Evaluation of thermal antinociceptive effects after intramuscular administration of buprenorphine hydrochloride to American kestrels (Falco sparverius).
To evaluate the thermal antinociceptive effects and duration of action of buprenorphine hydrochloride after IM administration to American kestrels (Falco sparverius). 12 healthy 3-year-old American kestrels. Buprenorphine hydrochloride (0.1, 0.3, and 0.6 mg/kg) and a control treatment (saline [0.9% NaCl] solution) were administered IM in a randomized crossover experimental design. Foot withdrawal response to a thermal stimulus was determined 1 hour before (baseline) and 1.5, 3, and 6 hours after treatment administration. Agitation-sedation scores were determined 3 to 5 minutes before each thermal stimulus. Adverse effects were monitored for 6 hours after treatment administration. Buprenorphine hydrochloride at 0.1, 0.3, and 0.6 mg/kg, IM, increased thermal threshold for 6 hours, compared with the response for the control treatment. There were no significant differences among buprenorphine treatments. A mild sedative effect was detected at a dose of 0.6 mg of buprenorphine/kg. At the doses tested, buprenorphine hydrochloride resulted in thermal antinociception in American kestrels for at least 6 hours, which suggested that buprenorphine has analgesic effects in this species. Further studies with longer evaluation periods and additional forms of noxious stimuli, formulations, dosages, and routes of administration are needed to fully evaluate the analgesic effects of buprenorphine in American kestrels.


Altered spermidine/spermine N1-acetyltransferase activity as a mechanism of cellular resistance to bis(ethyl)polyamine analogues.
To develop a model system to investigate mechanisms of antiproliferative action of bis(ethyl)polyamine analogues, intermittent analogue treatments followed by recovery periods in drug-free medium were used to select an N(1), N(12)-bis(ethyl)spermine-resistant derivative of the Chinese hamster ovary cell line C55.7. The resulting C55.7Res line was at least 10-fold resistant to N(1),N(12)-bis(ethyl)spermine and N(1), N(11)-bis(ethyl)norspermine. The stability of the resistance in the absence of selection pressure was >/=9 months, indicating that a heritable genotypic change was responsible for the resistance phenotype. Polyamine transport alterations and multi-drug resistance were eliminated as causes of the resistance. Spermidine/spermine N(1)-acetyltransferase (SSAT) activity and regulation were altered in C55.7Res cells as basal activity was decreased, and no activity induction resulted from exposure to analogue concentrations, which caused 300-fold enzyme induction in parental cells. SSAT mRNA levels in the absence and presence of analogue were unchanged, but no SSAT protein was detected in C55.7Res cells. A point mutation, which results in the change leucine156 (a fully conserved residue) to phenylalanine, was identified in the C55.7Res SSAT cDNA. Expression of wtSSAT activity in C55.7Res cells restored sensitivity to bis(ethyl)polyamines. These results provided definitive evidence that SSAT activity is a critical target of the cytotoxic action of these analogues.


Angiogenic imbalance in maternal and cord blood is associated with neonatal birthweight and head circumference biometrics in major fetal congenital heart defects.
To ascertain whether abnormalities in fetal head circumference and/or estimated body weight are associated with angiogenic factors in maternal and cord blood and if the specific type of congenital heart defect (CHD) influences this association. Multicentric case-control study for major CHD. Recruitment was carried out between June 2010 and July 2018 at four tertiary care hospitals in Spain. Maternal venous blood was drawn at study inclusion and at delivery. Cord blood samples from fetuses with CHD were obtained at birth when possible. Placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and soluble endoglin (sEng) were measured in maternal and cord blood. PlGF, sFlt-1, and sEng levels were measured in maternal and cord blood in 237 cases with CHD and 260 healthy controls. Compared to controls, median PlGF values in maternal blood were significantly lower in the CHD group (MoM: 0.959 vs. 1.022; P <0.0001) and the median sFlt-1/PlGF was significantly higher (MoM: 1.032 vs. 0.974; P=0.0085); no between-group differences were observed in sEng values (MoM: 0.981 vs. 1.011; P=0.4673). Levels of sFlt-1 and sEng were significantly higher in cord blood obtained from fetuses with CHD versus controls (447 ± 51 vs. 264 ± 20 pg/mL; P=0.0470 and 8.30 ± 0.92 vs. 5.69 ± 0.34 ng/mL, P=0.0430, respectively). Maternal concentrations of sFlt-1 and the sFlt-1/PlGF ratio at study inclusion were negatively associated with birth weight and head circumference in CHD group. These data demonstrate the presence of an anti-angiogenic profile in maternal and cord blood in women carrying a fetus with CHD. This study shows, for the first time, that this imbalance is adversely associated with fetal head circumference and birth weight. This article is protected by copyright. All rights reserved.


Role of glucose in corneal metabolism.
Glucose catabolism by glycolysis and the Krebs cycle was examined in the isolated rabbit cornea incubated with [6-14C]glucose. The production of [14C]lactate and 14CO2 from this substrate provided minimal values for the fluxes through these pathways since the tissue was in metabolic steady state but not isotopic steady state during the 40-min incubation. The specific activity of lactate under these conditions was one-third of that for [6-14C]glucose, and label dilution by exchange with unlabeled alanine was minimal, suggesting that glycogen degradation was primarily responsible for this dilution of label in the Embden-Meyerhof pathway. In addition, considerable label accumulation was found in glutamate and aspartate. Calculations revealed that these endogenous amino acid pools were not isotopically equilibrated after the incubation period, suggesting that they were responsible for the isotopic nonsteady state by exchange dilution through transaminase reactions with labeled intermediates. An estimate of glucose oxidation by the Krebs cycle, which was corrected for label dilution by exchange, indicated that glucose could account for most of the measured corneal oxygen consumption that was coupled to oxidative phosphorylation. A minor component of this respiration could not be accounted for by glucose or glycogen oxidation. Additional experiments suggested that endogenous fatty acid oxidation was probably also active under these conditions. Finally, reciprocal changes in plasma membrane Na+-K+-ATPase activity induced by ouabain and nystatin were found to concomitantly alter oxygen consumption rates and [14C]lactate production from [6-14C]glucose. These results demonstrated the capacity for regulating glycolysis and the Krebs cycle in response to changing energy demands in the cornea.


Healthcare-associated carbapenem-resistant OXA-72-producing Acinetobacter baumannii of the clonal complex CC79 colonizing migratory and captive aquatic birds in a Brazilian Zoo.
Carbapenem resistance in Acinetobacter baumannii is a public health issue globally, mainly due to the production of carbapenem hydrolyzing class D β-lactamases (CHDLs). In Brazil, OXA-23 and OXA-143 CHDLs have been prevalent in A. baumannii from clinical settings, with some OXA-23 reports in the environmental samples, whereas OXA-72 has begun to be increasingly reported. This study aims to perform the genomic and microbiological characterization of carbapenem-resistant A. baumannii isolates recovered from migratory birds and captive birds inhabiting a lake within a Brazilian Zoo. Four hundred and eighty-one gram-negative bacilli were recovered from choanal and cloacal swabs obtained from 50 migratory birds and 37 captive birds present at the zoo's lake between July and August of 2012. Among all GNB, nine OXA-72-producing A. baumannii were detected from the microbiota of four migratory and five captive aquatic birds. The OXA-72-producing A. baumannii isolates were submitted to antimicrobial susceptibility test and PFGE, exhibiting a multidrug-resistant profile and clonal relatedness with OXA-72-positive human isolates circulating for eighteen years in a hospital setting. MLST, plasmid analysis and whole-genome sequencing revealed which all carbapenem-resistant A. baumannii from bird and human hosts belonged to clonal complex 79, and harboured a small plasmid (⁓16.6-kb in size), named pAC1-BRL, which carried blaOXA-72 gene, macrolide resistance genes msrE and mphE, and the toxin-antitoxin system AbkAB. To determine the impact of pAC1-BRL acquisition in the the capacity of a microorganism to survive in a competitive environment (in the following called fitness), the laboratory strain A. baumannii ATCC 19606 was used in the fitness experiments and suggested an increase of its relative fitness after the pAC1-BRL acquisition. In summary, the detection of OXA-72-producing A. baumannii strains belonging to CC79 in aquatic birds is a piece of epidemiological evidence demonstrating that dissemination of high-risk bacteria is extending beyond the hospital.


Oligodendroglioma.
Oligodendroglial tumors have historically been a fatal disease, despite maximum medical and surgical treatment. However, in the past 10 years, effective adjuvant therapies have been developed that have been found to significantly prolong patient survival and, in some instances, provide a cure. Improvements in our understanding of the molecular biology of these tumors, refinements in surgical technique, and advances in chemotherapeutic treatment have combined to produce this improvement in survival with little additional toxicity to patients. At the time of diagnosis, patients should undergo maximum surgical resection or needle biopsy if maximum surgical resection is not possible. Patients with low-grade lesions may be followed, receiving radiation only at the time of progression. Patients with high-grade lesions should be irradiated up front. In addition, selected patients should receive chemotherapy. Clinical trials remain critical to advancing our understanding of these tumors and improving our ability to cure these patients.


Synthesis and biological evaluation of novel urea, thiourea and squaramide diastereomers possessing sugar backbone.
A series of novel chiral 14 urea, thiourea and squaramide stereoisomers possessing carbohydrate backbones as well as amide functional groups was synthesized and characterized by their, 1H NMR, 13C NMR, FT-IR, HRMS, optical rotation, and melting points. Their antiproliferative activities were investigated against HeLa and PC3 cell lines. The compounds 9, 11 and 12 showed better activities at 25 μM against PC3 cell line with respect to the standard 5-fluorouracil (5-FU). Especially, the compounds 9 and 11 showed higher activities than the standard 5-FU even at low concentration (5 μM) against HeLa cell line. IC50 results also confirm these activities. The compounds 9, 10 and 11 have the IC50 values of 1.10 μM, 1.51 μM and 1.02 μM, respectively while 5-FU has 2.51 μM. Moreover, their cytotoxicity tests have proven that their viabilities were in between 50% and 100%.


