Physiological bases of the synchronized population spikes and slow wave of the magnetic field generated by a guinea-pig longitudinal CA3 slice preparation.
The physiological bases of evoked magnetic fields were examined in a guinea-pig hippocampal slice preparation, motivated by new concepts in central nervous system (CNS) electrophysiology brought about by discoveries of active conductances in the dendrites and soma of neurons. Their origins were elucidated by comparing them with intracellular and extracellular field potentials. With excitatory synaptic transmissions blocked, the magnetic signal elicited by an electrical stimulus applied to the pyramidal cell layer consisted of a spike and a depolarizing afterpotential-like waveform. With the excitatory synaptic transmissions intact, but with inhibitory synaptic transmissions blocked, the magnetic signal was bi- or triphasic depending on whether the cell layer or the apical dendrite area of the pyramidal cells was, respectively, depolarized. In both cases the signal consisted of a train of synchronized population spikes superimposed on a brief wave followed by a longer, slow wave. The spike train was correlated with synaptically mediated intracellular spikes. The underlying currents for the slow wave were directed from the apical to the basal side for both types of stimulation. It was most likely generated by depolarization of the apical dendrites, caused by recurrent excitatory synaptic activation. This analysis illustrates how synaptic connections and intrinsic conductances in a disinhibited mammalian CNS structure can generate spikes and waves of the magnetic field and electrical potential.


The hippocampus as a visual area organized by space and time: A spatiotemporal similarity hypothesis.
The hippocampus is the canonical memory system in the brain and is not typically considered part of the visual system. Yet, it sits atop the ventral visual stream and has been implicated in certain aspects of vision. Here I review the place of the hippocampal memory system in vision science. After a brief primer on the local circuity, external connectivity, and computational functions of the hippocampus, I explore what can be learned from each field about the other. I first present four areas of vision science (scene perception, imagery, eye movements, attention) that challenge our current understanding of the hippocampus in terms of its role in episodic memory. In the reverse direction, I leverage this understanding to inform vision science in other ways, presenting a working hypothesis about a unique form of visual representation. This spatiotemporal similarity hypothesis states that the hippocampus represents objects according to whether they co-occur in space and/or time, and not whether they look alike, as elsewhere in the visual system. This tuning may reflect hippocampal mechanisms of pattern separation, relational binding, and statistical learning, allowing the hippocampus to generate visual expectations to facilitate search and recognition.


DETECTION OF HIV INFECTION IN MEN SUFFERING FROM SEXUALLY TRANSMITTED DISEASES IN NORTH EAST REGION.
In a prospective study, 715 men in the age group 18-45 years with various sexually transmitted diseases (STD) from Jan 1993 to June 1996 were examined for presence of human immunodeficiency virus (HIV) infection. Majority (86%) were young adults in the age group of 21-35 years. Five hundred and fifty eight (78.04%) men were married and 157 (21.9%) were single. Majority men (87.3%) gave history of heterosexual exposures with female commercial sex workers. None had used condom during sexual intercourse. Out of 715, majority (30.9%) cases had chancroid. Blood samples were tested for HIV 1-2 antibodies during treatment and surveillance period by Enzyme Linked Immunosorbent Assay (ELISA) technique. Nine cases of STDs were positive for HIV 1-2 antibodies by ELISA test and 8 (1.1%) were confirmed by Western blot assay. All HIV seropositive men got infection from female commercial sex workers which were detected during their surveillance period. This study highlights the importance of screening of STD patients for HIV infection during treatment as well as surveillance period.


Failure of nitroglycerin and diltiazem to reduce platelet-mediated vasoconstriction in dogs with coronary artery stenosis and endothelial injury: further evidence for thromboxane A2 and serotonin as mediators of coronary artery vasoconstriction in vivo.
This study was designed to test the efficacy of nitroglycerin and diltiazem in inhibiting in vivo platelet aggregation and reducing platelet-mediated vasoconstriction in a canine model of coronary artery stenosis and endothelial injury. Coronary artery diameter was measured in vivo by means of ultrasonic crystals sutured on the left anterior descending coronary artery (LAD) immediately distal to an external constrictor (LAD1), 1 cm below (LAD2), and on the left circumflex coronary artery. Coronary diameter was continuously measured before, during cyclic flow variations (progressive declines in blood flow followed by sudden restorations of flow due to recurrent intracoronary platelet aggregation), during cyclic flow variations and intravenous infusion of nitroglycerin (5 micrograms/kg per min) or diltiazem (15 micrograms/kg per min), and after cyclic flow variations were abolished by administration of LY53857, a serotonin receptor antagonist (n = 7), or SQ29548, a thromboxane A2 receptor antagonist (n = 7). During control cyclic flow variations, at the nadir of coronary flow (6% to 11% of the nonstenosed values), LAD1 cross-sectional area decreased by 43 +/- 8% and 44 +/- 3% in the two groups of dogs subsequently treated with LY53857 and SQ29548, respectively. Neither nitroglycerin nor diltiazem caused changes in cyclic flow variation frequency or severity. Furthermore, neither drug significantly reduced the vasoconstriction associated with cyclic flow variations, whereas they significantly increased circumflex artery cross-sectional area. In contrast, LY53857 and SQ29548 were very effective in abolishing cyclic flow variations and the coronary vasoconstriction related to them. Five additional dogs received an intracoronary infusion of nitroglycerin (21 +/- 5 micrograms/kg per min) and later diltiazem (15 micrograms/kg per min).(ABSTRACT TRUNCATED AT 250 WORDS)


Kinetics and mechanism of degradation of some 2-sulfanilamidopyrimidine derivatives. Part V. Mechanism of sulfadimidine solvolysis.
The products of spontaneous hydrolysis of sulfadimidine are: sulfanilamide, aniline, 2-hydroxy- 4,6-dimethylpyrimid and ammonium carbonate. The mechanism of spontaneous hydrolysis of sulfadimidine is proposed.


Anaesthetists stress is induced by patient ASA grade and may impair non-technical skills during intubation.
The aims of this study were to determine if patient ASA grade was associated with increased stress in anaesthetists with a subsequent effect on non-technical skills. Stress was measured using a validated objective (heart rate variability or heart rate) and subjective tool. We studied eight consultant anaesthetists at baseline (rest) and during 16 episodes of intubation with an ASA 1 or 2 patient vs. an ASA 3 or 4 patient. The primary outcome for the study was objective and subjective stress between both patient groups. Secondary outcomes were non-technical skill ratings and the association between stress measurements. ASA 3 or 4 patients were associated with increases in objective stress when compared to baseline (mean 4.6 vs. 6.7; P = 0.004). However, ASA 1 or 2 patients were not associated with increases in stress when compared to baseline (mean 4.6 vs. 4.7; P = 1). There was no significant difference in subjective stress between the groups (P = 0.18). Objective stress negatively affected situational awareness (P = 0.03) and decision-making (P = 0.03); however, these did not decline to a clinically significant threshold. Heart rate variability (r = 0.60; P = 0.002) better correlated with subjective stress when compared to heart rate (r = 0.30; P = 0.15). Agreement between raters for Anaesthetic Non-Technical Skills (ANTS) scores was acceptable (ICC = 0.51; P = 0.003). This study suggests that higher patient ASA grade can increase stress in anaesthetists, which may impair non-technical skills.


Quantitative optimization of drainage strategy of coalbed methane well based on the dynamic behavior of coal reservoir permeability.
The development of coalbed methane (CBM) is not only affected by geological factors, but also by engineering factors, such as artificial fracturing and drainage strategies. In order to optimize drainage strategies for wells in unique geological conditions, the characteristics of different stages of CBM production are accurately described based on the dynamic behavior of the pressure drop funnel and coal reservoir permeability. Effective depressurization is achieved by extending the pressure propagation radius and gas desorption radius to the well-controlled boundary, in the single-phase water flow stage and the gas-water flow stage, respectively, with inter-well pressure interference accomplished in the single-phase gas flow stage. A mathematic model was developed to quantitatively optimize drainage strategies for each stage, with the maximum bottom hole flow pressure (BHFP) drop rate and the maximum daily gas production calculated to guide the optimization of CBM production. Finally, six wells from the Shizhuangnan Block in the southern Qinshui Basin of China were used as a case study to verify the practical applicability of the model. Calculation results clearly indicate the differences in production characteristics as a result of different drainage strategies. Overall, if the applied drainage strategies do not achieve optimal drainage results, the coal reservoir could be irreversibly damaged, which is not conducive to expansion of the pressure drop funnel. Therefore, this optimization model provides valuable guidance for rational CBM drainage strategy development and efficient CBM production.


Iatrogenic hypoglossal nerve palsy, a rare complication post suspension laryngoscopy.
The hypoglossal nerve (CN XII) is a pure motor nerve arising as a paired nerve from its nuclei in the medulla, exiting the skull base via the hypoglossal canal, and descending the neck to innervate the muscles of the tongue. Iatrogenic hypoglossal nerve palsy is uncommon, but cases have been reported, especially after airway management in general anaesthesia and suspension laryngoscopy. We report a case of iatrogenic hypoglossal nerve palsy post-suspension laryngoscopy, which was managed conservatively with full recovery after three months. We discuss the importance of minimal consent for suspension laryngoscopy and possible methods to prevent this uncommon yet unpleasant complication.


Lin- PU.1dim GATA-1- defines haematopoietic stem cells with long-term multilineage reconstitution activity.
Despite extensive characterization of the state and function of haematopoietic stem cells (HSCs), the use of transcription factors to define the HSC population is still limited. We show here that the HSC population in mouse bone marrow can be defined by the distinct expression levels of Spi1 and Gata1. By using a double fluorescence knock-in mouse model, PGdKI, in which the expression levels of PU.1 and GATA-1 are indicated by the expression of GFP and mCherry, respectively, we uncover that the HSCs with lymphoid and myeloid repopulating activity are specifically enriched in a Lin- PU.1dim GATA-1- (LPG) cell subset. In vivo competitive repopulation assays demonstrate that bone marrow cells gated by LPG exhibit haematopoietic reconstitution activity which is comparable to that of classical Lin- Sca1+ c-kit+ (LSK). The integrated analysis of single-cell RNA sequence data from LPG and LSK-gated cells reveals that a transcriptional network governed by core TFs contributes to regulation of HSC multipotency. These discoveries provide new clues for HSC characterization and functional study.


