal condition at the time the sample was taken. Of the 72 delta OD450 samples, 36 (50 per cent) were performed before 27 weeks, and these included all four of the severely affected samples and 11 of the 13 moderately affected samples. The sensitivity of the Queenan chart in predicting the severely affected pregnancies was 100 per cent, with specificity of 79.4 per cent, positive predictive value of 22.2 per cent and negative predictive value of 100 per cent. For prediction of moderate/severely affected pregnancies, the sensitivity was 83.3 per cent, with specificity of 94.4 per cent, positive predictive value of 83.3 per cent and negative predictive value of 96.3 per cent. In conclusion, an delta OD450 chart which includes gestations less than 27 weeks is necessary with our changing caseload of rhesus iso-immunized patients, where severely affected pregnancies seemed to occur early and intervention even in moderately affected pregnancies seemed appropriate. We found that the Queenan chart is a suitable alternative to the Liley chart.


Scavenging microplastics and heavy metals from water using jujube waste-derived biochar in fixed-bed column trials.
Extensive production and utilization of plastic products have resulted in the generation of microplastics (MPs), subsequently polluting the environment. The efficiency of biochars (BCs) derived from jujube (Ziziphus jujube L.) biomass (300 °C and 700 °C) for nylon (NYL) and polyethylene (PE) removal from contaminated water was explored in fixed-bed column trials. The optimum pH for the removal of both MPs was found 7. Both of the produced biochars demonstrated >99% removal of the MPs, while the sand filter exhibited a maximum of 78% removal of MPs. BC produced at 700 °C (BC700) showed 33-fold higher MPs retention, while BC produced at 300 °C (BC300) exhibited 20-fold higher retention, as compared to sand filters, indicating the higher efficiency of BC produced at higher pyrolysis temperature. Entrapment into the pores, entanglement with flaky structures of the BCs, and electrostatics interactions were the major mechanism for MPs retention in BCs. The efficiency of MPs-amended BCs was further explored for the removal of Pb(II) and Cd(II) in fixed-bed column trials. BC700 amended with PE and NYL exhibited the highest 50% breakthrough time (2114.23 and 2024.61 min, respectively, for Pb(II) removal and 2107.92 and 1965.19 min, respectively, for Cd(II) removal), as compared to sand filters (38.07 and 60.49 min for Pb(II) and Cd(II) removal, respectively). Thomas model predicted highest adsorption capacity was exhibited by BC700 amended with PE (584.34 and 552.80 mg g-1, for Pb(II) and Cd(II) removal, respectively), followed by BC700 amended with NYL (557.65 and 210.59 mg g-1 for Pb(II) and Cd(II) removal, respectively). Therefore, jujube waste-derived BCs could be used as efficient adsorbents to remove PE and NYL from contaminated water, while MPs-loaded BCs can further be utilized for higher adsorption of Pb(II) and Cd(II) from contaminated aqueous media. These findings suggest that BC could be used as an efficient adsorbent to remove the co-existing MPs-metals ions from the environment on a sustainable basis.


Is there a long-term health legacy of required physical education?
This article documents current literature on the potential long-term effects of school physical education on various outcomes in adults. A first observation is the rarity of publications on this topic. Nevertheless, the available literature suggests that physical education should offer a variety of either lifelong physical activities or sports in order to reach children with differing interests. In some children, competitive sports may generate a lifelong interest in physical activity, but most children may be better socialized by lifelong physical activities. In order to expose children to such a wide choice of physical activities, more time should be allocated to physical education instruction. Substantial further research is needed to increase our understanding of the long-term impact of school physical education programmes.


AIE-enabled transfection-free identification and isolation of viable cell subpopulations differing in the level of autophagy.
3-MA, 3-methyladenine; AIE, aggregation-induced emission; AIEgens, aggregation-induced emission luminogens; ATG5, autophagy related 5; BMDM, bone marrow-derived macrophage; CQ, chloroquine; DiD, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine perchlorate; DiO, 3,3'-dioctadecyloxacarbocyanine perchlorate; DMSO, dimethyl sulfoxide; d-THP-1, differentiated THP-1; FACS, fluorescence activated cell sorting; FBS, fetal bovine serum; FCCP, carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone; GABARAP, GABA type A receptor-associated protein; GFP, green fluorescent protein; HBSS, Hanks' balanced salt solution; HPLC, high-performance liquid chromatography; HRP, horseradish peroxidase; IL1B, interleukin 1 beta; KT, an AIE probe composed of a cell-penetrating peptide and an AIEgen tetraphenyl ethylene; LC3-II, lipidated LC3; LDH, lactate dehydrogenase; LIR, LC3-interacting region; LKR, engineered molecular probe composed of an LC3-interacting peptide, a cell-penetrating peptide and a non-AIE fluorescent molecule rhodamine; LKT, engineered molecular probe composed of an LC3-interacting peptide, a cell-penetrating peptide and an AIEgen tetraphenyl ethylene; LPS, lipopolysaccharide; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MEF, mouse embryonic fibroblast; mRFP, monomeric red fluorescent protein; NHS, N-hydroxysuccinimide; NLRP3, NLR family pyrin domain containing 3; PBS, phosphate-buffered saline; PCC, pearson's correlation coefficient; PL, photoluminescence; PMA, phorbol 12-myristate 13-acetate; RAP, rapamycin; RIM, restriction of intramolecular motions; s.e.m., standard error of the mean; SPR, surface plasmon resonance; SQSTM1/p62, sequestosome 1; TAX1BP1, Tax1 binding protein 1; TPE, tetraphenylethylene; TPE-yne, 1-(4-ethynylphenyl)-1,2,2-triphenylethene; Tre, trehalose; u-THP-1: undifferentiated THP-1; UV-Vis, ultraviolet visible.


Modification of the centerline method for assessment of echocardiographic wall thickening and motion: a comparison with areas of risk.
The ability of the centerline method to discern regional myocardial risk area was evaluated using two-dimensional echocardiographic measurements and coronary artery occlusion in 16 open chest, anesthetized dogs. The centerline method was modified to allow determination of both wall thickening and wall motion at control and during coronary artery occlusion. End-systolic and end-diastolic echocardiographic images were analyzed at 100 equally spaced points around the centerline of the short-axis view of the left ventricle to determine shortening and thickening abnormalities. In vivo risk regions were assessed by microsphere injection during occlusion, and autoradiographic analysis revealed a mean (+/- SD) circumferential risk area of 37.5 +/- 7.7%. Abnormal function was established by three criteria on the basis of the control values for both fractional shortening and wall thickening: 1) less than 2 SD, 2) less than 95% tolerance limits, and 3) dyskinesia. The criterion of less than 2 SD estimated a risk area of 45.9 +/- 16.7% for fractional shortening and 37.2 +/- 16.8% for wall thickening. Although neither value was significantly different from the actual mean value for the risk region, the results for fractional shortening were greater than for wall thickening (p less than 0.01). The less than 95% tolerance limit method significantly underestimated risk area for both shortening (25.6 +/- 15.1%, p less than 0.05) and thickening (19.1 +/- 12.7%, p less than 0.001), as did analysis by dyskinesia (13.1 +/- 12.1% for shortening, p less than 0.001; 20.6 +/- 12.1% for thickening, p less than 0.01). Thus, modification of the centerline method allowed determination of both fractional shortening and wall thickening from echocardiographic images.(ABSTRACT TRUNCATED AT 250 WORDS)


Do hospitals that participate in COVID-19 research differ from non-trial hospitals? A cross-sectional study of US hospitals.
To compare hospitals that did and did not participate in clinical trials evaluating potential inpatient COVID-19 therapeutics. We conducted a cross-sectional study of hospitals participating in trials that were registered on clinicaltrials.gov between April and August 2020. Using the 2019 RAND Hospital Dataset and 2019 American Community Survey, we used logistic regression modeling to compare hospital-level traits including demographic features between trial and non-trial hospitals. We included 488 hospitals that were participating in 298 interventional trials and 4232 non-participating hospitals. After controlling for demographic and other hospital traits, we found that teaching status (OR 2.11, 95% CI 1.52-2.95), higher patient acuity (OR 7.48, 4.39, 13.1), and location in the Northeast (OR 1.83, 95% CI 1.18, 2.85) and in wealthier counties (OR: 1.32, 95% CI 1.16-1.51) were associated with increased odds of trial participation, while being in counties with more White residents was associated with reduced odds (OR 0.98, 95% CI 0.98-0.99). Hospitals participating and not participating in COVID-19 inpatient treatment clinical trials differed in many ways, resulting in important implications for the generalizability of trial data.


Predicting prosthetic use in elderly patients after major lower limb amputation.
The main determinants of prosthetic use known from literature apply to the younger patient with lower limb amputation. Studies aimed at identifying determinants of outcome of lower limb amputation in elderly patients with multimorbidity that rehabilitate in skilled nursing facilities (SNFs) are scarce. To predict prosthetic use and physical mobility in geriatric patients admitted to SNFs for rehabilitation after lower limb amputation and the impact of multimorbidity. Prospective design. Univariate and multivariate logistic and linear regression analyses were used to identify determinants that were independently related to prosthetic use and the timed-up-and-go test (TUG test). Of 55 eligible patients, 38 had complete assessments on admission and at discharge. Fifty per cent was provided with a prosthesis. Multimorbidity was present in 53% of the patients. Being able to ambulate independently, and having a transtibial amputation (rather than a higher level of amputation), without phantom pain determined prosthetic use (R(2)=56%), while cognitive abilities, low amputation level, and pre-operative functional abilities were independently associated with the TUG test (R(2)=82%). Elderly patients referred to an SNF for prosthetic training have a high probability of using a prosthesis when having an independent ambulation after transtibial amputation, without phantom pain. These patients should be considered for prosthetic training.