Antitumoral actions of the anti-obesity drug orlistat (XenicalTM) in breast cancer cells: blockade of cell cycle progression, promotion of apoptotic cell death and PEA3-mediated transcriptional repression of Her2/neu (erbB-2) oncogene.
Orlistat (Xenicaltrade mark), a US Food and Drug Administration (FDA)-approved drug for bodyweight loss, has recently been demonstrated to exhibit antitumor properties towards prostate cancer cells by virtue of its ability to block the lipogenic activity of fatty acid synthase (FAS). FAS (oncogenic antigen-519) is up-regulated in about 50% of breast cancers, is an indicator of poor prognosis, and has recently been functionally associated with the Her2/neu (erbB-2) oncogene. We assessed the antitumoral effects of orlistat against the human breast cancer cell line SK-Br3, an in vitro paradigm of FAS and Her2/neu overexpression in breast cancer. Cell cycle analyses revealed that micromolar concentrations of orlistat induced, in a time- and dose-dependent manner, significant changes in the distribution of cell populations including a complete loss of G2-M phase, S-phase accumulation and a concomitant increase in the emerging sub-G1 (apoptotic) cells. Poly (ADP-ribose) polymerase (PARP) cleavage, an early event required for cells committed to apoptosis, was more predominant in orlistat-treated G1 phase cells. When we characterized signaling molecules participating in the cellular events following orlistat-induced inhibition of FAS activity and preceded inhibition of breast cancer cell proliferation, a dramatic down-regulation of Her2/neu-coded p185(Her2/neu) oncoprotein was found in orlistat-treated SK-Br3 cells (>90% reduction). Interestingly, a significant accumulation of the DNA-binding protein PEA3, a member of the Ets transcription factor family that specifically targets a PEA3-binding motif present on the Her2/neu gene promoter and down-regulates its activity, was observed in orlistat-treated SK-Br3 cells. When a Luciferase reporter gene driven by the Her2/neu promoter was transiently transfected in SK-Br3 cells, orlistat exposure was found to dramatically repress the promoter activity of Her2/neu gene, whereas a Her2/neu promoter bearing a mutated binding DNA sequence was not subject to negative regulation by orlistat, thus demonstrating that the intact PEA3 binding site on the Her2/neu promoter is required for the orlistat-induced transcriptional repression of Her2/neu overexpression. RNA interference (RNAi)-mediated silencing of FAS gene expression similarly repressed Her2/neu gene expression in a PEA3-dependent manner, thus ruling out a role for non-FAS orlistat-mediated effects. When the combination of orlistat and the anti-Her2/neu antibody trastuzumab (Herceptintrade mark) in either concurrent (orlistat + trastuzumab) or sequential (orlistat --> trastuzumab; trastuzumab --> orlistat) schedules was tested for synergism, addition or antagonism using the combination index (CI) method of Chou-Talalay, co-exposure of orlistat and trastuzumab demonstrated strong synergistic effects (CI10-90 = 0.110-0.847), whereas sequential exposure to orlistat followed by trastuzumab (CI10-90 = 0.380-1.210) and trastuzumab followed by orlistat (CI10-90 = 0.605-1.278) mainly showed additive or antagonistic interactions. Indeed, orlistat-induced FAS inhibition synergistically promoted apoptotic cell death when concurrently combined with trastuzumab as determined by an ELISA for histone-associated DNA fragments. Importantly, the degree of FAS expression in a panel of human breast cancer cell lines was predictive of sensitivity to orlistat-induced anti-proliferative effects as determined by a MTT-based characterization of metabolically viable breast cancer cells. Moreover, hypersensitivity to orlistat-induced cytotoxicity was observed in MCF-7 breast cancer cells engineered to overexpress Her2/neu (MCF-7/Her2-18 cells), which exhibit a significant up-regulation of FAS expression and activity. These findings reveal that the development of more potent and/or bioavailable orlistat's variants targeting the lipogenic activity of FAS may open a novel therapeutic avenue for treating Her2/neu-overexpressing breast carcinomas.


[Results of clinical application of methods of individual selection of chemotherapeutic preparations in the treatment of gliomas].
The method of autoradiography for testing the efficacy of cytostatics with subsequent individually chosen chemotherapy is one of the components of rational therapy for neuro-oncological patients. Purposeful chemotherapy was applied in 17 cases with gliomas. Favourable results were recorded in 70.6% of them. Twelve patients received regular courses of treatment with one agent which inhibited DNA synthesis in vitro most potently (in 7 the therapeutic result was favourable), 5 patients were given course of polychemotherapy (favourable effect in 100%). Prolonged survival and a good remission allow autoradiography to be recommended as a method for the individual choice of antiblastic agents.


Beta-adrenergic agents increase the phosphorylation of phosphofructokinase in isolated rat epididymal white adipose tissue.
Pieces of rat epididymal adipose tissue were incubated in medium containing [32P]phosphate for 2 h to achieve steady-state labelling of intracellular phosphoproteins and then with or without hormones for a further 15 min. Phosphofructokinase was rapidly isolated from the tissue by use of either Blue Dextran-Sepharose chromatography or immunoprecipitation with antisera raised against phosphofructokinase purified from rat interscapular brown adipose tissue. Similar extents of incorporation of 32P into phosphofructokinase were measured by both techniques. Exposure of the tissue to adrenaline or the beta-agonist isoprenaline increased phosphorylation by about 5-fold (to about 1.4 mol of phosphate/mol of enzyme tetramer). No change in phosphorylation was detected with the alpha-agonist phenylephrine, but exposure to insulin resulted in an approx. 2-fold increase. The increased phosphorylation observed with isoprenaline was found to be associated with a decrease in the apparent Ka for fructose 2,6-bisphosphate similar to that observed on phosphorylation of phosphofructokinase purified from rat epididymal white adipose tissue with the catalytic subunit of cyclic AMP-dependent protein kinase. These results support the view [Sale & Denton (1985) Biochem. J. 232, 897-904] that an increase in cyclic AMP in adipose tissue may result in an increase in glycolysis through the phosphorylation of phosphofructokinase by cyclic AMP-dependent protein kinase.


Heme oxygenase-1 levels and oxidative stress-related parameters in non-alcoholic fatty liver disease patients.
Non-alcoholic steatohepatitis (NASH) is a disorder that is histologically characterized by macrovesicular steatosis and lobular hepatitis with necrosis or ballooning degeneration and fibrosis. NASH can range from a benign condition to end-stage liver disease. The mechanisms promoting transition from steatosis to NASH appear to involve multiple cellular adaptations to the oxidative stress occurring when fatty acid metabolism is altered. We evaluated the relationship between lipid peroxidation and other oxidative stress biomarkers with changes in expression of heme oxygenase-1 (HO-1) in human hepatic steatosis ranging from simple steatosis to NASH. HO-1 expression, lipid peroxidation, ferritin and GSH levels were assayed from liver biopsies obtained from 60 subjects: 35 with NASH, 15 with simple steatosis and 10 controls. The HO-1 expression was significantly increased in NASH patients and the increase reflected the severity of the disease. A significant correlation was observed between the increased levels of HO-1 and ferritin, and between the increased levels of HO-1 and lipid peroxidation. Moreover, NASH patients with lower levels of GSH exhibited higher expression of HO-1. The induction of HO-1 is an adaptive response against oxidative damage elicited by lipid peroxidation and it may be critical in the progression of the disease.


Metabolic variables associated with response to cognitive behavioural therapy for depression in females: A Canadian biomarker integration network for depression (CAN-BIND) study.
Cognitive behavioural therapy (CBT) is an established first-line treatment for depression; however, it remains unclear which factors predict a positive outcome with this approach. Prior work suggests that co-morbid obesity predicts a poorer response to antidepressant medication. The current study examined whether there is an association between weight parameters and improvement of depressive symptoms with CBT. This was a secondary analysis of data from the "Clinical and Biological Markers of Response to Cognitive Behavioural Therapy for Depression - 6" (CANBIND-6; https://clinicaltrials.gov/ct2/show/NCT02883257) study. Adult participants (n = 41) with a diagnosis of Major Depressive Disorder (MDD) or Persistent Depressive Disorder (PDD) were recruited from an outpatient tertiary psychiatric centre in Canada. Participants completed 20 individual sessions of CBT over 16 weeks. The primary measure for treatment outcome was the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 16. Thirty-seven participants completed assessments pre and post CBT. Baseline weight parameters were not correlated with treatment response to CBT in the entire group. There was a significant sex*waist circumference (WC) (B:-1.34; p = 0.004) and sex*body mass index (BMI) interaction (B:-2.03; p:0.009). In female participants, baseline waist circumference, but not BMI, significantly predicted week 16 MADRS after controlling for age and baseline MADRS (B:0.422 p:0.049). The major limitation of our preliminary finding is the small sample size. Our preliminary findings suggest that higher waist circumference may be associated with a better treatment response to CBT for depression in females. This result could be of clinical relevance and warrants further investigation in larger and independent samples.


EphA2 engages Git1 to suppress Arf6 activity modulating epithelial cell-cell contacts.
ADP-ribosylation factor (Arf) 6 activity is crucially involved in the regulation of E-cadherin-based cell-cell adhesions. Erythropoietin-producing hepatocellular carcinoma (Eph)-family receptors recognize ligands, namely, ephrins, anchored to the membrane of apposing cells, and they mediate cell-cell contact-dependent events. Here, we found that Arf6 activity is down-regulated in Madin-Darby canine kidney cells, which is dependent on cell density and calcium ion concentration, and we provide evidence of a novel signaling pathway by which ligand-activated EphA2 suppresses Arf6 activity. This EphA2-mediated suppression of Arf6 activity was linked to the induction of cell compaction and polarization, but it was independent of the down-regulation of extracellular signal-regulated kinase 1/2 kinase activity. We show that G protein-coupled receptor kinase-interacting protein (Git) 1 and noncatalytic region of tyrosine kinase (Nck) 1 are involved in this pathway, in which ligand-activated EphA2, via its phosphorylated Tyr594, binds to the Src homology 2 domain of Nck1, and then via its Src homology 3 domain binds to the synaptic localizing domain of Git1 to suppress Arf6 activity. We propose a positive feedback loop in which E-cadherin-based cell-cell contacts enhance EphA-ephrinA signaling, which in turn down-regulates Arf6 activity to enhance E-cadherin-based cell-cell contacts as well as the apical-basal polarization of epithelial cells.


[Yersinia pseudotuberculosis and Yersinia enterocolitica].
Yersinia pseudotuberculosis is a very homogeneous species, with only six sero-groups and which can not also be lysotyped. The essential reservoir is made up of rodents, birds, cats and soil and is the origin of human infection. Y. enterocolitica has 5 biochemical types, 57 serotypes (types 03 and 09 are the most commonly involved in human pathology) and 11 lysotypes. Contamination is essentially by direct human-human contact from healthy carriers or, more rarely, via infected food. The aetiological diagnosis of the arthritis occurring after an episode of abdominal Yersinia (enteritis, mesenteric adenitis) depends on the simultaneous search for bacteria in the stools and for antibodies.