Proposed mechanism for increased insulin-mediated glucose transport in adipose cells from young, obese Zucker rats. Large intracellular pool of glucose transporters.
The mechanism for hyperresponsive insulin-mediated glucose transport in adipose cells from 30-day-old obese Zucker rats was examined. Glucose transport was assayed by measuring 3-O-methylglucose transport, and the concentration of glucose transporters was estimated by measuring specific D-glucose-inhibitable cytochalasin B binding. Insulin increased glucose transport activity by approximately 17 fmol/cell/min in cells from obese rats compared to 3 fmol/cell/min in lean littermates. Insulin increased the concentration of glucose transporters in the plasma membrane fraction by about 15 pmol/mg of membrane protein in both groups. The insulin-mediated decrease in the concentration of transporters in the low-density microsomal fraction was 30 pmol/mg of membrane protein for the obese rats compared to 15 pmol/mg of membrane protein for the lean controls. An estimated number of glucose transporters was calculated using membrane protein and enzyme recoveries for each group. Insulin increased the number of transporters in the plasma membrane by 3 X 10(6) sites/cell for the obese rats and only 0.6 X 10(6) sites/cell for the lean controls. In addition, insulin decreased the number of transporters/cell in the intracellular membrane pool by approximately 4 X 10(6) sites/cell for the obese rats and 0.9 X 10(6) sites/cells for the lean rats. The total number of transporters/cell was about 7 X 10(6) sites/cell for the obese animals and 1.6 X 10(6) sites/cell for the lean controls. In the basal state, more than 80% of these transporters were located in the intracellular pool for both the lean and obese rats. Thus, the marked hyperresponsive insulin-mediated glucose transport observed in adipose cells from 30-day-old obese Zucker rats may be the consequence of a marked increase in the number of glucose transporters in the intracellular pool.


Frequency of angiotensin-converting enzyme gene polymorphism in Turkish type 2 diabetic patients.
We aimed to investigate the angiotensin-converting enzyme (ACE) gene polymorphism, ACE activity and their associations with diabetic complications in Turkish patients with type 2 diabetes mellitus. A total of 143 patients and 133 controls were screened for ACE gene I/D polymorphism by using polymerase chain reaction. Serum ACE activities were determined spectrophotometrically. There was no significant difference in the distribution of ACE I/D genotypes between patients and controls. The patients with DD genotype had a higher ACE activity than those with ID and II. Hypertensive diabetic patients with DD genotype had higher ACE activities than those with ID and II. There was no significant difference in the distribution of ACE I/D genotypes between patients with and without nephropathy, retinopathy and hypertension except for patients with and without neuropathy. In patients with DD genotype, creatinine clearance correlated with duration of diabetes. The grade of retinopathy was correlated with duration of diabetes in DD and ID genotypes. The highest ACE activity was measured in hypertensive diabetics with DD genotype. ID genotype was suggested to be a risk factor and II was suggested to be protective for diabetic neuropathy. The DD and ID genotypes might be a predictor for the development of retinopathy in relation to duration of diabetes.


Personal health records: an emerging trend.
While today PHRs seem far from the world of working oncology offices, that may change soon.


On the analysis of iodine-129 and iodine-127 in environmental materials by accelerator mass spectrometry and ion chromatography.
Based on a review of literature about the abundances of 129I (T1/2 = 15.7 Ma) in the environment we show that there is a severe lack of knowledge, in particular about natural, pre-nuclear levels. Among the two analytical techniques which are sensitive enough to investigate 129I in environmental materials, namely radiochemical neutron activation analysis (RNAA) and accelerator mass spectrometry (AMS), only AMS is capable of covering the natural, pre-nuclear levels. Since such AMS measurements require chemical separation of iodine from the matrix, a wide variety of separation schemes are necessary for environmental analyses. We report here on such schemes for the analysis of soils, plants and soft tissue. They are applied exemplarily to analyses of soils from the vicinity of Chernobyl. For chemical separations prior to analysis, contamination control and blank analyses are essential. Here, we discuss quality control procedures in detail, both for RNAA and AMS. In the case of AMS we use ion-chromatography (IC) for the determination of stable iodine. The IC analysis is included in the separation schemes for environmental materials. First AMS-analyses of terrestrial biospheric materials demonstrate that natural environmental levels of 129I are lower than previously deduced from investigations using RNAA, but higher than expected from model calculations. AMS is capable of providing the missing knowledge about the radioecology of 129I.


Energetics of amino acid transport into brain slices: effects of glucose depletion and substitution of Krebs' cycle intermediates.
Amino acid uptake by slices of brain is greatly diminished by incubation of the slices in glucose-free media. Uptake can be restored by the addition of a number of substrates, e.g., lactate, citrate, or oxaloacetate. The mixture of succinate, malate, and pyruvate (SMP, 20, 5, and mM) restored amino acid uptake better than glucose after brain slices were incubated in glucose-free media to deplete endogenous energy stores. The degree of restoration of uptake was different with the various amino acid transport classes and was independent of the restoration of ATP levels in the tissue. After restoration of uptake with SMP the amino acid uptake was resistant to NaF, but was markedly more sensitive to arsenite and oligomycin. The results indicate the coupling of mitochondrial energy transducing systems to transport.


Factors controlling accumulation of organic carbon in a rift-lake, Oligocene Vietnam.
Understanding of the processes of petroleum source rock (SR) accumulation in lacustrine rift basins and the behavior of lake systems as long-term carbon sinks is fragmentary. Investigation of an 800 m thick (500 m core and ~ 300 m outcrop), deep-lacustrine, Oligocene section in Vietnam, provides a rare insight into the controls and deposition of organic carbon (OC) and SR formation in continental rift basins. A multidisciplinary dataset, combining elemental data, inorganic and organic geochemistry with sedimentology, shows that the richest alginite-prone, sapropelic SR developed during periods of relative tectonic quiescence characterized by moderate primary productivity in a mainly dysoxic lacustrine basin. Increased rift activity and further development of graben morphology intensified water column stratification and anoxia, which hindered nutrient recycling. Sapropelic organic matter (OM) continued to accumulate, but with increasing amorphous OM content and decreasing total OC values. Periods of increased seasonality were characterized by thermocline weakening, enhanced mixing of water columns, increased primary productivity and diatom blooming. The results suggest that a change from dysoxia towards anoxia or extreme primary productivity does not necessarily enhance OC burial and SR quality. External nutrient input from a phosphate-rich hinterland is sufficient for sapropel formation, whereas the main limiting factor is methanogenesis.


Hyperkeratinization and hyperplasia of the forestomach epithelium in vitamin A deficient rats.
Specific pathogen free F-344 rats were kept on a vitamin A deficient diet for 3-5 months. After 3 months on this diet the forestomach epithelium showed a mild atrophy. Stereological cytology showed a marked increase in the volume density of cytoplasmic filament bundles and decrease in the volume density of non-bundled cytoplasmic filaments. The volume fraction of keratohyalin granules increased whereas the volume fraction of membrane coating granules decreased. Some animals maintained for 4-5 months on the hypovitaminic diet exhibited the same mild atrophic forestomach epithelium accompanied by hyperkeratinization. Others showed a marked epithelial atrophy and 4 out of 12 animals revealed a marked hyperplasia with increased 3H thymidine labeling index and several papillomatous proliferations. Although many of these alterations reflect a decrease in proliferation as well as hyperkeratinization, the latter changes were not unlike those produced by known carcinogens, and support the putative important role of vitamin A in both carcinogenesis and chemoprevention.


Posterior approach shoulder arthroplasty: a cadaveric study assessing access.
Posterior shoulder arthroplasty is an approach to shoulder replacement. The goal of this cadaveric study was to determine anatomic feasibility for posterior approach shoulder arthroplasty by evaluating access to the glenoid, humerus, and canal. Twelve fresh frozen shoulders (10 males; 2 females) (mean age, 76 [range, 55-92 years]; weight, 79 kg [range, 34-125 kg]) were used. Traditional exposure techniques and retractors were used to evaluate direct access. Exposure to the glenoid and humerus was evaluated using digital imaging software. Successful placement from stemmed arthroplasty was evaluated using digital radiographs and imaging software. The posterior approach permitted direct access to 88.8% ± 8.1% of the glenoid. There was access to the center of the humeral head cut surface in 12 of 12 specimens. In 10 specimens, there was 100% access to the entire cut surface of the humerus and peripheral edges. The average access to the humerus was 95.3% ± 13.4%. Average angulation with stem placement was 0.73° of varus (range, 4.4° of varus to 3.5° of valgus). Regarding lateral plane angulation, there was an average of 0.33° of posterior angulation (range, 3.3° of posterior angulation to 2.5° of anterior angulation). Access to the center of the glenoid and humerus was achieved in all cases. More research is needed to evaluate the clinical efficacy of posterior shoulder arthroplasty, including mid- and long-term outcome and safety studies.


Student debt amongst junior doctors in New Zealand; part 2: effects on intentions and workforce.
To assess the effects of student debt on the intentions of first-year house officers in relation to location of practice and vocation, and to evaluate the relative importance of incentives to remain practising in New Zealand (NZ). A questionnaire sent to all 296 New Zealand-graduate first-year house officers practicing in New Zealand. The response rate was 53%. Eighty percent of respondents intended to practice in New Zealand for the bulk of their careers; however, 65% of respondents intended to leave New Zealand within 3 years of graduating. The most important factors influencing the decision to leave NZ were overseas travel, financial opportunities, and job/training opportunities. Fifty-five percent of respondents had considered leaving the country, specifically because of the student loan debt. The most important factors influencing vocational intentions were interest, lifestyle, and intellectual challenge. Forty-three percent of respondents stated that their student debt had influenced their intended specialty, and only 9% of respondents indicated their intention to pursue a career in general practice. The highest rated incentives for staying in New Zealand were increased salaries, employer contributions towards student loans, and training opportunities within New Zealand. Student debt influences both emigration and specialty choice intentions of junior doctors in New Zealand. This effect is an unintended but important consequence of our current tertiary education system in New Zealand. These results paint a worrying picture for the junior doctor and general practitioner workforce in New Zealand's future.


Differentiation of interstitial cells and stromal proteins in the secondary septum of early postnatal rat: effect of maternal chronic exposure to whole cigarette smoke.
The intention of this investigation was to ascertain the effect of maternal exposure to cigarette smoke on the early postnatal morphogenesis of pulmonary interstitium in offspring. Female rats were chronically exposed to whole cigarette smoke. Offspring of these and control animals were sacrificed at postnatal day 15, and their tissues were prepared for quantitative and qualitative analyses. Results indicate a diminished quantitative representation of parenchymal tissue (P less than 0.01) and a slower pace of secondary septal growth (P less than 0.07) in the experimental lung. Furthermore, a greater cellular volume density (P less than 0.0002) and, inversely, a lesser quantitative representation of extracellular matrix (P less than 0.0002) was ascertained for the experimental septal interstitium. There was proportionately less of elastin substances (P less than 0.009), collagen together with basal laminae (P less than 0.0008), and nonfibrillar, amorphous matrix (P less than 0.02) in the experimental extracellular stroma. Fibrillar collagen and nonfibrillar matrix were represented quantitatively 6.3 times more in the experimental extracellular interstitium than elastin, whereas that ratio for the control tissue was only 4.2. Most experimental interstitial cells (80%) contained numerous lipid globules, which, in contrast, were only occasionally present in control cells (7.3%). Experimental cells, consequently, possessed a larger cross-sectional diameter and a smaller nucleus-to-cytoplasm volume ratio than control cells. These divergent developmental patterns are possibly suggestive of a delayed differentiation of interstitial cells and a modified production to degradation balance of stromal proteins in offspring of animals chronically exposed to whole cigarette smoke.


