Plasma D-dimer and interleukin-6 are associated with treatment response and progression-free survival in advanced NSCLC patients on anti-PD-1 therapy.
Response to therapy after using immune checkpoint inhibitors (ICIs) is unpredictable due to significant interindividual variation in efficacy among advanced non-small cell lung cancer (NSCLC) patients. The current study centered on the identification of perivascular blood biomarkers for predicting the effectiveness of anti-programmed cell death protein 1 (anti-PD-1) treatment and progression-free survival (PFS) in advanced NSCLC patients, that could be applied to help determine how to change treatment plans therapeutic regimens for optimizing clinical benefits. A comprehensive review of 100 advanced or recurrent NSCLC patients receiving anti-PD-1 therapy (Camrelizumab, pembrolizumab, sintilimab, or nivolumab) was conducted between January 2018 and April 2021 in Tianjin Medical University Cancer Hospital. The cutoff values of D-dimer were selected from rom our previous study, and interleukin-6 (IL-6) was divided according to the median. Using computed tomography, tumor response was evaluated in accordance with the Response Assessment Criteria in Solid Tumors, version 1.1. High IL-6 level in advanced NSCLC patients was predictive of low efficacy and a short PFS duration after anti-PD-1 therapy. An increased D-dimer value of 981 ng/mL was significantly predictive of disease progression in NSCLC patients treated with anti-PD-1 and high D-dimer expression predictive of short duration of PFS. Further studies on the correlation between IL-6, D-dimer, and anti-PD-1 efficacy in NSCLC patients stratified by gender revealed that D-dimer and IL-6 levels were significantly associated with the risk of PFS in male patients. High IL-6 content in peripheral blood in patients with advanced non-small cell lung cancer may contribute to poor anti-PD-1 efficacy and short duration of PFS through inducing alterations in the tumor microenvironment. D-dimer in peripheral blood is predictive of hyperfibrinolysis and contributes to the release of tumor-driven specific factors, leading to poor effects of anti-PD-1 therapy.


Detection of trace organophosphorus vapor with a self-assembled bilayer functionalized SiO2 microcantilever piezoresistive sensor.
Using piezoresistive SiO2 microcantilever technology, we present an ultra-sensitive chemical sensor for trace organophosphorus vapor detection. A self-assembled composite layer of Cu2+/11-mercaptoundecanoic acid is modified on the surface of the sensing cantilever as a specific coating to capture P=O containing compounds. Experimental results indicate that the sensor can be quite sensitive to DMMP vapor (well known as a simulant of nerve agent). The signal-noise-limited detection resolution of the sensor is experimentally obtained as low as several parts per billion. Besides that the sensor can yield reversible and repeatable response to DMMP vapor, adsorption of DMMP on the self-assembled composite layer is well fit to the Langmuir isotherm model.


Employing components-of-variance to evaluate forensic breath test instruments.
The evaluation of breath alcohol instruments for forensic suitability generally includes the assessment of accuracy, precision, linearity, blood/breath comparisons, etc. Although relevant and important, these methods fail to evaluate other important analytical and biological components related to measurement variability. An experimental design comparing different instruments measuring replicate breath samples from several subjects is presented here. Three volunteers provided n = 10 breath samples into each of six different instruments within an 18 minute time period. Two-way analysis of variance was employed which quantified the between-instrument effect and the subject/instrument interaction. Variance contributions were also determined for the analytical and biological components. Significant between-instrument and subject/instrument interaction were observed. The biological component of total variance ranged from 56% to 98% among all subject instrument combinations. Such a design can help quantify the influence of and optimize breath sampling parameters that will reduce total measurement variability and enhance overall forensic confidence.


Calcium blockers and atherosclerosis: lessons from the Stanford Transplant Coronary Artery Disease/Diltiazem Trial.
Accelerated coronary artery disease (TxCAD) in the long term heart transplant patient remains the major limitation to long term survival, with approximately 50% of patients developing an angiographic event of TxCAD by five years post-transplant. This accelerated vasculopathic process is believed to be due to chronic immune injury to the endothelium with coronary intimal proliferation developing rapidly. Subsequent lipid deposition develops in these proliferated areas, leading to a diffuse progressive occlusive CAD which can be seen on serial coronary arteriography as a progressive luminal narrowing. Based on multiple annual studies demonstrating a protective effect of calcium blockers in diet- or injury-induced vascular disease in animals, the authors undertook a randomized trial of diltiazem versus no calcium blocker begun early after heart transplantation in 1986. Serial quantitative coronary arteriographic measurements have demonstrated no significant change in the diltiazem group versus a decrease in mean coronary lumen diameter, from 2.41 +/- 0.27 to 2.19 +/- 0.28 mm, in the no calcium blocker group. These differences persisted at two and three years of follow-up. Freedom from CAD based on qualitative angiographic data confirmed this protective effect of diltiazem. These observations are supported by other reported retrospective studies of calcium blockers post-heart transplantation and in non-TxCAD. Therefore, calcium blockers appear to prevent the early coronary intimal proliferation in response to chronic immune injury, as well as the later lipid deposition. The cardiac transplant patient may serve as a useful model for study of antiatherosclerotic agents in humans.


Endothelial Cell Apoptosis Induces TGF-β Signaling-Dependent Host Endothelial-Mesenchymal Transition to Promote Transplant Arteriosclerosis.
Endothelial cells (ECs) apoptosis is an initial event in transplant arteriosclerosis (TA), resulting in allograft function loss. To elucidate the precise mechanisms of ECs apoptosis leading to neointimal smooth muscle cells (SMCs) accumulation during TA. We induced apoptosis in cultured ECs by overexpressing p53 through lentivirus-mediated transfection. ECs apoptosis induced the production of transforming growth factor (TGF)-β1 in both apoptotic and neighboring viable cells, leading to increased TGF-β1 in the culture media. Conditioned media from Ltv-p53-transfected ECs further promoted transition of cultured ECs to SM-like cells by activating TGF-β/Smad3, PI3K/Akt/mTOR, and MAPK/ERK signaling in a TGF-β-dependent manner. In transgenic rat aorta transplantation models, inhibition of ECs apoptosis in Bcl-xL(+/+) knock-in rat aortic allografts significantly reduced TGF-β1 production both in allograft endothelia and in blood plasma, which in turn decreased accumulation of SM22α+ cells from transgenic recipient ECs originally marked with EGFP knock-in in neointima and alleviated TA. Systemic treatment with SIS3, AP23573, or PD98059 also prevented recipient ECs-originated SM-like cells accumulation and intima hyperplasia in aortic allografts. These data suggest that allograft EC apoptosis induced recipient endothelial-mesenchymal (smooth muscle) transition via TGF-β signaling, resulting in recipient EC-derived SMC accumulation as a major mechanism of vascular remodeling during TA.


Left ventricular function in ischemic mitral regurgitation--a precatheterization assessment.
The clinical characteristics of 150 patients with unstable ischemic heart disease were evaluated for the ability to diagnose mitral regurgitation (MR). A careful assessment of physical findings, ECG- and radionuclide-determined global and regional left ventricular function was performed in all patients to characterize the population with ischemic MR. Twenty-nine patients were found to have MR and in 65% the degree of MR was 2+ or more. All of the patients with significant MR had a systolic murmur on physical examination, and although this finding was 90% sensitive for MR it had a poor predictive value (42%). Even a characteristic apical holosystolic murmur, although specific for MR (90%), had a low sensitivity and predictive value. Two regional wall motion abnormalities (inferoposterior akinesis and apical dyskinesis with an ejection fraction less than or equal to 35%) identified 26 of 29 patients with MR and all with 2+ or more MR, as well as the 10 patients who required mitral valve replacement in addition to coronary artery bypass grafting. This finding was complementary to the results of physical examination and when used together improved the diagnostic accuracy of identifying MR. The radionuclide regurgitant index was evaluated for its predictive value in assessing MR in this group of patients but was found to be a poor discriminator in patients with abnormal ejection fractions and regional wall motion abnormalities. The precatheterization assessment of left ventricular function with radionuclide angiography can provide important insight into the presence of ischemic MR.


Design of oxobenzimidazoles and oxindoles as novel androgen receptor antagonists.
Oxobenzimidazoles (e.g., 1), a novel series of androgen receptor (AR) antagonists, were discovered through de novo design guided by structure-based drug design. The compounds in this series were reasonably permeable and metabolically stable, but suffered from poor solubility. The incorporation of three dimensional structural features led to improved solubility. In addition, the observation of a 'flipped' binding mode of an oxobenzimidazole analog in an AR ligand binding domain (LBD) model, led to the design and discovery of the novel oxindole series (e.g., 2) that is a potent full antagonist of AR.


Effect of the large-scale green tide on the species succession of green macroalgal micro-propagules in the coastal waters of Qingdao, China.
In order to evaluate the effect of the large-scale green tide on micro-propagule community in the coastal waters of Qingdao, a year-round survey was conducted to investigate the abundance and species succession of the green macroalgal micro-propagules. Five Ulva and one Blidingia species were detected and an evident shift on species composition was observed in summer when the large-scale floating biomass of Ulva prolifera approached the coasts of Qingdao. Propagules of U. prolifera were only dominant in summer. Detection of the 'floating' type of U. prolifera in summer, a unique strain responsible for the green tide in Yellow Sea, supported that large-scale floating U. prolifera biomass could affect local micro-propagule community. There were, however, no 'floating' U. prolifera propagules were detected in the following winter, indicating that influence from the large-scale green tide was transient, and it has not leave prolonged seeds in Qingdao coastal waters.