Simple, fast, and flexible framework for matrix completion with infinite width neural networks.
Matrix completion problems arise in many applications including recommendation systems, computer vision, and genomics. Increasingly larger neural networks have been successful in many of these applications but at considerable computational costs. Remarkably, taking the width of a neural network to infinity allows for improved computational performance. In this work, we develop an infinite width neural network framework for matrix completion that is simple, fast, and flexible. Simplicity and speed come from the connection between the infinite width limit of neural networks and kernels known as neural tangent kernels (NTK). In particular, we derive the NTK for fully connected and convolutional neural networks for matrix completion. The flexibility stems from a feature prior, which allows encoding relationships between coordinates of the target matrix, akin to semisupervised learning. The effectiveness of our framework is demonstrated through competitive results for virtual drug screening and image inpainting/reconstruction. We also provide an implementation in Python to make our framework accessible on standard hardware to a broad audience.


Spatial-temporal distribution characteristics of pollutants of heavy-duty diesel vehicles in urban road networks: a case study of Kunming City.
With the continuous promotion of urbanization in China, the economic level of small and medium-sized cities has been further improved. The transportation industry is crucial in promoting urban-rural integration and construction. Still, motor vehicle emissions also bring air pollution problems to cities, with heavy-duty diesel vehicle emissions severely impacting the urban environment. This study used a bottom-up approach to analyze the spatial emission characteristics of heavy-duty diesel vehicles under different road types in Kunming, a typical medium-sized city in China. A high-resolution emission inventory (1 km × 1 km) of heavy-duty diesel vehicles was developed using the vehicle emission inventory model (VEIN) and ArcGIS, and the vehicle emission standards were determined by the Weibull survival rate curve. The VEIN emission model was optimized using a velocity correction curve. The results showed that heavy-duty vehicles had a more significant impact on the emissions during the morning and evening peak hours, with low emission levels during the day and high emission levels at night and early morning. The total daily emissions of carbon monoxide (CO), hydrocarbons (HC), nitrogen oxides (NOx), and particulate matter (PM10 and PM2.5) from heavy-duty diesel vehicles in Motorway, Trunk, Primary, Secondary, and Tertiary were 14.44 tons, 5.26 tons, 4.78 tons, 7.02 tons, and 3.83 tons, respectively. China III heavy-duty diesel vehicles mainly contributed to CO, HC, NOx, and PM emissions. This study can be used as an essential reference for controlling the exhaust emissions of HDDVs in Kunming.


Single-molecule imaging of pore-forming toxin dynamics in droplet interface bilayers.
Single-channel recording from pore-forming toxins (PFTs) provides a clear and direct molecular readout of toxin action. However to complete any mechanistic understanding of PFT behavior, this functional kinetic readout must be linked to the underlying changes in toxin structure, binding, conformation, or stoichiometry. Here we review how single-molecule imaging methods might be used to further our understanding of PFTs, and provide detailed practical guidance on the use of droplet interface bilayers as a method capable of examining both single-molecule fluorescence and single-channel electrical signals from PFTs.


[A retrospective study for the analysis of collateral effects of amiodarone].
We analyzed retrospectively 130 patients treated with amiodarone. They were seen at the Arrhythmias Clinic of this Institute from march 1981 until may 1988 with the purpose of evaluate the frequency of the side effects of the drug. The group of patients consisted of 67 men and 63 women, the mean age was 32 years and they were followed for about 32 months. The average dose of the drug was 1.069 gr per week. All of them had a physical and radiological examination, an ECG and laboratory tests. Besides, 86 patients went through an electrophysiological study at least once. One hundred and eighteen patients had periodical tests for thyroid function. All of the patients had a check up every 3 or 6 months. the response to the drug was good or even excellent in 83% of patients. They did not show electrocardiographic changes of statistic significance (duration of the PR, QRS or QT). The ophthalmologic examination showed corneal deposits in 48% of patients, but in no case there was indication to stop the treatment. Ten patients had a spontaneous regression of these deposits. Alterations of the thyroid function were seen in 33.8% of patients, 14 had hypothyroidism and seven hyperthyroidism, the others simple goitre. In four of these cases the drug was discontinued. Dermatologic lesions were seen in only 4% of patients. Despite the high frequency of side effects the need for stopping the treatment was low, with a high percentage of drug efficacy.


The effect of urapidil on cardiac alpha- and beta-adrenoceptors.
In the present study the effects of the antihypertensive drug urapidil on cardiac adrenoceptors in various regions of the heart were analyzed. On the isolated rabbit papillary muscle urapidil was found to produce a competitive antagonism against the alpha 1-agonist phenylephrine with a pA2-value of 6.4 in the presence of the beta-antagonist sotalol (5 X 10(-5) mol/l). In the same preparation urapidil also antagonized the positive inotropic effects evoked by the beta-adrenoceptor agonist isoprenaline yielding a pA2-value of 5.9. An antagonism against the positive inotropic effect of isoprenaline with the same pA2-value could also be demonstrated in guinea pig left atria. For further characterization of urapidil its effect against the beta 2-adrenoceptor agonist fenoterol on the carbachol contracted tracheal chain of the guinea pig was investigated. A weak antagonism with a pA2-value of 4.9 was observed. Thus the beta 1-adrenolytic potency of urapidil was found to be about 10 times higher than the beta 2-adrenolytic one. On the isolated perfused rabbit heart urapidil inhibited the electrically evoked increase in heart rate by 27 and 63% in a concentration of 10(-6) and 10(-5) mol/l, respectively, whereas the stimulation induced noradrenaline release was increased by 25 and 51%. This rise in noradrenaline release by urapidil was antagonized by clonidine 10(-7) and 10(-6) mol/l. From these results it can be concluded that urapidil acts not only as an antagonist at cardiac alpha 1- and beta-adrenoceptors, but also on alpha 2-adrenoceptors located presynaptically. The antagonism at these receptors against endogenous noradrenaline leads to an enhanced transmitter release.(ABSTRACT TRUNCATED AT 250 WORDS)


Translation, cultural adaptation, and psychometric properties of the Spanish version of the Combat Exposure Scale (CES-S) with U.S. military Spanish speaking Latino veterans living in the Caribbean: A cross-sectional preliminary data study.
The Combat Exposure Scale (CES) is one of the most used self-report instruments to assess various combat situations experienced by military personnel. This article presents a comprehensive translation and cultural adaptation of the CES to Spanish and its psychometric properties. Fifty-five (n = 55) U.S. military Spanish-speaking Latino veterans diagnosed with combat-related PTSD were recruited from 2018 to 2020 to participate in this cross-sectional preliminary data study at the VA Caribbean Health Care System. The translation and cultural adaptation followed the recommendations by Chavez & Canino (2005). Statistical analysis included principal component factor analysis, internal consistency analysis, and content validity analysis. It included two different expert bilingual committees composed of veterans with combat experience and university professors at a doctoral level. The CES-S consists of seven items. The principal component factor analysis resulted in one factor and the content validity of =1. CES-S has an internal consistency of α=.84. The CES-S is suitable for its use with Spanish-speaking Latino veteran samples. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Extracorporeal human whole blood in motion, as a tool to predict first-infusion reactions and mechanism-of-action of immunotherapeutics.
First infusion reactions along with severe anaphylactic responses can occur as a result of systemic administration of therapeutic antibodies. The underlying mechanisms by which monoclonal antibodies induce cytokine release syndrome (CRS) can involve direct agonistic effects via the drug target, or a combination of target-engagement along with innate receptor interactions. Despite the wide variety of pathways and cells that can play a role in CRS, many currently used assays are devoid of one or more components that must be present for these responses to occur. One assay that has not been assessed for its capacity to predict CRS is the modified Chandler loop model. Herein we evaluate a plethora of commercially available monoclonal antibodies to evaluate the modified Chandler loop model's potential in CRS prediction. We demonstrate that in a 4-hour loop assay, both the superagonistic antibodies, anti-CD3 (OKT3) and anti-CD28 (ANC28.1), display a clear cytokine response with a mixed adaptive/innate cytokine source. OKT3 induce TNFα and IFN-γ release in 20 out of 23 donors tested, whereas ANC28.1 induce TNF-α, IL-2 and IFN-γ release in all donors tested (n=18-22). On the other hand, non-agonistic antibodies associated with no or low infusion reactions in the clinic, namely cetuximab and natalizumab, neither induce cytokine release nor cause false positive responses. A TGN1412-like antibody also display a clear cytokine release with an adaptive cytokine profile (IFN-γ and IL-2) and all donors (n=9) induce a distinct IL-2 response. Additionally, the value of an intact complement system in the assay is highlighted by the possibility to dissect out the mechanism-of-action of alemtuzumab and rituximab. The loop assay can either complement lymph node-like assays or stand-alone to investigate drug/blood interactions during preclinical development, or for individual safety screening prior to first-in-man clinical trial.


[Ocular surface acidity and buffering system (by studying the conjunctival sac)].
As any mucous membrane the conjunctiva is characterized by a definite pH value which guarantees-physiological functioning of the ocular surface. The most commonly used method of assessment is potentiometric pH measurement with ion-specific glass microelectrodes. The results, however, can be affected by such factors, as conjunctival sac zoning, tissue acidity, epithelial trauma, and reflex tear secretion. Few data and hypotheses are available on mechanisms of maintaining the acid-base balance of the conjunctival sac (bicarbonate buffering system in particular). to study spatial variability of conjunctival tear fluid pH and possible mechanisms of its maintenance using original methods of acidity measurement and mineral content assessment. Tear pH was determined in 42 healthy participants (84 eyes) by means of litmus test strips and computer- aided colorimetry. Electron probe microanalysis in combination with energy dispersive spectrometry was performed in 8 healthy participants (8 eyes, 8 samples). In the group of 42 healthy participants (84 eyes) the pH value of conjunctival tear fluid varied from 6.30 to 7.23 with the average of 6.76 and pH mode 6.74. The pH value of conjunctival mucous discharge was measured in 25 healthy participants (28 eyes) and varied from 7.00 to 8.00 with the average of 7.26 and pH mode 7.30. The main mineral components of tear fluid are chlorine, sodium, potassium, and boron. Borate buffer is regarded as a mechanism of maintaining the acid-base balance of the ocular surface. The developed method of pH measurement ensuresreliable determination of conjunctival sac acidity in accordance with zoning and heterogeneity of its media as well as the complex structure of the tear film. In a healthy population, the acidity of tear significantly differs from that of conjunctival mucous discharge. Soluble chlorine, sodium, potassium, and boron compounds are the prevailing mineral components of tear fluid. Borate buffer appears to be the most stable of all mechanisms of maintaining the acid-base status of tear fluid.