A combined adenine-phosphate effect inhibits the reactivation of eye lens epithelial cells in primary culture.
A low molecular weight component from serum, which in combination with adenine strongly retards the spreading of lens epithelial cells in primary culture, could be identified as inorganic phosphate. The possible mechanism of the combined action of adenine and phosphate is discussed.


The solid state VCD of a novel N-acylhydrazone trifluoroacetate.
A novel N-acylhydrazone with pharmaceutical importance was subject of structural and IR/VCD investigations in the solid state. In the crystal structure, dimers of anion-cation pairs are stabilized by H-bonding and ionic interactions. Some less common interaction types, like C=N···C-NH3+ (σ-hole) interactions, hydrazone-aromatic interactions and dispersive contacts of the CF3 groups are also present in the crystal. Satisfactory reproduction of the solid state IR and VCD spectra required that quantum-chemical calculations be done on a tetramer (four cation-anion pairs) cut out from the crystal structure, exhibiting key intermolecular interactions. Ten DFT functionals were assessed as to the agreement between the calculated and experimental spectra. Various approaches to scaling of the calculated frequencies were applied. The best results were yielded with individual (optimized) frequency scaling factors (FSFs) and band half-widths at half maximum-(HWHM) for four separate spectral subregions. The best matching between the experimental and theoretical spectra (according to SimIR, SimVCD and SimVDF indices) was found for the B3PW91 functional, however, a few other functionals follow closely in the ranking. Based on the quantum chemical calculations, spectral assignments have been made.


Chemical reactivity of an HLA-B27 thiol group.
Techniques have been developed to measure the reactivity of free thiols in the HLA class I antigen-binding cleft. HLA-B27, which sequencing predicts has a free cysteine at position 67, reacts rapidly with the positively charged thiol reagent monobromotrimethyl-ammoniobimane bromide (qBBr) to give products which are identifiable by isoelectric focusing. HLA-B38, B39, B64 and B65, all of which have a similar Cys 67, react less strongly. Several other class I molecules, notably HLA-C antigens, are reactive in this system, and it may be capable of recognizing subtypes such as A*0207 which also carry free cysteine. The accessibility of thiol to qBBr depends both on the chemistry of the class I molecule and other factors in the cell. Two human cell lines which are known to carry identical B27 genes but do not present the same peptides, differ considerably in the accessibility of their B27 thiol. Evidence from mouse cells transfected with mutant B27 genes suggests that a unique lysine at position 70 in the wild-type molecule increases reactivity to thiol-reactive metabolites. The failure of B27 to give a complete reaction with qBBr in our model systems suggests that it can exist in more than one chemical form. This may leave the molecule susceptible to oxidation, causing errors in T cell recognition and an exaggerated inflammatory response.


Repealing the Affordable Care Act and Implications for Cancer Care.
Calls to repeal the Affordable Care Act (ACA) have become increasingly frequent. Most attempts to repeal the ACA have targeted specific policies rather than the ACA as a whole. This article describes the specific policies under debate and the ramifications of repealing each of them. Specific attention is given to insurance coverage, individual premiums, and budgetary impact. Based on the literature regarding the ACA's impact to date, the impact of ACA repeal on Surgical oncology care is predicted.


Brown-Sequard syndrome due to isolated blunt trauma.
Blunt trauma without associated fracture or ligamentous injury is a rare cause of Brown-Sequard syndrome. We report a case of Brown-Sequard syndrome after a direct blow to the cervical spine that did not cause injury to adjacent bone or ligaments. Characteristic neurologic findings, including a unilateral hemiparesis with associated contralateral sensory findings, were noted at the time of presentation. High-dose steroids were instituted after recognition of the patient's injury, and magnetic resonance imaging of the cervical spine revealed a unilateral cord contusion with no associated fractures. After 1 month, the patient had recovered much of his function and was able to ambulate unassisted.


Pseudomonas biofilm formation and antibiotic resistance are linked to phenotypic variation.
Colonization of the lungs of cystic fibrosis (CF) patients by the opportunistic bacterial pathogen Pseudomonas aeruginosa is the principal cause of mortality in CF populations. Pseudomonas aeruginosa infections generally persist despite the use of long-term antibiotic therapy. This has been explained by postulating that P. aeruginosa forms an antibiotic-resistant biofilm consisting of bacterial communities embedded in an exopolysaccharide matrix. Alternatively, it has been proposed that resistant P. aeruginosa variants may be selected in the CF respiratory tract by antimicrobial therapy itself. Here we report that both explanations are correct, and are interrelated. We found that antibiotic-resistant phenotypic variants of P. aeruginosa with enhanced ability to form biofilms arise at high frequency both in vitro and in the lungs of CF patients. We also identified a regulatory protein (PvrR) that controls the conversion between antibiotic-resistant and antibiotic-susceptible forms. Compounds that affect PvrR function could have an important role in the treatment of CF infections.


Expression of genes of glutathione transferase isoforms GSTP1-1, GSTA4-4, and GSTK1-1 in tumor cells during the formation of drug resistance to cisplatin.
We studied the expression of genes encoding glutathione-S-transferase isoforms GSTP1-1, GSTA4-4, and GSTK1-1 during the development of the resistance of human erythroleukemia (K562), mammary adenocarcinoma (MCF-7) and ovary adenocarcinoma (SKOV-3) cells to cisplatin (CDDP). It was found that drug resistance development in all three strains of tumor cells is associated with significant increase in hGSTP1 and hGSTA4 gene expression, whereas increased hGSTK1 gene expression was detected only in resistant K562/CDDP and MCF-7/CDDP cells.


Formulation, characterization of glucosamine loaded transfersomes and in vivo evaluation using papain induced arthritis model.
The aim of current study was to develop the transdermal transfersomes of glucosamine for better drug delivery. Stretch ability and plasticity of transfersomes membranes mitigate the risk of vesicle rupture in the skin and allows the drug carrying transfersome to pass through the epidermis following the natural water gradient. Transdermal delivery of Glucosamine has an advantage over oral route, having greater local concentration and fewer systemic effects. Thin Film Rotary method was use to prepare transfersomes, and characterization was carried out physio-chemically using electron microscopic studies, zeta potential evaluation, entrapment efficiency studies. To add on in the stability, development of a secondary topical vehicle using Carbopol 940 was carried out to enhance the shelf life of transfersomes. Furthermore, in vivo studies on rabbits were also carried out using the papain induced arthritis model to support the effectiveness of treatment. The radiology studies of knee joint of rabbits proved the effectiveness of glucosamine loaded transfersomes in healing the osteoarthritis with the blood plasma analysis remain unaltered. In vitro characterization showed the successful development of nano-deformable entities with good entrapment efficiency but with little stability, therefore modified into a gel. In a nut shell this modified new dosage from can be best alternative to other conventional options that owe lot of demerits.


The design and synthesis of inhibitors of the cysteinyl protease, Der p I.
Prototype irreversible inhibitors of the cysteinyl protease Der p I were designed, synthesised and evaluated in vitro. Candidates were designed using a modular approach, whereby a peptide sequence was appended with known thiophilic moieties. This hinged on utilizing peptide sequences from substrate specificity data compiled using proprietary RAPiD technology.


Common vetch (Vicia sativa) for improving the nutrition of working equids in Campesino systems on hill slopes in Central Mexico.
Campesino systems on hill slopes in Central Mexico rely on equids for multiple activities and have a problem in adequately feeding them. A participatory trial was conducted to evaluate the inclusion of common vetch in the traditional forage oat crop to improve its feeding value. An agronomic evaluation was undertaken by intersowing common vetch at 40 kg seed/ha with oats at 80-100 kg/ha in small plots, recording the yield and the chemical composition of the fresh forage in ten plots at harvest. The data were analysed as a completely random design, taking each farmer/plot as a treatment. A feeding trial compared the live weight of 7 donkeys fed oats and vetch against 17 donkeys fed traditional forage. There were differences between farmers in forage yields (p < 0.01) that could not be explained as due to soil types or management. The mean yield of 31.0 t/ha of fresh forage of oats-vetch was 20.5% higher than that from monoculture, and had a higher crude protein content. Donkeys fed the oats-vetch were heavier (p < 0.001). The farmers evaluated the oats-vetch association positively, appreciating the higher yields and good condition of their equids. The combination is an appropriate technology for these campesino farming systems.


Sufentanil sublingual tablet system versus oral oxycodone for management of postoperative pain in enhanced recovery after surgery pathway for total knee arthroplasty: a randomized controlled study.
Effectiveness of sufentanil sublingual tablet system (SSTS) compared to oral oxycodone in the management of postoperative pain after total knee arthroplasty (TKA) within an enhanced recovery after surgery (ERAS) protocol. This pragmatic, parallel, open label, randomized controlled, trial enrolled 72 adult patients scheduled for TKA under spinal anesthesia following ERAS pathway. In addition to multimodal analgesia, patients received SSTS 15 mcg (SSTS group) or oral oxycodone extended release 10 mg twice daily and oral oxycodone immediate-release 5 mg up to four times daily on demand (Oxy group) to control pain during 48 h postoperatively. The primary endpoint was pain measured using a numeric rating scale at 24 h postoperatively. Time to first mobilization, side effects and patient satisfaction were also recorded. Median pain score at 24 h at rest was 3 [2-4] for Oxy group vs 2 [1.75-3] for SSTS group (p = 0.272) whereas median pain score on movement was 4 [3-6] vs 3 [2-5] respectively (p = 0.059). No difference in time to first mobilization was found between the two groups. The method of pain control was judged good/excellent for 83.9% of patients in the SSTS group compared with 52.9% in the Oxy group (p = 0.007). The incidence of nausea was 33% in SSTS group and 9% in Oxy group (p = 0.181). In complement to ERAS multimodal analgesia, sublingual sufentanil 15 mcg tablet system did not show clinically significant pain improvement compared to oral oxycodone after total knee arthroplasty. Clinical Trials: NCT04448457 ; retrospectively registered on June 24, 2020. https://clinicaltrials.gov/ct2/show/NCT04448457?cond=sublingual+sufentanil&cntry=BE&draw=2&rank=3.


Electrodiagnosis of striated urethral sphincter dysfunction.
In many centers urethral striated sphincter electromyography has become an essential component of urodynamic testing. The urologist who uses this modality of investigation in an attempt to understand the pathophysiology of striated sphincter dysfunction must have some basic knowledge of electromyography. Attempts have been made to provide such basic information, especially relating to the methods of evaluation and interpretation. We also have incorporated our own views based on our experience with more than 200 subjects with neuropathic vesicourethral dysfunctions.