Percutaneous absorption of Octopirox.
[14C]Octopirox administered to rats by intubation or injection was excreted mostly in the faeces (65-85% of the dose) with smaller amounts (6-19%) in the urine. Blood levels after intubation of Octopirox (4.8 mg/kg body weight) reached a maximum equivalent to 0.137 micrograms/ml at 2 hr and declined to 0.007 micrograms/ml at 48 hr after administration. Tissue levels were low, the greatest was the liver with the equivalent of 3 micrograms Octopirox at 6 hr after intubation. With female rats skin penetration of Octopirox at 1% (v/v) in shampoo without rinsing was 65.1 micrograms/cm2 under non-occlusive conditions for 48 hr. When the skin was rinsed after a 10-min contact, penetration was reduced to 3.4 micrograms/cm2 under occlusive, and 2.0 micrograms/cm2 under non-occlusive conditions. Skin penetration of Octopirox was dependent on duration of contact up to 10 min before rinsing. Penetration at 1% Octopirox increased significantly from 2.4 micrograms/cm2 after 2.5 min exposure to 4.5 micrograms/cm2 after 10 min contact, but there was no further increase in penetration with a 20-min application. Skin penetration and deposition of Octopirox were both proportional to Octopirox concentration between 0.1 and 1% (w/v); skin penetration increased from 0.31 to 3.6 micrograms/cm2 while deposition increased from 0.8 to 7.6 micrograms/cm2. There was no significant difference between the penetration through clipped skin and hairy skin from an application of 1% Octopirox for 5 min followed by rinsing. Under non-occlusive conditions, penetration was 1.5 micrograms/cm2 for both types of skin. Blood levels after topical application (15.4 mg/kg body weight) without rinsing and with occlusion reached the equivalent of 0.32 micrograms/ml at 6 hr. However, when the skin was rinsed and protected with a non-occlusive patch blood levels were reduced to a maximum equivalent to 0.02 micrograms/ml at 1 hr after application. The safety factor estimated for the consumer using a shampoo containing 1% Octopirox is 29,400, so that the possibility of systemic effects due to absorption through the skin is remote.


Optimization of Protoplast Isolation from Leaf Mesophylls of Chinese Cabbage (Brassica rapa ssp. pekinensis) and Subsequent Transfection with a Binary Vector.
Chinese cabbage is an important dietary source of numerous phytochemicals, including glucosinolates and anthocyanins. The selection and development of elite Chinese cabbage cultivars with favorable traits is hindered by a long breeding cycle, a complex genome structure, and the lack of an efficient plant transformation protocol. Thus, a protoplast transfection-based transformation method may be useful for cell-based breeding and functional studies involving Chinese cabbage plants. In this study, we established an effective method for isolating Chinese cabbage protoplasts, which were then transfected with the pCAMBIA1303 binary vector according to an optimized PEG-based method. More specifically, protoplasts were isolated following a 4 h incubation in a solution comprising 1.5% (v/v) cellulase, 0.25% (v/v) macerozyme, 0.25% (v/v) pectinase, 0.5 M mannitol, 15 mM CaCl2, 25 mM KCl, 0.1% BSA, and 20 mM MES buffer, pH 5.7. This method generated 7.1 × 106 protoplasts, 78% of which were viable. The gfp reporter gene in pCAMBIA1303 was used to determine the transfection efficiency. The Chinese cabbage protoplast transfection rate was highest (68%) when protoplasts were transfected with the 40 μg binary vector for 30 min in a solution containing 40% PEG. The presence of gusA and hptII in the protoplasts was confirmed by PCR. The methods developed in this study would be useful for DNA-free genome editing as well as functional and molecular investigations of Chinese cabbage.


Uptake of radioiodide by Paenibacillus sp., Pseudomonas sp., Burkholderia sp. and Rhodococcus sp. isolated from a boreal nutrient-poor bog.
Radionuclides, like radioiodine ((129)I), may escape deep geological nuclear waste repositories and migrate to the surface ecosystems. In surface ecosystems, microorganisms can affect their movement. Iodide uptake of six bacterial strains belonging to the genera Paenibacillus, Pseudomonas, Burkholderia and Rhodococcus isolated from an acidic boreal nutrient-poor bog was tested. The tests were run in four different growth media at three temperatures. All bacterial strains removed iodide from the solution with the highest efficiency shown by one of the Paenibacillus strains with >99% of iodide removed from the solution in one of the used growth media. Pseudomonas, Rhodococcus and one of the two Paenibacillus strains showed highest iodide uptake in 1% yeast extract with maximum values for the distribution coefficient (Kd) ranging from 90 to 270L/kg DW. The Burkholderia strain showed highest uptake in 1% Tryptone (maximum Kd 170L/kg DW). The Paenibacillus strain V0-1-LW showed exceptionally high uptake in 0.5% peptone +0.25% yeast extract broth (maximum Kd>1,000,000L/kg DW). Addition of 0.1% glucose to the 0.5% peptone +0.25% yeast extract broth reduced iodide uptake at 4°C and 20°C and enhanced iodide uptake at 37°C compared to the uptake without glucose. This indicates that the uptake of glucose and iodide may be competing processes in these bacteria. We estimated that in in situ conditions of the bog, the bacterial uptake of iodide accounts for approximately 0.1%-0.3% of the total sorption of iodide in the surface, subsurface peat, gyttja and clay layers.


Effect of thymectomy on lymphocyte subpopulations in the pig. Demonstration of a thymus-dependent 'null' cell.
Thymectomy in neonatal pigs results in marked lymphopenia. Surface Ig immunofluorescence, Fc rosettes and SRBC rosettes have been used to identify blood lymphocyte subpopulations. There was no marked reduction in numbers of cells in these subpopulations after thymectomy, although their proportion increased. This change was explained by a 90% reduction in 'null' lymphocytes, defined as those lacking sIg and Dextran SRBC receptor, which comprised 30-45% of blood lymphocytes.


Clinical review of 23 patients with tuberculous peritonitis: presenting features and diagnosis.
To better identify which clinical, laboratory, radiological and invasive procedures were most useful in diagnosing tuberculous peritonitis and to assess the methods in order to reach the diagnosis in future cases. Tuberculous peritonitis cases diagnosed between 2000 and 2006 were reviewed retrospectively. Their clinical presentation, physical examination, laboratory and diagnostic methods were evaluated. Twenty-three cases oftuberculous peritonitis were diagnosed. The mean age of the patients were 30 +/- 11 years and 16 were women. The mean duration of symptoms prior to diagnosis was 3.6 months. All patients presented with abdominal pain. Abdominal swelling (91.3%), loss of appetite (87%) and weight loss (82.6%) were the other commonest symptoms. The major physical findings were ascites (78.3%) and fever (60.9%). The serum ascites albumin gradient was < 1.1 g/dL in all. An ascites fast bacilli smear was positive in 12 (52.2%) patients. Skin tests with purified protein derivative, adenosine deaminase and polymerase chain reaction were performed in seven, four and five patients, respectively. The tuberculous culture was positive in only two. The most common radiological findings were ascites (100%) and omental involvement (65.2%). A laparoscopy was performed in nine of 23 patients. A total of 22 patients completed anti-tuberculous therapy successfully and were cured, except one with cirrhosis. Tuberculous peritonitis may be fatal but is medically cured if diagnosed in a timely fashion. Although both non-invasive and invasive tests have additional benefits, clinician suspicion is still the first step for the diagnosis of tuberculous peritonitis.


Revealing and utilizing receptor recognition mechanisms in a high-throughput world.
Recent genomic mapping promises to identify essentially all of the proteins that underpin normal and aberrant biology in humans. What genomics leaves undone is to determine how these proteins interact and integrate into molecular pathways in health and disease. Specific molecular interactions provide the fundamental mechanism for selectivity in virtually every aspect of biological structure and function. The convergence of structural and mutational studies makes it possible to define what parts of a protein are important for recognition. Still, knowing what is important does not necessarily foretell how binding epitopes actually function. We have applied the approach of epitope randomization on phage to explore how structural elements in such receptor recruitment systems as interleukin-5 (IL-5) and HIV-1 function in receptor recognition. This work has led in the IL-5 case to differentiation of recognition and activation epitopes, and this in turn has potential to help in the design of non-activating mimetics that could stimulate development of therapeutic antagonists for allergic inflammations such as asthma. Whether it is possible to differentiate recognition and activation in designing inhibitors in cases such as HIV-1 cell attachment and infection remains a tantalizing, but unsolved goal at present. Overall, these studies portray advances as well as limitations in the effort to decipher protein recognition mechanisms and utilize the wisdom gained for mechanism-based antagonist design in an increasingly high throughput world stimulated by the advent of genomics and proteomics.


Modified Forms of Cytosine in Eukaryotes: DNA (De)methylation and Beyond.
5-Methylcytosine (5mC) is an epigenetic mark known to contribute to the regulation of gene expression in a wide range of biological systems. Ten Eleven Translocation (TET) dioxygenases oxidize 5mC to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine in metazoans and fungi. Moreover, two recent reports imply the existence of other species of modified cytosine in unicellular alga Chlamydomonas reinhardtii and malaria parasite Plasmodium falciparum. Here we provide an overview of the spectrum of cytosine modifications and their roles in demethylation of DNA and regulation of gene expression in different eukaryotic organisms.


The risk of colorectal cancer in patients with inflammatory bowel diseases in Finland: a follow-up of 20 years.
Data on the relative risk of colorectal cancer in inflammatory bowel diseases (IBD) are inconsistent. To prevent the development of cancer, endoscopic facilities should be targeted correctly. We report here the results of a 20-year follow-up in Finland and evaluate the efficacy of endoscopic surveillance in cancer prevention. The data were based on an IBD register in our catchment area in 1986-2007. The population-based cohort comprised 1915 patients, 1254 with ulcerative colitis, 550 with Crohn's disease and 111 with inflammatory bowel unclassified. Colorectal cancer cases were obtained from the IBD register; the colorectal cancer figures in the respective population were obtained from the Finnish Cancer Registry. Colorectal cancer was found in 21 patients, the standardized incidence ratio (SIR) being 1.83 (95% confidence interval (CI) 1.13-2.79) for IBD. Colorectal cancer risk was 3.09 (CI 1.50-5.75) for extensive UC, and 3.62 (CI 2.00-11.87) for Crohn's disease affecting the colon. Eleven (52%) of the colorectal cancer cases were TNM stage 3 or 4. In the same observation period 10 colectomies with ileoanal anastomosis were performed with the indication of cancer risk in ulcerative colitis; of these 10 patients only two had no additional risk factors for colorectal cancer, for example primary sclerosing cholangitis, pseudopolyposis or active disease. The risk of colorectal cancer in the cohort was only moderately increased. In the absence of additional risk factors, endoscopic surveillance was of limited benefit. We therefore suggest intensive endoscopy surveillance to be targeted on patients with definite risk factors.