Regional distribution of amino acids in Friedreich's ataxia brains.
The distribution of amino acids in two Friedreich's ataxia brains is compared to 4 control brains. Glutamate and GABA were decreased in the cerebellar hemispheres and/or in the vermis. Taurine concentrations were uniformly elevated throughout the areas studied. Taurine/glutamate and taurine/GABA ratios were consistently elevated in Friedreich's ataxia brains, whereas glutamate/glutamine ratios were consistently decreased (with normal glutamine concentrations).


Mitochondrial uncoupling protein 2 (UCP2) gene polymorphism - 866 G/A in the promoter region is associated with type 2 diabetes mellitus among Kashmiri population of Northern India.
The study aimed to evaluate the association of UCP2 gene polymorphism - 866 G/A and its expression with diabetes predisposition in the North Indian population. The study involved 850 subjects, including 425 each T2DM and control subjects. The serum metabolic and clinical parameters were estimated using standard protocols. The PCR-RFLP based genotyping was performed to determine UCP2 gene polymorphism, while the expression was measured by real-time quantitative PCR. The genotypic and allelic frequencies showed a significant difference in cases compared to controls (p < 0.05). The diabetes patients had a 4.2-fold decrease in UCP2 gene expression. The expression was 29.8 and 8.4 fold lower in diabetes patients with homozygous (AA) and heterozygous (GA) mutation at - 866 locus of UCP2 nucleotide sequence, respectively. When categorized according to age and BMI, the T2DM subjects with age ≥ 50 and BMI ≥ 25 had a 5.53 and 8.2-fold decrease in UCP2 expression, respectively. The diabetes subjects with homozygous and heterozygous mutation demonstrated a pathological increase in serum metabolic and clinical parameters, which corroborated with UCP2 gene expression, indicating a strong association between the two. Intriguingly, we did not find any association between - 866 G/A polymorphism of UCP2 with serum insulin levels. Our investigation is the first among the studies conducted in Jammu and Kashmir to work on adipose tissue and UCP2 gene polymorphism. The association of - 866 G/A SNP of the UCP2 gene with its expression in diabetes patients appears to be an important genetic determinant in the progression of T2DM. Moreover, age ≥ 50 years and BMI ≥ 25 could be considered risk factors for developing T2DM in the studied population.


Ventricular fibrillation and defibrillation thresholds in sheep and dogs.
Ventricular defibrillation studies normally use dogs rather than other large species. To investigate the suitability of sheep, which are often cheaper and more readily available, we compared ventricular fibrillation and defibrillation thresholds (VFT, DFT) in sheep and dogs. A total of 12 sheep (31 +/- 5 kg) and six dogs (19 +/- 1 kg) were anesthetised with halothane. Fibrillation was induced via epicardial pacing leads, using a 1 s 50 Hz pulse. Biphasic defibrillation shocks were delivered across epicardial patches. Voltage-response curves for both fibrillation and defibrillation were generated. Logistic regression analysis was used to determine 50 and 90% probability of success for fibrillation induction and defibrillation. VFT was similar in sheep and dogs. DFT at 50% probability of success was significantly higher in sheep (369 +/- 14 V) than in dogs (299 +/- 31 V, P < 0.04) but within each species there was no correlation between heart weight and DFT. After defibrillation sheep took longer to return to sinus rhythm than dogs and electro-mechanical dissociation was observed in sheep, but not in dogs. Thus, sheep may not be an ideal model for ventricular defibrillation research but further studies of the intrinsic differences between sheep and dogs may provide insights into basic mechanisms of defibrillation.


Human isolated bronchial muscle preparations from asthmatic patients: effects of indomethacin and contractile agonists.
Airway reactivity to histamine was determined in a group of non-asthmatic and asthmatic patients prior to thoracotomy. The latter group was more reactive to histamine provocation than the former (PC40: 28.40 +/- 6.27 mg/ml and 1.15 +/- 0.19 mg/ml, respectively). Subsequent to the surgical intervention, isolated human bronchial muscle preparations were obtained from both groups (15 non-asthmatic and 5 asthmatic subjects). Histamine concentration-effect curves were generated both in the absence and in the presence of indomethacin (1.7 microM; 30 min). Neither the basal tone nor the histamine response and sensitivity of the preparations were altered by the antiinflammatory drug. In bronchial preparations from one asthmatic subject, indomethacin significantly reduced the prostaglandin production during histamine contraction. Prostaglandin E2 and F2 alpha contracted isolated human bronchial muscle preparations from these asthmatic individuals. These data suggest that endogenous prostaglandins may not regulate the contractile response to histamine in vitro.


Thermodynamic and phase characterization of phosphatidylethanolamine and ganglioside GD1a mixtures.
By employing diphenylhexatriene steady-state fluorescence anisotropy, pyrenedecanoic acid excimer formation, and high sensitivity scanning calorimetry we have demonstrated that the liposomes containing phosphatidylethanolamine (PE) and various mole fractions of ganglioside GD1a had a gel-liquid crystalline phase transition between 15 and 25 degrees C. Calorimetric measurements indicated that these phase transitions were broad and centered between 17 and 21 degrees C. The enthalpy change of the transition was linearly dependent on the ganglioside concentration up to 10.0 mol% and plateaued between 11.4-16.2 mol%. The high enthalpy change (37 kcal/mol of GD1a added into the PE bilayer) indicates the existence of PE-GD1a complex structure in the liposomal membrane. It is proposed that semi-fluid domains containing six PE and one ganglioside molecule are present in the PE-GD1a membranes at temperatures above gel-liquid crystalline phase transition. The Sendai virus induced leakage of PE-GD1a liposomes has been investigated by using an entrapped, self-quenching fluorescent dye, calcein. The leakage rate was dependent on the mole fraction of ganglioside GD1a and was maximal at 6.3 mol%. Arrhenius plots of the leakage rates showed breaks in the 20-25 degrees C temperature range, which correspond to the gel-liquid crystalline phase transition of the target liposomes. These data suggest that the rate of Sendai virus-induced leakage can be regulated via fluidity modulation by changing the PE to GD1a ratio at constant temperatures.


Oxidative stress is involved in Dasatinib-induced apoptosis in rat primary hepatocytes.
Dasatinib, a multitargeted inhibitor of BCR-ABL and SRC kinases, exhibits antitumor activity and extends the survival of patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). However, some patients suffer from hepatotoxicity, which occurs through an unknown mechanism. In the present study, we found that Dasatinib could induce hepatotoxicity both in vitro and in vivo. Dasatinib reduced the cell viability of rat primary hepatocytes, induced the release of alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) in vitro, and triggered the ballooning degeneration of hepatocytes in Sprague-Dawley rats in vivo. Apoptotic markers (chromatin condensation, cleaved caspase-3 and cleaved PARP) were detected to indicate that the injury induced by Dasatinib in hepatocytes in vitro was mediated by apoptosis. This result was further validated in vivo using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays. Here we found that Dasatinib dramatically increased the level of reactive oxygen species (ROS) in hepatocytes, reduced the intracellular glutathione (GSH) content, attenuated the activity of superoxide dismutase (SOD), generated malondialdehyde (MDA), a product of lipid peroxidation, decreased the mitochondrial membrane potential, and activated nuclear factor erythroid 2-related factor 2 (Nrf2) and mitogen-activated protein kinases (MAPK) related to oxidative stress and survival. These results confirm that oxidative stress plays a pivotal role in Dasatinib-mediated hepatotoxicity. N-acetylcysteine (NAC), a typical antioxidant, can scavenge free radicals, attenuate oxidative stress, and protect hepatocytes against Dasatinib-induced injury. Thus, relieving oxidative stress is a viable strategy for reducing Dasatinib-induced hepatotoxicity.


Nitric oxide protects Cu,Zn-superoxide dismutase from hydrogen peroxide-induced inactivation.
Reaction of Cu,Zn-superoxide dismutase (SOD1) and hydrogen peroxide generates a putative oxidant SOD-Cu2+-.OH that can inactivate the enzyme and oxidize 5,5'-dimethyl-1-pyrroline-N-oxide (DMPO) to DMPO-.OH. In the presence of nitric oxide (.NO), the SOD1/H2O2 system is known to produce peroxynitrite (ONOO-). In contrast to the proposed cytotoxicity of .NO conferred by ONOO-, we report here a protective role of .NO in the H2O2-induced inactivation of SODI. In a dose-dependent manner, .NO suppressed formation of DMPO-.OH and inactivation of the enzyme. Fragmentation of the enzyme was not affected by .NO. Bicarbonate retarded formation of ONOO-, suggesting that .NO competes with bicarbonate for the oxidant SOD-Cu2+-.OH. We propose that .NO protects SOD1 from H2O2-induced inactivation by reducing SOD-Cu2+.OH to the active SOD-Cu2+ with concomitant production of NO+ which reacts with H2O2 to give ONOO-.


Food-mediated exposure of Hofmeister ions in Oryza sativa (Rice) from selected CKDu endemic regions in Sri Lanka.
The objectives of this study were to determine selected Hofmeister anions and cations that are important for kidney health, in raw rice samples from selected Chronic Kidney Disease of unknown etiology (CKDu) endemic and non-endemic areas in Sri Lanka and their intake. The anions and cations were analyzed by Ion Chromatography and Microwave Plasma Atomic Emission Spectrometry (MP-AES), respectively, after alkaline and acid digestion in thirty raw rice samples each from CKDu endemic and non-endemic areas, and the dietary intake was estimated. The mean concentrations of fluoride (F-), chloride (Cl-), phosphate (PO43-), sulfate (SO42-), sodium (Na+), magnesium (Mg2+), potassium (K+), and calcium (Ca2+) in raw rice in CKDu endemic areas were 53.317, 1515.3, 2799.6, 2704.9, 30.603, 300.76, 1001.3, and 90.075 mg/kg, respectively. The mean concentration of the anions and cations in raw rice from CKDu non-endemic areas were 22.850, 947.52, 4418.7, 6080.2, 23.862, 364.45, 955.78, and 96.780 mg/kg, respectively. Significantly higher differences (p < 0.05) were reported in the mean concentration of F-, Cl-, and Na+ in raw rice from CKDu endemic areas in comparison with the samples from non-endemic areas. The aggregated estimated daily intake (EDI) and cumulative EDI of F- via consumption of cooked non-traditional samba rice from CKDu endemic areas for adults were the highest (0.155 and 0.172 mg/kg bw/d, respectively), which were higher than the recommended tolerable upper intake value (0.15-0.2 mg/kg bw/d). In contrast, the traditional rice from CKDu non-endemic areas for adolescents, reported the lowest values (0.0210 and 0.0470 mg/kg bw/d, respectively). Adults who consume non-traditional samba rice from CKDu endemic areas were at health risk, while children were the most vulnerable group due to their low body weight. These results indicate that the consumption of rice rich in Hofmeister ions may contribute to the total intake and act as risk factors to negatively affect weak kidneys in CKDu endemic areas. Further research to analyze Hofmeister ions in cooked rice and rice from different countries is recommended.