The Brain Trauma Foundation. The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care. Trauma systems.
Published case series and cohort comparison studies of patients treated in regions where planned trauma systems are in place compared to regions without trauma systems, or before and after instituting a trauma system, conclude that mortality is reduced after major trauma in patients treated in a trauma system. For optimal care of neurotrauma, neurosurgeons should be involved in the planning and implementation of trauma systems and in support of a system once it is in place.


Tubular sodium handling in cirrhotic patients with ascites as analysed by the renal lithium clearance method.
The proximal and distal sodium reabsorption were calculated from lithium clearance in 21 healthy controls and 24 cirrhotic patients with ascites after 4 days under a sodium-restricted diet. The values of fractional lithium clearance were lower in patients than in controls (7.37 +/- 0.87 vs. 18.13 +/- 1.76%, P less than 0.001). Fractional proximal sodium reabsorption was increased in patients compared with controls (92.8 +/- 1.1 vs. 81.8 +/- 1.7%, P less than 0.001). No differences were found in fractional distal sodium reabsorption between controls and patients (96.9 +/- 0.8 vs. 98.6 +/- 0.1%). When patients were separated into two subgroups according to their sodium balance, it was found that fractional distal sodium reabsorption was increased in patients whose balance remained positive, compared with patients on a negative sodium balance (98.99 +/- 0.26 vs. 94.11 +/- 1.50%, P less than 0.05). In addition, the natriuretic response to a specific dose of spironolactone was higher in patients on positive sodium balance compared with patients on negative sodium balance (per cent increase in natriuresis after spironolactone 300 mg day-1: 355.24 +/- 73.98 vs. 84.21 +/- 15.8%, P less than 0.01). We conclude that proximal sodium reabsorption is increased in cirrhotics with ascites. In addition, distal sodium reabsorption is enhanced only in those patients which exhibit avid sodium retention.


Expression of KIAA 0864 protein in neuroepithelial tumors: an analysis based on the presence of monoclonal antibody HFB-16.
The KIAA 0864 (KA) protein is a putative protein of a cDNA from 100 cDNA clones that was newly determined from a set of size-fractionated human brain cDNA libraries and their coding potentials of large proteins (180-200 kD) by using in vitro transcription assays. To elucidate the correlation between the KA protein and neuroepithelial tumors (NETs), the present study assessed the KA expression by the NETs using immunohistochemical and Western blot analyses with HFB-16 monoclonal antibody. Among the 55 NETs, a moderate-to-intense KA protein immunoreactivity was observed in 8 of 8 medulloblastomas, 1 of 1 central nervous system supratentorial primitive neuroectodermal tumor (CNS supratentorial PNET), 4 of 4 retinoblastomas, 1 of 1 neuroblastoma, 8 of 8 central neurocytomas, 4 of 4 oligodendrogliomas, 4 of 4 oligoastrocytomas, 1 of 1 extraventricular neurocytoma, and 1 of 1 gangliocytoma. No or a weak KA protein immunoreactivity was observed in 11 of 11 glioblastomas (GBs), 4 of 4 anaplastic astrocytomas, 4 of 4 astrocytomas, and 4 of 4 pilocytic astrocytomas. These results indicate that the antibody HFB-16 could be a useful marker for neuronal tumors and primitive neuroectodermal tumors that may originate from immature neural progenitor cells. In addition, it could be a useful tool for performing the differential diagnosis between GBs and CNS supratentorial PNET.


Association of trace element status in COVID-19 patients with disease severity.
Caused by the new SARS-CoV-2 coronavirus, COVID-19 (coronavirus disease 2019) evolves with clinical symptoms that vary widely in severity, from mild symptoms to critical conditions, which can even result in the patient's death. A critical aspect related to an individual response to SARS-CoV-2 infection is the competence of the immune system, and it is well known that several trace elements are essential for an adequate immune response and have anti-inflammatory and antioxidant properties that are of particular importance in fighting infection. Thus, it is widely accepted that adequate trace element status can reduce the risk of SARS-CoV-2 infection and disease severity. In this study, we evaluated the serum levels of Cu, Zn, Se, Fe, I and Mg in patients (n = 210) with clinical conditions of different severity ("mild", "moderate", "severe" and "exitus letalis", i.e., patients who eventually died). The results showed significant differences between the four groups for Cu, Zn, Se and Fe, in particular a significant trend of Zn and Se serum levels to be decreased and Cu to be increased with the severity of symptoms. For Mg and I, no differences were observed, but I levels were shown to be increased in all groups.


Alix is required during development for normal growth of the mouse brain.
Alix (ALG-2 interacting protein X) drives deformation and fission of endosomal and cell surface membranes and thereby intervenes in diverse biological processes including cell proliferation and apoptosis. Using embryonic fibroblasts of Alix knock-out mice, we recently demonstrated that Alix is required for clathrin-independent endocytosis. Here we show that mice lacking Alix suffer from severe reduction in the volume of the brain which affects equally all regions examined. The cerebral cortex of adult animals shows normal layering but is reduced in both medio-lateral length and thickness. Alix controls brain size by regulating its expansion during two distinct developmental stages. Indeed, embryonic surface expansion of the Alix ko cortex is reduced because of the loss of neural progenitors during a transient phase of apoptosis occurring between E11.5 and E12.5. Subsequent development of the Alix ko cortex occurs normally until birth, when Alix is again required for the post-natal radial expansion of the cortex through its capacity to allow proper neurite outgrowth. The need of Alix for both survival of neural progenitor cells and neurite outgrowth is correlated with its role in clathrin-independent endocytosis in neural progenitors and at growth cones. Thus Alix-dependent, clathrin independent endocytosis is essential for controlling brain size.


Cis-p-tau plays crucial role in lysolecithin-induced demyelination and subsequent axonopathy in mouse optic chiasm.
Multiple sclerosis (MS) is an autoimmune demyelinating disease that leads to axon degeneration as the major cause of everlasting neurological disability. The cis-phosphorylated tau (cis-p-tau) is an isoform of tau phosphorylated on threonine 231 and causes tau fails to bind micro-tubules and promotes assembly. It gains toxic function and forms tangles in the cell which finally leads to cell death. An antibody raised against cis- p-tau (cis mAb) detects this isoform and induces its clearance. Here, we investigated the formation of cis-p-tau in a lysophosphatidylcholine (LPC)-induced prolonged demyelination model as well as the beneficial effects of its clearance using cis mAb. Cis -p-tau was increased in the lesion site, especially in axons and microglia. Behavioral and functional studies were performed using visual cliff test, visual placing test, and visual evoked potential recording. Cis-p-tau clearance resulted in decreased gliosis, protected myelin and reduced axon degeneration. Analysis of behavioral and electrophysiological data showed that clearance of cis-p-tau by cis mAb treatment improved the visual acuity along with the integrity of the optic pathway. Our results highlight the opportunity of using cis mAb as a new therapy for protecting myelin and axons in patients suffering from MS.


Individual assignments of the heme resonances in the 360 MHz 1H NMR spectra of cytochrome c-557 from Crithidia oncopelti.
With the use of nuclear Overhauser effects, spin decoupling and saturation transfer experiments individual assignments for numerous resonances of the heme group in the 360 MHz 1H NMR spectra of reduced and oxidized cytochrome c-557 from Crithidia oncopelti were obtained. These data provide direct evidence that the heme substituent in position 2 is a vinyl group. They further show that in spite of the different covalent structures of the heme groups the heme crevice and the electronic heme structure in the oxidized state are nearly identical in cytochrome c-557 and in mammalian cytochromes c.


Long non-coding RNA EWSAT1 promoted metastasis and actin cytoskeleton changes via miR-24-3p sponging in osteosarcoma.
Non-coding RNAs are closely associated with tumorigenesis in multiple malignant tumours, including osteosarcoma (OS). Long non-coding RNA Ewing sarcoma-associated transcript 1 (EWSAT1) plays a role in metastasis, and actin cytoskeletal changes in OS remain unclear. In the current study, we showed that EWSAT1 expression was up-regulated in OS and that an elevation in the EWSAT1 expression level was correlated with poor prognosis in patients with OS. Functionally, we showed that knockdown of EWSAT1 suppressed migration and induced actin stress fibre degradation in MNNG/HOS and 143B cells. Moreover, we found that ROCK1 was a key downstream effector in EWSAT1-mediated cell migration and actin stress fibre changes. Furthermore, we demonstrated that ROCK1 and EWSAT1 shared a similar microRNA response element of microRNA-24-3p (miR-24-3p). Moreover, we verified that miR-24-3p suppressed ROCK1 and its mediated migration and actin stress fibres change by direct targeting. EWSAT1 promoted ROCK1-mediated migration and actin stress fibre formation through miR-24-3p sponging. Lastly, through an in vivo study, we demonstrated that EWSAT1 promoted lung metastasis in OS. According to the above-mentioned results, we suggest that EWSAT1 acts as an oncogene and that EWSAT1/miR-24-3p/ROCK1 axial could be a new target in the treatment of OS.


Immunologic cell markers of peripheral blood and lymph node lymphocytes in chronic lymphocytic leukemia.
The immunologic phenotype of the lymphocytes of 100 patients with chronic lymphocytic leukaemia (CLL) was investigated. Peripheral blood lymphocytes (PBL) were examined in all cases; in 46 patients with lymphadenopathy, a lymph node was biopsied and the histologic and immunologic patterns were assessed: 24 had a lymphocytic-lymphoplasmocytoid histology and 22 the follicular variant of lymphocytic lymphoma (mantle zone lymphoma, MZL). For comparison, lymph node suspensions from 19 patients with non-leukemic centrocytic lymphoma (CCL) were also studied. Significant differences in the PBL immunologic features were found between stage O and stage I patients. The phenotype of the lymphocytes of patients with lymphocytic histology was similar to that of stage 0 CLL patients, whereas major differences were found between these patients and those with mantle zone histology. This enables these patients to be recognized easily on immunologic grounds.


Stress management for essential hypertension: comparison with a minimally effective treatment, predictors of response to treatment, and effects on reactivity.
Few studies of psychological interventions for essential hypertension have incorporated comprehensive coping skills treatment programs, evaluated the efficacy of such programs against credible, minimally effective controls, examined the effects of these interventions on pressor responses, or clarified the nature of person by treatment interactions. The present study examined the relative effectiveness of multimodal stress management training and a minimally effective treatment control (i.e. GSR biofeedback training) in the treatment of essential hypertensives' blood pressure at rest and in response to simulated stressful interpersonal situations. At the conclusion of an 8 week training period, stress management participants exhibited reliably lower resting diastolic blood pressure and tended to exhibit lower systolic pressure than controls. The former condition maintained their lower pressures through a 6-month follow-up period, but decreases in controls over follow-up rendered the conditions equivalent in blood pressure. No differences between conditions emerged in analyses on pressor responses. Stress management training was somewhat more effective for individuals scoring low rather than high on measures of trait anxiety and irritability.