Effect of anemoside B4 on milk whey in clinical mastitis-affected cows elucidated using tandem mass tag (TMT)-based quantitative proteomics.
Intramuscular injection of anemoside B4 (AB4) has a superior therapeutic effect on clinical mastitis in lactating cows. Here, we explored AB4's effect on milk whey in clinical mastitis-affected cows using proteomics. Among fifty clinical mastitis cows received AB4 administration (0.05 ml/kg/day, for 7 days), twelve healed cows were selected and marked as group T. Twelve clinically heathy cows received the same dose of saline for 7 days, marked as group C. Collected milk whey of group T before and after AB4 administration marked as T1 and T2, respectively. The milk whey of group C after saline injection marked as C1. Milk whey protein changes were detected using tandem mass tag-based quantitative proteomic. We identified 872 quantifiable proteins in the samples. Among them, 511 proteins between T1 and C1, and 361 proteins between T2 and T1 were significantly altered. T1 than C1 had significantly more proteins associated with inflammatory damage and trans-endothelial migration of leukocytes, whereas these proteins were reduced in T2 treated with AB4. Compared with C, proteins associated with fibrin clot degradation and complement system activation were downregulated in T1 but upregulated in T2. In summary, AB4 can exert its therapeutic effect on clinical mastitis in cows mainly by reducing inflammatory damage, activating the complement system, inhibiting trans-endothelial migration of leukocytes, and promoting degradation of milk fibrin clots.


Floating behaviour in the tellinid bivalve Macoma balthica (L.).
The tellinid bivalve Macoma balthica from the Dutch Wadden Sea mudflats achieved secondary distribution by a floating behaviour after stimulation by low ambient temperature in slow-moving sea water (salinity 25‰). Floating behaviour among responding mussels began with burrowing displacements as their foot was directed towards the sediment surface. After extreme protrusion of the foot they became buoyant and were able to float. Floating behaviour was observed to last for periods of 1.5 h. During this active sequence frequent stops (range 2-6) were followed by resting periods on the sediment. In stagnant water at a constant temperature, mussels displayed burrowing displacement in a rhythmic manner with one peak of activity during the dark period of the day. Mussels previously acclimatized at high temperatue showed significantly stronger responses to current and temperature stimuli. Adult mussels as well as juveniles performed the floating behaviour. The paper discusses the ecological significane of secondary distribution.


Ascorbic acid conjugates isolated from the phloem of Cucurbitaceae.
Analysis of phloem exudates from the fruit of Cucurbitaceae revealed the presence of several compounds with UV-visible absorption spectra identical to that of l-ascorbic acid. In Cucurbita pepo L. (zucchini), the compounds could be isolated from phloem exudates collected from aerial parts of the plant but were not detected in whole tissue homogenates. The compounds isolated from the phloem exudates of C. pepo fruit were eluted from strong anion exchange resin in the same fraction as l-ascorbic acid and were oxidised by ascorbate oxidase (E.C. 22.214.171.124). The major compound purified from C. pepo fruit exudates demonstrated similar redox properties to l-ascorbic acid and synthetic 6-O-glucosyl-l-ascorbic acid (6-GlcAsA) but differed from those of 2-O-glucosyl-l-ascorbic acid (2-GlcAsA) isolated from the fruit of Lycium barbarum L. Parent and fragment ion masses of the compound were consistent with hexosyl-ascorbate in which the hexose moiety was attached to C5 or C6 of AsA. Acid hydrolysis of the major C. pepo compound resulted in the formation of l-ascorbic acid and glucose. The purified compound yielded a proton NMR spectrum that was almost identical to that of synthetic 6-GlcAsA. A series of l-ascorbic acid conjugates have, therefore, been identified in the phloem of Cucurbitaceae and the most abundant conjugate has been identified as 6-GlcAsA. The potential role of such conjugates in the long-distance transport of l-ascorbic acid is discussed.


Computer-Based Visualization System for the Study of Deep Brain Structures Involved in Parkinson's Disease.
Parkinson's Disease is characterized by alterations in deep brain structures and pathways involved in movement control. However, the understanding of neuroanatomy and spatial relationships of deep brain structures remains a challenge for medical students. Recent developments in information technology may help provide new instructional material that addresses this problem. This paper aims to develop an interactive and digital tool to enhance the study of the anatomical and functional neurological basis involved in Parkinson's Disease. This tool allows the organization and exploration of complex neuroanatomical contents related with Parkinson's Disease in an attractive and interactive way. Educational implications of this tool are analyzed.


Pharmacokinetics of captopril in healthy subjects and in patients with cardiovascular diseases.
Captopril, the first orally active inhibitor of angiotensin-converting enzyme, is used widely in the treatment of hypertension and congestive heart failure. The pharmacokinetics of this agent have been studied extensively in healthy subjects and in patients with hypertension, congestive heart failure, and chronic renal failure. Captopril contains a sulphydryl group and binds readily to albumin and other plasma proteins. The drug also forms mixed disulphides with endogenous thiol-containing compounds (cysteine, glutathione), as well as the disulphide dimer of the parent compound. These components in blood and urine are measured collectively as total captopril. Because of the reversibility of the formation of these inactive disulphides, total captopril may serve as a reservoir of the pharmacologically active moiety, and thus contribute to a duration of action longer than that predicted by blood concentrations of unchanged captopril. To measure free or unchanged captopril concentrations, a chemical stabiliser must be added to the biological samples to prevent the formation of captopril disulphides ex vivo. In healthy subjects given captopril intravenously, the body clearance of captopril and steady-state volume of distribution were about 0.7 L/h/kg and 0.8 L/kg, respectively. The elimination half-life of unchanged captopril was approximately 2 hours. The primary route of elimination of captopril is the kidney. The renal clearance of unchanged captopril exceeds the glomerular filtration rate, due to active tubular secretion of the drug. In healthy subjects, about 70 to 75% of an oral dose is absorbed and the bioavailability of captopril is approximately 65%. Peak blood concentrations are reached about 45 to 60 minutes after oral administration. The bioavailability of captopril is not altered by age or concomitant medications including diuretics, procainamide, allopurinol, cimetidine or digoxin. However, the co-administration of food or antacids, or probenecid with captopril has been shown to diminish the bioavailability of the latter and decrease its clearance, respectively. The decreased bioavailability of captopril when taken with meals does not significantly alter clinical responses to the drug. Over a wide range of oral (10 to 150 mg) and intravenous doses (2.5 to 10 mg) captopril had linear kinetics in healthy volunteers. In healthy subjects with normal renal function and patients with congestive heart failure given captopril 3 times daily, blood concentrations of total captopril accumulated, whereas those of unchanged captopril did not. Severe renal insufficiency was associated with an accumulation of both unchanged and total captopril.(ABSTRACT TRUNCATED AT 400 WORDS)


A 920-kilometer optical fiber link for frequency metrology at the 19th decimal place.
Optical clocks show unprecedented accuracy, surpassing that of previously available clock systems by more than one order of magnitude. Precise intercomparisons will enable a variety of experiments, including tests of fundamental quantum physics and cosmology and applications in geodesy and navigation. Well-established, satellite-based techniques for microwave dissemination are not adequate to compare optical clocks. Here, we present phase-stabilized distribution of an optical frequency over 920 kilometers of telecommunication fiber. We used two antiparallel fiber links to determine their fractional frequency instability (modified Allan deviation) to 5 × 10(-15) in a 1-second integration time, reaching 10(-18) in less than 1000 seconds. For long integration times τ, the deviation from the expected frequency value has been constrained to within 4 × 10(-19). The link may serve as part of a Europe-wide optical frequency dissemination network.


Mitochondrial disruption occurs downstream from β-adrenergic overactivation by isoproterenol in differentiated, but not undifferentiated H9c2 cardiomyoblasts: differential activation of stress and survival pathways.
β-Adrenergic receptor stimulation plays an important role in cardiomyocyte stress responses, which may result in apoptosis and cardiovascular degeneration. We previously demonstrated that toxicity of the β-adrenergic agonist isoproterenol on H9c2 cardiomyoblasts depends on the stage of cell differentiation. We now investigate β-adrenergic receptor downstream signaling pathways and stress responses that explain the impact of muscle cell differentiation on hyper-β-adrenergic stimulation-induced cytotoxicity. When incubated with isoproterenol, differentiated H9c2 muscle cells have increased cytosolic calcium, cyclic-adenosine monophosphate content and oxidative stress, as well as mitochondrial depolarization, increased superoxide anion, loss of subunits from the mitochondrial respiratory chain, decreased Bcl-xL content, increased p53 and phosphorylated-p66Shc as well as activated caspase-3. Undifferentiated H9c2 cells incubated with isoproterenol showed increased Bcl-xL protein and increased superoxide dismutase 2 which may act as protective mechanisms. We conclude that the differentiation of H9c2 is associated with differential regulation of stress responses, which impact the toxicity of several agents, namely those acting through β-adrenergic receptors and resulting in mitochondrial disruption in differentiated cells only.


Negatively Charged Disordered Regions are Prevalent and Functionally Important Across Proteomes.
Intrinsically disordered regions (IDRs) of proteins are often characterized by a high fraction of charged residues, but differ in their overall net charge and in the organization of the charged residues. The function-encoding information stored via IDR charge composition and organization remains elusive. Here, we aim to decipher the sequence-function relationship in IDRs by presenting a comprehensive bioinformatic analysis of the charge properties of IDRs in the human, mouse, and yeast proteomes. About 50% of the proteins comprise at least a single IDR, which is either positively or negatively charged. Highly negatively charged IDRs are longer and possess greater net charge per residue compared with highly positively charged IDRs. A striking difference between positively and negatively charged IDRs is the characteristics of the repeated units, specifically, of consecutive Lys or Arg residues (K/R repeats) and Asp or Glu (D/E repeats) residues. D/E repeats are found to be about five times longer than K/R repeats, with the longest found containing 49 residues. Long stretches of consecutive D and E are found to be more prevalent in nucleic acid-related proteins. They are less common in prokaryotes, and in eukaryotes their abundance increases with genome size. The functional role of D/E repeats and the profound differences between them and K/R repeats are discussed.


Murine typhus: a newly recognised problem in the Waikato region of New Zealand.
To characterise and investigate patients diagnosed with murine typhus in the Waikato District Health Board (DHB) region during 2006. We reviewed the hospital and general practitioner records of all patients presenting with clinical and serological evidence of murine typhus. All patients were interviewed by telephone using a semi-structured questionnaire to identify environmental risk factors for infection. A limited, retrospective serosurvey was undertaken and surveillance was enhanced. 12 patients were identified, all had either lived, or spent considerable time, in rural areas; 7 patients had seen rats on their properties 'regularly' and 3 remembered fleabites within the incubation period of the illness. The classic triad of symptoms is fever, headache, and rash--these symptoms were seen in 12, 11, and 8 patients respectively; lethargy, myalgias, nausea, and vomiting were also common. 11 patients had abnormal liver function tests at presentation, and 7 had low platelets. Treatment with doxycycline was associated with a shorter hospital stay. Murine typhus has now been confirmed in rural areas throughout the Waikato DHB region. Rats are likely associated with disease in rural communities and rat control is a complex issue. However, a greater awareness of the disease should lead to earlier diagnosis and treatment.