IRAK4 inhibitor mitigates joint inflammation by rebalancing metabolism malfunction in RA macrophages and fibroblasts.
Recent studies show a connection between glycolysis and inflammatory response in rheumatoid arthritis (RA) macrophages (MΦs) and fibroblasts (FLS). Yet, it is unclear which pathways could be targeted to rebalance RA MΦs and FLS metabolic reprogramming. To identify novel targets that could normalize RA metabolic reprogramming, TLR7-mediated immunometabolism was characterized in RA MΦs, FLS and experimental arthritis. We uncovered that GLUT1, HIF1α, cMYC, LDHA and lactate were responsible for the TLR7-potentiated metabolic rewiring in RA MΦs and FLS, which was negated by IRAK4i. While in RA FLS, HK2 was uniquely expanded by TLR7 and negated by IRAK4i. Conversely, TLR7-driven hypermetabolism, non-oxidative PPP (CARKL) and oxidative phosphorylation (PPARγ) were narrowly dysregulated in TLR7-activated RA MΦs and FLS and was reversed by IRAK4i. Consistently, IRAK4i therapy disrupted arthritis mediated by miR-Let7b/TLR7 along with impairing a broad-range of glycolytic intermediates, GLUT1, HIF1α, cMYC, HK2, PFKFB3, PKM2, PDK1 and RAPTOR. Notably, inhibition of the mutually upregulated glycolytic metabolites, HIF1α and cMYC, was capable of mitigating TLR7-induced inflammatory imprint in RA MΦs and FLS. In keeping with IRAK4i, treatment with HIF1i and cMYCi intercepted TLR7-enhanced IRF5 and IRF7 in RA MΦs, distinct from RA FLS. Interestingly, in RA MΦs and FLS, IRAK4i counteracted TLR7-induced CARKL reduction in line with HIF1i. Whereas, cMYCi in concordance with IRAK4i, overturned oxidative phosphorylation via PPARγ in TLR7-activated RA MΦs and FLS. The blockade of IRAK4 and its interconnected intermediates can rebalance the metabolic malfunction by obstructing glycolytic and inflammatory phenotypes in RA MΦs and FLS.


Problems in the detection of carriers of hemophilia A: the influence of stress and thrombin.
After exposure to stress, factor VIII coagulant activity and factor VIII antigen were determined in healthy volunteers for about 3 days. Three out of four volunteers at different time showed results resembling a carrier state. In vitro incubation of plasma with thrombin in decreasing concentrations showed increased factor VIII coagulant activity, although no fibrin clot or fibrin monomers were formed. The concentration of factor VIII antigen remained constant. The action of thrombin can explain the misclassification of known carriers.


Self-Reported Severity, Characteristics, and Functional Limitations of Chemotherapy-Induced Peripheral Neuropathy.
The early identification of chemotherapy-induced peripheral neuropathy (CIPN) (e.g., numbness or tingling in the fingers or toes) is important due to its frequency and the few effective treatment options available. The identification of common patient-reported CIPN characteristics and associated functional limitations may help to facilitate patient-clinician discussions of CIPN in practice. To quantify the severity, duration, location, characteristics, and associated functional limitations of chemotherapy-induced peripheral neuropathy (CIPN) in patients receiving neurotoxic chemotherapy. Exploratory secondary analysis of a prospective, two-phase study SETTING: Breast, gastrointestinal, and multiple myeloma clinics at Dana-Farber Cancer Institute. 142 individuals who planned to receive at least three more cycles of neurotoxic chemotherapy after consent. Participants self-reported CIPN using standardized measures (i.e., PRO-CTCAE™ Numbness and Tingling Items or 0-10 numerical rating scale of worst CIPN pain intensity) and/or study team generated follow up questions about CIPN location, duration, characteristics, and functional limitations prior to three consecutive clinic visits (T1, T2, T3). Participants' responses to the CIPN self-report questionnaires were described by chemotherapy type and age. Over approximately 36.5 days (T1-T3), the percentage of participants reporting at least mild CIPN increased from 59.3% to 71%. At T3, patients with non-painful (n = 98) or painful neuropathy (n = 34) frequently reported symptoms in the fingers (non-painful = 83.5%, painful = 76.5%) or toes (non-painful = 49.5%, painful = 41.2%) and characterized symptoms as numbness (non-painful = 54.1%, painful = 50%) or tingling (non-painful = 68.4%, painful = 82.4%). Self-reported CIPN functional limitations (n = 55) included difficulties with buttoning a shirt (38.2%) or walking (25.5%). Paclitaxel-related CIPN (n = 33) was frequently characterized as "continuous" (30.3%), whereas oxaliplatin-related CIPN (n = 51) was frequently characterized as "intermittent" (41.2%). Young adults (15-39 years old, n = 15) frequently reported moderate-severe non-painful CIPN (46.7%), painful CIPN (40%), and CIPN interference (33.3%). Consistent with qualitative research, participants frequently described CIPN as numbness and/or tingling in the fingers and/or toes.


Laboratory-acquired skin infections in a clinical microbiologist: Is wearing only gloves really safe?
Laboratory-acquired infection is one of the leading occupational health hazards. On a laboratory worker's hands, carbuncles occurred. Staphylococcus aureus was isolated from pus samples of the carbuncles, with the same pulsed field gel electrophoresis band pattern with one of the recently studied strains in the laboratory. Incorrect or inadequate application of infection control measures may result in pathogen acquisition from the clinical samples, and wearing only gloves is not sufficient for the biosafety of laboratory workers in clinical diagnostic laboratories.


Highly sensitive determination of chlorpheniramine as fluorescence derivative by high-performance liquid chromatography.
A new method has been developed for the quantitative analysis of chlorpheniramine in human blood using high-performance liquid chromatography with a fluorescence detector. Benzyl chloroformate was found to be suitable as a fluorometric derivatizing reagent. A linear calibration curve ranging from 0 to 40 ng was obtained for chlorpheniramine, and the minimum detectable concentration was 0.1 ng/ml (whole blood) at a signal-to-noise ratio of 2. It was confirmed that chlorpheniramine levels in the blood of healthy adult volunteers could be precisely determined up to 96 h after a single oral administration of a tablet containing 4 mg of chlorpheniramine.


Using human genetics to make new medicines.
Jeffrey Barrett, Ian Dunham and Ewan Birney discuss the initiatives of the newly founded Centre for Therapeutic Target Validation, including a range of approaches to use human genetics to inform drug discovery and make better medicines.


Prognostic role of inflammatory biomarkers in HIV-infected patients with a first diagnosis of hepatocellular carcinoma: A single-center study.
To assess hepatocellular carcinoma (HCC) survival and to investigate the prognostic role of immunonutritional biomarkers, as neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and prognostic nutritional index (PNI), in a cohort of human immunodeficiency virus (HIV)-infected patients. All HIV-positive patients diagnosed with HCC at our Department from January 2000 to December 2013 were included. The outcomes were overall survival (OS), recurrence-free survival (RFS), and liver-related death (LRD). To examine the role of inflammatory biomarkers on the outcomes, univariate and multivariable Cox regression models were used. Receiver operating characteristic (ROC) curves were implemented to evaluate the prediction role of NLR, PLR, and PNI. A total of 40 patients (90% males) with a mean age of 48.3 years (SD = 5.6) were recruited. NLR ≥ 2.9 was associated with all causes mortality, as well as, PLR ≥ 126. NLR and PLR were predictors of OS, RFS, and LRD, while PNI did not emerge as a prognostic marker. According to the multivariate analysis, no HCC treatment was the only risk factor associated with risk of death. The areas under the ROC curves were 68.3 (95% confidence interval [CI], 54.5-82.1) for PLR and 66.3 (95% CI, 54.3-78.2) for NLR at 3 years; similar results were found at 5 years of follow-up. Although, if examined singularly, NLR and PLR are prognostic factors for HCC recurrence and survival in HIV-infected patients, at the multivariate analysis, "no HCC treatment" remains the only independent risk factor associated with fatal outcome.


Nitrogen addition and drought affect nitrogen uptake patterns and biomass production of four urban greening tree species in North China.
Nitrogen (N) is an essential nutrient element limiting plant growth and production, and plant N uptake capacity varies with environmental change. Recently, global climate changes such as N deposition and drought have important impacts on the terrestrial ecosystems, especially for urban greening trees. However, it's still unclear how N deposition and drought affect plant N uptake and biomass production and the underlying relationship between them. Therefore, we conducted a 15N isotope labeling experiment on four common tree species of urban green spaces in North China, including Pinus tabulaeformnis, Fraxinus chinensis, Juniperus chinensis, and Rhus typhina in pots. Three N addition treatments (0, 3.5, and 10.5 gN m -2 year -1; "no", "low", and "high" N treatments, respectively) and two water addition treatments (300 and 600 mm year-1; "drought" and "normal water", respectively) were set up in a greenhouse. Our results showed that N and drought significantly affected tree biomass production and N uptake rates, and the relationship between them depended on the species specificity. Trees could transform their N uptake preference to adapt to the changing environment, from ammonium to nitrate or vice versa, which was also reflected in total biomass. Furthermore, the variation of N uptake patterns was also related to distinct functional traits, including aboveground (specific leaf area and leaf dry matter content) or belowground (specific root length, specific root area, and root tissue density) traits. There was a transformation of plant resource acquisitive strategy in a high N and drought environment. In general, there were tight connections among N uptake rates, functional traits, and biomass production of each target species. This finding comes up with a new strategy that tree species can modify their functional traits and plasticity of the N uptake forms for survival and growth in the context of high N deposition and drought.