Diabetes mellitus promoted lymph node metastasis in gastric cancer: a 15-year single-institution experience.
Previous studies have revealed that diabetes mellitus (DM) promotes disease progress of gastric cancer (GC). This study aimed to further investigating whether DM advanced lymph nodes (LNs) metastasis in GC. The clinicopathologic data of GC patients with >15 examined LN (ELN) between October 2004 and December 2019 from a prospectively maintained database were included. The observational outcomes included the number (N3b status) and anatomical distribution (N3 stations) of metastatic LN (MLN). A total of 2142 eligible patients were included in the study between October 2004 and December 2019. N3 stations metastasis (26.8% in DM vs. 19.3% in non-DM, P = 0.026) and N3b status (18.8% in DM vs. 12.8% in non-DM, P = 0.039) were more advanced in the DM group, and multivariate logistic regression analyses confirmed that DM was an independent factor of developing N3 stations metastasis (odds ratio [OR] = 1.771, P = 0.011) and N3b status (OR = 1.752, P = 0.028). Also, multivariate analyses determined DM was independently associated with more MLN (β = 1.424, P = 0.047). The preponderance of N3 stations metastasis (DM vs. non-DM, T1-2: 2.2% vs. 4.9%, T3: 29.0% vs. 20.3%, T4a: 38.9% vs. 25.8%, T4b: 50.0% vs. 36.6%; ELN16-29: 8.6% vs. 10.4%, ELN30-44: 27.9% vs. 20.5%, ELN ≥ 45: 37.7% vs. 25.3%), N3b status (DM vs. non-DM, T1-2: 0% vs. 1.7%, T3: 16.1% vs. 5.1%, T4a: 27.8% vs. 19.1%, T4b: 44.0% vs. 28.0%; ELN16-29: 8.6% vs. 7.9%, ELN30-44: 18.0% vs. 11.8%, ELN ≥ 45: 26.4% vs. 17.3%), and the number of MLN (DM vs. non-DM, T1-2: 0.4 vs. 1.1, T3: 8.6 vs. 5.2, T4a: 9.7 vs. 8.6, T4b: 17.0 vs. 12.8; ELN16-29: 3.6 vs. 4.6, ELN30-44: 5.8 vs. 5.5, ELN ≥ 45: 12.0 vs. 7.7) of DM group increased with the advancement of primary tumor depth stage and raising of ELN. DM was an independent risk factor for promoting LN metastasis. The preponderance of LN involvement in the DM group was aggravated with the advancement of tumor depth.


Tetrodotoxin enhances initial neurite outgrowth from fetal rat cerebral cortex cells in vitro.
The effect of two different concentrations of the sodium channel blocker tetrodotoxin on neurite outgrowth from fetal rat cerebral cortex neurons was studied in vitro. A concentration of 10(-6) M tetrodotoxin enhanced after two days in vitro: the percentage of isolated cells and reaggregates which formed neurites, the number of neurites per cell soma, and neurite elongation and subsequent branching. The effects observed after treatment with 10(-7) M tetrodotoxin were on the whole intermediate between control and 10(-6) M tetrodotoxin.


Epidural spinal cord stimulation for the treatment of painful legs and moving toes syndrome.
A case of 51-year-old male with painful legs and moving toes syndrome was successfully treated with epidural spinal cord stimulation. He was previously treated with varieties of medication, epidural block, transcutaneous nerve stimulation, lumbar sympathetic block, with no or only a transient effect. Epidural spinal cord stimulation was applied by means of percutaneously inserted epidural electrodes connected to a percutaneous extension for 2-week test stimulation period and later to a permanent device (ITREL). Pain and involuntary movement were relieved almost completely during the stimulation and the effect was still evident 6 months later.


Coarticulation and phonology.
Many sound patterns in languages are cases of fossilized coarticulation, that is, synchronic or phonetic contextual variation became diachronic or phonological variation via sound change. An examination of languages' phonologies can therefore yield insights into the mechanisms of coarticulation. In this paper I discuss (a) the need to differentiate between phonological processes that are and are not due to coarticulation, (b) the need to differentiate between 'on-line' synchronic variation and comparable fossilized diachronic variation, (c) how to determine some of the constraints on coarticulation--especially the higher priority of maintaining acoustic-auditory, rather than articulatory, norms for the shape of speech elements, and (d) how coarticulation presents a "parsing" problem to the listener and, of course, to systems for automatic speech recognition.


Aggression as an independent entity even in psychosis- the role of inflammatory cytokines.
Aggression is very common in psychosis (prevalence ranging from 34% to 70%) and is often the main or first symptom for which the patient receives medical attention. Studies have associated alteration in cytokine profiles among healthy persons with aggressive traits. We hypothesise that even among those with psychosis, aggression is an independent entity, irrespective of psychotic state and is associated with cytokine alterations. To our knowledge, this is the first study attempting to look at the inflammatory cytokines in aggressive psychotic patients. Study included 80 participants divided into four groups viz. aggressive diseased, non aggressive diseased, aggressive non diseased and non aggressive non diseased depending upon presence or absence of aggression and psychosis. Interferon gamma(IFN-G), Interleukin 10(IL10) plasma concentrations and their ratio were measured using ELISA based assay kits read at absorbance of 450 nm wavelength using Double beam spectrophotometer. The four groups were compared on measures of aggression, psychosis, Interferon Gamma levels, Interleukin 10 levels, Proinflammatory: Antiinflammatory cytokine ratio using standard statistical instruments. In patients with psychosis, the cytokines IFN-G and IL10 were significantly lower compared to those without. The cytokines IFN-G and IL10 are both significantly associated both with aggression and psychosis. IL10, but not IFN-G is associated with aggression in absence of psychosis. The proinflammatory: antiinflammatory cytokine ratio, is more significantly associated with aggression, irrespective of psychosis. In fact, there is no significant relationship between the above ratio and psychosis. Strong correlation exists between the proinflammatory: antiinflammatory cytokine ratio and aggression scores, even after controlling for severity of psychosis. It may be concluded from this study that in spite of a high prevalence of aggression in patients of psychosis, it is more likely to be an independent entity associated with individual cytokine changes and increased proinflammatory: antiinflammatory cytokine ratio as its hallmark.


NFATc1 releases BCL6-dependent repression of CCR2 agonist expression in peritoneal macrophages from Saccharomyces cerevisiae infected mice.
The link between the extensive usage of calcineurin (CN) inhibitors cyclosporin A and tacrolimus (FK506) in transplantation medicine and the increasing rate of opportunistic infections within this segment of patients is alarming. Currently, how peritoneal infections are favored by these drugs, which impair the activity of several signaling pathways including the Ca(++) /CN/NFAT, Ca(++) /CN/cofilin, Ca(++) /CN/BAD, and NF-κB networks, is unknown. Here, we show that Saccharomyces cerevisiae infection of peritoneal resident macrophages triggers the transient nuclear translocation of NFATc1β isoforms, resulting in a coordinated, CN-dependent induction of the Ccl2, Ccl7, and Ccl12 genes, all encoding CCR2 agonists. CN inhibitors block the CCR2-dependent recruitment of inflammatory monocytes (IM) to the peritoneal cavities of S. cerevisiae infected mice. In myeloid cells, NFATc1/β proteins represent the most prominent NFATc1 isoforms. NFATc1/β ablation leads to a decrease of CCR2 chemokines, impaired mobilization of IMs, and delayed clearance of infection. We show that, upon binding to a composite NFAT/BCL6 regulatory element within the Ccl2 promoter, NFATc1/β proteins release the BCL6-dependent repression of Ccl2 gene in macrophages. These findings suggest a novel CN-dependent cross-talk between NFAT and BCL6 transcription factors, which may affect the outcome of opportunistic fungal infections in immunocompromised patients.


Evans blue extravasation in rat dental pulp and oral tissues induced by electrical stimulation of the inferior alveolar nerve.
Whether increased extravasation of plasma protein may occur in the rat incisor pulp as a result of antidromic stimulation of afferent nerves was investigated, and this preinflammatory reaction compared with that in adjacent soft tissues. In anaesthetized rats, the inferior alveolar nerve was exposed and stimulated electrically (10-15 V, 2 ms, 10 Hz for 30 s or 5 min). Blood flow changes in the lower lip and incisor pulp were recorded by laser Doppler flowmetry. Increased vascular permeability in the lip, gingiva and pulp was indirectly determined by means of the Evans blue dye method and spectrophotometric analysis. Stimulation of the inferior alveolar nerve for 30 s, in the presence of the alpha-adrenergic blocker phenoxybenzamine (3 mg/kg), increased blood flow in the lip by 172 +/- 16% and in the pulp by 38 +/- 5% as compared to basal blood flow. Intravenous (i.v.) administration of atropine (1 mg/kg), chlorisondamine (3 mg/kg), timolol (150 micrograms/kg), cimetidine plus mepyramine (3 mg/kg of each), methysergide (1 mg/kg) and diclofenac sodium (3 mg/kg) was without effect on this response. Acute pretreatment with capsaicin (1-3 mg/kg, i.v.), however, abolished the vasodilation in the pulp and reduced that in the lip by 58% (p < 0.05). In untreated animals, stimulation of the inferior alveolar nerve for 5 min increased the Evans blue content in the ipsilateral lip by 164% (p < 0.001), gingiva by 55% (p < 0.01) and pulp by 67% (p < 0.01). Pretreatment (i.v.) with a combination of cimetidine and mepyramine counteracted the dye extravasation only in the gingiva.(ABSTRACT TRUNCATED AT 250 WORDS)


Reproducibility of a Parkinsonism-related metabolic brain network in non-human primates: A descriptive pilot study with FDG PET.
We have previously defined a parkinsonism-related metabolic brain network in rhesus macaques using a high-resolution research positron emission tomography camera. This brief article reports a descriptive pilot study to assess the reproducibility of network activity and regional glucose metabolism in independent parkinsonian macaques using a clinical positron emission tomography/CT camera. [(18)F]fluorodeoxyglucose PET scans were acquired longitudinally over 3 months in three drug-naïve parkinsonian and three healthy control cynomolgus macaques. Group difference and test-retest stability in network activity and regional glucose metabolism were evaluated graphically, using all brain images from these macaques. Comparing the parkinsonian macaques with the controls, network activity was elevated and remained stable over 3 months. Normalized glucose metabolism increased in putamen/globus pallidus and sensorimotor regions but decreased in posterior parietal cortices. Parkinsonism-related network activity can be reliably quantified in different macaques with a clinical positron emission tomography/CT scanner and is reproducible over a period typically employed in preclinical intervention studies. This measure can be a useful biomarker of disease process or drug effects in primate models of Parkinson's disease.