Multisource feedback to assess pediatric practice: a systematic review.
The assessment and maintenance of competence for pediatricians has recently received increased attention. The aim of the present study was to investigate further the use of multisource feedback for assessing pediatricians in practice. A systematic literature review was conducted using the electronic databases EMBASE, PsycINFO, MEDLINE, PUBMED, and CINAHL for English-language articles. 762 articles were identified with the initial search and 756 articles were excluded for a total of six studies that met the inclusion criteria for this systematic review. Internal consistency reliability was reported in five studies with α ≥ 0.95 for both subscales and full scales. Generalizability was also reported in two studies with Ep (2) generally ≥ 0.78. These adequate Ep (2) coefficients were achieved with different numbers of raters. Evidence for content, criterion-related (e.g., Pearson's r) and construct validity (e.g., principal component factor analysis) was reported in all 6 studies. Multisource feedback is a feasible, reliable, and valid method to assess pediatricians in practice. The results indicate that multisource feedback system can be used to assess key competencies such as communication skills, interpersonal skills, collegiality, and medical expertise. Further implementation of multisource feedback is desirable.


Cardiovascular effects of apamin and BRL 34915 in rats and rabbits.
1. The cardiovascular effects of apamin, a selective blocker of certain calcium-activated potassium channels, and BRL 34915, a vasodilator thought to act by opening of potassium channels, have been investigated in vivo in rats and rabbits. 2. In anaesthetized normotensive rats, apamin (0.05 and 0.15 mg kg-1, i.v.) potentiated angiotensin II pressor responses but did not modify baseline blood pressure or heart rate. 3. Apamin (0.15 mg kg-1, i.v.) was without cardiovascular effects in rabbits. 4. BRL 34915 (0.1 and 0.3 mg kg-1, i.v.) lowered blood pressure in rats dose-dependently and caused reflex tachycardia. The heart rate increase was abolished by prior administration of the beta-adrenoceptor blocker bopindolol (0.1 mg kg-1, i.v.). 5. In anaesthetized rabbits, regional blood flow measurements (with radioactive tracer microspheres) showed that BRL 34915 (3 to 30 micrograms kg-1, i.v.) caused marked vasodilatation in the stomach, with increases in flow also to the heart and small intestine. Brain blood flow also tended to increase. Blood flow to the kidneys was reduced by BRL 34915, whereas flow to skeletal muscle was unchanged. 6. Apamin pretreatment did not modify the blood pressure lowering activity of BRL 34915 in rats. The site at which BRL 34915 acts to cause vasodilatation in vivo thus appears to be apamin-insensitive.


'A tool we need': Midwives' descriptions and recommendations of an ideal obstetric triage tool.
The obstetric triage tool (OBTT) is used to record the clinical findings following obstetric triage (OBT). The recorded OBTT provides midwives with clinical information leading to diagnosis of existing and potential maternal and foetal problems that may lead to intrapartum complications, planning of specific midwifery care and communication among the midwifery team about the woman in labour. This study aimed to explore and describe midwives' experiences of the OBTT used during admission of women in labour in the Bojanala district. This study was conducted in the two selected facilities in Bojanala district in North West province. This study is a derivative of a major study, entitled 'Midwives' experiences of OBT by midwives in the Bojanala district'. A qualitative, explorative and descriptive research design was followed. Nine purposefully sampled midwives with over 5 years of clinical midwifery experience, employed in the Bojanala district, attended a semistructured interview. Data obtained were analysed using Colaizzi's descriptive method of data analysis according to the themes and categories which emerged. One central theme with 10 subthemes emerged. Midwives verbalised their dissatisfaction with the current OBTT and made recommendations for the revision of the tool. The study highlighted midwives' experiences of the OBTT and recommendations for an ideal tool based on their knowledge of admission of a woman in labour. This study provides a new OBTT from midwives' perspectives that could be useful in improving pregnancy and labour outcomes in clinical midwifery practice.


Respiratory infections among junior high school students in upper northern Thailand: The role of building dampness and mould, biomass burning and outdoor relative air humidity (RH).
Few studies exist on environmental risk factors for respiratory infections in Thai school children. To study associations between home and outdoor environment and respiratory infections among school children in Northern Thailand in dry and wet season. A repeated questionnaire survey among the children (N = 1159). Data on ambient temperature and relative air humidity (RH) and PM10 and ozone was collected from nearby monitoring stations. We used logistic regression to calculate odds ratios (OR). 14.1% had current respiratory infections (last 7 days), 32.1% had any respiratory infection last 3 months, and 26.1% had any respiratory infection last 12 months with antibiotic treatment. Students with diagnosed allergy (7.7%) and diagnosed asthma (4.7%) had more often respiratory infections (ORs 1.40-5.40; p < 0.05). Current respiratory infections were more common in dry (18.1%) than in wet season (10.4%) (p < 0.001) and was associated with indoor mould (OR 2.16; p = 0.024) and outdoor RH (OR 1.34 per 10% RH; p = 0.004.) in the total material. In wet season, mould (OR 2.32; p = 0.016), window pane condensation (OR 1.79; p = 0.050), water leakage (OR 1.82; p = 0.018), environmental tobacco smoke (ETS) (OR 2.34; p = 0.003) and outdoor RH (OR 2.70 per 10% RH; p = 0.01) were risk factors for current respiratory infections. In dry season, mould (OR 2.64; p = 0.004) and outdoor RH (OR 1.34 per 10% RH; p = 0.046) were associated with current respiratory infections. Irrespectively of season, biomass burning inside or outside the home was a risk factor for respiratory infections (ORs 1.32-2.34; p < 0.05). Living in a wooden house decreased the risk of respiratory infections (OR 0.56: p = 0.006). Dry season, high outdoor RH, household dampness, indoor mould and ETS can increase childhood respiratory infections. Living in a traditional wooden house can reduce respiratory infections, possibly due to better natural ventilation. Smoke from biomass burning can increase childhood respiratory infections in northern Thailand.


Lyme borreliosis.
Lyme borreliosis is a multi-organ infection caused by spirochetes of the Borrelia burgdorferi sensu lato group with its species B burgdorferi sensu stricto, Borrelia garinii, and Borrelia afzelii, which are transmitted by ticks of the species Ixodes. Laboratory testing of Lyme borreliosis includes culture, antibody detection using ELISA with whole extracts or recombinant chimeric borrelia proteins, immunoblot, and PCR with different levels of sensitivity and specificity for each test. Common skin manifestations of Lyme borreliosis include erythema migrans, lymphocytoma, and acrodermatitis chronica atrophicans. The last two conditions are usually caused by B garinii and B afzelii, respectively, which are seen more frequently in Europe than in America. Late extracutaneous manifestations of Lyme borreliosis are characterised by carditis, neuroborreliosis, and arthritis. We present evidence-based treatment recommendations for Lyme borreliosis and review the prevention of Lyme borreliosis, including the Lyme vaccines.


Effect of body mass on future long-term care use.
Obesity is a known predictor of disability and functional limitations, and, in turn, of health care use. In this study, we aim to explore whether obesity is also a significant risk factor for future long-term care use, overall and by type of care. We use multinomial logistic regression analysis on data from the English Longitudinal Study of Ageing (ELSA) for individuals aged 65 and older between 2002 and 2011. Selection issues are tackled using the rich set of control variables, exploiting the data's longitudinal structure and accounting for loss to follow-up (including death). Control factors include health-related behaviours (physical activity, alcohol and tobacco consumption), functional limitations (related to ADLs, iADLs and mobility) and specific existing health conditions, notably diabetes, high blood pressure and cardio-vascular diseases. We find that obese older people are 25% (p < 0.01) more likely to receive informal or privately-paid care in the future, but this does not hold for formal care. This is an additional direct effect after controlling for a wide range of health conditions and functional limitations. We document some evidence that this effect is due to the development of new functional limitations. Sensitivity analyses suggest that the results are robust to controlling for prediabetes, subjective health, depression, or unobserved heterogeneity. This study provides new evidence of a positive direct effect of obesity on the future use of long-term care services. Accordingly, it adds evidence of further economic benefits to any overall evaluation of policies to promote a healthy weight in the population, particularly in the older population.


Alternative splicing of intron 23 of the human cystic fibrosis transmembrane conductance regulator gene resulting in a novel exon and transcript coding for a shortened intracytoplasmic C terminus.
The cystic fibrosis transmembrane conductance regulator (CFTR) gene, the gene responsible for the lethal hereditary disorder cystic fibrosis, codes for a membrane protein functioning as a cAMP-regulated Cl- channel. Evaluation of human CFTR mRNA transcripts from epithelial and nonepithelial cells demonstrated a CFTR cDNA containing a 260-base pair (bp) insertion between the known CFTR exons 23 and 24, introducing a premature stop codon that would result in a CFTR protein shortened by 61 amino acids at the carboxyl terminus compared to that expected from the normal reported human CFTR coding sequences. Sequence analysis of intron 23 of the CFTR gene demonstrated that the 260-bp insertion (named exon 24a), a part of the reported intron 23 and located consecutive to exon 24, is likely generated by an alternative splice acceptor site. The exon 24a+ CFTR mRNA transcripts represented 3-16% of the total CFTR transcripts in epithelial and nonepithelial cells. These observations suggest an unexpected plasticity of expression of the CFTR gene, where alternative splicing of precursor CFTR mRNA transcripts permits the use of an alternative exon derived from a genomic segment previously believed to function as an intron.


Extreme-ultraviolet high-harmonic generation in liquids.
High-harmonic generation (HHG) in gases has been the main enabling technology of attosecond science since its discovery. Recently, HHG from solids has been demonstrated, opening a lively area of research. In contrast, harmonic generation from liquids has so far remained restricted to low harmonics in the visible regime. Here, we report the observation and detailed characterization of extreme ultraviolet HHG from liquid water and several alcohols extending beyond 20 eV. This advance was enabled by the implementation of the recent liquid flat-microjet technology, which we show to facilitate the spatial separation of HHG from the bulk liquid and the surrounding gas phase. We observe striking differences between the HHG spectra of water and several alcohols. A comparison with a strongly-driven few-band model establishes the sensitivity of HHG to the electronic structure of liquids. Our results suggest liquid-phase high-harmonic spectroscopy as a new method for studying the electronic structure and ultrafast scattering processes in liquids.