Review of available "extraction + purification" methods of natural ceramides and their feasibility for sewage sludge analysis.
Natural ceramide, a biologically active compound present in plants, has been used widely in food, cosmetics, and pharmaceutical industries. Abundant ceramide has been detected in sewage sludge, which has inspired the idea to recycle ceramide from it. Therefore, the methods of extracting, purifying, and detecting ceramides from plants were reviewed, with the aim to establish methods to get condensed ceramide from sludge. Ceramide extraction methods include traditional methods (maceration, reflux, and Soxhlet extraction) and green technologies (ultrasound-assisted, microwave-assisted, and supercritical fluid extraction). In the past two decades, more than 70% of the articles have used traditional methods. However, green extraction methods are gradually improved and showed high extraction efficiency with lower solvent consumed. The preferred technique for ceramide purification is chromatography. Common solvent systems include chloroform-methanol, n-hexane-ethyl acetate, petroleum ether-ethyl acetate, and petroleum ether-acetone. For structural determination of ceramide, infrared spectroscopy, nuclear magnetic resonance spectroscopy, and mass spectrometry are used in combination. Among quantitative analysis methods for ceramide, liquid chromatography-mass spectrometry was the most accurate. This review concludes that with our prilemenary experiment results it is feasible to apply the plant "extraction + purification" process of ceramide to sludge, but more optimization need to be performed to get better results.


Microarray Analysis of lncRNA and mRNA Expression Profiles in Patients with Neuromyelitis Optica.
For the epigenetic characterization of neuromyelitis optica (NMO), we determined whether messenger RNAs (mRNAs) and long noncoding RNAs (lncRNAs) are expressed differentially in subjects with and without NMO. lncRNA and mRNA expression profiles of NMO patients and healthy controls were generated by using microarray analysis. For comparison, the differentially expressed mRNA functions were annotated by using gene ontology (GO) and pathway analyses. The microarray revealed that 1310 lncRNAs and 743 mRNAs differed in NMO patients from those in healthy controls. Pathway analysis then demonstrated that IL23-mediated signaling events, interferon gamma signaling, natural killer (NK)-κB signaling pathway, chemokine receptors that bind chemokines, GPCR ligand binding, and metabolic disorders of biological oxidation enzyme pathways play important roles in NMO. Several GO terms including cytokine stimulus, response to cytokine, immune response, cytokine-mediated signaling pathway, and response to chemical cytokine activity were enriched in gene lists, suggesting a potential correlation with NMO. Co-expression network analysis indicated that 183 lncRNAs and 458 mRNAs were included in the co-expression network. Our present study showed that these differentially expressed mRNAs and lncRNAs may play important roles in NMO and could provide basic information for new biomarkers or treatment targets to alleviate NMO.


Factors Impacting Electron Transfer in Cyano-Bridged {Fe2Co2} Clusters.
A cyano-bridged {Fe(III)2Co(II)2} complex exhibits reversible thermally and photoinduced intramolecular charge transfer. Its desolvated, MeOH-d4, and other analogues were compared to disclose the impact factors on the electron-transfer behavior of these {Fe(III)2Co(II)2} clusters.


Simulation of the electron-paramagnetic-resonance spectrum of the iron-protein of nitrogenase. A prediction of the existence of a second paramagnetic centre.
The e.p.r. spectra of the Fe-proteins of nitrogenase from all sources studied have unusual features in that they have very anisotropic linewidths and low integrated intensities. These characteristics can be explained by assuming that one of the two electrons accepted by these proteins is located at a rapidly relaxing paramagnetic centre that is unobservable by e.p.r., but causes anisotropic broadening of the e.p.r. signal of the other electron. Complex-formation between Fe-proteins and MgATP is described in terms of a 50-60 degrees rotation of the e.p.r.-observable centre.


Three-step surgical treatment of aortoesophageal fistula after thoracic endovascular aortic repair: A case report.
Aortoesophageal fistula (AEF) is a fatal complication results in sudden massive hematemesis. Although thoracic endovascular aortic repair (TEVAR) is an established method of treating aortic aneurysms or aortic dissection, the number of AEF after TEVAR is recently increasing due to the spread of TEVAR. However, the therapeutic strategy for AEF remains controversial. We describe a 71-year-old man with Stanford B aortic dissection and aortic aneurysm rupture treated by TEVAR who developed AEF between the thoracic aorta and upper thoracic esophagus 20 months thereafter. We applied a three-step surgical procedure for this patient comprising resection of the esophagus as the infectious source, removal of an aortic aneurysm with stent-graft and replacement of the aorta, and final reconstruction of the esophagus. Thereafter, the patient resumed oral intake and has remained relapse-free for 24 months without adverse events. Previous reports have described simultaneous resection of the esophagus and aortic stent-graft via a left thoracotomy followed by a two-step surgical reconstruction of the esophagus. We applied a three-step procedure consisting of resections of the esophagus and aortic stent-graft on separate occasions followed by esophageal reconstruction in this patient. The first procedure in the three-step approach is less stressful than that of the two-step approach. The three-step surgical approach to treating AEF after TEVAR resulted in a good outcome for this patient. Thus, this surgical strategy is a useful option for treating AEF after TEVAR.


Complete genome sequence of Coriobacterium glomerans type strain (PW2(T)) from the midgut of Pyrrhocoris apterus L. (red soldier bug).
Coriobacterium glomerans Haas and König 1988, is the only species of the genus Coriobacterium, family Coriobacteriaceae, order Coriobacteriales, phylum Actinobacteria. The bacterium thrives as an endosymbiont of pyrrhocorid bugs, i.e. the red fire bug Pyrrhocoris apterus L. The rationale for sequencing the genome of strain PW2(T) is its endosymbiotic life style which is rare among members of Actinobacteria. Here we describe the features of this symbiont, together with the complete genome sequence and its annotation. This is the first complete genome sequence of a member of the genus Coriobacterium and the sixth member of the order Coriobacteriales for which complete genome sequences are now available. The 2,115,681 bp long single replicon genome with its 1,804 protein-coding and 54 RNA genes is part of the G enomic E ncyclopedia of Bacteria and Archaea project.


Pharmacokinetics of dextromoramide in surgical patients.
The pharmacokinetics of the narcotic analgesic dextromoramide was investigated by means of a specific GC-MS method in 9 patients who were given a single oral dose of the drug (7.5 mg) together with an anticholinergic before undergoing minor orthopedic surgery. Dextromoramide was rapidly absorbed from the gastrointestinal tract, with peak plasma levels between 68 and 177 micrograms/L usually achieved within 0.5-4.0 h after dosing. In 5 patients, the decline of plasma concentrations after the peak followed a biphasic pattern, with half-lives of 0.4-1.6 h for the first phase and 6.3-21.8 h for the terminal phase. In the remaining patients, no clear-cut biphasic pattern was seen and half-lives calculated over the period between 4 h and 10 h after administration ranged from 1.5 to 4.7 h. Apparent clearance and volume of distribution values ranged from 0.06 to 0.36 1.h-1.kg-1 and from 0.6 to 2.4 l.kg-1, respectively. Less than 0.06% of the dose was excreted unchanged in urine within 8 h of administration. The concentration of the drug in a CSF sample collected 1 h after dosing was below the limit of detection (2 micrograms/L) in all subjects.


Orabase formulation with cashew gum polysaccharide decreases inflammatory and bone loss hallmarks in experimental periodontitis.
This study aimed to investigate the chemical characteristics and the effects of an orabase gel with Cashew Gum Polysaccharide (CG-P) from Anacardium occidentale L. on alveolar bone loss and relative mRNA expression of TNF-α, IL-1β, RANK, RANKL, and OPG in the periodontal tissue of Wistar rats (Rattus norvegicus) subjected to ligature-induced periodontitis. Crude cashew gum was collected and purified by chemical processes; then, the CG-P was mixed with orabase gel. Female rats were randomly divided into four groups of six animals each: saline 0.9% (Sal Group); orabase gel (Gel Group); 50mg CG-P/1g orabase gel (CG-P50 Group) and 150mg CG-P/1g orabase gel (CG-P150 Group). Periodontitis was induced in the animals; they were treated for 20days with one daily topical application. The purification process of CG-P presented high yield and resulted in a protein-free product. The treatment with CG-P150 (150mg CG-P/1g orabase gel) significantly reduced alveolar bone loss, decreased the relative mRNA expression of TNF-α, IL-1β, RANKL and the RANKL/OPG ratio, and caused a significant decrease in myeloperoxidase activity of the gingival tissue. Thus, the CG-P in orabase represents a potential adjuvant drug for the treatment of periodontitis and possible source of new biotechnological discoveries.


Resistance to antimicrobial drugs in Ghana.
Antimicrobial drug resistance is a global issue that affects health, economic, and social development. The problem has been attributed to misuse of antimicrobial agents. To identify the agents of bacterial infection in Ghana, determine their antibiogram, and the possibility of setting up a surveillance program. A prospective quantitative study set in various hospitals including two teaching hospitals, seven regional hospitals, and two district hospitals in Ghana. A total of 5099 bacterial isolates from various clinical specimens were collected over a period of 1 year, including data related to the patients. Susceptibility of the isolates was determined by the Kirby-Bauer method. In addition, the minimum inhibitory concentration (MIC) of multidrug-resistant isolates of epidemiological significance was also determined using the E-test. A wide range of bacterial isolates were identified in both teaching and regional hospitals. High percentage of resistance was observed for tetracycline (82%), cotrimoxazole (73%), ampicillin (76%), and chloramphenicol (75%). Multidrug resistance was observed to a combination of ampicillin, tetracycline, chloramphenicol, and cotrimoxazole. On the other hand, a lower percentage of resistance was observed for ceftriaxone (6.3%), ciprofloxacin (11%), and amikacin (9.9%). Generally, the prevalence of multidrug resistance was widespread among the various isolates. Some multidrug-resistant strains of Staphylococcus aureus, Salmonella typhi, and non-typhoidal Salmonella (NTS) had high MIC to cefuroxime (>256), gentamicin (>256), and ciprofloxacin (>32).