Development of an instrument to assess and predict satisfaction and poor tolerance among patients undergoing endoscopic procedures.
We aimed to test the reliability of a developed questionnaire that measures and predict aversive endoscopic experience. Two questionnaires (pre- and postprocedure) were given to patients presenting for routine endoscopy. The first questionnaire elicited demographics, prior endoscopic experience, history of drug or alcohol use, patient expectations, and levels of anxiety and nervousness before procedure. After endoscopy, tolerance and willingness to repeat the examination were determined. The primary outcome of "adverse endoscopic experience" (AEE) was defined as a score of > or =5 on the postprocedure overall level of satisfaction or unwillingness to repeat endoscopy. Thirteen of 148 subjects reported an AEE. Items measuring the primary outcome were internally validated by reliability analysis which significantly correlated with measures of aversive experience like pain, nervousness, and suffering during the procedure. Preprocedure factors that were associated with AEE in the univariate analysis and multivariate analysis were nervousness (P = 0.02) and chronic use of psychotropic drugs or alcohol (P = 0.03). In conclusion, we have developed a questionnaire that reliably measures aversive endoscopic experience. Nervousness before procedure and chronic use of psychotropic drugs are reliable predictors of such experience.


Extracorporeal Stromal Cell Therapy for Subjects With Dialysis-Dependent Acute Kidney Injury.
The pathophysiology of acute kidney injury (AKI) involves damage to renal epithelial cells, podocytes, and vascular beds that manifests into a deranged, self-perpetuating immune response and peripheral organ dysfunction. Such an injury pattern requires a multifaceted therapeutic to alter the wound healing response systemically. Mesenchymal stromal cells (MSCs) are a unique source of secreted factors that can modulate an inflammatory response to acute organ injury and enhance the repair of injured tissue at the parenchymal and endothelial levels. This phase Ib/IIa clinical trial evaluates SBI-101, a combination product that administers MSCs extracorporeally to overcome pharmacokinetic barriers of MSC transplantation. SBI-101 contains allogeneic human MSCs inoculated into a hollow-fiber hemofilter for the treatment of patients with severe AKI who are receiving continuous renal replacement therapy (CRRT). SBI-101 therapy is designed to reprogram the molecular and cellular components of blood in patients with severe organ injury. This study is a prospective, multicenter, randomized, double-blind, sham-controlled, study of subjects with a clinical diagnosis of AKI who are receiving CRRT. Up to 32 subjects may be enrolled to provide 24 evaluable subjects (as a per protocol population). Subjects will receive CRRT in tandem with a sham control (0 MSCs), or the low- (250 × 106 MSCs) or high-dose (750 × 106 MSCs) SBI-101 therapeutic. The study will measure dose-dependent safety, renal efficacy, and exploratory biomarkers to characterize the pharmacokinetics and pharmacodynamics of SBI-101 in treated subjects. This first-in-human clinical trial will evaluate the safety and tolerability of SBI-101 in patients with AKI who require CRRT.


Parenteral fat emulsions based on olive and soybean oils: a randomized clinical trial in preterm infants.
To evaluate in premature infants a new parenteral lipid emulsion based on olive and soybean oils (ratio 4:1), with less polyunsaturated fatty acids (PUFA) and more alpha-tocopherol than standard soybean oil emulsion. Premature infants (gestational age, 28-<37 weeks) were randomized to receive one of the two emulsions within the first 72 hours of life. The triglyceride dose was increased to 2 g/kg/day within 3 days. Plasma phospholipid fatty acids, alpha-tocopherol/lipid ratio, and urinary malondialdehyde (MDA) excretion were determined at baseline and after 7 days. Of 45 recruited infants, 33 completed the study per protocol (15 soybean oil, 18 olive oil emulsion). At study end, groups did not differ in plasma phospholipid arachidonic acid, total n-6 and n-3 metabolites, but the olive oil group showed higher values of the PUFA intermediates C18:3n-6 (0.19% +/- 0.01% vs. 0.13% +/- 0.02%, P < 0.05) and C20:3n-6 (2.92% +/- 0.12% vs. 2.21% +/- 0.17%, P = 0.005). The plasma alpha-tocopherol/total lipd ratio was higher in the olive oil group (2.45 +/- 0.27 micromol/mmol vs. 1.90 +/- 0.08 micromol/mmol, P = 0.001), whereas urinary MDA excretion did not differ. The lower PUFA supply with the olive/soybean oil emulsion appears to enhance linoleic acid conversion. The reduced PUFA content, combined with a higher antioxidant intake in the olive oil group, results in an improved vitamin E status. The olive oil-based emulsion is a valuable alternative for parenteral feeding of preterm infants who are often exposed to oxidative stress, while their antioxidative defense is weak.


Rat subthalamic stimulation: Evaluating stimulation-induced dyskinesias, choosing stimulation currents and evaluating the anti-akinetic effect in the cylinder test.
In experimental deep brain stimulation of the subthalamic nucleus (STN HFS), stimulation currents just below the appearance threshold of stimulation-induced dyskinesias has often been used. The behavioral effect of STN HFS can be measured by the reversal of forelimb use asymmetry produced by hemiparkinsonism can be measured with the cylinder test among other tests. We used 18 Wistar rats with 6-hydroxydopamine induced hemiparkinsonism to test a customized scale to rate the severity of stimulation-induced dyskinesia; we then used these ratings to choose low and high stimulation currents. Subsequent cylinder tests showed that stimulation at the higher current, inducing mild and short-lived dyskinesias, was required for robust improvement in forelimb use, contradicting the use of currents below stimulation-induced dyskinesia threshold. It was also beneficial to separately count both all touches and first touches with the cylinder wall; this provided additional sensitivity and robustness to our results. •Scoring stimulation-induced dyskinesias can be used as a quantitative measure of dyskinesias and to choose stimulation currents.•Cylinder test scoring separately for both first and all touches can improve both sensitivity and reliability.•STN HFS at a current producing short-lived dyskinesias was required for robust improvement in forelimb use asymmetry.


The protective effect of acute phase reactants in neonatal sepsis.
Phase reactants were evaluated prospectively in babies suspected of having sepsis. Among 318 babies, there were 22 proven and 10 "very probable" cases of neonatal sepsis. Of the proven cases 14 survived and 8 died. The survivors had a positive latex C-reactive protein (CRP) in 11 cases and an alpha1-acid glycoprotein (AGP) level greater than 0.5 g/l in 12 cases. Among those who died, one had a positive latex CRP and none had AGP greater than 0.5 g/l. These findings were supported by positive CRP and elevated AGP in almost all "very probable" cases, all of whom survived. These data in newborn infants support the hypothesis that acute phase reactants have a functional role in combating infection.


Population analysis of the pharmacokinetic variability of high-dose metoclopramide in cancer patients.
Metoclopramide infusions are used to prevent nausea and vomiting in cancer patients during chemotherapy. 47 patients received metoclopramide during 109 chemotherapeutic treatments as a loading (dose range = 0.55 to 4.5 mg/kg over 15 minutes) and maintenance (dose range = 0.57 to 4.8 mg/kg over 8 hours) infusion. During and up to 24 hours after the end of the maintenance infusion between 4 and 10 blood samples were collected per treatment. Metoclopramide was analysed in plasma by liquid chromatography. Pharmacokinetic and demographic data of 83 treatments were analysed by the NONMEM program using a linear 2-compartment model. It was found that bodyweight and serum alkaline phosphatase activity explain some of the interindividual variability in clearance (CL). The typical pharmacokinetic parameters for an average individual (70kg, alkaline phosphatase = 100 IU/L) were: CL = 20 L/h; volume of distribution at steady state (Vdss) = 190L; terminal half-life = 8h. The interindividual variabilities in clearance, volume of central compartment and Vdss were 50%, 35% and 35%, respectively. The residual variability in plasma concentrations was estimated as 13%.


Development of anangiogenesis-focused cDNA chip and validation of its functionality.
DNA chip has been used as a powerful tool to study the genetic reprogramming of cells and its link to cellular phenotype such as angiogenesis. To evaluate the angiogenesis related genetic reprogramming more efficiently, we here developed an angiogenesis-focused cDNA chip containing 153 angiogenesis related genes arrayed in duplicate on a slide glass. In order to validate the functionality of the angiogenesis-focused cDNA chip, we examined gene expression profiles in HT1080 cells treated with either fetal bovine serum, a well known pro-angiogenic factor, or trichostatin A, a known angiogenesis inhibitor, using the cDNA chip. All duplicate data from the analysis are well matched with each other and gene expression profiles are well consistent with previously reported data. These results demonstrate that the angiogenesis-focused cDNA chip developed here can be a useful tool towards angiogenesis- related researches.


Applications of deep eutectic solvents in microextraction and chromatographic separation techniques: Latest developments, challenges, and prospects.
Deep eutectic solvents (DESs) have recently sparked considerable attention in a variety of scientific and technological fields. The unique properties of DESs include biodegradability, easy preparation, low cost, and tuneability, rendering them a new and prospective alternative to hazardous solvents. Analytical chemistry is one of the most appealing fields where DESs proved to be applicable in either sample preparation or chromatographic separation. This review summarizes the new horizons dedicated to the application of DESs in microextraction and chromatographic separation. The utilization of DESs in microextraction, in chromatography as mobile phase additives, and in chromatographic material preparation processes is outlined. The enhancements in chromatographic performance achieved using DESs and any potential explanations deduced from the experimental findings were primarily discussed. An additional brief discussion on DESs preparation, characterization, and properties is addressed in this work. Finally, current challenges and future trends are also presented, supplying evidence for distinct possibilities regarding new research approaches involving DESs. This review can represent a guide and stimulate further research in this field.


"Inverted" Deep Eutectic Solvents Based on Host-Guest Interactions.
Herein, the concept of "inverted" (the mode "molecules mainly interact with cations") deep eutectic solvents (DESs) is proposed. A strategy to form inverted DESs by host-guest interactions was developed, and thus numerous DESs could be designed and formed by a combination of host and guest molecules. These liquids are expected to be used as nonaqueous electrolytes in potassium-ion batteries or other fields for further exploration.


Central Sensitization Inventory is a useless instrument for detection of the impairment of the conditioned pain modulation in patients with chronic musculoskeletal pain.
The current study aimed to evaluate the concurrent validity and the diagnostic accuracy of the Central Sensitization Inventory (CSI) in detecting the impairment of the pain modulation in patients with chronic musculoskeletal pain. A cross-sectional study was conducted in 267 patients with chronic musculoskeletal pain enrolled consecutively in an outpatient department. The CSI (index method) were compared with the cold pressor test, which was the psychophysical test used to assess the conditioned pain modulation (CPM), (reference standard). Spearman's correlations assessed the concurrent validity, and measurements of the diagnostic accuracy were performed. Ninety-three (34.8%) patients had CSI scores≥40. No significant correlation was found between CSI findings and the results of the CPT (dorsal forearm site or tibialis anterior site) was found. The cutoff point of 40 of the CSI showed values of sensitivity (35.1%, 95% CI: 22.6, 49.3) and specificity (65.2%, 95% CI: 58.4, 71.6) below 70%, and an accuracy of 59.1 (95% CI: 53.0, 65.1) when compared to the CPT to detect deficit. The ROC curve analysis yielded an area under the curve of 0.54 (95% CI: 0.45, 0.63, P>0.05). The CSI is a useless instrument to detect the deficit in the CPM in patients with chronic musculoskeletal pain due to the absence of correlation with the psychophysical test result and the insufficient measurements of diagnostic accuracy.