Mitochondrial malic enzyme from crustacean and fish muscle.
1. In contrast to mammalian skeletal muscle mitochondria, the only substrate that crustacean and fish mitochondria oxidize at a high rate is malate. 2. The mitochondria isolated from muscles of fish and crayfish exhibit a high activity of malic enzyme. 3. Assuming that malic enzyme is responsible for the conversion of malate to pyruvate in animal muscle, it could be expected that the mitochondria which possess high activity of this enzyme should oxidize malate very rapidly when oxygen is available. 4. Some properties of different molecular forms of malic enzyme are reviewed.


Preservation of myocardial contractility in hemorrhagic shock with methylprednisolone.
The left anterior descending or left circumflex coronary artery was cannulated selectively in 10 dogs. Methylprednisolone, 1 mg per kilogram of body weight, was injected into the artery and the cannula was withdrawn. The animals were then subjected to hemorrhagic shock for 90 minutes. Retransfusion to prestudy blood pressure was then accomplished. The electrocardiogram, arterial blood pressure, contractile force, and first derivative of contractile force were recorded continously both from the areas that were pretreated and those that were not, the controls. Contractile force in the control area was reduced to 32 +/- 3.2% of the preshock period after 90 minutes of shock, whereas in the pretreated area it was twice as high at the same time. Ten minutes after transfusion, the contractile force of the pretreated area exceeded the preshock level, whereas the recovery of contractile force in the control area reached only 70% of the preshock level. This study shows that intracoronary infusion of methylpredisolone can afford myocardial protection in hemorrhagic shock to a significant degree.


Sources of organic matter and carbon stocks in two mangrove sediment cores and surface sediment samples from Qinglan Bay, China.
The carbon stocks (Corg stocks) in mangrove sediments and the distribution and source changes of sedimented organic matter in Qinglan Bay are not understood as the mangrove forests decrease. In this paper, we collected two sediment cores in the interior mangrove and 37 surface sediment samples from mangrove-fringe, tidal flat and subtidal habitats and then analysed the total organic carbon (TOC), total nitrogen (TN), and the stable organic carbon isotope (δ13C) and nitrogen isotope (δ15N) in the sediment samples to obtain the organic matter sources and carbon stocks in two different mangrove sediment cores from Qinglan Bay. The δ13C and TOC/TN values showed that mangrove plants and algae were the main sources of organic matter. Relatively high contributions of mangrove plants (>50 %) were distributed in the mangrove areas in Wenchang estuary, the northern region of Bamen Bay and the eastern side of the Qinglan tidal inlet. The enriched δ15N values might be related to anthropogenic nutrient inputs, including increased aquaculture wastewater, human sewage and ship wastewater. The Corg stocks in cores Z02 and Z03 were 357.79 Mg C ha-1 and 265.78 Mg C ha-1, respectively. This Corg stock difference might have been related to the salinity and the benthos activities. The high Corg stock values measured in Qinglan Bay were caused by the mangrove maturity and stand age. The total Corg storage of the mangrove ecosystem in Qinglan Bay was estimated to be approximately 263.93 Gg C. This study contributes to organic carbon stocks and sources of sedimented organic matter in global mangroves.


Characterization of the immune response in patients with cancer of the oral cavity after neoadjuvant immunotherapy with the IRX-2 regimen.
IRX-2 is a homologous cell-derived multi-cytokine biologic with multifaceted immune modulatory effects that has been shown to induce increased lymphocyte infiltration into primary tumors in oral cavity carcinoma. Our objective was to characterize tumor immune gene expression and epigenomic changes after neoadjuvant IRX-2 immunotherapy in patients with squamous cell carcinoma of the oral cavity. A randomized phase II trial was conducted of the IRX regimen 3 weeks prior to surgery for previously untreated patients with Stage II-IV oral cavity carcinoma. The treatment regimen consisted of low dose (300 mg/m2) cyclophosphamide (day 1) followed by 10 days of regional perilymphatic IRX-2 cytokine injections and daily oral indomethacin, zinc and omeprazole (Regimen 1) compared to the identical regimen without the IRX-2 cytokines (Regimen 2). The NanoString immune panel (730 genes) and Infinium MethylationEPIC BeadChip were performed to assess the gene expression and DNA methylation signatures, respectively, in pre- and post-immunotherapy tumor samples. A total of 51 and 79 immune-related genes were found upregulated and downregulated, respectively, in the samples from Regimen 1 patients after treatment, while 51 and 56 were found upregulated and downregulated in the samples for Regimen 2. When comparing the changes between the two regimens, we identified 9 genes significantly different, including DMBT1, a potential tumor suppressor, functioning in tumor invasion of head and neck cancer. The exploration of DNA methylation showed slight overall hypermethylation after treatment in both regimens, especially for Regimen 1 immune responders, and methylation-based cell type deconvolution demonstrated high concordance with tumor infiltrating T lymphocyte cell counts. While a consistent patient response after treatment was observed, most changes were similar between regimens, indicating a subtle, targeted, or patient-specific effect of IRX-2 cytokines. Change in DMBT1 expression was a unique finding that will require further study to better understand its significance.


[Capillary malformation-arteriovenous malformation syndrome].
Capillary malformation-arteriovenous malformation syndrome is an autosomal dominant condition in which multifocal capillary malformations and arteriovenous fistulas form in different organs. RASopathies include a set of common syndromes that have mutations on the Ras/MAPK pathway. We discuss the clinical implications and tests necessary for its diagnosis.


Enhanced performance of Candida rugosa lipase immobilized onto alkyl chain modified-magnetic nanocomposites.
Lipase-immobilized nanomaterials with high activity and stable reusability would have a great impact in different fields. However, developing such materials has proven to be challenging. Herein, polymer (pAcDED)-coated magnetic nanoparticles (MNPs) displaying long alkyl chains, either octyl (C8) or hexadecyl (C16), have been prepared and used for immobilization of Candida rugosa lipase. The aim of the study was to develop magnetic supports able to bind enzyme via interfacial activation thus to stabilized the lipase open conformation. Among the developed nanosupports, the one endowed with the longest alkyl chains (MNPs-pAcDED-C16) provided the best efficiencies of the immobilized enzyme (70% vs. tributyrin and 130% vs. ethyl butyrate). Such results suggest both enzyme adsorption in open conformation and a change of enzyme specificity during immobilization. The MNPs-pAcDED-C16 system also showed better resistance to temperature inactivation in the 25-70 °C temperature range compared to free lipase and good reusability (4 consecutive cycles). The overall performances together with the convenience in the recovery offered by magnetic separation indicate our surface-modified MNPs as efficient and environmentally compatible materials for lipase immobilization.


Responses of lean and obese Zucker rats to centrally administered leptin.
Obese (Lepr(fa)/Lepr(fa)) Zucker rats have a missense mutation in the leptin receptor gene. One amino acid substitution in the extracellular domain common to all known leptin receptor proteins results from this mutation. Obese Zucker rats are unable to respond behaviorally to leptin which is peripherally administered. However, conflicting reports exist on whether obese Zucker rats can respond to centrally administered leptin. The purpose of this study was to determine whether obese Zucker rats responded behaviorally and metabolically to intracerebroventricularly (i.c.v.) administered leptin and to compare the responses of lean and obese Zucker rats. We found that both lean and obese Zucker rats had similar body weight and food intake responses when administered a single i.c.v. leptin injection in a range of doses (1.25, 2.5, 5, and 10 microg), as well as daily i.c.v. administered leptin for five consecutive days. Both single and daily leptin administration also decreased respiratory quotient (RQ) similarly in lean and obese Zucker rats, indicating mobilization of fat as an energy source for leptin-treated rats. After withdrawal of daily leptin treatment, lean and obese Zucker rats exhibited different recovery responses. It is concluded that obese Zucker rats can respond to exogenous leptin when leptin is delivered into the brain ventricles.


Effect of APOE Gene Polymorphism on Early Cerebral Perfusion After Aneurysmal Subarachnoid Hemorrhage.
High mortality following aneurysmal subarachnoid hemorrhage (aSAH) occurs in the early phase, but the underlying mechanism of early brain injury (EBI) in aSAH was less elucidated. In this study, we aimed to investigate the association of apolipoprotein E (APOE) genotypes and early cerebral perfusion after aSAH. We collected venous blood of aSAH patients on admission for APOE genotype identification, applying computed tomography perfusion (CTP) scanning within 24 h after onset. The CTP parameters between patients with different APOE genotypes were compared. Then, a positive item was chosen for separate uni- and multivariate logistic regression analyses to seek its risk factors. Our results showed mean transit time (MTT) rather than other parameters was significantly longer in patients with the APOEε4 allele, compared to those without APOEε4 (6.45 ± 1.17 versus 5.83 ± 0.84 s, P = 0.019). APOEε4 acted as an independent risk factor for MTT prolongation (>5.9 s) in uni- (P = 0.031, OR = 3.960, 95 % CI = 1.131-13.863) and multivariate (P = 0.019, OR = 9.822, 95 % CI = 1.458-66.193) logistic regression analyses, respectively. APOEε4 may induce cerebral perfusion impairment in the early phase, contributing to EBI following aSAH, and assessment of APOE genotypes could serve as a useful tool in the prognostic evaluation and therapeutic management of aSAH.


Chronic Niemann-Pick disease with sphingomyelinase deficiency in two brothers with mental retardation.
Clinical, biochemical, and electron microscopic studies are presented in two brothers with Niemann-Pick disease. The clinical features include hepatosplenomegaly and mental retardation without any other neurological signs. Roentgenograms of the chest showed bilateral diffuse reticular infiltration. The amounts of sphingomyelin and cholesterol in liver were increased, and sphingomyelinase activities in both liver and skin fibroblasts were markedly reduced in Case 1. Numerous foam cells and myelin figures were observed in the liver, kidneys, bone marrow, and lymph nodes on electron microscopical examination. These cases were regarded as a variant of Niemann-Pick disease from our investigations as they have mental retardation as an exceptional symptom when they are diagnosed as type B.