Clade-related amphotericin B resistance among South African Candida albicans isolates.
Molecular epidemiology revealed 5 distinct clades among clinical isolates of Candida albicans, using DNA fingerprinting with the complex Ca3 probe. Certain clades were found to be highly enriched in particular geographical areas (e.g., clade E in Europe and clade SA in South Africa, whereas clade II is completely absent in the southwest United States). From fingerprinting data, it is concluded that little interclade recombination takes place, and therefore, it would not be unusual to expect clade-specific phenotypic characteristics. The first clade-related phenotypic difference was found with 5-flucytosine resistance being almost exclusively restricted to clade I. When in vitro antifungal susceptibility testing revealed 8.4% of South African oral yeast isolates to be naturally resistant to amphotericin B, it was decided to investigate a possible clade relationship for this relatively high resistance. Thirty-eight amphotericin B-resistant C. albicans isolates were fingerprinted, and a mixed dendrogram was constructed, including previously fingerprinted isolates of known clade affiliation. With the exception of clade III, resistant isolates occurred in all clades (clade I=3; clade II=3; clade NG=3; and clade SA=29), except clade III. However, the higher number of resistant isolates that clustered in clade SA was statistically significant (P<or=0.02, chi2=11.32).


Cannabis-related problems and social anxiety: The roles of sex and cannabis use motives updated.
Individuals with elevated social anxiety are particularly susceptible to cannabis problems, and sex differences in factors underlying this relation have been identified - e.g., among those with elevated social anxiety, men may use cannabis to cope with negative affect (NA) generally whereas women may use to cope with social anxiety specifically. This study examined the relations between social anxiety and cannabis-related behaviors by sex among 401 (75.3% female) undergraduates who endorsed past-month cannabis use. Among both sexes, social anxiety was related to more cannabis problems and coping (to decrease NA generally) and social anxiety (to manage NA in social situations) motives. Among men (not women), social anxiety was related to less frequent cannabis use and more conformity (to fit in with others) motives. Among women (not men), social anxiety was related to more enjoyment, experimentation, boredom alleviation, altered perceptions (to modulate perceptual experiences), and relatively low risk (perceived low risk) motives. The relation between social anxiety and cannabis problems occurred indirectly via coping motives for both sexes, and among men (not women) via conformity motives. Among women (not men), social anxiety was indirectly related to cannabis problems via enjoyment, experimentation, boredom, altered perceptions, and social anxiety motives. Findings suggest that among those with elevated social anxiety, men and women appear to use cannabis for different reasons, and that these reasons may play different roles in cannabis problem risk among men and women. Data highlight the importance of considering sex in efforts to understand the role of social anxiety in cannabis-related behaviors.


Cardioprotective and neuroprotective roles of oleuropein in olive.
Traditional diets of people living in the Mediterranean basin are, among other components, very rich in extra-virgin olive oil, the most typical source of visible fat. Olive is a priceless source of monounsaturated and di-unsaturated fatty acids, polyphenolic antioxidants and vitamins. Oleuropein is the main glycoside in olives and is responsible for the bitter taste of immature and unprocessed olives. Chemically, oleuropein is the ester of elenolic acid and 3,4-dihydroxyphenyl ethanol, which possesses beneficial effects on human health, such as antioxidant, antiatherogenic, anti-cancer, anti-inflammatory and antimicrobial properties. The phenolic fraction extracted from the leaves of the olive tree, which contains significant amounts of oleuropein, prevents lipoprotein oxidation. In addition, oleuropein has shown cardioprotective effect against acute adriamycin cardiotoxicity and an anti-ischemic and hypolipidemic activities. Recently, oleuropein has shown neuroprotection by forming a non-covalent complex with the Aβ peptide, which is a key hallmark of several degenerative diseases like Alzheimer and Parkinson. Thus, a large mass of research has been accumulating in the area of olive oil, in the attempt to provide evidence for the health benefits of olive oil consumption and to scientifically support the widespread adoption of traditional Mediterranean diet as a model of healthy eating. These results provide a molecular basis for some of the benefits potentially coming from oleuropein consumption and pave the way to further studies on the possible pharmacological use of oleuropein to prevent or to slow down the cardiovascular and neurodegenerative diseases.


Using 2nd generation basal insulins in type 2 diabetes: Costs and savings in a comparative economic analysis in Italy, based on the BRIGHT study.
To evaluate the economic impact of using 2nd generation basal insulin analogs, Glargine 300 Units/ml (Gla-300) vs Degludec 100 Units/ml (IDeg-100), in patients with type 2 diabetes (T2D). An economic analysis was conducted using findings from the BRIGHT study (the first controlled, head-to-head study comparing Gla-300 vs IDeg-100), and costs for the Italian National Healthcare Service (NHS). A cost-minimization analysis (CMA) and a budget impact analysis (BIA) were conducted. Only pharmacological costs were included in the analysis. The CMA estimated patient treatment costs at 24 weeks and 1 year; the BIA assessed the economic impact of treating the overall Italian population of T2D insulin-naïve patients, who initiated insulin treatment during the period September 2017-August 2018 (N = 55 318). In the BIA, four different scenarios were compared: i) all patients receive IDeg-100 (Scenario A); ii) 61% of patients receive Gla-300, 39% IDeg-100 (Scenario B); iii) 80% of patients receive Gla-300, 20% IDeg-100 (Scenario C); iv) all patients treated with Gla-300 (Scenario D). The average treatment costs per patient were lower with Gla-300 vs IDeg-100 (at 24 weeks: €129 vs €161; at 1 year: €324 vs €409, respectively). Results of the BIA showed that comparing Scenario D vs Scenario A, total savings would amount to €1.76 million at 24 weeks, €4.73 million at 1 year, €5.53 million at 2 years. A larger use of Gla-300 vs IDeg-100 for the treatment of T2D patients would lead to a relevant reduction of therapy costs in Italy.


Modifications of adrenocortical responses following frontal cortex simulation in rats with hypothalamic deafferentations and medial forebrain bundle lesions.
With the purpose of delineating the neural pathways in the rat which mediate adrenocortical responses following frontal cortex stimulation, the effects of partial hypothalamic deafferentations and medial forebrain bundle lesion were studied. In intact and sham-operated animals, cortical stimulation through permanently implanted electrodes caused a significant increase in plasma corticosterone levels. In rats with anterior hypothalamic deafferentation and bilateral medial forebrain bundle lesions the adrenal response to cortical stimulation was blocked completely, while in animals with posterior hypothalamic deafferentation there occurred a normal rise in plasma corticosterone. These studies demonstrate that the frontal cortex effects on adrenocortical secretion are neurally mediated and involve an anterior hypothalamic input, more specifically the medial forebrain bundle.


Design, synthesis, and biological evaluation of 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)sulfonyl)benzamide derivatives as potent HIV-1 Vif inhibitors.
Viral infectivity factor (Vif) is one of the accessory protein of human immunodeficiency virus type I (HIV-1) that inhibits host defense factor, APOBEC3G (A3G), mediated viral cDNA hypermutations. Previous work developed a novel Vif inhibitor 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide (1) with strong antiviral activity. Through optimizations on the two side branches, a series of compound 1 derivatives (2-18) were designed, synthesized and tested in vitro for their antiviral activities. The biological results showed that compound 5 and 16 inhibited the virus replication efficiently with EC50 values of 9.81 and 4.62 μM. Meanwhile, low cytotoxicities on H9 cells were observed for the generated compounds by the MTT assay. The structure-activity relationship of compound 1 was preliminarily clarified, which gave rise to the development of more potent Vif inhibitors.


Contribution of presenilin transmembrane domains 6 and 7 to a water-containing cavity in the gamma-secretase complex.
Gamma-secretase is a multiprotein complex responsible for the intramembranous cleavage of the amyloid precursor protein and other type I transmembrane proteins. Mutations in Presenilin, the catalytic core of this complex, cause Alzheimer disease. Little is known about the structure of the protein and even less about the catalytic mechanism, which involves proteolytic cleavage in the hydrophobic environment of the cell membrane. It is basically unclear how water, needed to perform hydrolysis, is provided to this reaction. Presenilin transmembrane domains 6 and 7 seem critical in this regard, as each bears a critical aspartate contributing to catalytic activity. Current models imply that both aspartyl groups should closely oppose each other and have access to water. This is, however, still to be experimentally verified. Here, we have performed cysteine-scanning mutagenesis of both domains and have demonstrated that several of the introduced residues are exposed to water, providing experimental evidence for the existence of a water-filled cavity in the catalytic core of Presenilin. In addition, we have demonstrated that the two aspartates reside within this cavity and are opposed to each other in the native complex. We have also identified the conserved tyrosine 389 as a critical partner in the catalytic mechanism. Several additional amino acid substitutions affect differentially the processing of gamma-secretase substrates, implying that they contribute to enzyme specificity. Our data suggest the possibility that more selective gamma-secretase inhibitors could be designed.