Changes in BMI and psychosocial functioning in partners of women who undergo gastric bypass surgery for obesity.
There is very little research exploring the effects of Roux-en-Y gastric bypass surgery (RYGB) on the patient's partner. The aim of the present study was to investigate longitudinally whether male partners of female RYGB patients were affected in terms of BMI, sleep quality, body dissatisfaction, depression, and anxiety. Thirty-seven women, with partners who were willing to participate, were recruited from RYGB waiting lists at five Swedish hospitals. Data collection took place during two home visits, 3 months before and 9 months after RYGB surgery. Anthropometrical data were documented, and both women and men completed the Hospital Anxiety and Depression Scale (HADS) and the Karolinska Sleep Questionnaire (KSQ). The men also completed the Male Body Dissatisfaction Scale (MBDS). The men's BMI changes between the two time points that were analysed using general estimating equation (GEE) regression. Their BMI decreased significantly (β = -0.9, p = 0.004). The change was more pronounced in the 26 men who had a baseline BMI of ≥25 (β = -1.4, p < 0.001). Fixed-effects regression showed a statistically significant association between the men's weight loss and that of the women (β = 0.3, p = 0.004). There were no significant changes in the men's HADS, KSQ, or MBDS scores. Overweight/obese male partners of RYGB patients also lose weight during the first 9 months post-operatively. However, symptoms of body dissatisfaction, anxiety, and depression remain unchanged, as does self-reported sleep quality.


Control of sensitivity to inactivation by H2O2 and broad-spectrum near-UV radiation by the Escherichia coli katF locus.
Mutations in the Escherichia coli katF gene (hydroperoxidase II) result in sensitivity to inactivation by H2O2 and broad-spectrum near-UV (NUV; 300 to 400 nm) radiation. Another mutation, nur, originally described as conferring sensitivity to inactivation by broad-spectrum and monochromatic NUV, also confers sensitivity to inactivation by H2O2. Genetic analysis via transduction suggests that the nur mutation allele of the katF locus. As previously reported for broad-spectrum and monochromatic NUV wavelengths, the sensitivity of a particular strain to H2O2 inactivation is also independent of the recA and uvrA alleles. Extracts of nur and katF strains lack catalase (hydroperoxidase II) as revealed by polyacrylamide gels stained for such activity, which is consistent with the genetic results.


Pathogen Detection in Ornithodoros sonrai Ticks and Invasive House Mice Mus musculus domesticus in Senegal.
Ornithodoros sonrai (O. sonrai) ticks are the only known vectors of Borrelia crocidurae, an agent of tick-borne relapsing fever (TBRF) borreliosis. Rodents serve as principal natural reservoirs for Borrelia. Our research objective was to detect TBRF Borrelia and other zoonotic bacterial infections in ticks and in house mice Mus musculus domesticus, an invasive species currently expanding in rural northern Senegal. Real-time and conventional PCR were utilized for detecting Borrelia and other bacterial taxa. The analyses were performed on 253 specimens of O. sonrai and 150 samples of brain and spleen tissue from rodents. Borrelia crocidurae was found in one O. sonrai tick and 18 Mus musculus domesticus samples, with prevalences of 0.39 percent and 12 percent, respectively, as well as Ehrlichia sp. in one Mus musculus domesticus. Further, we were able to detect the presence of a potentially infectious novel species belonging to the Anaplasmataceae family for the first time in O. sonrai ticks. More attention should be paid to the house mouse and O. sonrai ticks, as they can be potential hosts for novel species of pathogenic bacteria in humans.


Identification of cryptic MHC I-restricted epitopes encoded by HIV-1 alternative reading frames.
Human immunodeficiency virus (HIV) 1 major histocompatibility complex (MHC) I-restricted epitopes are widely believed to be derived from viral proteins encoded by primary open reading frames. However, the HIV-1 genome contains alternative reading frames (ARFs) potentially encoding small polypeptides. We have identified a panel of epitopes encoded by ARFs within the gag, pol, and env genes. The corresponding epitopic peptides were immunogenic in mice humanized for MHC-I molecules. In addition, cytotoxic T lymphocytes recognizing these epitopes were found in HIV-infected patients. These results reveal the existence of atypical mechanisms of HIV-1 epitope generation. They indicate that the repertoire of epitopes recognized by the cellular anti-HIV-1 immune response is broader than initially thought. This should be taken into account when designing vaccine strategies aimed at activating these responses.


Tolerance Induction in Liver.
Liver is an exclusive anatomical and immunological organ that displays a considerable tolerance effect. Liver allograft acceptance is shown to occur spontaneously within different species. Although in human transplant patients tolerance is rarely seen, the severity level and cellular mechanisms of transplant rejection vary. Non-paranchymal liver cells, including Kupffer cells, liver sinusoidal endothelial cells, hepatic stellate cells, and resident dendritic cells may participate in liver tolerogenicity. The mentioned cells secret anti-inflammatory cytokines such as TGF-β and IL-10 and express negative co-stimulatory molecules like PD-L1 to mediate immunosuppression. Other mechanisms such as microchimerism, soluble major histocompatibility complex and regulatory T cells may take part in tolerance induction. Understanding the mechanisms involved in liver transplant rejection/tolerance helps us to improve therapeutic options to induce hepatic tolerance.


Comparative analysis of processing methods in fat grafting.
Centrifugation is a popular processing method, with an unclear mechanism of action. Hypotheses include fat concentration, reduced inflammatory response by removal of blood, and concentration of adipose-derived stem cells. The authors performed multiple experiments to determine the role of centrifugation and compared it with a different processing method (mesh/gauze technique). Lipoaspirate components were quantified after centrifugation at increasing speed to determine concentration efficacy. For comparison, the authors quantified the concentration efficacy of mesh/gauze. They also compared the number of adipose-derived stem cells isolated by either method. To determine the effects of each component, they compared fat alone to fat mixed with various spinoff components in a mouse model. They also compared centrifugation to mesh/gauze. The adipocyte fraction remains constant above 5000 g, whereas 1200 g results in 91 percent concentrated fat. Mesh/gauze also results in 90 percent concentrated fat. The number of adipose-derived stem cells in 1 g of fat was 1603 ± 2020 and 1857 ± 1832 in the centrifuge and mesh/gauze groups, respectively (p = 0.86). Five "add-back" groups were created: fat plus oil, fat plus surgical tumescence, fat plus fresh tumescence, fat plus cell pellets and fresh tumescence, and fat plus cell pellets. The fat-only group had better retention than the groups mixed with tumescence, regardless of whether it was surgical, fresh, or had cell pellets. Oil did not affect grafts. Centrifugation at 1200 g was equivalent to mesh/gauze (0.73 ± 0.12 g and 0.72 ± 0.13 g, respectively). Centrifugation improves graft retention by concentration of the adipocyte fraction. The concentration efficacy of mesh/gauze is equivalent to centrifugation at 1200 g, with equivalent in vivo outcomes.


Numerical magnitude representations influence arithmetic learning.
This study examined whether the quality of first graders' (mean age = 7.2 years) numerical magnitude representations is correlated with, predictive of, and causally related to their arithmetic learning. The children's pretest numerical magnitude representations were found to be correlated with their pretest arithmetic knowledge and to be predictive of their learning of answers to unfamiliar arithmetic problems. The relation to learning of unfamiliar problems remained after controlling for prior arithmetic knowledge, short-term memory for numbers, and math achievement test scores. Moreover, presenting randomly chosen children with accurate visual representations of the magnitudes of addends and sums improved their learning of the answers to the problems. Thus, representations of numerical magnitude are both correlationally and causally related to arithmetic learning.


Glyceollins, a novel class of soy phytoalexins, inhibit angiogenesis by blocking the VEGF and bFGF signaling pathways.
Glyceollins are a novel class of soybean phytoalexins with potential cancer-preventive and antiestrogenic effects. The angiogenic cascade during tumor development consists of the release of angiogenic factors and binding of angiogenic factors to receptors on endothelial cells to activate downstream signaling pathways. However, the potential medicinal value of glyceollins, especially in antiangiogenesis, remains unexplored. Here, we investigated the antiangiogenic activity of glyceollins and their underlying mechanisms. Glyceollins inhibited vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) induced in vitro angiogenic activity. Glyceollins inhibited VEGF receptor-2 or FGF receptor-1 activity and their downstream signaling pathways such as extracellular regulated kinase 1/2, c-Jun N-terminal kinase, as well as p38 mitogen-activated protein kinase and focal adhesion kinase induced by VEGF or bFGF. Glyceollins significantly suppressed VEGF receptor-2 kinase activity assayed by the ELISA. Glyceollins significantly attenuated in vivo and ex vivo microvessel development in a dose-dependent manner and tumor growth by suppressing microvessel density in Lewis lung carcinoma (LLC) mouse xenograft. Thus, glyceollins, elicited ingredients of soy source, target the signaling pathways mediated by VEGF or bFGF, providing new perspectives into potential therapeutics for preventing and treating hypervascularized diseases including cancer.


Evaluation of the efficiency of continuous wavelet transform as processing and preprocessing algorithm for resolution of overlapped signals in univariate and multivariate regression analyses; an application to ternary and quaternary mixtures.
Wavelets have been adapted for a vast number of signal-processing applications due to the amount of information that can be extracted from a signal. In this work, a comparative study on the efficiency of continuous wavelet transform (CWT) as a signal processing tool in univariate regression and a pre-processing tool in multivariate analysis using partial least square (CWT-PLS) was conducted. These were applied to complex spectral signals of ternary and quaternary mixtures. CWT-PLS method succeeded in the simultaneous determination of a quaternary mixture of drotaverine (DRO), caffeine (CAF), paracetamol (PAR) and p-aminophenol (PAP, the major impurity of paracetamol). While, the univariate CWT failed to simultaneously determine the quaternary mixture components and was able to determine only PAR and PAP, the ternary mixtures of DRO, CAF, and PAR and CAF, PAR, and PAP. During the calculations of CWT, different wavelet families were tested. The univariate CWT method was validated according to the ICH guidelines. While for the development of the CWT-PLS model a calibration set was prepared by means of an orthogonal experimental design and their absorption spectra were recorded and processed by CWT. The CWT-PLS model was constructed by regression between the wavelet coefficients and concentration matrices and validation was performed by both cross validation and external validation sets. Both methods were successfully applied for determination of the studied drugs in pharmaceutical formulations.


Evaluation of valine requirement of the commercial layer using a corn-soybean meal basal diet.
An experiment was conducted with Hy-Line W-36 hens to evaluate the Val requirement in a corn-soybean meal diet. Eight experimental diets were fed with Val levels of 0.700, 0.665, 0.630, 0.595, 0.560, and 0.525%. A positive control (0.765% Val) was fed. Egg production (EP) was increased by addition of Val to 0.630%. Egg weight (EW) was increased by addition of Val to 0.655%. Broken-line regression indicated a daily Val requirement of 592.5, 677.7, and 619.0 mg/hen per d for EP, EW, and egg contents (EC), respectively. This requirement was 13.1 mg/g of EC.