Correlation between progressive adsorption of plasminogen to blood clots and their sensitivity to lysis.
The binding of plasminogen to preformed human plasma clots immersed in citrated human plasma was measured and correlated with the sensitivity of these clots to lysis with recombinant tissue-type plasminogen activator (rt-PA), recombinant single-chain urokinase-type plasminogen activator (rscu-PA) or two chain urokinase-type plasminogen activator (tcu-PA, urokinase). When 0.15 ml plasma clots were compressed mechanically to about 1% of their original weight, and immersed in 0.15 ml plasma, 131I-labeled native plasminogen (Glu-plasminogen) adsorbed progressively from the plasma milieu onto the clot; binding was 3 +/- 1% (n = 10) after 1 h, 7 +/- 1% after 12 h and 12 +/- 1% after 48 h. This was associated with an increased sensitivity of the clot to lysis; 50% clot lysis in 4 h was obtained with 65 +/- 5 ng/ml (n = 3) rt-PA before and 30 +/- 5 ng/ml (n = 3) after 48 h preincubation in plasma (p less than 0.01), with corresponding values of 660 +/- 55 ng/ml (n = 3) and 280 +/- 25 ng/ml (n = 3) for rscu-PA, (p less than 0.01), and 800 +/- 85 ng/ml (n = 3) and 270 +/- 35 ng/ml (n = 3) for urokinase (p less than 0.01). Additional binding of plasminogen and increased sensitivity to lysis were reduced or abolished when the clot was preincubated in plasminogen-depleted or in t-PA-depleted plasma, or when 20 mM 6-aminohexanoic acid or 2,000 KIU/ml aprotinin were added.(ABSTRACT TRUNCATED AT 250 WORDS)


The dorsal spino-olivocerebellar system in the cat. II. Somatotopical organization.
The somatotopical organization of the projection through the dorsal spino-olivocerebellar path (DF-SOCP) to the c3 zone in the cerebellar anterior lobe was studied by recording climbing fiber field potentials in the cerebellar cortex evoked on stimulation of peripheral nerves. The c3 zone was shown to contain a detailed and systematic representation of the ipsilateral body half with the follwing characteristics: 1. Single nerves project to one or two sagittal strips of cortex which extend across several folia. The width of the strips varies between 0.2 and 1 mm and the length may be as long as 15-20 mm along the unfolded cortex. 2. The strips activated from different nerves occur in an order which usually follows the segmental innervation, the hindlimb being represented rostrally and the forelimb caudally in the zone. 3. The double representation of some nerves makes it possible to distinguish one medial and one lateral part of the c3 zone with the projection areas organized approximately as mirror images. Additional observations on other zones activated by the DF-SOCP system (Ekerot and Larson, 1979a) indicate that the c1 zone, has a somatotopical organization which is reminiscent of that of the c3 zone, whereas the x and d1 zones have different topographical organizations.


Microbiologic aspects of infection in the compromised host.
The severe morbidity and mortality associated with infection in the compromised host is a serious problem. Many infections are caused by organisms considered to have a low degree of pathogenicity under normal circumstances. It is essential to have rapid procedures available to isolate and identify these etiologic agents of infections so that rational therapy is begun.


Evidence-based goals versus achievement in clinical practice in secondary prevention of coronary heart disease: findings in EUROASPIRE II.
Recommendations for reducing risk of recurrence in patients with established coronary heart disease (CHD) or other atherosclerotic disease were published by the Joint European Societies in 1994 and 1998. The first EUROASPIRE survey of clinical practice of secondary CHD prevention, performed in 1995 and 1996, found that 19% of CHD patients smoked cigarettes, 25% had body mass index (BMI) > or =30 kg/m(2), 53% had blood pressure > or =140/90 mmHg, and 44% had plasma total cholesterol > or =5.5 mmol/l. EUROASPIRE II, conducted in 1999 and 2000, found that 21% of patients smoked cigarettes, 31% had BMI > or =30 kg/m(2), 50% had blood pressure > or =140/90 mmHg, and 58% had serum total cholesterol > or =5.0 mmol/l. It is clear that there are still considerable opportunities in Europe to reduce risk of recurrent CHD through lifestyle changes, rigorous control of other risk factors, and more effective use of proven drug therapies.


A phase 1 evaluation of the safety and tolerability of niraparib in combination with everolimus in advanced ovarian and breast cancers.
Phase 1 trial to determine the safety and tolerability of everolimus and niraparib in patients with advanced ovarian and breast malignancies. Fourteen heavily pretreated patients were enrolled (12 high-grade serous ovarian cancer, 1 clear cell ovarian cancer, and 1 triple negative breast cancer). All patients were PARP naïve and received comprehensive genomic profiling prior to enrollment. Two DLTs were experienced in cohort 2 (niraparib 200 mg daily and everolimus 5 mg 3 days per week) with one patient experiencing prolonged thrombocytopenia and the other experiencing severe hypertension. Four additional patients were enrolled after dose de-escalation with one patient again experiencing severe hypertension leading to conclusion of the study. The most frequent grade 3 or greater adverse events were thrombocytopenia, hypertension, anemia, fatigue, neutropenia, and elevated alkaline phosphatase. Two patients had a PR and five patients had SD. ORR was 18% and the CBR was 45% in 11 evaluable patients. Median PFS was 6 months, and median OS is approximately 18 months with three patients still alive at the data cutoff. The combination of everolimus and niraparib demonstrated significant toxicity at lower doses and is not feasible due to rapid onset and severe hypertension. This limitation possibly blunted the efficacy of the combination as PFS was modest, but OS was surprisingly robust due to three patients with ovarian cancer remaining alive with platinum refractory disease. Further investigation of multiagent blockade of the PI3K pathway combined with PARP is warranted.


A spontaneous temperature sensitive mutant of Japanese encephalitis virus: preliminary characterization.
A spontaneously arising temperature sensitive (ts) mutant of Japanese encephalitis virus (JEV), ts104, was isolated from chick fibroblast (CF) cell cultures of JEV strain M 1/311. Strain ts104 was plaque purified and characterized to ascertain its potential as a candidate for a live vaccine. Parameters of its growth, temperature lability, immunogenicity and virulence were examined. Ts104 has been shown to be stable ts JEV strain, multiplying as well as the parent strain in CF cultures at 35 degrees C, but not mutiplying at 39 degrees C. It was avirulent for embryonated chicken eggs incubated at 39 degrees C and of reduced virulence for intracerebrally (i.c.) inoculated mice as measured by LD50 in weanling mice and average day of death in weanling and suckling mice. Intraperitoneal injection of adult mice with either parent or ts strain resulted in similar levels of protection against challenge with either strain. The potential of ts104 as a candidate live JEV vaccine strain is discussed.


Glibenclamide, an antagonist of ATP sensitive K+ channels, blocks free radical generation in the rat myocardium.
The present study examined the effect of glibenclamide, an ATP-sensitive K+ (K(ATP)) channels antagonist, on the potassium chloride (KCl)-induced hydroxyl free radical (.OH) generation. Sodium salicylate in Ringer's solution (0.5 nmol/microl per min) was infused directly through a microdialysis probe to detect the generation of .OH as reflected by the formation of dihydroxybenzoic acid (DHBA) in the myocardium of anesthetized rat. The high concentration of KCl (70 mM) significantly increased the level of 2,3- and 2,5-DHBA by the action of depolarization by KCl. However, in the presence of glibenclamide (10 microM), KCl failed to increase the 2,3- and 2,5-DHBA formation. Moreover, when allopurinol (10 mg/kg), a xanthine oxidase inhibitor, was administered by i.v. injection, the elevation of DHBA was not observed. These results suggest that openings of cardiac K(ATP) channel by depolarization evokes .OH generation via xanthine oxidase reaction.


Dominant lethal test with rats exposed to 1,3-dichloropropene by inhalation.
The potential of 1,3-dichloropropene (1,3-DCP) to induce dominant lethal mutations in the germ cells of male CD rats following inhalation exposure was investigated. Groups of 11-week-old males (30 animals/group) were exposed to 1,3-DCP vapors by inhalation at targeted concentrations of 0 (negative control), 10, 60, and 150 ppm for 10 weeks (6 hr/day, 7 days/week). An additional group of 30 males (designated the pairfed group) was kept on dietary restriction for 10 weeks. This group served as a control for any effects of decreased feed consumption and the associated body weight loss on the dominant lethal indices in the males exposed to 1,3-DCP. At the termination of the exposures, each male was cohoused with naive adult virgin CD females for two consecutive mating trials (1 week/trial, 2 females/male). Females were necropsied 13 days after the conclusion of each weekly mating trial and the number of corpora lutea, live implantations, and resorptions were determined. There were no statistically significant increases in either the pre- or postimplantation embryonic/fetal loss in females mated with 1,3-DCP-exposed males relative to controls at any weekly mating period. Based on these results, it can be concluded that 1,3-DCP is not mutagenic to the male germ cells of CD rats at exposure levels < or = 150 ppm, the highest concentration tested.


Investigation of some basic water quality parameters of the north Bengal Terai river Kaljani--a tributary of river Torsa, and comparison thereof with the mainstream.
Some physico-chemical parameters of Kaljani River were studied in and around Alipurduar municipality. The principal characteristics of Kaljani River are high TSS, Mg-hardness, COD, and Phosphate 'P' Comparison of water quality parameters of the two rivers demonstrated higher range of alkalinity, ammonia 'N' content and chloride content in Torsa than Kaljani. River Kaljani showed higher COD range than Torsa. Mean BOD value of both these rivers ranged between 0.93-1.65 mg/l. Overall TDS content of Kaljani was found to be lower than Torsa. Maximum phosphate 'P' content was observed at the downstream of both the rivers.