Minimal clinically important differences in health-related quality of life after total hip or knee replacement: A systematic review.
We aimed first to summarise minimal clinically important differences (MCIDs) after total hip (THR) or knee replacement (TKR) in health-related quality of life (HRQoL), measured using the Short-Form 36 (SF-36). Secondly, we aimed to improve the precision of MCID estimates by means of meta-analysis. We conducted a systematic review of English and non-English articles using MEDLINE, the Cochrane Controlled Trials Register (1960-2011), EMBASE (1991-2011), Web of Science, Academic Search Premier and Science Direct. Bibliographies of included studies were searched in order to find additional studies. Search terms included MCID or minimal clinically important change, THR or TKR and Short-Form 36. We included longitudinal studies that estimated MCID of SF-36 after THR or TKR. THREE STUDIES MET OUR INCLUSION CRITERIA, DESCRIBING A DISTINCT STUDY POPULATION: primary THR, primary TKR and revision THR. No synthesis of study results can be given. Although we found MCIDs in HRQoL after THR or TKR have limited precision and are not validated using external criteria, these are still the best known estimates of MCIDs in HRQoL after THR and TKR to date. We therefore advise these MCIDs to be used as absolute thresholds, but with caution.


Pectins from the sea grass Enhalus acoroides (L.f.) Royle: Structure, biological activity and ability to form nanoparticles.
Two pectins from the seagrass Enhalus acoroides (L.f.) Royle were isolated for the first time. Their structures and biological activities were investigated. NMR spectroscopy showed one of them to consist exclusively from the repeating →4-α-d-GalpUA→ residue (Ea1), while the other had a much more complex structure that also included 1→3-linked α-d-GalpUA residues, 1→4-linked β-apiose residues and small amounts of galactose and rhamnose (Ea2). The pectin Ea1 showed noticeable dose-dependent immunostimulatory activity, the Ea2 fraction was less effective. Both pectins were used to create pectin-chitosan nanoparticles for the first time, and the influence of pectin/chitosan mass ratio on their size and zeta potential was investigated. Ea1 particles were slightly smaller than Ea2 particles (77 ± 16 nm vs 101 ± 12 nm) and less negatively charged (-23 mV vs -39 mV). Assessment of their thermodynamic parameters showed that only the second pectin could form nanoparticles at room temperature.


Mutations in bglY, the structural gene for the DNA-binding protein H1 of Escherichia coli, increase the expression of the kanamycin resistance gene carried by plasmid pGR71.
bglY mutants of Escherichia coli K12 which show higher levels of kanamycin resistance (Kmr) in the presence of plasmid pGR71 have been previously described. In this work, we show that this increased resistance to an aminoglycoside antibiotic is not due either to low drug uptake or to alteration of its target, the ribosome. The copy number of plasmid pGR71 is not modified. The fact that increased antibiotic resistance is observed with only some of the Kmr determinants used in this study suggests a specific role for the bglY gene product. Moreover, for one such determinant, a higher level of resistance was observed when it was inserted in the chromosome but not when harbored by a plasmid. This discrepancy can be explained by the twin transcriptional-loop model, which proposes that transcription can lead to local variation in topology. A kan-lacZ fusion was constructed from the Kmr gene of plasmid pGR71 and inserted into a low copy number vector. Assay of beta-galactosidase in wild-type and mutant strains showed that expression of the antibiotic resistance gene was directly affected by H1 protein, the bglY gene product.


Cultural adaptation is associated with atopy and wheezing among children of Turkish origin living in Germany.
Turkish children have been found to suffer less from atopic diseases than their German peers. The underlying causes are unknown. To evaluate rates of sensitization and atopic disease among children in Germany with German or Turkish ethnicity and different degrees of cultural adaptation. This was a cross-sectional study. The setting was screening for school eligibility in an inner-city district of Berlin/Germany. The participants were preschool children born in Germany with double German or double Turkish parental citizenship. Cultural adaptation of Turkish children was assessed by the language parents used to communicate with their child: only Turkish (n = 60, group A); Turkish and German (n = 269, group B); and only German (n = 103, group C). Group D contained children from German parents (n = 383). The main outcome measures were specific sensitization to common aeroallergens (CAP-System, Pharmacia Phadiatop >or= 0.35 kU/L), and lifetime and 1-year prevalences of allergic disease symptoms (ISAAC questionnaire in German and Turkish, Mantel-Haenszel test for trend). Sensitization rates for groups A, B, C and D were 8.0%, 6.8%, 18.9% and 18.3%, respectively (P = 0.004). The corresponding prevalence rates for wheeze ever were 6.7%, 9.3%, 12.6% and 21.3% (P < 0.001), wheeze in the past year 3.3%, 3.7%, 9.7% and 10.2% (P = 0.001), itchy rash ever 3.3%, 6.3%, 8.7% and 13.7% (P < 0.001), itchy rash in the past year 1.7%, 3.7%, 4.9% and 9.5% (P < 0.001), respectively. No significant differences were found for hay fever symptoms. Higher cultural adaptation is correlated with higher rates of allergic sensitization and disease among children of Turkish origin living in Berlin. This correlation suggests that environmental rather than genetic differences are responsible for the differences observed.


Adrenocortical function in rats chronically exposed to high altitude.
In rats exposed to a simulated altitude of 5,486 m for 3 mo, pituitary and adrenal glands hypertrophied and plasma levels of corticosterone increased more than threefold over sea-level controls. The in vitro rates of corticosterone production by the quartered adrenal gland were significantly enhanced, but the responsiveness of the adrenal gland to ACTH remained normal.


Localization of the ibuprofen molecule in model lipid membranes revealed by spin-label-enhanced NMR relaxation.
Non-steroidal anti-inflammatory drugs (NSAIDs) have antipyretic, anti-inflammatory and analgesic effects, and can be used in the treatment of various diseases. These drugs have also a number of side effects, which may be related to their interaction with lipid membranes. In this study, we use the spin-labeled NSAID ibuprofen (ibuprofen-SL) as a relaxation enhancer to study its interaction with model lipid membranes employing liquid-state 1H NMR at 500 MHz. The high magnetic moment of unpaired electron in the spin label made it possible to reduce the concentration of the studied drug in the membrane to tenths of a mole percent. As model membranes, unilamellar POPC liposomes and bicelles consisting of a 2:1 mixture of DHPC:DMPC or DHPC:POPC lipids were used. An increase in the rate of proton spin-lattice relaxation, T1-1, selectively detected for protons at different positions in the lipid molecule, showed that ibuprofen-SL is localized in the hydrophobic part of the lipid bilayer. As the concentration of ibuprofen-SL increases to 0.5 mol%, the distribution of positions of ibuprofen-SL across the bilayer becomes wider. In the presence of 20 mol% of cholesterol, ibuprofen-SL is displaced from the core of the membrane to a region closer to the head group of the bilayer. This displacement was also confirmed by the NMR NOESY experiment conducted with unlabeled ibuprofen. For bilayers containing unsaturated POPC lipids, the distribution of ibuprofen positions across the bilayer becomes narrower compared to the presence of saturated DMPC lipids.


Integrating patient complexity into health policy: a conceptual framework.
Objective Clinicians across all health professions increasingly strive to add value to the care they deliver through the application of the central tenets of people-centred care (PCC), namely the 'right care', in the 'right place', at the 'right time' and 'tailored to the needs of communities'. This ideal is being hampered by a lack of a structured, evidence-based means to formulate policy and value the commissioning of services in an environment of increasing appreciation for the complex health needs of communities. This creates significant challenges for policy makers, commissioners and providers of health services. Communities face a complex intersection of challenges when engaging with healthcare. Increasingly, complexity is gaining prominence as a significant factor in the delivery of PCC. Based on the World Health Organization (WHO) components of health policy, this paper proposes a policy framework that enables policy makers, commissioners and providers of health care to integrate a model of complexity into policy, subsequent service planning and development of models of care. Methods The WHO components of health policy were used as the basis for the framework. Literature was drawn on to develop a policy framework that integrates complexity into health policy. Results Within the framework, complexity is juxtaposed between the WHO components of 'vision', 'priorities' and 'roles'. Conclusion This framework, supported by the literature, provides a means for policy makers and health planners to conduct analyses of and for policy. Further work is required to better model complexity in a manner that integrates consumer needs and provider capabilities. What is known about the topic? There is a growing body of evidence regarding patient complexity and its impact on the delivery of health services, but there is little consideration of patient complexity in policy, which is an important consideration for service provision. What does this paper add? This paper presents an argument for the inclusion of patient complexity in health policy and provides a framework for how that might occur. What are the implications for practitioners? The inclusion of patient complexity in policy could provide a means for policy makers to consider the factors that contribute to patient complexity in service provision decisions.


New statistical methods for estimation of recombination fractions in F2 population.
Dominant markers in an F2 population or a hybrid population have much less linkage information in repulsion phase than in coupling phase. Linkage analysis produces two separate complementary marker linkage maps that have little use in disease association analysis and breeding. There is a need to develop efficient statistical methods and computational algorithms to construct or merge a complete linkage dominant marker maps. The key for doing so is to efficiently estimate recombination fractions between dominant markers in repulsion phases. We proposed an expectation least square (ELS) algorithm and binomial analysis of three-point gametes (BAT) for estimating gamete frequencies from F2 dominant and codominant marker data, respectively. The results obtained from simulated and real genotype datasets showed that the ELS algorithm was able to accurately estimate frequencies of gametes and outperformed the EM algorithm in estimating recombination fractions between dominant loci and recovering true linkage maps of 6 dominant loci in coupling and unknown linkage phases. Our BAT method also had smaller variances in estimation of two-point recombination fractions than the EM algorithm. ELS is a powerful method for accurate estimation of gamete frequencies in dominant three-locus system in an F2 population and BAT is a computationally efficient and fast method for estimating frequencies of three-point codominant gametes.