Electroacupuncture-induced neural activation detected by use of manganese-enhanced functional magnetic resonance imaging in rabbits.
To investigate the effects of acupuncture on neural activity detected by use of manganese-enhanced functional magnetic resonance imaging (fMRI) and elucidate the relationship between somatic acupoint stimulation and brain activation. 40 New Zealand White rabbits. Manganese-enhanced fMRI was performed in anesthetized rabbits manipulated with electroacupuncture (EA) on Zusanli (ST-36) and Yanglingquan (GB-34) acupoints. Image acquisition was performed on a 1.5T superconductive clinical scanner with a circular polarized extremity coil. T1-weighted images were acquired sequentially as follows: baseline, after mannitol injection, after manganese infusion, and 5 and 20 minutes after initiation of EA. Changes in focal neural activity were detected by use of manganese-enhanced fMRI. Stimulation on Zusanli (ST-36) for 5 minutes resulted in activation of the hippocampus, whereas stimulation on Yanglingquan (GB-34) resulted in activation of the hypothalamus, insula, and motor cortex. Activation became less specific after 20 minutes of EA. Furthermore, stimulation on ipsilateral acupoints led to bilateral brain activation. Each acupoint has a corresponding cerebral linkage, and stimulation on these points resulted in time-dependent neural activation. Understanding the linkage between peripheral acupoint stimulation and central neural pathways may provide a useful guide for clinical applications of acupuncture.


Apparent Optical Properties of the Sea Illuminated by Sun and Sky: case of the optically Deep Sea.
The influence of illumination by direct sunlight and the diffuse light of the sky on the apparent optical properties of seawater are studied. This study is based on the earlier self-consistent approach for solution of the radiative transfer equation. The resulting set of equations couples diffuse reflectance and diffuse attenuation coefficients and other apparent optical properties of the sea with inherent optical properties of seawater and parameters of illumination by the Sun and the sky. The resulting equations in their general form are valid for any possible values of absorption and backscattering coefficients.


[Controversial aspects of the genesis of megaureter].
The cause of congenital ureter dilatation as well as its nomenclature are controversial. The question arises as to whether there is a common denominator for this multiform syndrome. There are abundant possibilities of disturbance during the development of the ureter. The muscle coat of the developing fetal ureter reacts with an alteration of the wall structure. In view of the multiplicity of etiological factors which can affect the development of the ureter, a disturbance of intrauterine urinary drainage which is transient or permanent probably has a functional or mechanical basis. At any events, a subvesical obstruction, which may also be the cause, must be excluded.


Successful termination of atrial flutter by ibutilide during pregnancy.
Sustained atrial fibrillation and atrial flutter during pregnancy are uncommon arrhythmias that can significantly complicate normal prenatal care. Direct current external cardioversion is the current method of terminating these arrhythmias. In practice, however, this technique is sometimes considered undesirable by both physician and patients due to the need for deep sedation or anesthesia. In the present study, we describe the use of ibutilide to safely terminate symptomatic persistent atrial flutter in a patient during her 24th week of pregnancy.


Biomedical nanomotors: efficient glucose-mediated insulin release.
We report herein the design of an autonomous glucose-responsive smart nanomachine for insulin (In) delivery based on ultrasound (US)-propelled nanomotors combined with an enzyme-based sensing-effector unit. Gold nanowire (AuNW) motors have been coupled with a mesoporous silica (MS) segment, which was gated with pH-responsive phenylboronic acid (PBA)-glucose oxidase (GOx) supramolecular nanovalves responsible for the insulin release. Glucose-induced protonation of the PBA groups triggers the opening of the pH-driven gate and uncapping of the insulin-loaded nanovalves. The insulin-loaded MS-Au nanomotors displayed an efficient US-driven movement that dramatically accelerates the glucose-triggered insulin release when compared to their static counterparts. Such coupling of the locomotion of nanovehicles with gated insulin-containing nanocontainers and glucose-responsive nanovalves holds great promise for the improved management of diabetes.


The importance of the serum quantitative levels of hepatitis B surface antigen and hepatitis B e antigen in children with chronic hepatitis B.
We aimed to investigate the clinical importance of quantitative levels of serum hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg), and to detect their correlation with hepatitis B virus (HBV) DNA load, alanine aminotransferase (ALT) levels, hepatic activity index (HAI) and fibrosis scores. A total of 56 HBeAg-positive children with chronic hepatitis B (CHB) were included in the study. Quantification of HBsAg and HBeAg was performed using an automated chemiluminescent microparticle immunoassay. Comparisons were performed using the paired t-test, Mann-Whitney U test or t-test for independent samples. Correlations were tested using the Pearson correlation analysis. Significant differences were found between groups of pre- and post treatment quantitative levels of HBsAg, HBeAg, HBV DNA, and ALT. Comparison of HBsAg, HBeAg, HBV DNA, and ALT levels before the treatment and decrease ratios of these levels after treatment according to HAI and fibrosis scores did not show any statistically significant differences. There was a positive correlation between pretreatment HBV DNA load and HBeAg levels, and a negative correlation between pretreatment HBV DNA and ALT levels. There was a negative correlation between decrease ratios of HBsAg and ALT levels after treatment. Patients with post treatment HBeAg seroconversion had a lower post treatment HBV DNA load and a higher decrease ratio of HBsAg than patients who did not have HBeAg seroconversion. The present study indicated that HBsAg and HBeAg levels significantly decreased during treatment and that HBeAg correlated with HBV DNA load. Quantitative HBeAg and HBsAg assays could therefore have an important role in treatment of CHB.


The transcription factor Krüppel-like factor 5 promotes cell growth and metastasis via activating PI3K/AKT/Snail signaling in hepatocellular carcinoma.
The transcription factor Krüppel-like factor 5 (KLF5) is highly expressed in many cancers and serves as a prognostic factor. However, the function of KLF5 in hepatocellular carcinoma (HCC) is unclear. In this study, we found that KLF5 was significantly overexpressed in HCC cell lines and specimens, and high KLF5 expression predicted a poor prognosis for HCC patients. Then, we studied the effects of KLF5 on the proliferation, apoptosis, migration and invasion of HCC cells in vitro and vivo. The inhibition of KLF5 markedly inhibited HCC growth and metastasis, while KLF5 overexpression promoted these processes. In addition, we observed that KLF5 could promote the epithelial-mesenchymal transition (EMT) in HCC via the PI3K/AKT/Snail signaling pathway. The silencing of KLF5 in HCC cell lines downregulated the expression of N-cadherin, Vimentin and Snail and increased the expression of the epithelial marker E-cadherin. The expression of MMP2 and MMP9 was also decreased in KLF5-silenced HCC cells. However, opposite results were observed in the KLF5-overexpressing group. These results indicate that KLF5 plays a significant role in HCC progression and metastasis and induces EMT via activating PI3K/AKT/Snail signaling, and the inhibition of KLF5 may be a potential treatment modality for patients with HCC.


Comparisons of distance methods for combining covariates and abundances in microbiome studies.
This article compares different methods for combining abundance data, phylogenetic trees and clinical covariates in a nonparametric setting. In particular we study the output from the principal coordinates analysis on UNIFRAC and WEIGHTED UNIFRAC distances and the output from a double principal coordinate analyses DPCOA using distances computed on the phylogenetic tree. We also present power comparisons for some of the standard tests of phylogenetic signal between different types of samples. These methods are compared both on simulated and real data sets. Our study shows that DPCoA is less robust to outliers, and more robust to small noisy fluctuations around zero.


Perspective on the Relationship between GABAA Receptor Activity and the Apparent Potency of an Inhibitor.
In electrophysiological experiments, inhibition of a receptor-channel, such as the GABAA receptor, is measured by co-applying an agonist producing a predefined control response with an inhibitor to calculate the fraction of the control response remaining in the presence of the inhibitor. The properties of the inhibitor are determined by fitting the inhibition concentration- response relationship to the Hill equation to estimate the midpoint (IC50) of the inhibition curve Objective: We sought to estimate sensitivity of the fitted IC50 to the level of activity of the control response Methods: The inhibition concentration-response relationships were calculated for models with distinct mechanisms of inhibition. In Model I, the inhibitor acts allosterically to stabilize the resting state of the receptor. In Model II, the inhibitor competes with the agonist for a shared binding site. In Model III, the inhibitor stabilizes the desensitized state. The simulations indicate that the fitted IC50 of the inhibition curve is sensitive to the degree of activity of the control response. In Models I and II, the IC50 of inhibition was increased as the probability of being in the active state (PA) of the control response increased. In Model III, the IC50 of inhibition was reduced at higher PA. We infer that the apparent potency of an inhibitor depends on the PA of the control response. While the calculations were carried out using the activation and inhibition properties that are representative of the GABAA receptor, the principles and conclusions apply to a wide variety of receptor- channels.


Comparing Ancient DNA Preservation in Petrous Bone and Tooth Cementum.
Large-scale genomic analyses of ancient human populations have become feasible partly due to refined sampling methods. The inner part of petrous bones and the cementum layer in teeth roots are currently recognized as the best substrates for such research. We present a comparative analysis of DNA preservation in these two substrates obtained from the same human skulls, across a range of different ages and preservation environments. Both substrates display significantly higher endogenous DNA content (average of 16.4% and 40.0% for teeth and petrous bones, respectively) than parietal skull bone (average of 2.2%). Despite sample-to-sample variation, petrous bone overall performs better than tooth cementum (p = 0.001). This difference, however, is driven largely by a cluster of viking skeletons from one particular locality, showing relatively poor molecular tooth preservation (<10% endogenous DNA). In the remaining skeletons there is no systematic difference between the two substrates. A crude preservation (good/bad) applied to each sample prior to DNA-extraction predicted the above/below 10% endogenous DNA threshold in 80% of the cases. Interestingly, we observe signficantly higher levels of cytosine to thymine deamination damage and lower proportions of mitochondrial/nuclear DNA in petrous bone compared to tooth cementum. Lastly, we show that petrous bones from ancient cremated individuals contain no measurable levels of authentic human DNA. Based on these findings we discuss the pros and cons of sampling the different elements.