Therapeutic effects of individual physical therapy in ankylosing spondylitis related to duration of disease.
Physical therapy in ankylosing spondylitis (AS) is considered important for maintaining or improving mobility, fitness, functioning, and global health. We studied the influence of disease duration on the short term effects of supervised individual therapy. One hundred forty-four AS outpatients (modified New York Criteria; mean age: 43 years; median duration of disease: 4 years; range: 0-33) received 12 supervised individual treatments in a 6-week course of 30 minutes. Endpoints were: spinal mobility (thoracic and lumbar flexion and extension, chest expansion, cervical rotation), fitness (maximum work capacity by ergometry), functioning (Sickness Impact Profile (SIP) and the Functional Index (FI)), and global patient assessment of change on a visual analogue scale. After 6 weeks patients had improved in all endpoints, but only significantly in rotation (8 degrees, 10%), fitness (6 watt, 4%), and SIP (0.6, 14%; t-test, p < 0.05). Global patient assessment improved by 1.1 (22%). Plots of change scores and disease duration showed no evident relation. We also divided the population into two groups, with the median disease duration as a cut-off. No relevant difference in improvement was found between 'short duration' and 'long duration' groups (t-test of change scores, p > 0.05). In addition, no relevant correlation was found between change scores and disease duration (p > 0.01). It may be concluded that irrespective of disease duration, short term supervised individual therapy is effective in AS, slightly improving mobility, fitness, functioning and global health.


Circulating tumor cells as a prognostic biomarker in patients with hepatocellular carcinoma.
Circulating tumor cells (CTCs) have been shown as a surrogate for cancer progression and prognostication. We aimed to determine an association between CTCs and survival of hepatocellular carcinoma (HCC) patients. Peripheral blood was obtained from 73 HCC patients to enumerate for epithelial CTCs/8 mL blood. CTCs were detected by immunoaffinity-based method using epithelial cell adhesion molecule (EpCAM) and mucin1 (MUC1). The CTCs detection rates of BCLC stages A, B, and C patients were 65.4% (17/26), 77.3% (17/22), and 96% (24/25), respectively, p = 0.018. Patients with CTCs < 5 cells/8 mL had significantly longer survival than those with CTCs ≥ 5 cells/8 mL (>36 vs. 4.6 months, p < 0.001). In multivariate analysis, CTP B, BCLC B, BCLC C, AFP ≥ 400 ng/mL, and CTC ≥ 5 cells/8 mL were independently associated with survival, with adjusted HRs (95%CI) of 4.1 (2.0-8.4), 3.5 (1.1-11.4), 4.7 (1.4-15.4), 2.4 (1.1-5.0), and 2.6 (1.2-8.4); p < 0.001, 0.036, 0.011, 0.025 and 0.012, respectively. The combination of CTCs ≥ 5 cells/8 mL and AFP ≥ 400 ng/mL provided additively increased HR to 5.3 (2.5-11.1), compared to HRs of 4.0 (2.0-8.0) and 3.5 (1.8-6.7) for CTCs ≥ 5 cells/8 mL and AFP ≥ 400 ng/mL, p < 0.001, respectively. The larger number of peripheral CTCs is correlated with higher tumor aggressive features and poorer survival of HCC patients. CTCs can potentially become novel prognostic biomarker in HCC.


An electrokinetic study on a synthetic adsorbent of crystalline calcium silicate hydrate and its mechanism of endotoxin removal.
A synthetic, disposable adsorbent of crystalline calcium silicate hydrate, LRA product by Advanced Minerals Corp., has been found highly effective for endotoxin removal from aqueous solutions. Endotoxin removal by this adsorbent is greatly enhanced by the addition of an electrolyte, such as NaCl or Tris-HCl. The electrophoretic method has been used to study the mechanism of endotoxin adsorption. In many cases, adding the electrolyte increases the magnitude of negative zeta potential of the adsorbent in water, while endotoxin adsorption reduces the magnitude. It is hypothesized that ion-exchange between monovalent cations from the aqueous phase and Ca2+ ions near the surface of the adsorbent shift zeta potential of the adsorbent to the more negative direction. It is further hypothesized that endotoxins form cationic species through binding between its phosphate groups and Ca2+ ions dissolved from the adsorbent. The adsorption of endotoxins in the form of cationic species is enhanced by the increased negative zeta potential of the adsorbent when an electrolyte is added.


The role of hepatic biotransformation in mediating the acute toxicity of the phosphorothionate insecticide chlorpyrifos.
The apparent (app) Km and app Vmax for mouse hepatic microsomal oxidative detoxification of chlorpyrifos to 3,5,6-tricholoro-2-pyridinol were 16.10 +/- 6.8 microM and 263.2 +/- 22.5 nmol/liver/min, respectively. The app Km and app Vmax for the oxidative activation of chlorpyrifos to chlorpyrifos oxon were 20.0 +/- 6.5 microM and 126.1 +/- 14.6 nmol/liver/min, respectively, whereas the app Km and app Vmax for hepatic microsomal hydrolysis of chlorpyrifos oxon to 3,5,6-trichloro-2-pyridinol were 1.87 +/- 0.36 mM and 89,450.7 +/- 12,087.3 nmol/liver/min, respectively. Under first-order conditions the capacity of mouse hepatic microsomes to detoxify chlorpyrifos oxon exceeded their capacity to generate this potent cholinesterase inhibitor from chlorpyrifos by a factor of 7.6. Pretreatment of mice with phenobarbital (70 mg/kg daily for 4 days) resulted in a 2.5-fold increase in the app Vmax's for oxidative activation and detoxification of chlorpyrifos, and a 1.6-fold increase in the app Vmax for hydrolysis of chlorpyrifos oxon. The app Km's were not altered by phenobarbital pretreatment. Administration of beta-naphthoflavone (80 mg/kg/daily for 2 days) to mice resulted in a slight decrease in the app Vmax's for oxidative activation and detoxification of chlorpyrifos, without altering the app Km's of the same reactions, or the hydrolysis of chlorpyrifos oxon. Phenobarbital and beta-naphthoflavone increased and decreased, respectively, the predicted hepatic clearance of chlorpyrifos. The acute toxicity of chlorpyrifos was slightly antagonized by phenobarbital pretreatment, but was potentiated by beta-naphthoflavone administration. These pretreatments did not affect cholinesterase, nonspecific esterase, or plasma A-esterase activities. Collectively, these results suggest that chlorpyrifos oxon formed within the liver does not escape hydrolysis by the liver, and that extrahepatic sites of activation are important in directly mediating the acute toxicity of chlorpyrifos.


Influence of gestational diabetes mellitus on the stereoselective kinetic disposition and metabolism of labetalol in hypertensive patients.
This study investigated the influence of gestational diabetes mellitus on the kinetic disposition and stereoselective metabolism of labetalol administered intravenously or orally. Thirty hypertensive women during the last trimester of pregnancy were divided into four groups: non-diabetic and diabetic women treated with intravenous or oral labetalol. The pharmacokinetics of labetalol was not stereoselective in diabetic or non-diabetic pregnant women receiving the drug intravenously. However, oral administration of labetalol resulted in lower values of the area under the plasma concentration versus time curve (AUC) for the β-blocker (RR) than for the other enantiomers in both diabetic and non-diabetic women. Gestational diabetes mellitus caused changes in the kinetic disposition of the labetalol stereoisomers when administered orally. The AUC values for the less potent adrenoceptor antagonist (SS) and for the α-blocking (SR) isomers were higher in diabetic than in non-diabetic pregnant women. The approximately 100% higher AUC values obtained for the (SR) isomer in diabetic pregnant women treated with oral labetalol may be of clinical relevance in terms of the α-blocking activity of this isomer.


Zinc oxide nanoparticles induce toxicity by affecting cell wall integrity pathway, mitochondrial function and lipid homeostasis in Saccharomyces cerevisiae.
Growing numbers of nanotoxicity research demonstrating that mechanical damage and oxidative stress are potential modes of nanoparticles (NPs) induced toxicity. However, the underlying mechanisms by which NPs interact with the eukaryotic cell and affect their physiological and metabolic functions are not fully known. We investigated the toxic effects of zinc oxide nanoparticles (ZnO-NPs) on budding yeast, Saccharomyces cerevisiae and elucidated the underlying mechanism. We observed cell wall damage and accumulation of reactive oxygen species (ROS) leading to cell death upon ZnO-NPs exposure. We detected a significant change in the cellular distribution of lipid biosynthetic enzymes (Fas1 and Fas2). Furthermore, exposure of ZnO-NPs altered the architecture of endoplasmic reticulum (ER) and mitochondria as well as ER-mitochondria encounter structure (ERMES) complex causing cellular toxicity due to lipid disequilibrium and proteostasis. We also observed significant changes in heat shock and unfolded protein responses, monitored by Hsp104-GFP localization and cytosolic Hac1 splicing respectively. Moreover, we observed activation of MAP kinases of CWI (Mpk1) and HOG (Hog1) pathways upon exposure to ZnO-NPs. Transcript level analyses showed induction of chitin synthesis and redox homeostasis genes. Finally, we observed induction in lipid droplets (LDs) formation, distorted vacuolar morphology and induction of autophagy as monitored by localization of Atg8p. However, we did not observe any significant change in epigenetic marks, examined by western blotting. Altogether, we provide evidence that exposure of ZnO-NPs results in cell death by affecting cell wall integrity and ER homeostasis as well as accumulation of ROS and saturated free fatty acids.


Heterogeneity and Molecular Markers for CNS Glial Cells Revealed by Single-Cell Transcriptomics.
Glial cells, including astrocytes, oligodendrocytes, and microglia, are the major components in the central nervous system (CNS). Studies have revealed the heterogeneity of each glial cell type and that they each may play distinct roles in physiological processes and/or neurological diseases. Single-cell sequencing (scRNA-seq) technology developed in recent years has extended our understanding of glial cell heterogeneity from the perspective of transcriptome profiling. This review summarizes the marker genes of major glial cells in the CNS and reveals their heterogeneity in different species, CNS regions, developmental stages, and pathological states (Alzheimer's disease and spinal cord injury), expanding our knowledge of glial cell heterogeneity on both molecular and functional levels.


Simultaneous adsorption and biodegradation processes in sequencing batch reactor (SBR) for treating copper and cadmium-containing wastewater.
The application of simultaneous adsorption and biodegradation processes in the same reactor is known to be effective in the removal of both biodegradable and non-biodegradable contaminants in various kinds of wastewater. The objective of this study is to evaluate the efficacy of the two processes under sequencing batch reactor (SBR) operation in treating copper and cadmium-containing synthetic wastewater with powdered activated carbon (PAC) as the adsorbent. The SBR systems were operated with FILL, REACT, SETTLE, DRAW and IDLE periods in the ratio of 0.5: 3.5: 1.0: 0.75 :0.25 for a cycle time of 6 h. In the presence of 10 mg/L Cu(II) and 30 mg/L Cd(II), respectively, the average COD removal efficiencies were above 85% with the PAC dosage in the influent solution at 143 mg/L compared to around 60% without PAC addition. Copper(II) was found to exert a more pronounced inhibitory effect on the bioactivity of the microorganisms compared to Cd(II). It was observed that the combined presence of Cu(II) and Cd(II) did not exert synergistic effects on the microorganisms. Kinetic study conducted for the REACT period showed that the addition of PAC had minimized the inhibitory effect of the heavy metals on the bioactivity of microorganisms.