Effect of pancreatic enzyme supplementation on postprandial plasma cholecystokinin secretion in patients with pancreatic insufficiency.
To test the hypothesis, based on studies in healthy man and dog, that patients with impaired digestion due to severe pancreatic insufficiency have impaired postprandial cholecystokinin (CCK) secretion that can be improved by the addition of pancreatic enzymes, we have studied plasma CCK responses to a test meal with and without addition of pancreatic enzymes in 10 patients with pancreatic insufficiency and steatorrhea, in 8 patients with chronic pancreatitis without steatorrhea, and in 6 healthy subjects. The patients with steatorrhea had a significantly (P less than 0.001) lower integrated plasma CCK response to the meal (177 +/- 23 pM.150 min) than the healthy subjects (468 +/- 41 pM.150 min), while patients with chronic pancreatitis without steatorrhea had an intermediate integrated postprandial CCK secretion (327 +/- 101 pM.150 min). Addition of pancreatic enzymes to the meal significantly augmented the integrated CCK response in both the patients with steatorrhea to 483 +/- 72 pM.150 min (P less than 0.01) and in those without steatorrhea to 480 +/- 85 pM.150 min (P less than 0.05). These values were not significantly different from those in the healthy subjects (521 +/- 86 pM.150 min). Integrated CCK secretion in the three groups during bombesin infusion was similar (patients with steatorrhea 134 +/- 23 pM.20 min, patients without steatorrhea 131 +/- 33 pM.20 min, and healthy subjects 146 +/- 28 pM.20 min), indicating a normal capacity to secrete CCK in response to a humoral stimulus. These data are in agreement with the suggestions from previous studies that digestion of nutrients by pancreatic enzymes plays an important role in the regulation of plasma CCK secretion after feeding.


Optic nerve cavitations in glaucoma suspect and glaucoma patients.
Glaucoma is associated with structural changes of the optic nerve head such as deformation, lamina cribosa defects, prelaminar schisis, and peripapillary retinal schisis. We describe optic nerve cavitations that were detected by routine spectral domain optical coherence tomography (OCT). OCT imaging showed cavitations in 5 eyes of 4 patients with an initial diagnosis of glaucoma or glaucoma suspect. The cavitations were seen as hyporeflective spaces that are sharply delineated from surrounding tissue. They were centered inferonasally, anterior to the lamina cribosa, and at least partially within the Bruch's membrane opening (BMO). They extended from 3 to 6 clock hours. AND IMPORTANCE: We describe a new OCT finding in patients with a diagnosis of glaucoma and glaucoma suspect. While previous reports describe cavitations in the choroid in patients with pathological myopia, our patients had minimal refractive error and the cavitations were located within the optic nerve. We will examine these patients over time to determine the impact of this finding on longitudinal changes in structure and function.


Purification and characterization of phospholipase B from Candida utilis.
Phospholipase B (PLB) from the asporogenous yeast Candida utilis was purified to homogeneity from a culture broth. The apparent molecular mass was 90-110 kDa by SDS-PAGE. The enzyme had two pH optima, one acidic (pH 3.0) and the other alkaline (pH 7.5). At acidic pH the enzyme hydrolyzed all phospholipids tested without metal ions. On the other hand, the PLB showed substrate specificity and required metal ions for alkaline activity. The cDNA sequence of the PLB was analyzed by a combination of several PCR procedures. The PLB encoded a protein consisting of 643 amino acids. The amino acid sequence contained a lipase consensus sequence (GxSxG) and catalytic arginine and aspartic acid motifs which were identified as the catalytic triad in the PLB from Kluyveromyces lactis, suggesting that the catalytic mechanism of the PLB is similar to that of cytosolic phospholipase A(2) (cPLA(2)), found in mammalian tissues.


Interactions Balancing Competition and Cooperation between Covalent-Organic Framework Additives and PEG Base Oil toward Advanced Lubrication.
Severe competition between nanolubricant additives and polar lubricating oil molecules for the formation of lubricant films has been hindering the progress of green and advanced lubricants. In this work, based on the tautomerism of cyanuric acid molecule (trione and triol configurations), two kinds of triazine-based covalent-organic frameworks (COFs), that is, Ton-COFs and Tol-COFs, were synthesized as additives of the polar PEG 400 oil, realizing compromise between them by providing delicate interactions. The triazine matrix bonding with intense polar groups in the framework of additives offers more powerful interactions to competitively form the adsorbed lubricant film on the surface of the metal substrate over PEG 400 oil and also bolts PEG 400 oil molecules by the hydrogen bonding inside the pore of the framework to cooperatively bear against the load. Molecular quantum chemical calculations further confirm that Ton-COFs can produce a more intense interaction with Fe atoms in the form of coordination and ions···π than Tol-COFs, far beyond PEG 400, and the cross-sectional profile of the worn surface definitely exhibits a protective lubricant film only composed of Ton-COFs. Consequently, at the low concentration of 0.3 wt %, the excellent friction reduction (41.2%) and antiwear property (97.4%) are achieved for the Ton-COFs compared to pure PEG 400 oil; moreover, 28.6% and 79.0% for Tol-COFs at the essential concentration of 0.7 wt % are achieved. This finding provides a novel insight from molecules to materials into guiding the development of additives for advanced lubricants.


Production of optically active esters and alcohols from racemic alcohols by lipase-catalyzed stereoselective transesterification in non-aqueous reaction system.
Microbial lipase-catalyzed transesterification between vinyl acetate and (RS)-2-octanol or (RS)-1-phenylethanol was investigated in a reaction system without addition of aqueous or organic solvents. From a screening test with various lipases, it was found that the enzymes from Pseudomonas species could efficiently catalyze the reaction, and R-enantiomers of the racemic alcohols were preferentially esterified by them. Enantiomeric purities of the optically active alcohols (S) and esters (R) obtained from (RS)-1-phenylethanol by the stereoselective transesterification of these lipases were all more than 95%.


Budget Impact Model for the Use of PCA3 Urine Testing in Prostate Cancer Screening.
Continued prostate cancer screening with serum prostate specific antigen in patients with a history of a negative prostate biopsy can result in unnecessary repeat prostate biopsies with significant morbidity and cost. The PCA3 molecular urine test has been shown to be an independent predictor of the diagnosis of significant prostate cancer in men who are still at risk after a negative prostate biopsy. We used a budget impact model to study the potential reduction in unnecessary prostate biopsies and the cost benefits in this population. In a theoretical population of 1 million people during a 1-year time frame, the number of prostate biopsies and the costs were compared between a traditional method of prostate cancer screening (eg prostate specific antigen screening) after an initial negative prostate biopsy and a new method incorporating the PCA3 urine test after an increased prostate specific antigen. Men with abnormal results would undergo repeat prostate biopsy. In the traditional method 959 repeat prostate biopsies would be performed at a fully weighted cost of $1,866,214. When PCA3 was used in the new method, 400 prostate biopsies would be performed at a fully weighted cost of $931,000, resulting in a cost savings of $935,214. The incorporation of the PCA3 urine test into our decision algorithm for men at risk for prostate cancer after an initial negative prostate biopsy will result in a significant reduction in unnecessary biopsies with significant cost savings.


Proposed continuing professional education programme for midwives in China: new mothers' and midwives' views.
Chinese midwifery is under threat and has been denigrated, with virtually all midwives practising in the labour wards. The present study aims to inform the development of a proposed continuing professional education programme. Questionnaire surveys and semi-structured interviews were used to investigate the views of new mothers after vaginal births and midwives. The questions focussed on midwives' education, practice and mothers' experience and knowledge of maternity care. Data were analysed using descriptive statistical techniques. Five researchers, 253 midwives and 214 women. Ten maternity units/hospitals in seven Chinese cities. Both mothers and midwives valued continuity of midwifery care. The majority of midwives were obstetric nursing educated; one-fifth had a midwifery background. A smaller minority had a maternity/childcare or obstetric education. Midwifery education is medico/nursing orientated, with only 11.6% of the curriculum midwifery-oriented. The perceived different needs reflect the different orientations of the respondents. The programme should be structured to meet mothers' and midwives' needs, cultivate midwives' lifelong learning capacity, and encourage evidence-based practice. The study has shown a fundamental problem in Chinese midwifery education, in that midwives do not have access to evidence-based material. Self-directed learning with portfolio assessment is likely to prove useful for the proposed programme; this may facilitate midwives' personal/professional development to update their knowledge, understanding and competence towards their full role as midwives.


Focal nodular hyperplasia--a review of myths and truths.
Focal nodular hyperplasia (FNH) is a benign hyperplastic lesion of the liver with no known malignant potential. It has generated much interest due to the frequency with which it presents with atypical features on radiological imaging. Often resulting in misdiagnosis. Moreover, the understanding of particular subtypes of this lesion at a molecular level has changed in recent years. This may have implications on how certain subtypes should be managed. This review aims to analyse current literature pertaining to FNH and to provide clinically relevant advice regarding diagnosis and management.


Distribution of the perivascular nerve Ca2+ receptor in rat arteries.
We recently showed that perivascular sensory nerves of mesenteric branch arteries express a receptor for extracellular Ca2+ (CaR), and reported data indicating that this CaR mediates relaxation induced by physiologic levels of Ca2+. We have now tested whether the perivascular sensory nerve CaR-linked dilator system is a local phenomenon restricted to the mesentery, or is present in other circulations. Vessels from the mesenteric, renal, coronary, and cerebral circulations were studied. Immunocytochemical analysis was performed using anti-CaR and anti-neural cell adhesion molecule (NCAM) antibodies. Wire myography was used to assess contraction and relaxation. Although perivascular nerves of all arteries stained for CaR protein, there were regional differences. A morphometric method used to estimate CaR positive nerve density revealed the following rank order: mesenteric branch artery > basilar artery = renal interlobar artery > main renal trunk artery > left anterior descending coronary artery. Vessels from the mesentery, renal, coronary, and cerebral circulations showed nerve-dependent relaxation in response to electrical field stimulation (EFS) when precontracted with serotonin in the presence of guanethidine. The degree of Ca2+-induced relaxation of mesenteric, renal, and cerebral arteries positively correlated with the magnitude of EFS-induced relaxation. In contrast, coronary arteries contracted at Ca2+ levels between 1.5 and 3 mmol L(-1), and relaxed to a small degree to 5 mmol L(-1) Ca2+. Thus, a functional perivascular sensory nerve CaR-linked dilator system is present to varying degrees in the mesenteric, renal, and cerebral circulations, but only to a very limited extent in the coronary circulation.


Insulin effect on thyroid hormone uptake in rat skeletal muscle.
Previous work has indicated that thyroid hormone entry into cells includes an energy-dependent, saturable process. In this study we investigated the effect of insulin on T3 uptake in rat skeletal muscle. Intact soleus muscles were preincubated for 30 minuted at 37 degrees C, pH 7.4, in modified Krebs-Ringer bicarbonate buffer in the presence or absence of insulin and then for 60 minutes after adding 50 pmol/L [125I] T3. The results showed a stimulatory effect of insulin that was half maximal at 33 nmol/L and maximal at 100 nmol/L. Addition of 10 mumol/L T3 to the incubation medium completely blocked the effect, showing that the action of insulin is exerted only on the specific component of T3 uptake. The substitution of extracellular sodium with an equimolar amount of lithium also prevented the insulin effect. [125I] T4 uptake was unaffected by insulin. These results indicate that T3 uptake in skeletal muscle is sensitive to insulin, that insulin stimulates the specific component of T3 uptake in a dose-dependent manner, and that its action requires extracellular sodium. In contrast, T4 uptake is insensitive to insulin action in accordance with previous results that indicated passive diffusion as its major pathway for cell entry.