Protease-activated receptor-2 expression in IgA nephropathy: a potential role in the pathogenesis of interstitial fibrosis.
An increasing body of evidence suggests that proteases may play a key role in the pathogenesis of tissue fibrosis. Protease-activated receptor-2 (PAR-2) is cleaved and activated by trypsin-like proteolytic enzymes, including tryptase and activated coagulation factor X (FXa). Both these soluble mediators have been demonstrated, directly or indirectly, at the interstitial level in progressive renal diseases, including IgA nephropathy (IgAN). PAR-2 mRNA and protein levels were investigated by RT-PCR and immunohistochemistry, respectively, in 17 biopsies from IgAN patients and 10 normal kidneys. PAR-2 expression was also evaluated, by RT-PCR and western blotting, in cultured human mesangial and proximal tubular cells. Finally, gene expression of plasminogen activator inhibitor-1 (PAI-1) and TGF-beta, two powerful fibrogenic factors, was evaluated in FXa-, trypsin-, and PAR-2 activating peptide-stimulated human proximal tubular cells by Northern blot. In normal kidneys, PAR-2 gene expression was barely detectable, whereas in IgAN biopsies the mRNA levels for this protease receptor were strikingly increased and directly correlated with the extent of interstitial fibrosis. Immunohistochemical staining demonstrated that PAR-2 protein expression in IgAN biopsies was mainly localized in the proximal tubuli and within the interstitial infiltrate. Proximal tubular cells in culture expressed PAR-2. Activation of this receptor by FXa in tubular cells induced a striking increase in intracellular calcium concentration. In addition, incubation of both cell lines with trypsin, FXa, or PAR-2 activating peptide caused a marked upregulation of PAI-1 gene expression that was not counterbalanced by an increased expression of plasminogen activators. Finally, PAR-2 activation induced a significant upregulation of TGF-beta gene and protein expression in both mesangial and tubular cells. On the basis of our data, we can suggest that PAR-2 expressed by renal resident cells and activated by either mast cell tryptase or FXa may induce extracellular matrix deposition modifying the PAI-1/PA balance and inducing TGF-beta expression. These molecular mechanisms may underlie interstitial fibrosis in IgAN.


Kinetochore "memory" of spindle checkpoint signaling in lysed mitotic cells.
The spindle checkpoint prevents errors in mitosis. Cells respond to the presence of kinetochores that are improperly attached to the mitotic spindle by delaying anaphase onset. Evidence suggests that phosphorylations recognized by the 3F3/2 anti-phosphoepitope antibody may be involved in the kinetochore signaling of the spindle checkpoint. Mitotic cells lysed in detergent in the absence of phosphatase inhibitors rapidly lose expression of the 3F3/2 phosphoepitope. However, when ATP is added to lysed and rinsed mitotic cytoskeletons, kinetochores become rephosphorylated by an endogenous, bound kinase. Kinetochore rephosphorylation in vitro produced the same differential phosphorylation seen in appropriately fixed living cells. In chromosomes not yet aligned at the metaphase plate, kinetochores undergo rapid rephosphorylation, while those of fully congressed chromosomes are under-phosphorylated. However, latent 3F3/2 kinase activity is retained at kinetochores of cells at all stages of mitosis including anaphase. This latent activity is revealed when rephosphorylation reactions are carried out for extended times. The endogenous, kinetochore-bound kinase can be chemically inactivated. Remarkably, a soluble kinase activity extracted from mitotic cells also caused differential rephosphorylation of kinetochores whose endogenous kinase had been chemically inactivated. We suggest that, in vivo, microtubule attachment alters the kinetochore 3F3/2 phosphoprotein, causing it to resist phosphorylation. This kinetochore modification is retained after cell lysis, producing a "memory" of the in vivo phosphorylation state.


Health supervision for children with Marfan syndrome.
Marfan syndrome is a systemic, heritable connective tissue disorder that affects many different organ systems and is best managed by using a multidisciplinary approach. The guidance in this report is designed to assist the pediatrician in recognizing the features of Marfan syndrome as well as caring for the individual with this disorder.


Increasing public awareness of the risk of cardiovascular disease using 'health activists' in a community health project in Israel: a feasibility study.
An innovative approach to health education in the field of cardiovascular risk factor control was implemented in an urban community in southern Israel. The objective of the project was to determine the efficiency of utilising lay health activists (HAs) to convey the health message to the community. After undergoing a selection process, 22 HAs completed the course of instruction which included: 24 hours of lectures on health topics given by medical experts; 25 hours of training in communication skills, group supervision and assistance in coping with problems encountered during their field work in the community. In the execution of their field work, the HAs paid home visits to members of the community in order that a) two questionnaires could be completed: one dealing with attitude to and knowledge of CVD risk factors and the other, with health habits; b) according to the outcome of the interview, advice concerning desirable changes in life-style could be offered, and c) a follow-up visit could be made in order to reinforce the health message and to evaluate any changes in knowledge, attitudes and behaviour. During the 18 weeks of the project, 612 homes were visited by the HAs. Evaluation of the project is based on an assessment of the changes in knowledge, attitudes and behaviour of the HAs themselves. Results of this study suggest that improving the efficiency of health promotion by utilising the services of lay health activists is a viable proposition. Finally, the applicability of the programme is discussed.


A warm antibody mediated acute hemolytic anemia with reticulocytopenia in a four-month-old girl requiring immunosuppressive therapy.
We present a four-month-old girl with severe hemolytic anemia and reticulocytopenia. This case is the youngest with hemolytic anemia encountered in our hospital. Findings of autoimmune hemolytic anemia were preceded by diphtheria-pertussis-tetanus (DPT) and oral polio vaccines which were given one month before. At admission, she had heart failure, her hemoglobin (Hb) was 27 gm/L, hematocrit (Hct) 8.5 percent, reticulocyte count 0.2 percent, and gamma and non-gamma Coombs tests were positive. Plasma Hb was 23 percent (N < 3%) and haptoglobin 0 mg/dl. Bone marrow aspiration smear revealed erythroid hyperplasia. No infection, immunodeficiency or malignancy could be established. She received multiple transfusions and did not respond to methyl prednisolone therapy of seven days' duration, but was successfully treated with a combination of immunosuppressive therapy (cyclophosphamide, 6-mercaptopurine, intravenous immunoglobulin and prednisolone, which was added later). This case is interesting in that the disease was preceded by DPT vaccination, was associated with reticulocytopenia and was resistant to steroids.


Apnea frequently persists beyond term gestation in infants delivered at 24 to 28 weeks.
Apnea of prematurity remains among the most commonly diagnosed conditions in the Newborn Intensive Care Unit and may prolong hospital stays in some infants. Because survival of extremely premature infants has improved markedly, the natural history of apnea in this population needs to be reassessed. To document the natural history of recurrent apnea and/or bradycardia events in infants delivered at 24 to 28 weeks' gestation. Medical records of all infants delivered at 24 to 28 weeks' gestation admitted to the Brigham and Women's Hospital Newborn Intensive Care Unit between January 1989 and March 1994 were reviewed to document the clinical course of apnea of prematurity. Subjects were included in the study sample if they were discharged home from the Brigham and Women's Hospital or after transfer to an affiliated hospital. Recordings of apnea and/or bradycardia events were based on nursing observations of monitor alarms and assessment of the infant's condition. Of 457 eligible infants, 226 were included in the study sample and stratified by gestational age at birth assigned by the attending neonatologist. The time to resolution of recurrent apnea/bradycardia events was longer with lower gestational age at birth. Apnea/bradycardia events were frequently observed beyond 36 weeks' postconceptional age in all gestational age groups. The incidence of apnea persisting beyond 38 weeks postconceptional age was significantly higher in the 24- to 27-week infants combined compared with the 28-week infants. Apnea of prematurity frequently persists beyond term gestation in infants delivered at 24 to 28 weeks' gestational age. These persistent apnea and/or bradycardia events may contribute to prolonged hospitalization. Programs to promote earlier discharge of premature infants should take into account the variability in resolution of apnea and specifically address management of persistent apnea.


MEG imaging of recurrent gliomas reveals functional plasticity of hemispheric language specialization.
In patients with gliomas, changes in hemispheric specialization for language determined by magnetoencephalography (MEG) were analyzed to elucidate the impact of treatment and tumor recurrence on language networks. Demonstration of reorganization of language networks in these patients has significant implications on the prevention of postoperative functional loss and recovery. Whole-brain activity during an auditory verb generation task was estimated from MEG recordings in a group of 73 patients with recurrent gliomas. Hemisphere of language dominance was estimated using the language laterality index (LI), a measure derived from the task. The initial scan was performed prior to resection; patients subsequently underwent surgery and adjuvant treatment. A second scan was performed upon recurrence prior to repeat resection. The relationship between the shift in LI between scans and demographics, anatomic location, pathology, and adjuvant treatment was analyzed. Laterality shifts were observed between scans; the median percent change was 29.1% across all patients. Laterality shift magnitude and relative direction were associated with the initial position of language dominance; patients with increased lateralization experienced greater shifts than those presenting more bilateral representation. A change in LI from left or right to bilateral (or vice versa) occurred in 23.3% of patients; complete switch occurred in 5.5% of patients. Patients with tumors within the language-dominant hemisphere experienced significantly greater shifts than those with contralateral tumors. The majority of patients with glioma experience shifts in language network organization over time which correlate with the relative position of language lateralization and tumor location.


An integrated microcredit, entrepreneurial training, and nutrition education intervention is associated with better growth among preschool-aged children in rural Ghana.
Poor diet quality is a determinant of the high prevalence rates of malnutrition in Ghana. There is little evidence on the effectiveness of a multisector intervention to improve children's diets and nutritional status. The project tested whether participation in an entrepreneurial and nutrition education intervention with microcredit was associated with the nutritional status of children 2-5 y of age. A quasi-experimental 16-mo intervention was conducted with microcredit loans and weekly sessions of nutrition and entrepreneurship education for 179 women with children 2-5 y of age [intervention group (IG)]. Nonparticipating women and their children from the same villages (nonparticipant, n = 142) and from similar neighboring villages (comparison, n = 287) were enrolled. Repeated measures linear regression models were used first to examine children's weight-for-age (WAZ), height-for-age (HAZ), and body mass index-for-age (BAZ) z scores at baseline and at 4 follow-up time points ∼4 mo apart. Time, intervention status, time-by-intervention interaction terms, region of residence, household wealth rank, household head occupation, number of children <5 y of age, and child sex and age were included. There was a significant interaction between the IG and time for BAZ (P = 0.02) with significant Bonferroni-corrected pairwise comparisons between the IG and comparison group (CG) at 8 mo (difference of 0.36 ± 0.09 z score, P < 0.0001). The WAZ group difference was significant between 4 and 16 mo (P = 0.01 for interaction) and peaked at 8-12 mo (differences of ∼0.28 z). The HAZ of children in the IG was significantly higher than that in the CG, reaching a 0.19 z difference at 16 mo (P < 0.05). When the fixed effects models were fitted in sensitivity analyses, some group anthropometric differences were of lower magnitude but remained significant. An integrated package of microcredit and education may improve nutritional outcomes of children living in poor, rural communities.