Change in Management of Status Epilepticus With the Addition of Neurointensivist-Led Neurocritical Care Team at a Rural Academic Medical Center.
Learning Objective: Status epilepticus (SE) is continuous clinical and/or electrographic seizures lasting 5 minutes or more without recovery and carries a high mortality. Medication management varies by institution, as well as administration, combination of antiepileptic drugs (AEDs), and dosing. Methods: Single-center retrospective review of medication management of SE patients admitted to West Virginia University Hospital before and after neurointensivist implemented guidelines. Patients admitted between January 2012 and June 2014 were grouped in the prior to neurointensivist group (pre-NI) and patients admitted between July 2014 and June 2016 were grouped in the postneurointensivist group (post-NI). Baseline demographics, hospital, intensive care unit (ICU), and ventilator length of stay were recorded. Medications reviewed included number of AEDs and maximum dose of lorazepam, phenytoin, levetiracetam, and lacosamide. Outcomes included number of continuous infusions of either midazolam or propofol at seizure suppression doses as well as pentobarbital, phenobarbital, or ketamine, and need for vasopressor use. Results: Of the 74 patients included, the pre-NI group (n = 40) utilized more AEDs (6 vs 4) compared with the post-NI group (n = 34). The pre-NI group had less midazolam continuous infusions meeting seizure suppression doses (8 vs 9), but higher average doses (49 vs 27 mg/h) compared with the post-NI group. More patients in the pre-NI group were on propofol seizure suppression doses (15 vs 10) and phenobarbital continuous infusions (11 vs 2) than the post-NI group. Patients had less vasopressor use in the post-NI group than the pre-NI group (11 vs 23). Frequency and dosing of lorazepam, phenytoin, levetiracetam, and lacosamide were similar between the 2 groups. Ventilator use, hospital, and ICU length of stay were also similar between groups. Discussion: Implementation of a neurointensivist and medication guidelines resulted in fewer AEDs and less vasopressor use in the management of SE. Midazolam use was slightly higher in the post-NI group but at lower doses overall.


What the radiologist needs to know about gastrointestinal endoscopic surgical procedures.
Natural orifice transluminal endoscopic surgery (NOTES) is a novel surgical approach, currently performed for an array of conditions. Endoscopic procedures offer significant benefits, including lower cost, no surgical incisions, and shorter hospital stays. These advantages align with the current trends in health care, namely a push for "cost-effective care." There are a multitude of health issues which are now being addressed by the endoscopic surgical approach, including peroral endoscopic myotomy (POEM), which is a relatively new technique used in the treatment of achalasia. Endoscopic treatment utilized for GERD includes transoral incisionless fundoplication. Endoscopic bariatric surgical procedures include intragastric balloon placement, endoscopic sleeve gastroplasty, and revision of prior bariatric procedures including Roux-en-Y gastric bypass and conventional gastric sleeve procedures. Endoscopic clips are routinely utilized for achieving hemostasis, treating iatrogenic gastric and bowel ulcerations and perforations and for the closure of enteric fistulization. Novel endoscopic procedures are now replacing conventional surgery due to their non-invasive nature, faster recovery and lower healthcare costs. Radiologists need to understand how these procedures are performed, as well as expected post-procedural imaging appearance and potential complications.


Substituted cysteine scanning in D1-S6 of the sodium channel hNav1.4 alters kinetics and structural interactions of slow inactivation.
Slow inactivation in voltage-gated Na+ channels (Navs) plays an important physiological role in excitable tissues (muscle, heart, nerves) and mutations that disrupt Nav slow inactivation can result in pathophysiologies (myotonia, arrhythmias, epilepsy). While the molecular mechanisms responsible for slow inactivation remain elusive, previous studies have suggested a role for the pore-lining D1-S6 helix. The goals of this research were to determine if (1) cysteine substitutions in D1-S6 affect gating kinetics and (2) methanethiosulfonate ethylammonium (MTSEA) accessibility changes in different kinetic states. Site-directed mutagenesis in the human skeletal muscle isoform hNav1.4 was used to substitute cysteine for eleven amino acids in D1-S6 from L433 to L443. Mutants were expressed in HEK cells and recorded from with whole-cell patch clamp. All mutations affected one or more baseline kinetics of the sodium channel, including activation, fast inactivation, and slow inactivation. Substitution of cysteine (for nonpolar residues) adjacent to polar residues destabilized slow inactivation in G434C, F436C, I439C, and L441C. Cysteine substitution without adjacent polar residues enhanced slow inactivation in L438C and N440C, and disrupted possible H-bonds involving Y437:D4 S4-S5 and N440:D4-S6. MTSEA exposure in closed, fast-inactivated, or slow-inactivated states in most mutants had little-to-no effect. In I439C, MTSEA application in closed, fast-inactivated, and slow-inactivated states produced irreversible reduction in current, suggesting I439C accessibility to MTSEA in all three kinetic states. D1-S6 is important for Nav gating kinetics, stability of slow-inactivated state, structural contacts, and state-dependent positioning. However, prominent reconfiguration of D1-S6 may not occur in slow inactivation.


Do elderly patients deserve a kidney graft?
Compare renal transplant long-term outcomes among recipients aged 60 years or older with those in younger patients. We analyzed 103 transplants in recipients above 60 years of age for the influence of key factors related to the graft and patient. The results were compared with 1060 transplant recipients aged 18 to 59 years. The mean ages were 62.93 and 40.35 years for the older and younger group. The older group showed a higher prevalence of obesity and unknown etiologies for the end-stage renal disease. Important comorbidity was significantly more frequent among recipients aged more than 60 years, mainly of a cardiovascular nature (56% vs 18.5%). Donor age (39.75 vs 31.59 years), cold ischemia time (22.43 vs 20.49 hours) and human leukocyte antigen compatibilities (2.59 vs 2.36) were significantly greater in the older subset. After a mean follow-up of 4.72 and 6.07 years for the older versus younger group, we found no differences in initial graft function, acute rejection rate, and serum creatinine/clearance. Patient and graft survivals at 1, 5, and 10 years were lower among the 60+ group. There were no differences in graft survival censored for death with a functioning graft, namely, 95.1%, 89.4%, and 81.2% for the 60+ cohort. The main cause of graft loss in the older group was death with a functioning graft. Renal transplantation should be considered for selected patients older than 60 years. Despite a shorter life expectancy, they benefit from it similar to younger recipients.


Facile preparation of silver nanoparticle decorated chitosan cryogels for point-of-use water disinfection.
In this study, silver nanoparticle decorated chitosan (CS/Ag NP) cryogels were fabricated through a simple freeze-drying process for point-of-use (POU) water disinfection. The CS/Ag NP cryogels showed high porosity, good mechanical properties, an excellent water absorption capability, and most importantly, an efficient bactericidal feature. The absorption capacity for water was found to be 47g/g, approximately 90% of which was recovered by simple squeezing. Three different sizes of Ag NPs were compared regarding their bactericidal capability against both Escherichia coli (E. coli) and Bacillus subtilis (B. subtilis). Under optimum conditions, a 3 log reduction of bacteria was observed by holding the bacteria suspension (108 colony forming units (cfu)/mL) in the cryogels for 5min. Reduction was further increased to a 4 log when the contact time was doubled. The silver content in the cryogels was found to only be 7.5mg/g. Furthermore, the total Ag in processed water was found to only be 22μg/L, half of the safety limit set by China (<50μg/L). The bactericidal effectiveness of the material for real surface water samples was also demonstrated by treating water samples with different water quality matrices, including lake water and sewage water samples. In all three treated lake water samples, both the total bacteria and E. coli met the regulations for drinking water in China (<100cfu/mL for total bacteria and negative for E. coli). CS/Ag NP cryogels can be used for drinking water disinfection during disaster relief and in contingency water supply applications.


Use of Biobrane in management of scalds.
A scald burn is a superficial to mid second-degree burn with a viable dermis beneath the blisters and a good blood flow. However, the burn may be incapacitating because of pain and fluid and heat loss. Biobrane adheres very well to this depth of burn and mechanically and biochemically closes the wound. We have used Biobrane on scald burns for the last 5 years and have found it to be an excellent method of treating superficial second-degree burns.


Cine gastric MRI reveals altered Gut-Brain Axis in Functional Dyspepsia: gastric motility is linked with brainstem-cortical fMRI connectivity.
Functional dyspepsia (FD) is a disorder of gut-brain interaction, and its putative pathophysiology involves dysregulation of gastric motility and central processing of gastric afference. The vagus nerve modulates gastric peristalsis and carries afferent sensory information to brainstem nuclei, specifically the nucleus tractus solitarii (NTS). Here, we combine MRI assessment of gastric kinematics with measures of NTS functional connectivity to the brain in patients with FD and healthy controls (HC), in order to elucidate how gut-brain axis communication is associated with FD pathophysiology. Functional dyspepsia and HC subjects experienced serial gastric MRI and brain fMRI following ingestion of a food-based contrast meal. Gastric function indices estimated from 4D cine MRI data were compared between FD and HC groups using repeated measure ANOVA models, controlling for ingested volume. Brain connectivity of the NTS was contrasted between groups and associated with gastric function indices. Propagation velocity of antral peristalsis was significantly lower in FD compared to HC. The brain network defined by NTS connectivity loaded most strongly onto the Default Mode Network, and more strongly onto the Frontoparietal Network in FD. FD also demonstrated higher NTS connectivity to insula, anterior cingulate and prefrontal cortices, and pre-supplementary motor area. NTS connectivity was linked to propagation velocity in HC, but not FD, whereas peristalsis frequency was linked with NTS connectivity in patients with FD. Our multi-modal MRI approach revealed lower peristaltic propagation velocity linked to altered brainstem-cortical functional connectivity in patients suffering from FD suggesting specific plasticity in gut-brain communication.


Clinical Experiences of Speech-Language Pathologists in the Rehabilitation of Unilateral Vocal Fold Paralysis.
Unilateral vocal fold paralysis (UVFP) is a neurological voice disorder that is often first treated by a speech-language pathologist (SLP). In literature, little consensus is found regarding voice therapy onset, duration, frequency, and content. The aim of the current study is to investigate the clinical practice of SLPs for treatment of UVFP regarding diagnostics and treatment characteristics. Additionally, the study examined the personal experiences of SLPs regarding UVFP care. An online survey was completed by 37 respondents, all SLPs with experience in treating UVFP. Demographic characteristics, experiences with voice assessments and treatment modalities were examined. Lastly, experiences and opinions of SLPs on evidence-based practice and their own clinical practice were surveyed. Almost all respondents used a multidimensional voice assessment with findings from laryngovideostroboscopy to assess UVFP. Laryngeal electromyography is not yet integrated in regular clinical practices. The most commonly used vocal techniques were resonant voice exercises, laryngeal manipulation, semioccluded vocal tract exercises (SOVTEs), vocal hygiene, and Vocal Function Exercises, with SOVTEs most often considered effective. A total of 75% of the respondents feel confident treating UVFP, and 87.6% believe it is important to stay updated on evidence-based practice. Variation in therapy timing and dosage was observed, and 48.4% of SLPs usually started early voice therapy within 4 weeks after UVFP onset. Flemish SLPs generally feel confident treating UVFP patients and show interest in improving evidence-based practice. Initiatives to train clinicians further in UVFP care and encouraging SLPs to provide practice-based evidence will enhance the knowledge base for evidence-based practice in UFVP.