Application of flow cytometry and PMA-qPCR to distinguish between membrane intact and membrane compromised bacteria cells in an aquatic milieu.
The paper compares two methods of distinguishing between alive and dead cells by differentiation on the basis of their membrane structure: LIVE/DEAD flow cytometry and PMA-qPCR. LIVE/DEAD flow cytometry was established using the LIVE/DEAD(®) BacLight™ Bacterial Viability Kit with different ratios of Legionella pneumophila and Escherichia coli cells with intact and compromised membranes (heat treated). The PMA-qPCR method was tested and modified, and results were compared with those from LIVE/DEAD flow cytometry using L. pneumophila cells. Ratios of membrane intact to membrane compromised cells were well shown by LIVE/DEAD flow cytometry in all combinations. PMA-qPCR seems to work best in even mixed ratios (1:1) of intact and compromised cells. In other respects, we noticed an overestimation of intact cells in the samples which contained a high percentage of membrane compromised cells, and an underestimation of intact cells in samples with a small percentage of membrane compromised cells. However, looking at total counts instead of ratios, the results were within an order of magnitude. This implies that the use of PMA-qPCR is appropriate only for a qualitative analysis to monitor the success of a process such as disinfection. Furthermore, we were able to assess that both methods have advantages and disadvantages: LIVE/DEAD flow cytometry as applied in this study works well on some bacteria monocultures, but does not distinguish between bacteria species. The PMA-qPCR method allows the possibility of distinguishing between membrane intact cells and membrane compromised cells and can be used to screen for specific bacteria.


A new retraction-suspension device for limited upper sternotomy.
A limited sternal splitting incision is useful for the surgical approach to different diseases of the upper mediastinum. To provide optimal exposure, a specifically designed sternal retractor has been developed. Through a V-shaped opening and elevation of the sternum, surgery of the thymus gland, mediastinal goiters, and, more generally, biopsy or resection of most anterior mediastinal masses are possible. The device has been used in 30 patients who had different diseases, with totally satisfactory results.


Evaluation of the parasitological and production responses of a cow/calf operation to an anthelmintic program with ivermectin.
The efficacy of a treatment schedule using ivermectin, given subcutaneously at the rate of 200 micrograms kg-1, to control gastrointestinal parasitism and its effect on liveweight gains was assessed. Two herds with a total of 466 Hereford X Brangus cow/calf pairs were used. Each herd was on six pasture plots of comparable size, stocking rate, and quality and quantity of forage. Pasture groups were paired across the two herds. Pasture groups from one herd were randomly assigned to nonmedicated control and the other three to ivermectin treatment. Treatment assignments per pasture group were reversed in the other herd. The control group contained 118 cows and 112 calves and the medicated group 121 cows and 115 calves. Cows were treated in early July and the calves in late July or early August. Cattle from one herd were weighed on Days -28, 0 (day of cow treatment), 30 (day of calf treatment), 58, and 86, while the other herd was weighed on Days -29, 0 (day of cow treatment), 27 (day of calf treatment), 61, and 89. Day 0 was not the same calendar day for the two herds. Fecal samples for parasite egg counts were obtained from the rectum on weight days from five cows and six calves from each pasture; in most cases the same cattle were sampled each time. Calves treated with ivermectin gained (P less than 0.05) more weight than control calves between day of treatment for cows and the end of the trial.(ABSTRACT TRUNCATED AT 250 WORDS)


Selective determination of closantel by artificial neural network-genetic algorithm optimized molecularly imprinted polypyrrole using UV-visible spectrophotometry.
A molecularly imprinted polymer (MIP) for the selective solid-phase extraction (SPE) was prepared applying polymerization of pyrrole monomer in the presence of closantel (CLS) as a template molecule. The quantitative measurements were carried out using UV-Vis spectrophotometry. Several important parameters control the performance of polypyrrole sorbent. The influence of seven factors including loading time, polymerization time, amount of sorbent, stirring rate, desorption time, initiator concentration and monomer to template ratio were investigated. The optimization of parameters was performed using Plackett-Burman design (PBD), central composite design (CCD), artificial neural network (ANN) and genetic algorithm (GA). The Pareto plot showed that the effects of loading time, reaction time and amount of sorbent are most important to the process. These significant factors were investigated using CCD and the obtained data were used to train the ANN. The predicted model obtained from the trained ANN was introduced to GA as the fitness function to be optimized. The calibration curve demonstrated linearity over a concentration range of 0.010-10 mM with a correlation coefficient (R2) of 0.9833 under optimal condition. The synthesized MIP sorbent showed a good selectivity and sensitivity toward CLS. The limit of detection (LOD) for CLS was obtained 1.0 μM. The real sample analysis was performed to determine CLS in pharmaceutical and human serum samples.


Mechanistic insight and structure activity relationship of isatin-based derivatives in development of anti-breast cancer agents.
Breast cancer is most common in women and most difficult to manage that causes highest mortality and morbidity among all diseases and posing significant threat to mankind as well as burden on healthcare system. In 2020, 2.3 million women were diagnosed with breast cancer and it was responsible for 685,000 deaths globally, suggesting the severity of this disease. Apart from that, relapsing of cases and resistance among available anticancer drugs along with associated side effects making the situation even worse. Therefore, it is a global emergency to develop potent and safer antibreast cancer agents. Isatin is most versatile and flying one nucleus which is an integral competent and various anticancer agent in clinical practice and widely used by various research groups around the globe for development of novel, potent, and safer antibreast cancer agents. This review will shed light on the structural insights and antiproliferative potential of various isatin-based derivatives developed for targeting breast cancer in last three decades that will help researchers in design and development of novel, potent, and safer isatin-based antibreast cancer agents.


[Can an aortic anomaly cause intense dyspnea in a patient with bronchial asthma?].
64 old man with bronchial asthma and a double arch of aorta was presented. Clinical symptoms and value of flow-volume curve before and after beta 2 agonist inhalation for differential diagnosis in this case were discussed.


Pollution simulation and remediation strategy of a zinc smelting site based on multi-source information.
Contaminated sites pose a significant risk to human health and the regional environment. A comprehensive study was dedicated to improving the understanding of the contamination condition of a smelting site by integrating multi-source information through 3D visualization techniques. The results showed that 3D visualization reveals excellent potential for application in the environmental studies to finely depict contamination in soils and establish relationships with geological features, hydrological conditions, and sources of contamination. The contamination plume model revealed that the soil environment at the site was seriously threatened by toxic metals, and dominated by multi-metal contamination, with contamination soil volume ranked as Cd > As > Pb> Zn > Hg. The stratigraphic model revealed the heterogeneous geological conditions of the site and identified the mixed fill layer as the primary remediation soil layer. The permeability model revealed that soil permeability significantly influenced contamination dispersion and contributed to delineate the contamination boundary accurately. The ecological hazard model targeted the high ecological hazard area and determined the high hazard contribution of Cd and Hg in the site soil. The outcomes can be directly applied to actual site remediation and provide a reference for the contaminated sites evaluation and restoration in the future.


Actin bundling and polymerisation properties of eukaryotic elongation factor 1 alpha (eEF1A), histone H2A-H2B and lysozyme in vitro.
Elongation factor 1 alpha (eEF1A) is a positively charged protein which has been shown to interact with the actin cytoskeleton. However, to date, a specific actin binding site within the eEF1A sequence has not been identified and the mechanism by which eEF1A interacts with actin remains unresolved. Many protein-protein interactions occur as a consequence of their physicochemical properties and actin bundle formation has been shown to result from non-specific electrostatic interaction with basic proteins. This study investigated interactions between actin, eEF1A and two other positively charged proteins which are not regarded as classic actin binding proteins (namely lysozyme and H2A-H2B) in order to compare their actin organising effects in vitro. For the first time using atomic force microscopy (AFM) we have been able to image the interaction of eEF1A with actin and the subsequent bundling of actin in vitro. Interestingly, we found that eEF1A dramatically increases the rate of polymerisation (45-fold above control levels). We also show for the first time that H2A-H2B has remarkably similar effects upon actin bundling (relative bundle size/number) and polymerisation (35-fold increase above control levels) as eEF1a. The presence of lysozyme resulted in bundles which were distinct from those formed due to eEF1A and H2A-H2B. Lysozyme also increased the rate of actin polymerisation above the control level (by 10-fold). Given the striking similarities between the actin bundling and polymerisation properties of eEF1A and H2A-H2B, our results hint that dimerisation and electrostatic binding may provide clues to the mechanism through which eEF1A-actin bundling occurs.


Relationship between placental traits and maternal intrinsic factors in sheep.
The relationship between maternal intrinsic factors and placental traits was investigated on three Southern Mediterranean breed of sheep; Cukurova Assaf (CA), Cukurova (C) and Cukurova Meat Sheep (CMS). The effect of parity and birth type were also considered in the study as a potential influencing factor. Our hypothesis was to show that while differences in placental traits between breed, parity and birth type affected lamb condition and survivability, its correlation to maternal intrinsic behavioral factors may also be a strong indicator. The study found breed related differences of maternal behavioral factors and also showed significant correlation of these behavioral patterns to various placental traits. It confirmed earlier findings that parity played a major role in the refinement of these behavioral patterns. Significant differences in birth weight (P<0.05), placental weight (P<0.05), number of cotyledons (P<0.01) and cotyledon length (P<0.05) was seen between breeds. Cotyledon weight (P<0.05), width (P<0.01) and length (P<0.05) were found to differ by parity. Breed and parity interaction significantly influenced cotyledon quantity. While we detected breed specific differences in relation to maternal intrinsic factors we also noticed significant variance within breeds to these behavioral patterns when linked to placental traits. Further study is required on the correlation between placental traits and postnatal behavior on not just the ewes but also on their lambs. This could have a significant bearing on how producers manage and maximize lamb survivability.