Tests of universal three-body physics in an ultracold bose-fermi mixture.
Recent measurements of Efimov resonances for a number of ultracold atom species have revealed an unexpected universality, in which three-body scattering properties are determined by the van der Waals length of the two-body interaction potential. To investigate whether this universality extends to heteronuclear mixtures, we measure loss rate coefficients in an ultracold trapped gas of 40K and 87Rb atoms. We find an Efimov-like resonance in the rate of inelastic collisions between 40K87Rb Feshbach molecules and 87Rb atoms. However, we do not observe any Efimov-related resonances in the rates of inelastic collisions between three atoms. These observations are compared to previous measurements by the LENS group of Efimov resonances in a 41K and 87Rb mixture as well as to recent predictions.


Genomics-guided analysis of NAD recycling yields functional elucidation of COG1058 as a new family of pyrophosphatases.
We have recently identified the enzyme NMN deamidase (PncC), which plays a key role in the regeneration of NAD in bacteria by recycling back to the coenzyme the pyridine by-products of its non redox consumption. In several bacterial species, PncC is fused to a COG1058 domain of unknown function, highly conserved and widely distributed in all living organisms. Here, we demonstrate that the PncC-fused domain is endowed with a novel Co(+2)- and K(+)-dependent ADP-ribose pyrophosphatase activity, and discuss the functional connection of such an activity with NAD recycling. An in-depth phylogenetic analysis of the COG1058 domain evidenced that in most bacterial species it is fused to PncC, while in α- and some δ-proteobacteria, as well as in archaea and fungi, it occurs as a stand-alone protein. Notably, in mammals and plants it is fused to FAD synthase. We extended the enzymatic characterization to a representative bacterial single-domain protein, which resulted to be a more versatile ADP-ribose pyrophosphatase, active also towards diadenosine 5'-diphosphate and FAD. Multiple sequence alignment analysis, and superposition of the available three-dimensional structure of an archaeal COG1058 member with the structure of the enzyme MoeA of the molybdenum cofactor biosynthesis, allowed identification of residues likely involved in catalysis. Their role has been confirmed by site-directed mutagenesis.


Octacalcium phosphate bone substitute materials: Comparison between properties of biomaterials and other calcium phosphate materials.
Octacalcium phosphate (OCP) is a material that can be converted to hydroxyapatite (HA) under physiological environments and is considered a mineral precursor to bone apatite crystals. The structure of OCP consists of apatite layers stacked alternately with hydrated layers, and closely resembles the structure of HA. The performance of OCP as a bone substitute differs from that of HA materials in terms of their osteoconductivity and biodegradability. OCP manifests a cellular phagocytic response through osteoclast-like cells similar to that exhibited by the biodegradable material β-tricalcium phosphate (β-TCP). The use of OCP for human cranial bone defects involves using its granule or composite form with one of the natural polymers, viz., the reconstituted collagen. This review article discusses the differences and similarities in these calcium phosphate (Ca-P)-based materials from the viewpoint of the structure and their material chemistry, and attempts to elucidate why Ca-P materials, particularly OCP, display unique osteoconductive property.


Principal Component Analysis Reveals the Proximal to Distal Pattern in Vertical Jumping Is Governed by Two Functional Degrees of Freedom.
The successful completion of motor tasks requires effective control of multiple degrees of freedom (DOF), with adaptations occurring as a function of varying performance constraints. In this study we sought to compare the emergent coordination strategies employed in vertical jumping under different task constraints [countermovement jump (CMJ) with arm swing-CMJas and no arm swing-CMJnas]. In order to achieve this, principal component analysis (PCA) was conducted on joint moment waveform data from the hip, knee and ankle. This statistical approach has the advantage of analyzing the whole movement within a time series and reduces multidimensional datasets to lower dimensions for analysis. Both individual and group analyses were conducted. For individual analysis, PCA was conducted on combined hip, knee, and ankle joint moment data for each individual across both CMJnas (thirty-eight participants), and CMJas (twenty-two participants) conditions. PCA was also performed comparing all data from each individual across CMJnas and CMJas conditions. The results revealed a maximum of three principal components (PC) explained over 90% of the variance in the data sets for both conditions and within individual and group analyses. For individual analysis, no more than 2PCs were required for both conditions. For group analysis, CMJas required 3PCs to explain over 90% of the variance within the dataset and CMJnas only required 2PCs. Reconstruction of the original NJM waveforms from the PCA output demonstrates a greater loading of hip and knee joint moments to PC1, with PC2 showing a greater loading to ankle joint moment. The reduction in dimensions of the original data shows the proximal to distal extension pattern in the sagittal plane, typical of vertical jumping tasks, is governed by only 2 functional DOF, at both a group, and individual level, rather than the typically reported 3 mechanical DOF in some forms of jumping.


Phosphorylation of troponin and myosin light chain by cAMP-independent casein kinase-2 from rabbit skeletal muscle.
Casein kinase-2 from rabbit skeletal muscle was found to phosphorylate, in addition to glycogen synthase, troponin from skeletal muscle, and myosin light chain from smooth muscle. Troponin T and the 20,000 Mr myosin light chain are phosphorylated by casein kinase-2 at much greater rates than glycogen synthase. The V values for the phosphorylation of troponin and myosin light chain are nearly an order of magnitude greater than that of glycogen synthase; however, the Km values for these two substrates are greater than that for glycogen synthase. The kinase activities with the various protein substrates are stimulated approximately three- and fivefold by 5 mM spermidine and 3 mM spermine, respectively. Heparin is a potent inhibitor of the kinase when casein, glycogen synthase, or myosin light chain is the substrate. However, with troponin as substrate the kinase is relatively insensitive to inhibition by heparin. The amount of heparin required for 50% inhibition with troponin as substrate is at least 10 times greater than with casein as substrate. The phosphorylation of troponin by casein kinase-2 results in the incorporation of phosphate into two major tryptic peptides, which are different from those phosphorylated by casein kinase-1. The site in myosin light chain phosphorylated by casein kinase-2 is different from that phosphorylated by myosin light chain kinase.


Neurophysiological observations on the effects of botulinum toxin treatment in patients with dystonic blepharospasm.
Botulinum toxin treatment improves dystonic blepharospasm by inducing transient paresis of the orbicularis oculi muscle. It is not known if it also reduces the enhanced brainstem neuronal excitability found in this disorder. We have performed conventional electromyography (EMG) and blink reflex excitability studies on fifteen patients with blepharospasm before and after botulinum toxin treatment. Denervation signs were found with needle EMG in all treated muscles. Amplitude of the facial compound muscle action potential (CMAP) and R1 response was reduced after botulinum toxin injections. In blink reflex excitability studies, the recovery of R2 response was enhanced after treatment even when patients were tested at the time of maximal benefit from botulinum toxin injections. The results suggest that there is little influence of botulinum toxin treatment upon the enhanced excitability of brainstem interneurons in patients with blepharospasm.


Exploring the relationship between weaning and infant mortality: an isotope case study from Aşıklı Höyük and Çayönü Tepesi.
We measured stable nitrogen isotope ratios in bone collagen of 60 individuals from the early Neolithic (9th-8th millennium Cal. BC) sites of Çayönü Tepesi and Aşıklı Höyük. Our aim was to identify the duration of exclusive breastfeeding (EBF), compare this with juvenile mortality at each site, and assess whether there was a relationship between them. The isotope analysis suggests that weaning commenced at about 1 year at Aşıklı Höyük and around 2 years at Çayönü Tepesi. The mortality data show equal numbers of infant deaths up to 24 months; however, after 24 months, the mortality rate increases at Çayönü Tepesi, and a Student's t-test confirms a significant difference in infant mortality between the sites. Weaning foods prepared in the early Neolithic from agricultural crops would have had low-iron content, poor nutritional value, and would have been prepared in nonsterilized containers. Therefore, later weaned infants in early Neolithic farming settlements, although capable of some immunological response, were probably undernourished putting them at a disadvantage when encountering bacteria in their weaning food. Our results suggest that infant feeding regimes that introduced infants to weaning foods in the first year of life may have had a positive effect on their survival.


Effect of dietary taurine supplementation on GSH and NAD(P)-redox status, lipid peroxidation, and energy metabolism in diabetic precataractous lens.
To evaluate changes in glutathione and NAD(P)-redox status, taurine and malondialdehyde (MDA) levels, glucose utilization, and energy metabolism in diabetic precataractous lenses and to assess whether these changes can be prevented with dietary taurine supplementation. The experimental groups included control and streptozotocin-diabetic rats with a 3-week duration of diabetes fed unsupplemented or taurine (1% or 5%)-supplemented diets. The levels of glucose, sorbitol, fructose, myo-inositol, oxidized glutathione (GSSG), glycolytic intermediates, malate, alpha-glycerophosphate, and adenine nucleotides were assayed in individual lenses spectrofluorometrically by enzymatic methods, reduced glutathione (GSH) spectrofluorometrically with O-phthaldialdehyde, MDA colorimetrically with N-methyl-2-phenylindole, and taurine by high-performance liquid chromatography. Free cytosolic NAD+/NADH and NADP+/NADPH ratios were calculated from the lactate dehydrogenase and malic enzyme systems. Sorbitol pathway metabolites and MDA were increased, and GSH and taurine levels were reduced in diabetic rats versus controls. The profile of glycolytic intermediates (an increase in glucose 6-phosphate, no change in fructose 6-phosphate and fructose 1,6-diphosphate, an increase in dihydroxyacetone phosphate, a decrease in 3-phosphoglycerate, phosphoenolpyruvate, and pyruvate, and no change in lactate), and a 9.2-fold increase in alpha-glycerophosphate suggest diabetes-induced inhibition of glycolysis. Free cytosolic NAD+/NADH ratios, ATP levels, ATP/ADP, and adenylate charge were reduced, whereas free cytosolic NADP+/NADPH ratios were elevated. Lens taurine levels in diabetic rats were not affected by supplementation with 1% taurine. With 5% taurine supplementation, they were increased approximately 2.2-fold higher than those in untreated diabetics but remained 3.4-fold lower than in controls. Lens GSH levels were similar in diabetic rats fed unsupplemented and 5% taurine-supplemented diets, whereas GSSG and MDA levels and GSSG/GSH ratios were reduced by 5% taurine supplementation. The decrease in free cytosolic NAD+/NADH, ATP/ADP, and adenylate energy charge were ameliorated by 5% taurine supplementation, whereas accumulation of sorbitol pathway intermediates, depletion of myoinositol, inhibition of glycolysis, a decrease in ATP and total adenine nucleotide, and an increase in free cytosolic NADP+/NADPH were not prevented. Dietary taurine supplementation ameliorates MDA levels, GSSG/GSH, and NAD+/NADH and fails to prevent the osmotically mediated depletion of GSH and taurine and the decrease in glucose utilization and ATP levels in diabetic precataractous lens. Dietary taurine supplementation cannot be regarded as an alternative to aldose reductase inhibition in eliminating antioxidant and metabolic deficits contributing to diabetes-associated cataractogenesis.