Bacteriophage P22 gene 23 product acts preferentially in cis.
The expression of the P22 late operon was measured while the activator of the late operon, the product of gene 23, was provided in cis or in trans. It was found that expression of the late operon, assayed from a late-gene-lacZ gene fusion, was reduced by more than twofold when the only functional copy of gene 23 was present in trans.


Long-term survival in an ovarian cancer patient with brain metastases.
Central nervous system (CNS) metastases from ovarian adenocarcinoma are uncommon. The long-term prognosis for these patients is poor, with studies reporting a mean survival of less than 12 months. We present a case involving a 57-year-old woman diagnosed and treated for primary ovarian cancer in 1994. She underwent optimal cytoreductive surgery and received adjuvant chemotherapy. In 1996, she was diagnosed with a right cerebellar metastatic lesion, and treated with surgery and whole-brain radiotherapy. She is currently 7 years post-treatment of her brain metastasis without evidence of recurrent disease. Brain metastases from primary ovarian cancer are a relatively rare finding. These patients have a poor prognosis, with studies reporting a mean survival of 12 months. However, the patient in this report remains disease-free since her treatment for metastatic disease. Aggressive surgical and radiation treatment for patients with isolated CNS metastases is reasonable.


[Leydig-cell tumors of the testicle].
Leydig's cells tumor account for 1-2% of all testicular tumors. The authors report a rare case of benign Leydig's cells tumor in a young man with gynecomastia. They examine the embryogenesis, the hormonal modifications, the criteria of malignancy, the treatment and results. They present a review of the literature pertaining to this rare tumors.


Moving from the quality of life concept to a theory.
The Special Interest Quality of Life Group has updated its set of statements defining the quality of life (QOL) construct to reflect emerging areas of agreement and the framework for understanding better the QOL construct. This article examines the major areas currently under discussion involving the objective-subjective dichotomy, needs, and core domains. It is concluded that while the new statements constitute a significant advance, further progress requires testable theory. In order to facilitate such future research, a conceptual model is proposed that distinguishes causal and indicator variables within the framework of a homeostatic management system. Several lines of empirical investigation are suggested to test this and similar theoretical models with a view to taking our conceptualization of QOL to the next level.


Eukaryotic ribosomal proteins stimulate Escherichia coli stringent factor to synthesize guanosine 5'-diphosphate, 3'-diphosphate (ppGpp) and guanosine 5'-triphosphate, 3'-diphosphate (ppGpp).
When supplemented with Escherichia coli stringent factor, 80S ribosomes from various sources failed to support guanosine tetra- and pentaphosphate ((p)ppGpp) synthesis. In contrast, ribosomal proteins from 80S, 60S or 40S particles (mouse embryos, rabbit reticulocytes) crossreacted with the E. coli stringent factor. Significant stimulation of (p)ppGpp synthesis was achieved with a concentration as low as 5 micrograms of ribosomal proteins/ml. These observations may provide additional crtieria to detect homologies between eukaryotic and prokaryotic ribosomal proteins.


Translational deficiencies in antibacterial discovery and new screening paradigms.
An impending disaster is currently developing in the infectious disease community: the combination of rapidly emerging multidrug-resistance among clinically relevant bacterial pathogens, together with an unprecedented withdrawal from industrial dedication to this disease area, is jeopardizing human health on a societal level. For those who remain focused and dedicated to identifying solutions to this growing problem, additional challenges await when in vitro activity does not correlate with in vivo efficacy. Thus the development of more effective translational assays will greatly improve and streamline the process of identifying novel antibacterial agents that can stand the test of preclinical and clinical development. Here we describe recent examples of research that justify the need for such assays.


Protective effects of the Terminalia bellirica tannin-induced Nrf2/HO-1 signaling pathway in rats with high-altitude pulmonary hypertension.
Oxidative stress and endothelial cell dysfunction induced by high-altitude hypoxia have important roles in the pathological process of high-altitude pulmonary hypertension (HAPH). Tannins present in Terminalia bellirica (Gaertn.) Roxb. (TTR) have pharmacological activities that produce oxidation resistance and exert anti-inflammatory effects. Whether TTR exerts a protective effect on HAPH remains unknown. A rat model of HAPH was established. The mean pulmonary arterial pressure (mPAP) of the animals was measured, the serum levels of SOD, MDA, and GSH-Px were measured using ELISA, and the expression of Bax, Bcl-2, Nrf2, and HO-1 proteins in the lung tissue of each group of rats was measured using Western blotting. Pathological changes in the lung tissue were also observed. A model of damage to H2O2-induced pulmonary artery endothelial cells (PAECs) was generated, and cell proliferation was measured using CCK-8 assays. Flow cytometry was used to measure ROS levels in PAECs. Western blotting was used to detect the expression of Bax, Bcl-2, Nrf2, and HO-1 proteins in PAECs. The hemodynamic and pathologic findings showed that the mPAP of HAPH rats increased markedly, and the vascular wall thickness increased (P < 0.05). TTR reduced mPAP, alleviated or slowed pulmonary arterial remodeling, increased GSH-Px and SOD activity, lowered the level of MDA (P < 0.05), and downregulated the expression of Bax in the lung tissues of HAPH rats, while the expression of Bcl-2, Nrf2, and HO-1 was upregulated (P < 0.05). The results of the cell experiments showed that TTR inhibited H2O2-induced PAEC apoptosis and ROS production (P < 0.05), downregulated the expression of Bax in PAECs, and upregulated the expression of Bcl-2, Nrf2, and HO-1 (P < 0.05). The results suggest that TTR reduces pulmonary arterial pressure, decreases oxidative stress during HAPH, and exerts protective effects in rats with HAPH and that its mechanism of action is related to regulation of the Nrf2/HO-1 signaling pathway.


Development of Fluorophosphoramidate as a Biocompatibly Transformable Functional Group and its Application as a Phosphate Prodrug for Nucleoside Analogs.
Synthetic phosphate-derived functional groups are important for controlling the function of bioactive molecules in vivo. Herein we describe the development of a new type of biocompatible phosphate analog, a fluorophosphoramidate (FPA) functional group that has characteristic P-F and P-N bonds. We found that FPA with a primary amino group was relatively unstable in aqueous solution and was converted to a monophosphate, while FPA with a secondary amino group was stable. Furthermore, by improving the molecular design of FPA, we developed a reaction in which a secondary amino group is converted to a primary amino group in the intracellular environment and clarified that the FPA group functions as a phosphate prodrug of nucleoside. Various FPA-gemcitabine derivatives were synthesized and their toxicity to cancer cells were evaluated. One of the FPA-gemcitabine derivatives showed superior toxicity compared with gemcitabine and its ProTide prodrug, which methodology is widely used in various nucleoside analogs, including anti-cancer and anti-virus drugs.


Estimation of the size of drug-like chemical space based on GDB-17 data.
The goal of this paper is to estimate the number of realistic drug-like molecules which could ever be synthesized. Unlike previous studies based on exhaustive enumeration of molecular graphs or on combinatorial enumeration preselected fragments, we used results of constrained graphs enumeration by Reymond to establish a correlation between the number of generated structures (M) and the number of heavy atoms (N): logM = 0.584 × N × logN + 0.356. The number of atoms limiting drug-like chemical space of molecules which follow Lipinsky's rules (N = 36) has been obtained from the analysis of the PubChem database. This results in M ≈ 10³³ which is in between the numbers estimated by Ertl (10²³) and by Bohacek (10⁶⁰).


Oligoovulatory and anovulatory cycles in women with polycystic ovary syndrome (PCOS): what's the difference?
Polycystic ovary syndrome (PCOS) is a heterogeneous disorder. The phenotype may differ between patients who exhibit signs of recent ovulation and anovulatory PCOS patients. Our objective was to study differences in clinical and endocrine characteristics and response to ovulation induction (OI) treatment comparing oligoovulatory and anovulatory PCOS patients. We conducted a retrospective cohort study at a tertiary hospital. PCOS patients (n=1750) presenting with oligo- or amenorrhea were diagnosed according to the Rotterdam 2003 consensus criteria. Arbitrarily, oligoovulatory PCOS was defined by a single random serum progesterone level of 10 nmol/liter or higher. We evaluated the incidence of oligo- or amenorrhea, menstrual cycle length, serum androgen levels, follicle count, and OI outcome parameters. Anovulatory women (n=1541 of 1750, 88.1%) were more often amenorrheic (P<0.001) and presented with a longer cycle duration (P<0.001) compared with oligoovulatory women (n=209 of 1750, 11.9%). Serum levels of testosterone (P<0.001), the free androgen index (P<0.001), and total follicle count (P<0.005) were higher in anovulatory compared with oligoovulatory patients. During clomiphene citrate OI, more oligoovulatory women gained regular menstrual cycles (P<0.05), whereas after second-line treatment with recombinant FSH, more anovulatory women became pregnant (P<0.05). Oligoovulatory women with PCOS exhibit a milder phenotype of ovarian dysfunction and have a more favorable response to OI treatment using clomiphene citrate compared with anovulatory PCOS patients. However, during second-line treatment with recombinant FSH, anovulatory PCOS patients presented with a higher chance of pregnancy compared with oligoovulatory patients.