Effects of hyperbaric oxygen treatment on liver functions, oxidative status and histology in septic rats.
The liver is thought to be responsible for multiple organ failure during sepsis. Increase in tissue oxygen consumption is a major component of the septic response. Hyperbaric oxygen (HBO) therapy provides more oxygenation in the whole body. This study examined the effect of HBO alone or in combination with cefepime (CEF) on the liver in septic rats. We divided 90 male rats into six groups; control, HBO, sepsis (SEP), SEP+HBO, SEP+CEF, and SEP+CEF+HBO. Sepsis was induced with an intraperitoneal injection of Escherichia coli (2.1 x 10(9) cfu). A total of six HBO sessions were performed at 2 atm absolute for 90 min at 6-h intervals. CEF was administered intraperitoneally at a dose of 50 mg/kg twice daily. Animals were killed 48 h after sepsis induction. Their liver and blood were removed for biochemical and histopathological analysis. Liver thiobarbituric acid reactive substances as well as serum alanine transaminase, aspartate transaminase and alkaline phosphatase levels increased while the activity of the antioxidant enzymes superoxide dismutase and catalase decreased significantly in septic rats. These parameters returned to nearly control levels in the SEP+CEF+HBO group. Histological observations supported these findings: Hepatocellular degeneration was observed and intensive polymorphonuclear cell infiltration appeared in all fields of septic animal livers. HBO alone could not sufficiently reverse these histopathological changes, but most liver sections presented normal histology when it was combined with CEF. HBO may be a useful adjuvant therapy modality to improve the efficacy of sepsis treatment.


Rural-urban disparities and factors associated with delayed care-seeking and testing for malaria before medication use by mothers of under-five children, Igabi LGA, Kaduna Nigeria.
Fever in under-five children (U5) is the commonest presenting complaint in general practice and mothers' recognition is an entry point for fever treatment, including malaria. This study describes rural-urban disparity in fever prevalence in U5, mothers' malaria knowledge, care-seeking, testing for malaria before anti-malarial medication and the associated factors. A cross-sectional survey was conducted among 630 mother-child pairs [rural (300) and urban (330)] selected randomly using a multi-stage sampling from 63 villages in Igabi LGA, Kaduna State, Nigeria. Trained female data collectors administered a pre-tested structured questionnaire to collect information on mother-child demographic profiles, malaria knowledge, fever episodes in birth order last child in two weeks prior to survey, blood testing before anti-malarial use, and delayed care-seeking defined as care sought for fever > 48 h of onset. Malaria knowledge was categorized into good, average, and poor if the final scores were ≥ 75th, 50th-74th, and < 50th percentiles, respectively. Frequency, proportions, and odds ratio were calculated. Statistically significant was set at p-value < 0.05. The median age (interquartile range) of rural mothers was 30 (IQR, 10) years compared to 27 (IQR, 6) years in urban. Of the 70.0% (441/629) U5 children with fever, 58.5% (258/441) were in rural settlements. A third of the mothers whose child had fever sought care. Mothers in rural settlements were 2.8 (adjusted OR: 2.8, CI 1.8-4.2, p < 0.01) times more likely to delay care-seeking for fever. Other significant factors were poor or no knowledge of malaria transmission, poor perception of malaria as a major health problem, and household size > 5. Also, mothers who had no formal education were four times more likely to receive anti-malarial medications without testing for malaria compared to their educated counterpart (adjusted OR: 4.0, 95% CI 1.6-9.9, p < 0.000). Rural-urban disparities existed between fever prevalence in U5 children, care-seeking practices by their mothers, and factors associated with delayed care-seeking and testing the fever for malaria before anti-malarial medication. Fever treatment for high impact malaria elimination in Nigeria needs a context-specific intervention rather than 'one-size-fits-all' approach.


Systemic angiotensin-induced drinking in the dog: a physiological phenomenon.
1. Intravenous infusion of the individual components of the renin-angiotensin system caused drinking in dogs in water balance. 2. Angiotensin II was the most potent and rapidly acting peptide inducing drinking. The minimum effective rate of infusion was between 8.3 and 16.6 X 10(-12) mole kg-1 min-1 which yield blood levels of angiotensin II that fell well within physiological limits for the dog and were mildly pressor. Angiotensin I and synthetic renin substrate caused less drinking than angiotensin II, and angiotensin III was the least effective dipsogen. 3. Renin caused significant drinking when infused I.V. at a rate of 0.5 u. min-1 for 15 min. Drinking was slower in onset and continued for longer than after other components of the renin-angiotensin system. 4. Within the dose range 1875-15,000 X 10(-12) mole of angiotensin II the amount of water drunk depended more on the rate of infusion than on the duration of the infusion. 5. During an I.V. infusion of angiotensin II lasting 2 hr, the rate of drinking was greatest during the first 15 min. After this declined progressively. 6. A delay of 1 hr after the start of an intravenous infusion of angiotensin II before access to water was allowed, did not significantly reduce the amount of water drunk. Nor did infusion of isotonic saline for 105 min reduce drinking in response to a subsequent infusion of angiotensin II. However, a preload of dilute milk approximately equal in volume to the amount of water normally drunk in response to I.V. angiotensin II significantly reduced drinking. Therefore the dog stopped drinking during long-term infusions of angiotensin II owing to the action of satiety mechanisms and not to tachyphylaxis or fatigue. 7. Intracarotid infusion of angiotensin II, angiotensin I, synthetic renin substrate and angiotensin III, at 40 X 10(-12) mole min-1 also caused drinking. Intakes of water were similar to the intakes after I.V. infusion at six times the arterial rate, except that angiotensin I was relatively less effective by intracarotid infusion than by I.V. infusion. 8. Renin, infused at 0.5 u. min-1 for 15 min, was much less effective by intracarotid infusion than by intravenous. 9. These results are compatible with a role for circulating angiotensin II in the thirst of hypovolaemia or moderate extracellular dehydration.


[In vitro aggregation of rat platelets by cumulative doses of ADP: influence of 3 antiaggregants and a protease inhibitor, aprotinin].
The authors describe the aggregation provoked on rat platelets using cumulative doses of ADP on the same sample. This model of aggregation is used to study the effects of three known aggregation inhibitors (aspirine, theophylline, isoproterenol) and one protease inhibitor, aprotinine.


The Correlation Between PINK-1/Parkin Mediated Mitophagy, Endoplasmic Reticulum Stress and Total Polyamines in Pediatric Bronchial Asthma: An Integrated Network of Pathways.
Pediatric bronchial asthma signifies a frequent chronic inflammatory airway disorder influencing many children. Despite its irrefutable importance, its exact pathogenesis is not completely elucidated. The study aimed to investigate the correlation between mitophagy machinery proteins, ER stress biomarkers and total polyamine and their role in disease progression via targeting NF-κB mechanisms. Sixty children with atopic bronchial asthma were enrolled in the study, they were allocated into 2 equal groups (mild/moderate and severe atopic asthmatic groups). Thirty age-matched healthy control subjects were also included in the study to represent the control group. Phosphatase and tensin homolog (PTEN)-induced kinase-1 (PINK-1) and Parkin messenger RNA (mRNA) expressions were assessed by (RT-PCR) technique. Levels of inositol requiring enzyme 1α (IRE1α), total polyamines, interleukin 6 & 8 (IL-6, IL-8) and nuclear factor kappa B (NF-κB) were assessed by enzyme-linked immunosorbent assay. Oxidative stress (OS) biomarkers were also measured. PINK-1 and PARK mRNA expressions were significantly upregulated in asthmatic patients. Likewise, the level of IRE1α, total polyamines, inflammatory cytokines, and OS biomarkers were significantly elevated in asthmatic groups comparing to control group with the highest levels noticed in severe atopic asthmatic group. the study documented a correlation between mitophagy machinery proteins, ER stress biomarkers and total polyamines that may pave a new platform to understand pediatric asthma pathogenesis and could be used as reliable biomarkers to evaluate disease progression.


Confounding factors in exposure-response analyses and mitigation strategies for monoclonal antibodies in oncology.
Dose selection and optimization is an important topic in drug development to maximize treatment benefits for all patients. While exposure-response (E-R) analysis is a useful method to inform dose-selection strategy, in oncology, special considerations for prognostic factors are needed due to their potential to confound the E-R analysis for monoclonal antibodies. The current review focuses on 3 different approaches to mitigate the confounding effects for monoclonal antibodies in oncology: (i) Cox-proportional hazards modelling and case-matching; (ii) tumour growth inhibition-overall survival modelling; and (iii) multiple dose level study design. In the presence of confounding effects, studying multiple dose levels may be required to reveal the true E-R relationship. However, it is impractical for pivotal trials in oncology drug development programmes. Therefore, the strengths and weaknesses of the other 2 approaches are considered, and the favourable utility of tumour growth inhibition-overall survival modelling to address confounding in E-R analyses is described. In the broader scope of oncology drug development, this review discusses the downfall of the current emphasis on E-R analyses using data from single dose level trials and proposes that development programmes be designed to study more dose levels in earlier trials.


Chronic granulocytic leukemia.
This article reviews the definition, etiology, epidemiology, cytogenetics, and diagnosis of chronic granulocytic leukemia (CGL). There is detailed consideration of clinical and laboratory findings, the natural history of CGL, and the selection of therapy at different stages of the disease. The roles of bone marrow transplantation and of newer experimental therapeutic approaches are discussed.


Ventricular repolarization components on the electrocardiogram: cellular basis and clinical significance.
Ventricular repolarization components on the surface electrocardiogram (ECG) include J (Osborn) waves, ST-segments, and T- and U-waves, which dynamically change in morphology under various pathophysiologic conditions and play an important role in the development of ventricular arrhythmias. Our primary objective in this review is to identify the ionic and cellular basis for ventricular repolarization components on the body surface ECG under normal and pathologic conditions, including a discussion of their clinical significance. A specific attempt to combine typical clinical ECG tracings with transmembrane electrical recordings is made to illustrate their logical linkage. A transmural voltage gradient during initial ventricular repolarization, which results from the presence of a prominent transient outward K(+) current (I(to))-mediated action potential (AP) notch in the epicardium, but not endocardium, manifests as a J-wave on the ECG. The J-wave is associated with the early repolarization syndrome and Brugada syndrome. ST-segment elevation, as seen in Brugada syndrome and acute myocardial ischemia, cannot be fully explained by using the classic concept of an "injury current" that flows from injured to uninjured myocardium. Rather, ST-segment elevation may be largely secondary to a loss of the AP dome in the epicardium, but not endocardium. The T-wave is a symbol of transmural dispersion of repolarization. The R-on-T phenomenon (an extrasystole originating on the T-wave of a preceding ventricular beat) is probably due to transmural propagation of phase 2 re-entry or phase 2 early after depolarization that could potentially initiate polymorphic ventricular tachycardia or fibrillation.