A prospective survey of the indications and morbidity of circumcision in children.
Both the British Medical Association and the American Academy of Pediatrics recommend that circumcision should only be performed for medical reasons. No one has ever described which reasons are actually used, nor measured the morbidity of the procedure. Of 140 boys coming to day-case elective circumcision between the ages of 3 months and 14 years (mean 4.3 years), the commonest cause was a congenital phimosis (42.8%). Four (2.8%) patients required acute readmission postoperatively, and a further 4 developed meatal stenosis, requiring a formal meatotomy. Of 99 patients followed up in detail, 46% vomited, 36% oozed, 19% did not pass urine for more than 12 h and 26% could not wear pants for more than 7 days. Childhood circumcision has an appreciable morbidity, and should not be recommended without a medical reason.


Metal-dependent photosensitivity of three isostructural 1D CPs based on the 1,1'-bis(3-carboxylatobenzyl)-4,4'-bipyridinium moiety.
To study the effect of metal ions on the photochromic behaviors of CPs, three new isostructural coordination polymers (CPs) based on a neutral viologen moiety, 1,1'-bis(3-carboxylatobenzyl)-4,4'-bipyridinium (bcbpy), have been obtained by choosing 1,2,4,5-benzenetetracarboxylic acid (H4BTEC) to coordinate with different metal ions, {[M(H2O)6][M(BTEC)(H2O)4]·(bcbpy)·4H2O}n (M = Co (1), Ni (2), Zn (3)), all of which exhibit metal-dependent photochromism and adjustable photosensitivity. Compounds 1 and 2 are only sensitive to UV light, while compound 3 is sensitive to sunlight, UV light and X-ray (Mo). The comparison of the photochromic behaviors of the three CPs indicates that the metal ions play an important role in regulating their photochromic properties.


Dose dependence of nicotinic acid-induced hyperbilirubinemia and its dissociation from hemolysis in Gilbert's syndrome.
The serum increments in unconjugated bilirubin and total iron were determined after intravenous administration of 5.90 mumol/kg body weight of nicotinic acid (NA) in 26 patients with Gilbert's syndrome (GS), seven patients with hemolytic anemia, and 13 healthy volunteers. The hyperbilirubinemic response, expressed as the area under time concentration curve of unconjugated bilirubin (AUCBR, milligrams per deciliter per 240 minutes) was significantly higher (P less than 0.01) in patients with GS than in controls and patients with hemolytic anemia, in whom no difference was observed. In contrast, comparable values of the hypersideremic effect (AUCFe, milligrams per deciliter per 240 minutes) were noticed among the three groups. In seven consecutive patients with GS, seven with hemolytic anemia, and four healthy volunteers, AUCBR, AUCFe, and the NA plasma half-life of the first fast slope of the curve were determined at three different doses of the drug (1.18, 2.95, and 5.90 mumol NA per kilogram body weight). A significant, dose-dependent increase in AUCBR was present in patients with GS, whereas it remained constant both in controls and in patients with hemolytic anemia. The NA plasma half-life was also significantly prolonged in GS with each of the three doses, but remained unchanged in the other two groups. In patients with GS, a linear correlation (r = 0.891, P less than 0.001) was present between AUCBR and NA plasma half-life. In contrast, the AUCFe value remained constant at the different doses used in the three groups.(ABSTRACT TRUNCATED AT 250 WORDS)


Exploring the Potential of Olfactory Receptor Circulating RNA Measurement for Preeclampsia Prediction and Its Linkage to Mild Gestational Hypothyroidism.
Gestational hypothyroidism may lead to preeclampsia development. However, this pathophysiological is unknown. We expect to find a shared mechanism by comparing hypothyroidism and preeclampsia. From our transcriptome data, we recognized olfactory receptors as that fingerprint. The reduction of taste and smell in hypothyroid patients has been known for a long time. Therefore, we decided to look to the olfactory receptors and aimed to identify genes capable of predicting preeclampsia (PEC). Methods: An Ion Proton Sequencer (Thermo Fisher Scientific, Waltham, MA, USA) was used to construct the transcriptome databases. RStudio with packages Limma v.3.50.0, GEOquery v.2.62.2, and umap v.0.2.8.8 were used to analyze the differentially expressed genes in GSE149440 from the Gene Expression Omnibus (GEO). The 7500 Real-Time PCR System (Applied Biosystems, Foster City, CA, USA) was used for RT-qPCR amplification of OR6X1 and OR4E2. Results: Our transcriptomic datasets analysis revealed 25.08% and 26.75% downregulated olfactory receptor (ORs) in mild nontreated gestational hypothyroidism (GHT) and PEC, respectively. In the GSE149440 GEO dataset, we found OR5H1, OR5T3, OR51A7, OR51B6, OR10J5, OR6C6, and OR2AG2 as predictors of early-onset PEC. We also evaluate two chosen biomarkers' responses to levothyroxine. The RT-qPCR demonstrated a difference in OR6X1 and OR4E2 expression between GHT and healthy pregnancy (p < 0.05). Those genes presented a negative correlation with TSH (r: -0.51, p < 0.05; and r: -0.44, p < 0.05), a strong positive correlation with each other (r: 0.89; p < 0.01) and the levothyroxine-treated group had no difference from the healthy one. We conclude that ORs could be used as biomarkers at the beginning of gestation, and the downregulated ORs found in GHT may be improved with levothyroxine treatment.


Evaluation of Anorexia in Cancer and Its Association with Autonomic Nervous System Activity Assessed by Heart Rate Variability.
Alterations in the central nervous system in cancer patients are pivotal in determining appetite dysregulation and body weight loss (BWL). Autonomic nervous system activity was tested by measuring heart rate variability (HRV) in cancer patients presenting with anorexia. We considered inpatients with different types of cancer and investigated anorexia using their FAACT scores. HRV was evaluated by a three-channel Holter ECG. The domains of low frequencies (LF, sympathetic activity) and high frequencies (HF, parasympathetic activity) were calculated. Also, SDNN (autonomic activity) and RMSSD (parasympathetic activity) were assessed. We enrolled 56 patients with cancer and 23 controls. In cancer patients, RMSSD and SDNN were lower than in controls (p < 0.001 and p = 0.009). Sympathetic activity (LF nu) was lower in cancer patients than in controls (p = 0.023), including sympathovagal balance (LF/HF nu ratio) (p = 0.025). RMSSD was reduced in anorexic (p < 0.001) and non-anorexic (p = 0.003) cancer patients compared to controls. The SDNN was lower in anorexic cancer patients than in non-anorexic cancer patients (p = 0.025), and it was lower in anorexic cancer patients than in controls (p = 0.001). LF nu was lower in anorexic cancer patients than in controls (p = 0.015), as was LF/HF (p = 0.031). SDNN was negatively correlated with BWL in the cancer group (rho = -0.40; p = 0.007). Our data support the hypothesis that autonomic nervous system dysregulation exists in patients with cancer presenting with anorexia, with implications for its diagnosis and treatment.


Comparison of two matrix-assisted laser desorption ionization-time of flight mass spectrometry methods with conventional phenotypic identification for routine identification of bacteria to the species level.
Bacterial identification relies primarily on culture-based methodologies requiring 24 h for isolation and an additional 24 to 48 h for species identification. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) is an emerging technology newly applied to the problem of bacterial species identification. We evaluated two MALDI-TOF MS systems with 720 consecutively isolated bacterial colonies under routine clinical laboratory conditions. Isolates were analyzed in parallel on both devices, using the manufacturers' default recommendations. We compared MS with conventional biochemical test system identifications. Discordant results were resolved with "gold standard" 16S rRNA gene sequencing. The first MS system (Bruker) gave high-confidence identifications for 680 isolates, of which 674 (99.1%) were correct; the second MS system (Shimadzu) gave high-confidence identifications for 639 isolates, of which 635 (99.4%) were correct. Had MS been used for initial testing and biochemical identification used only in the absence of high-confidence MS identifications, the laboratory would have saved approximately US$5 per isolate in marginal costs and reduced average turnaround time by more than an 8-h shift, with no loss in accuracy. Our data suggest that implementation of MS as a first test strategy for one-step species identification would improve timeliness and reduce isolate identification costs in clinical bacteriology laboratories now.


Anatomical considerations to prevent facial nerve injury.
Injury to the facial nerve during a face lift is a relatively rare but serious complication. A large body of literature has been dedicated toward bettering the understanding of the anatomical course of the facial nerve and the relative danger zones. Most of these prior reports, however, have focused on identifying the location of facial nerve branches based on their trajectory mostly in two dimensions and rarely in three dimensions. Unfortunately, the exact location of the facial nerve relative to palpable or visible facial landmarks is quite variable. Although the precise location of facial nerve branches is variable, its relationship to soft-tissue planes is relatively constant. The focus of this report is to improve understanding of facial soft-tissue anatomy so that safe planes of dissection during surgical undermining may be identified for each branch of the facial nerve. Certain anatomical locations more prone to injury and high-risk patient parameters are further emphasized to help minimize the risk of facial nerve injury during rhytidectomy.


Tumor Occupancy Ratio-An Imaging Characteristic Prognosticating the Surgical Outcome of Benign Intradural Extramedullary Spinal Cord Tumors.
Intradural extramedullary (IDEM) spinal cord tumors are two thirds of all spinal tumors. We have prospectively analyzed the importance of the tumor occupancy ratio as a factor for predicting the course of the disease and in prognosticating the surgical outcome in patients with IDEM tumors. We prospectively analyzed 44 consecutive cases of IDEM tumors, diagnosed as cervical, thoracic, and lumbar IDEM tumors (excluding conus/cauda equina lesion) by magnetic resonance imaging (MRI), that were operated on at our institution between 2014 and 2016. We measured the tumor occupancy ratio and noted the sagittal and axial location of the tumor in the preoperative MRI and performed the laminectomy and unilateral medial facetectomy. A primary outcome has been noted according to the gait disability score in the preoperative period and in the follow-up period of 1 year. In the statistical analysis, categorical variables were compared using a chi-square test, and an analysis of variance and student t tests were used for the continuous variables. P < .05 was considered statistically significant. The tumor occupancy ratio showed a significant association to the preoperative gait disability score (P < .001) and also predicted that the surgical outcome is much better in patients with tumors with a low tumor occupancy ratio than in patients with tumors with a high occupancy ratio (P < .001). No difference in the tumor occupancy ratio was noted in 2 different pathological tumors, and there was also no difference in the tumor occupancy ratio at different sagittal and axial locations of the tumor. Tumor occupancy ratio has shown a significant impact on the preoperative course and also predicts the surgical outcome in patients with IDEM tumors. Hence, it is an important imaging characteristic to prognosticate the outcome in IDEM tumors and should be noted in each case.